TOPIC 20. DISEASES OF THE VEINS. SYNDROME OF SUPERIOR VENA CAVA. SYNDROME OF INFERIOR VENA CAVA. CAUSES, DIAGNOSTIC, DIFFERENTIAL DIAGNOSTIC, TREATMENT TACTIC.
VARICOSE VEINS
Epidemiology of Chronic Peripheral Venous Disease
The term chronic venous disease, or more specifically of interest here, chronic peripheral venous disease (CPVD) has been used more generally to refer to either visible and/or functional abnormalities in the peripheral venous system. The most widely used classifi cation of such abnormalities is the CEAP (Clinical, Etiological, Anatomic, Pathophysiologic), which includes both anatomic (superfi cial, deep, or perforating veins) and pathophysiologic (reflux, obstruction, both) categories.
The CEAP classification was created by an international committee of clinical experts, and reflects the clinical situation in patients typically referred to a vascular specialist for clinically significant venous disease. In contrast to the clinical situation, population studies of CPVD typically have focused on broader categories determined by visual inspection only. The three major categories of interest have been varicose veins (VV), chronic venous insufficiency (CVI), and venous ulcers. However, there has not been a standard definition of these categories. VV has been defined bothincluding and excluding telangiectasias (spider veins), and at differing levels of visible disease severity. CVI typically has been defined by skin changes and/or edema in the distal leg. Venous ulcers, both active and healed, have been defined by visual inspection and subjective inference as to etiologic origin.
Two studies have now reported results on defined free-living populations with simultaneous assessment of both visible abnormalities and functional impairment by Duplex ultrasound.
The Duplex examination for the San Diego Population Study (SDPS) determined both obstruction and reflux, whereas the
Although these discrepancies occurred in a minority of cases, they were frequent enough to lead us to separately classify visible and functional CPVD in each limb evaluated in the SDPS. Specially, we classified each limb into four visible categories: normal, telangectasias/spider veins (TSV), VV, and trophic changes (TCS), the latter category being one or more of hyperpigmentation, lipodermatosclerosis, or active or healed ulcer. The presence/absence of edema was not by itself a criterion for TCS. For functional disease, we determined the presence of obstruction and reflux separately for the superficial, perforating, and deep systems. The presence of either reflux or obstruction in superficial or deep veins was categorized as functional disease, and because of small numbers, abnormalities of the perforating veins were considered as deep disease. Three functional categories were defined: normal, superficial functional disease (SFD), and deep functional disease (DFD). Here, the term “functional” is essentially interchangeable with “anatomic.” Also, in this population study obstruction was uncommon, and virtually all legs with obstruction also had reflux, such that SFD and DFD essentially refer to reflux.
In addition to separately assessing edema, we asked about a history of superficial venous thrombosis (SVT) and deep venous thrombosis (DVT), with or without pulmonary embolism.
AGE AND CVPD
Using mutually exclusive categories for both visible and functional CVPD, we found a graded relationship with increasing age for VV, with those aged 70–79 years having nearly twice the prevalence of those aged 40–49 years. TSV also increased with age, but this difference was obscured by the mutually exclusive categories with increasing numbers of participants with TSV also having VV or TCS at older ages. TCS showed the most dramatic age-related increase, with the oldest age group having more than four times the prevalence of the youngest.
These findings for visible disease are consistent with most previous population studies, which generally have found a linear increase in TSV or VV with age (reviewed in Reference 4). Earlier studies typically defined CVI only by venous (assumed) ulcers, and reported exponential increases in CVI with age, findings similar to the dramatic age increase we reported for the broader TCS category.
For functional CVPD, SFD was more than twice as common and DFD was 64% more common in the oldest age group. SFD showed both a higher prevalence and a steeper age gradient than did DFD.
The only other population data on functional disease were from the
Edema was strongly age-related as expected, but history of SVT and DVT were somewhat less so, perhaps reflecting selective recall bias in older participants.
Nonetheless, our data for DVT overall are quite similar to the lifetime prevalence in a large population-based study.
GENDER AND CPVD
For visible disease, we found nearly twice as much VV in women as in men, but TCS were 50% more common in men. These findings for VV are consistent with earlier studies, but earlier studies also have suggested a small excess of CVI in women, in contrast to our findings for the broader category of TCS. However, more concordant with our findings, the
Edema was about 50% more common in men than women, consistent with a 50% greater history of DVT in men. The
ETHNICITY AND CPVD
The SDPS reported data for four ethnicities, nonHispanic White, Hispanic, African-American, and Asian. Non-Hispanic Whites showed the highest prevalence of CPVD, with only 14.3% with a normal examination. Non-Hispanic Whites had the highest rates of TSV, TCS, and DFD, and the second highest rates (after Hispanics) of VV and SFD. African-Americans and Asians had a somewhat lower prevalence of CPVD. Consistent with the visible and functional findings, Non-Hispanic Whites also had the highest rates of edema and DVT by history, and Hispanics the highest rate of SVT by history.
Several previous studies have suggested a higher prevalence in developed than developing countries, although these studies are not entirely consistent. The SDPS is the first population study to evaluate multiple ethnic groups who were residents of the same geographical area.
RISK FACTORS FOR CPVD
Age was positively consistently related to all levels of visible and functional disease in both sexes. In comparison with non Hispanic whites (NHW), African-American Asian had less TSV and VV in both sexes, less TCS in men, and less DFD in women. Our results thus confirm that older age and NHW ethnicity are risk factors for CPVD.
Family history of venous disease based on subject recall was a risk factor for all levels of visible and functional disease. Although this finding could be biased, it is consistent with many other studies, although not all.
Ankle motility was a risk factor for visible disease SFD in women and for TSV in men. It was protective for women with DFD and men with SFD. The association of increasing laxity in connective tissue with venous disease corroborated previous research.
The protective associations could reflect increased ankle motility leading to decreased venous pressure by increasing pumping action.
Lower limb injury was a risk factor in women for DFD. Coughlin et al., in a case-control study, found serious lower limb trauma to be a risk factor for CVI.
CVD-related factors, such as angina, PTCA, hypertension, and diastolic pressure were associated with less TSV, SFD, and DFD for men and women and less VV for men. Although some studies have found a relationship between atherosclerosis and venous disease, others have not.
The reason for any protective effect of cardiovascular disease and hypertension on CPVD is not readily apparent, although venous vasoconstriction and microthrombosis could conceivably be involved.
Hours spent walking or standing was positively associated with VV, TCS, and SFD in men and women. Fowkes et al. found that walking was a risk factor for women with venous insufficiency when age-adjusted, but less so when multiply adjusted. They found walking to be related to lessened risk of venous insufficiency in men. Our data indicate that standing was a strong risk factor for venous disease in women. This is concordant with a number of studies, and contrasts with some other studies.
Weight, height, waist, and BMI, defined as weight in kg divided by height squared in meters squared, were positively associated with TCS, and DFD in men and VV, TCS, and SFD in women. Weight, waist circumference, the waist/hip ratio, and body mass index are all measures of adiposity.
A number of studies have found an association of obesity with venous disease. Gourgou et al. found a relationship in both men and women with VV. Our finding of increased waist circumference in men with TCS was consistent with findings that both obesity and male gender were associated with CVI and with the finding that weight was an independent risk factor for CVI in multivariate analysis In contrast, Coughlin et al. and Fowkes et al. both found that obesity was not a factor in venous insufficiency among women. Fowkes et al. extended this finding to men as well. Other studies also have found no association between obesity and venous disease.
However, the
During exercise the venomuscular pump is activated, which leads to a transient decrease in venous pressure, which should be protective for venous disease. This is consistent with our results in men.
HRT duration or parity was positively associated with all levels of visible and functional disease in women. Gourgou et al. found increasing VV prevalence with increasing numbers of births. Coughlin et al. found that multiparity was associated with varicose veins in pregnant women.
Some studies have found that the changes are effected with only one pregnancy. The increase of CPVD with HRT duration may indicate yet another underexamined systemic effect of HRT.
Our data indicate that age and family history were the strongest risk factors for CPVD, and neither is subject to intervention. Other significant findings on inherent factors included associations with connective tissue laxity and height. CVD-related factors were associated with lower rates of venous disease. Among volitional factors important findings were a relationship of CPVD with central adiposity, positional factors such as hours spent standing or sitting, exercise, and selected hormonal factors in women. In contrast with prior studies, we found no relationship with dietary fiber intake. In women but not men we confirmed the importance of a previous lower limb injury for DFD.
VENOUS ANATOMY, PHYSIOLOGY, AND PATHOPHYSIOLOGY
ANATOMY
The venous system in the lower extremities can be divided, for purposes of understanding, into three systems: the deep system, which parallels the tibia and femur; the superficial venous system, which resides in the superficial tissue compartment between the deep muscular fascia and the skin; and the perforating or connecting veins, which join the superficial to the deep systems. It is because these latter veins penetrate anatomic barriers, they are called perforating veins.
Although the superficial veins are the targets of most therapy, the principal return of blood flowfrom the lower extremities is through the deep veins. In the calf, these deep veins are paired and named for their accompanying arteries.
Therefore, the anterior tibial, posterior tibial, and peroneal arteries are accompanied by their paired veins, which are interconnected. These crural veins join and form the popliteal vein. Occasionally the popliteal veins as well as more proximal deep veins are also paired like the calf veins.
As the popliteal vein ascends, it becomes the femoral vein. Formerly, this was called the superficial femoral vein, but that term has been abandoned. Near the groin the femoral vein is joined by the deep femoral vein, and the two become the common femoral vein, which ascends to become the external iliac vein proximal to the inguinal ligament.
Ultrasound imaging has shown that the superficial compartment of the lower extremities consists of two compartments, one enclosing all the structures between the muscular fascia and the skin, and the other, within the superficial compartment enclosing the saphenous vein and bounded by the muscular fascia inferiorly and the superficial fascia superiorly, is termed the saphenous compartment (see Figure 1). The importance of this anatomic structure is underscored by its being targeted during percutaneous placement of endovenous catheters and the instillation of tumescent anesthesia.
Fig. 1 This diagram of the Saphenous Compartment shows its relationships with the Superficial and Deep compartments as well as the Saphenous Vein (SV) and Nerve and their relationships to the Medial, Anterior, and Lateral
Accessory Saphenous Veins (ASV).
The main superficial veins are the great saphenous vein and the small saphenous vein. These receive many interconnecting tributaries, and these tributaries may be referred to as communicating veins. They are correctly called tributaries rather than branches of the main superficial veins. The great saphenous vein has its origin on the dorsum of the foot.
It ascends anterior to the medial malleolus of the ankle and further on the anteromedial aspect of the tibia. At the knee, the great saphenous vein is found in the medial aspect of the popliteal space. It then ascends through the anteromedial thigh to join the common femoral vein, just below the inguinal ligament. Throughout its course, it lies within the saphenous compartment. The small saphenous vein originates laterally from the dorsal venous arch of the foot and travels subcutaneously behind the lateral malleolus at the ankle. As it ascends in the calf, it enters the deep fascia and ascends between the heads of the gastrocnemius muscle to join the popliteal vein behind the knee (see Figure 2). In fact, there are many variations of the small saphenous vein as it connects both to the popliteal vein and to cranial extensions of the saphenous vein, as well as connections to the posteromedial circumfl ex vein (vein of Giacomini).
Fig.2. This diagrammatic representation of the Great Saphenous
Vein emphasizes it relationship to perforating veins and the Posterior Arch
Vein.
The third system of veins is called the perforating vein system. As indicated earlier, they connect the superficial and deep systems of veins. There is a fundamental fact, which confuses understanding of perforating veins. This relates to flow direction. Some perforating veins produce normal flow from the superficial to the deep circulation, others conduct abnormal outflow from the deep circulation to the superficial circulation. This is termed perforating vein reflux. Any of these perforating veins may demonstrate bidirectional flow (see Table 1).
Table 1. Summary of Important Changes in
Nomenclature of Lower Extremity Veins
In the leg, the principal clinically important perforating veins are on the medial aspect of the ankle and leg, and are found anatomically at approximately
Fig.3. Deep connections of the main thigh and leg perforating
veins are shown in this diagram of the deep veins of the lower extremity.
Conversely, when they are dysfunctional, they allow muscular compartment pressure to be transmitted directly to unsupported cutaneous and subcutaneous veins and venules.
VENOUS PHYSIOLOGY
It is estimated that 60 to 75% of the blood in the body is to be found in the veins. Of this total volume, about 80% is contained in the veins that are less than 200 μm in diameter. It is important to understand this reservoir function as it is related to the major components. The splanchnic venous circulation and the veins of the skin are richly supplied by the sympathetic nervous system fibers, but muscular veins have little or none of these. The veins in skeletal muscle, on the other hand, are responsive to catecholamines.
Although arterial pressures are generated by muscular contractions of the heart, pressures in the venous system largely are determined by gravity. In the horizontal position, pressures in the veins of the lower extremity are similar to the pressures in the abdomen, chest, and extended arm. However, with the assumption of the upright position, there are dramatic changes in venous pressure. The only point in which the pressure remains constant is the hydrostatic indifferent point just below the diaphragm. All pressures distal to this point are increased due to the weight of the blood column from the right atrium. When assuming the upright position, there is an accumulation of approximately 500 ml of blood in the lower extremities, largely due to reflux through the valveless vena cava and iliac veins. There is some loss of fluid into the tissues, and this is collected by the lymphatic system and returned to the venous system.
Venous valves play an important role in transporting blood from the lower extremities to the heart. In order for valve closure to occur, there must be a reversal of the normal transvalvular pressure gradient. A pressure and generated velocity flow exceeding 30 cm/second leads to valve closure. Direct observation of human venous valves has been made possible by specialized ultrasound techniques.
Venous flow is not in a steady state but is normally pulsatile, and venous valves undergo regular opening and closing cycles. Even when fully opened, the cross-sectional area between the leaflets is 35% smaller than that of the vein distal to the valve. Flow through the valve separates into a proximally directed jet and vortical flow into the sinus pocket proximal to the valve cusp. The vortical flow prevents stasis and ensures that all surfaces of the valve are exposed to sheer stress. Valve closure develops when the vortical flow pressure exceeds the proximally directed jet flow.
The role of venous valves in an individual quietly standing is not well understood. Pressures in the superficial and deep veins are essentially the same during quiet standing, but as Arnoldi has found, the pressure in the deep veins is
Normally functioning perforating vein valves protect the skin and subcutaneous tissues from the effects of muscular contraction pressure. This muscular contraction pressure may exceed 100 to 130 mmHg.
Intuitively, the role of venous valves during muscular exercise is obvious, since their major purpose is to promote antegrade flow from superficial to deep. Volume and pressure changes in veins within the calf occur with muscular activity. In the resting position, with the foot fl at on the floor, there is no flow. However, in the heel strike position, the venous plexus under the heel and plantar surface of the foot (Bejar’s plexus) is emptied proximally. Blood flows from the foot and ankle into the deep veins of the calf. Then, calf contraction transports this blood into the deep veins of the thigh, and henceforth, blood flow proceeds to the pelvic veins, vena cava, and ultimately to the heart all due to the influence of lower extremity muscular contraction.
PATHOPHYSIOLOGY
Abnormal functioning of the veins of the lower extremities is recognized clinically as venous dysfunction or, more commonly, venous insufficiency. Cutaneous telangiectases and subcutaneous varicose veins usually are grouped together under the title Primary Venous Insufficiency, and limbs with skin changes of hyperpigmentation, edema, and healed or open venous ulceration are termed Chronic Venous Insufficiency (CVI).
Primary Venous Insufficiency
Explanations of venous pathophysiology as published in reviews, texts, and monographs are now for the most part out of date. The new science as we now know it is incorporated in the following summary.
A dysfunctional venous system follows injury to vein walls and venous valves. This injury is largely due to inflammation, an acquired phenomenon. Factors, which are not acquired, also enter into such injury. These include heredity, obesity, female gender, pregnancy, and a standing occupation in women. Vein wall injury allows the vein to elongate and dilate thus producing the visual manifestations of varicose veins. An increase in vein diameter is one cause of valve dysfunction that results in reflux. The effect of persistent reflux through axial veins is a chronic increase in distal venous pressure. This venous pressure increases as one proceeds from the inguinal ligament past the knee to the ankle.
Prolonged venous hypertension initiates a cascade of pathologic events. These manifest themselves clinically as lower extremity edema, pain, itching, skin discoloration, and ulceration.
The earliest signs of venous insufficiency often are elongated and dilated veins in the epidermis and dermis, called telangiectasias. Slightly deeper and under the skin are fl at, blue-green veins of the reticular (network) system. These may become dilated and elongated as well (see Figure 4).
And finally, still deeper but still superficial to the superficial fascia are the varicose veins themselves. All of these abnormal veins and venules have one thing in common: they are elongated, tortuous, and have dysfunctional venous valves.
This implies a common cause, which is inflammation.
Fig. 4. This cross-sectional view of the subcutaneous venous circulation shows how venous hypertension is transmitted to the unsupported veins of the dermis and subcutaneous tissues from axial veins (GSV) and the deep veins
of the muscular compartments.
Chronic Venous Insufficiency
Skin changes of hyperpigmentation, scarring from previous ulceration, and active ulcerations are grouped together under the term chronic venous insufficiency (CVI). Numerous theories have been postulated regarding the cause of chronic venous insufficiency and the cause of venous ulceration.
All the theories proposed in the past century have been disproved. An example is the theory of venous stasis, first proposed in a manuscript by John Homans of Harvard in 1916.
It was a treatise on diagnosis and management of patients with chronic venous insufficiency, and in it, Dr. Homans coined the term “post-phlebitic syndrome” to describe the skin changes of CVI. He stated that, “Over-stretching of the vein walls and destruction of the valves . . . interferes with the nutrition of the skin . . . there-fore, skin which is bathed under pressure with stagnant venous blood will form permanent open sores or ulcers.”
That statement, like many others that describe venous conditions and their treatments, is steeped in dogma and is short of observational fact. The erroneous term stasis ulcer honors that misconception, as do the terms venous stasis disease and stasis dermatitis.
Alfred Blalock, who later initiated cardiac surgery, disproved the stasis theory by studying oxygen content from varicose veins and normal veins.
He pointed out that the oxygen content of the femoral vein in patients with severe chronic venous insufficiency was greater than the oxygen content of the contralateral nonaffected limb. Because oxygen content was higher, some investigators felt that arteriovenous fi stulas caused venous stasis and varicose veins.
That explanation, though disproved, has some basis in fact since the entire thermal regulatory apparatus in limbs depends on the opening and closing of arteriovenous shunts. These shunts are important as they explain some terrible accidents that happen during sclerotherapy when sclerosant entering a vein is shunted into the arterial system and distributed in its normal territory.
Microsphere investigations have failed to show any shunting and the theory of arteriovenous communications has died despite the fact that these shunts actually exist and do open under the influence of venous hypertension.
Hypoxia and its part in causation of chronic venous insufficiency was investigated throughout the last 25 years of the twentieth century. English investigators thought that a fi brincuff, observed histologically, blocked transport of oxygen and was responsible for skin changes of CVI at the ankles and distally.
That theory has been abandoned even though a true periarteriolar cuff is easily identified histologically.
The two elements that make up all the manifestations of lower extremity venous insufficiency are failure of the vein valves and vein walls and skin changes at the ankles, both of which are related to venous hypertension.
Failure of Vein Walls and Valves
Our work suggests that venous hypertension causes a shear stress dependent leukocyte-endothelial interaction, which has all the manifestations of chronic inflammation.
These are leukocyte rolling, firm adhesion to endothelium, and subsequent migration of the cells through the endothelial barrier into parenchyma of valves and vein walls.
There, macrophages elaborate matrix metalloproteases, which destroy elastin and possibly collagen as well. Vein walls become stretched and elongated. Vein valves become perforated, torn, and even scarred to the point of near total absence. These changes are seen both macroscopically and angioscopically.
Similar changes have been produced in the experimental animal by constructing an arteriovenous fistula to mimic the venous hypertension of venous dysfunction in humans.
Skin Changes
The second manifestation of chronic venous insufficiency is expressed in the skin where leukocytes also are implicated in the observed changes. There is evidence that leukocyte activation in the skin, perhaps related to venous hypertension, plays a major role in the pathophysiology of CVI. Thomas, working with Dormandy, reported that 25% fewer white cells and platelets left the dependent foot of the patients with venous hypertension. When the foot was elevated there was a significant washout of white cells but not platelets, suggesting platelet consumption within the microcirculation of the dependent foot. They concluded that the decrease in white cell exodus was due to leukocyte trapping in the venous microcirculation secondary to venous hypertension. They further speculated that trapped leukocytes may become activated, resulting in release of toxic metabolites causing damage to the microcirculation and overlying skin. Apparently, the primary injury in the skin is extravasation of macromolecules and red blood cells into the dermal interstitium. Red blood cell degradation products and interstitial protein extravasations are potent chemoattractants and represent the initial chronic inflammatory signal responsible for leukocyte recruitment.
The important observations of Dormandy’s group were historically the first to implicate abnormal leukocyte activity in the pathophysiology of CVI.
The importance of leukocytes in the development of dermal skin alterations was further emphasized by Coleridge Smith and his team. They obtained punch biopsies from patients with primary varicose veins, lipodermatosclerosis, and patients with lipodermatosclerosis and healed ulcers. They counted the mediaumber of white blood cells per high power field in each group but there was no attempt to identify the types of leukocytes. In patients with primary varicose veins, lipodermatosclerosis, and healed ulceration there was a median of 6, 45, and 217 WBCs per mm2, respectively. This demonstrated a correlation between clinical disease severity and the number of leukocytes in the dermis of patients with CVI.
The types of leukocytes involved in dermal venous stasis skin changes remain controversial. T-lymphocytes, macrophages, and mast cells have been observed on immunohistochemical and electron microscopic examinations.
The variation in types of leukocytes observed may reflect the types of patients investigated. The
SYMPTOMS OF PRIMARY VENOUS INSUFFICIENCY
It is well known that the presence and severity of symptoms do not correlate with the size or severity of the varicose veins present. Symptoms usually attributable to varicose veins include feelings of heaviness, tiredness, aching, burning, throbbing, itching, and cramping in the legs (see Table 2). These symptoms are generally worse with prolonged sitting or standing and are improved with leg elevation or walking. A premenstrual exacerbation of symptoms is also common. Generally, patients find relief with the use of compression in the form of either support hose or an elastic bandage. Weight loss or the commencement of a regular program of lower extremity exercise may also lead to a diminution in the severity of varicose vein symptoms. Clearly, these symptoms are not specific, as they may also be indicative of a variety of rheumatologic or orthopedic problems. However, their relationship to lower extremity movement and compression is usually helpful in establishing a venous origin for the symptoms. Significant symptoms suggestive of venous disease should prompt further evaluation for valvular insufficiency and calf muscle pump dysfunction. If a venous etiology is suspected but all examinations are negative, repeat examination during a symptomatic period is warranted and often fruitful.
The recent development of an extremely painful area on the lower leg at the ankle associated with an overlying area of erythema and warmth may be indicative of lipodermatosclerosis, which may be associated with insufficiency of an underlying perforator vein, and examination for this lesion should be performed. Lipodermatosclerosis may precede ulceration and has been shown to be improved by stiff compression and certain pharmacologic interventions. Patients with a history of iliofemoral thrombophlebitis who describe “bursting” pain with walking may be suffering from venous claudication. In these patients an evaluation for persistent hemodynamically significant obstruction, possibly treatable with angioplasty and stenting, may be in order.
Table 2. Symptoms of Varicose Veins and
Telangiectasias
PHYSICAL EXAMINATION
Using no special equipment, the practitioner can obtain a degree of information regarding overall venous out flow from the leg, the sites of valvular insuffi ciency, the presence of primary versus secondary varicose veins, and the presence of DVT. The screening physical examination consists of careful observation of the legs. Any patient with the following conditions should be examined more fully: large varicose veins; bulges in the thigh, calf, or the inguinal region representative of incompetent perforating veins (IPVs) or a saphena varix; signs of superficial venous hypertension such as an accumulation of telangiectasias in the ankle region (corona phlebectatica); or any of the findings suggestive of venous dermatitis (pigmentation, induration, eczema). This includes patients with obvious cutaneous signs of venous disease such as venous ulceration, atrophie blanche, or lipodermatosclerosis. An obvious but often forgotten point is the necessity of observing the entire leg and not confining the examination simply to the area that the patient feels is abnormal.
Finally, because the veins of the leg empty into the pelvic and abdominal veins, inspection of the abdomen is very important, since dilation of veins on the abdominal wall or across the pubic region suggests an old iliofemoral thrombus. Dilated veins along the medial or posterior aspect of the proximal thigh or buttocks most often arise from varicosities involving the pudendal or other pelvic vessels, and these can be of ovarian reflux origin.
CLINICAL TESTING
Historically important tests of venous function have been part of the physical examination of venous insufficiency (see Table 3). These tests have been laid aside largely because of their lack of specificity and sensitivity. The continuouswave Doppler examination has replaced most of these tests, and confirmatory duplex testing has relegated them to an inferior role. However, the educated physician who treats venous insufficiency must have knowledge of these tests and their physiologic background, such as the Trendelenburg test or Brodie-Trendelenburg test.
Table 3. Tests of Historic Interest
Trendelenburg Test
A tourniquet may be placed around the patient’s proximal thigh while the patient is standing. The patient then assumes the supine position with the affected leg elevated 45 degrees. The tourniquet is removed, and the time required for the leg veins to empty, which is indicative of the adequacy of venous drainage, is recorded. When compared with the contralateral leg, the method just described may demonstrate a degree of venous obstructive disease. Another approach is to elevate the leg while the patient is supine and to observe the height of the heel in relation to the level of the heart that is required for the prominent veins to collapse. Unfortunately, neither procedure is sufficiently sensitive nor accurate and does not differentiate acute from chronic obstruction, thus being of minimal assistance in current medical practice.
Cough Test
One hand is placed gently over the GSV or SFJ, and the patient is asked to cough or perform a Valsalva maneuver. Simply palpating an impulse over the vein being examined may be indicative of insufficiency of the valve at the SFJ and below to the level of the palpating hand.
Percussion/Schwartz Test
One hand is placed over the SFJ or SPJ, and the other hand is used to tap very lightly on a distal segment of the GSV or SSV. The production of an impulse in this manner implies insufficiency of the valves in the segment between the two hands. Confirmation of the valvular insufficiency can be achieved by tapping proximally while palpating distally. This test can also be used to detect whether an enlarged tributary is in direct connection with the GSV or SSV by palpating over the main trunk and tapping lightly on the dilated tributary, or vice versa. The presence of a direct connection results in a palpable impulse being transmitted from the percussing to the palpating hand. As might be expected, these tests are far from infallible.
Perthes’ Test
The Perthes’ test has several uses, including distinguishing between venous valvular insufficiency in the deep, perforator, and superficial systems and screening for DVT. To localize the site of valvular disease, the physician places a tourniquet around the proximal thigh with the patient standing. When the patient walks, a decrease in the distension of varicose veins suggests a primary process without underlying deep venous disease because the calf muscle pump effectively removes blood from the leg and empties the varicose veins. Secondary varicose veins do not change caliber (if there is patency of the deep venous system) because of the inability to empty blood out of the veins as a result of impairment of the calf muscle pump. In the setting of a current DVT, they may increase in size. If there is significant chronic or acute obstructive disease in the iliofemoral segment, the patient may note pain (venous claudication) as a result of the obstruction to outflow through both the deep and superficial systems. The Perthes’ test is now of more historical than actual clinical importance.
CLASSIFYING VENOUS DISEASE
The Swedish physician and scientist Carl von Linné published a classification of plants based on the number of stamina and pistils in
Clinical Classification
C0: No visible or palpable signs of venous disease
C1: Telangiectasias or reticular veins
C2: Varicose veins
C3: Edema
C4a: Pigmentation and/or eczema
C4b: Lipodermatosclerosis and/or atrophie blanche
C5: Healed venous ulcer
C6: Active venous ulcer
S: Symptoms including ache, pain, tightness, skin irritation, heaviness,
muscle cramps, as well as other complaints attributable to venous
dysfunction
A: Asymptomatic
Etiologic Classification
Ec: Congenital
Ep: Primary
Es: Secondary (postthrombotic)
En: No venous etiology identified
Anatomic Classification
As: Superficial veins
Ap: Perforator veins
Ad: Deep veins
An: No venous location identified
Pathophysiologic Classification
Basic CEAP:
Pr: Reflux
Pr,o: Reflux and obstruction
Pn: No venous pathophysiology identifiable
Same as basic, with the addition that any of 18 named venous segments
can be utilized as locators for venous pathology:
Superficial veins:
1. Telangiectasias/reticular veins
2. Great saphenous vein (GSV) above knee
3. GSV below knee
4. Small saphenous vein
5. Nonsaphenous veins
Deep veins:
6. Inferior vena cava
7. Common iliac vein
8. Internal iliac vein
9. External iliac vein
10. Pelvic: gonadal, broad ligament veins, other
11. Common femoral vein
12. Deep femoral vein
13. Femoral vein
14. Popliteal vein
15. Crural: anterior tibial, posterior tibial, peroneal veins (all paired)
16. Muscular: gastrocnemial, soleal veins, other
Perforating veins:
17. Thigh
18. Calf
TREATMENT OF VENOUS INSUFFICIENCY
The term venous insufficiency implies that normal functioning is deranged. Terms used to describe the various manifestations of venous insufficiency lend confusion to the general topic. Some of these terms, such as telangiectasias, thread veins, and spider veins are descriptive but imply different conditions. And it is in the chronic disorders, dominated by venous reflux through failed check valves causing hyperpigmentation, ulceration, and corona phlebectatica, where disorientation reigns. Some order can come from subscribing to a unifying theory of primary venous insufficiency and of a common theory of effects of an inflammatory cascade that clarify both situations.
The manifestations of simple primary venous insufficiency appear to be different from one another. However, reticular varicosities, telangiectasias, and major varicose veins are all elongated, dilated, and are tortuous. Investigations into valve damage and venous wall abnormalities eventually may lead to an understanding of the problem, and therefore, a solution by surgery or pharmacotherapy.
Scanning electron microscopy has shown varying degrees of thinning of the varicose venous wall. These areas of thinning coincide with areas of varicose dilation and replacement of smooth muscle by collagen, which is also a characteristic of varicose veins. Our approach to this has been to assume that both the venous valve and the venous wall are affected by the elements that cause varicose veins. We and others have observed that in limbs with varicose veins, an absence of the subterminal valve at the saphenofemoral junction is common. Further, perforation, splitting, and atrophy of saphenous venous valves have been seen both by angioscopy and by direct examination of surgical specimens.
Supporting the theory of weakness of the venous wall leading to valvular insufficiency is the observation that there is an increase in the vein wall space between the valve leaflets. This is the first and most commonly observed abnormality associated with valve reflux. Realizing these facts, our investigations have led us to explore the possible role of leukocyte infiltration of venous valves and the venous wall as part of the cause of varicose veins. In our investigations of surgical specimens, leukocytes in great number have been observed in the venous valves, and wall and monoclonal antibody staining has revealed their precise identification as monocytes. Similar findings are present in the skin of patients with venous insufficiency.
SURGICAL TREATMENT
Removal of the Great Saphenous vein (GSV) from the circulation is one of two essential steps in treating lower limb varicose veins. Incompetent valves along the GSV allow blood to reflux down the vein and into its tributaries, transmitting high pressure into smaller tributaries, which become varicose as a result. Much emphasis has been placed on the correct technique of high sapheno-femoral ligation, in which meticulous attention is paid to identifying, ligating, and dividing all the tributaries of the GSV as they join the vein in the groin. It has always been a matter of surgical dogma that overlooking any of these allows continued reflux into the residual tributary and subsequent development of recurrent varicose veins.
A number of studies have confirmed that patients in whom the GSV is stripped tend to have fewer than those undergoing simple high ligation of the Sapheno-femoral junction (SFJ). Sarin et al. studied 89 limbs in 69 patients with LSV incompetence.
Legs were randomized to SFJ ligation with or without stripping, and evaluated by photoplethysmography (PPG), duplex scanning, clinical examination, and patient satisfaction. The follow-up period was 18 months. Significant differences in favor of the stripped group were found in all four parameters at final evaluation.
Asimilar study of 78 patients (110 limbs) was reported by Dwerryhouse et al. in 1999, with a longer follow-up period of five years. This demonstrated a significantly lower reoperation rate among patients undergoing GSV stripping (6%), as opposed to 20% in those undergoing high SFJ ligation alone.
Duplex scanning showed a much lower incidence of residual reflux in the remaining GSV when the proximal vein had been stripped to the knee than when it had not. However, the patient satisfaction rate was not significantly different between the two groups. Ninety percent of the stripped groups were satisfied as opposed to 87% in the nonstripped group (p = ns).A further study from Jones et al. came to similar conclusions.
One hundred patients (133 limbs) were randomized as before. After two years, 43% of those who had not had GSV stripping demonstrated recurrent varicose veins as opposed to 25% who had. There was a statistically significant difference.
NEOVASCULARIZATION
Of great importance was the fact that duplex scanning showed that neovascularization in the groin was the commonest cause of varicose recurrence. It was often seen in the ligation group that reflux through the neovascularization entered the residual saphenous vein and perpetuated the old varices while new ones developed. The authors concluded that by stripping the GSV, one was removing the run-off into which the new vessels could drain. Again, however, the satisfaction was broadly similar between the two groups: 91% in the stripped group and 87% in the unstripped.
All these authors concluded that stripping the long GSV gave better long-term results than simple high saphenous ligation. This appears to be true in terms of objective assessment of recurrence rates and in objective measurement of post-operative venous function but is not generally reflected in patient satisfaction rates, which tend to be similar which-ever procedure is performed. This led Woodyer and Dormandy to reach a contrary conclusion—that stripping the LSV was a procedure based on surgical dogma, and one that did not confer subjective benefit to the patients so treated. This leads one to conclude that a better method of evaluation of treatment results should be developed.
NONSURGICAL TREATMENT
In recent years, endovenous ablation has been found to be safe and effective in eliminating the proximal portion of the GSV from the venous circulation, with even faster recovery and better cosmetic results than stripping. The two currently available methods used to achieve ablation of the GSV are the Closure© procedure using a radiofrequency (RF) catheter and generator (VNUS Medical Technologies, Inc.,
The major difficulty with defining success as reduction or absence of refl ux is that attempts to establish whether reflux is present in a portion of a previously closed GSV may be inaccurate. Also, most recurrent patency is seen in the proximal portion of the treated GSV. Therefore, distal compression of the closed portion of the GSV to identify reflux in a proximal segment is futile. Likewise, using the Valsalva maneuver is unreliable and lacks reproducibility. Finally, the importance of distinguishing a partially patent channel with flow, from one with reflux, is academic, since the valves are just as thoroughly destroyed as the rest of the vein wall.
CHEMICAL VENOUS CLOSURE
Some phlebologists have advocated liquid sclerotherapy of the saphenous vein, but the results of such treatment have been disappointing, and published long-term results are absent. Comparisons between liquid and foam sclerotherapy have been done and the results strongly favor foam.
Ultrasound-guided sclerotherapy (USGS) with foam must be considered as a completely new treatment of varicose veins. Although it needs proper training and some skill, it is simple, affordable, and extremely efficient.
Sclerosing agents produce a lesion of the venous wall, predominantly of the endothelium and, to a minor extent, of the media. The reaction that follows depends on the concentration of the agent and on the duration of the contact. If the venous diameter is greater than
Making the foam is easy and quick. Based on the technique initially described by Tessari, it can be prepared with two 5 cc syringes and a three-way stopcock. Only detergent sclerosing agents can be used: Sotradecol and Polidocanol at any desired concentration from 0.25% to 3%. Microbubbles of foam sclerosing agents are hyperechogenic and represent an excellent contrast medium for ultrasound techniques. They appear as a shadow within the lumen early, and like a hyperechogenic mass later with a acoustic shadow. Massaging the sclerosing agent to the desired part of the varicose network with the duplex probe or the hand is also very easily carried out. Progression from the varicose clusters to the GSV and then to the SFJ is always visible, provided a sufficient volume has been injected. Venous spasm usually is observed within minutes. The importance of the initial spasm has been emphasized in several studies and protocols.
Post-sclerotherapy compression is mandatory: on the varicose clusters for 48 hours, and then whole limb compression with 20–30 mmHg thigh-high medical elastic stockings. They must be worn during the daytime for at least 15 days. Patients must be examined both clinically and with duplex at 7 to 15 days.
The absolute risk of deep venous thrombosis is not confirmed. A few cases have been reported: most of them are gastrocnemius vein thrombosis, typically after telangiectasia and reticular vein sclerotherapy. Most frequent complications are visual disorders. These adverse reactions have been observed also with liquid sclerosing agents but their incidence is much higher with foam; they can be estimated at 0.5–1 per 100 foam sessions.
They are observed more frequently in patients suffering from migraine with visual aura. They usually reproduce this aura. The patho-physiology of this phenomenon has been questioned but has received no answer so far. The existence of a patent foramen ovale is the most likely explanation, as has been the liberation of toxic component associated with endothelial cell destruction (endothelin).
All published results demonstrate an immediate effiacy better than 80% in terms of immediate/primary venous occlusion. Repetition of injections in case of initial failure allows closure to approach 95% of efficacy with two to three sessions. Early and mid-term results demonstrate a recurrence rate of about 20%. The re-do injections remain as simple as primary injections and at least as effiient.
INVERSION STRIPPING OF THE SAPHENOUS VEIN
One of the cornerstones of surgery for varicose veins is removal of the Great Saphenous vein (GSV) from the circulation. This can be done using minimally invasive techniques described elsewhere in this volume, but specific indications for performing saphenous surgery remain. These are largely institutional and geographic but they justify the following exposition.Indications for intervention in primary venous insufficiency are listed in Table 4 Often, it is the appearance of telangiectatic blemishes or protuberant varicosities that stimulates consultation. Ultimately, this may be the only indication for intervention.
Table 4.Varicose Veins: Indications for Intervention
Characteristic symptoms include aching, pain, easy leg fatigue, and leg heaviness, all relieved by leg elevation, and worsened on the first day of a menstrual peritod. Other indications for intervention for venous varicosities include superficial thrombophlebitis in varicose clusters, external bleeding from high-pressure venous blebs, or advanced changes of chronic venous insufficiency such as severe ankle hyperpigmentation, subcutaneous lipodermatosclerosis, atrophie blanche, or frank ulceration. Symptoms are frequent throughout the CEAP Classes 1 through 6. Clinical Disability Scores parallel the clinical classification.
Objectives of treatment should be ablation of the hydrostatic forces of axial refl ux and removal of the effects of hydrodynamic forces of perforator vein reflux. The latter can be accomplished by removal of the saphenous vein in the thigh and the varicose veins without specific perforating vein interruption. In
Ligation of the saphenous vein at the saphenofemoral junction has been practiced widely in the belief that this would control gravitational reflux while preserving the vein for subsequent arterial bypass. It is true that the saphenous vein is largely preserved after proximal ligation. Unfortunately, refl ux continues and hydrodynamic forces are not controlled. Less refl ux persists when the long saphenous vein has been stripped. There is a better functional outcome after stripping and fewer junctional recurrences. Randomized trials show efficacy of stripping compared to simple proximal ligation.
Earlier comparisons of saphenous ligation versus stripping were fl awed by today’s standards. Subjective evaluation was the only means of measuring outcome for a time.
Duplex scanning came into use, verifying that stripping was superior to proximal ligation; this fact was supported by PPG. Despite those facts, it was acknowledged that the period of disability after stripping was greater than that after simple ligation. In attempts to decrease disability and improve efficacy, high tie was added to saphenous vein sclerotherapy, but foot volumetry showed that radical surgery, including stripping produced superior results.
Ultimately, attention became focused on saphenous nerve injury associated with ankle to groin stripping. It was concluded that nerve injury was reduced by groin to ankle stripping (see Figure 5). Preservation of calf veins by stripping to the knee was shown to reduce nerve injury and did not adversely affect early venous hemodynamic improvement.
Fig. 5.
This fact is contraintuitive, and the subject deserves further study.Attempts to reduce nerve injury and simultaneously clean up varicose vein surgery led to use of the hemostatic tourniquet. In a study with level 1 evidence, it was shown that use of a hemostatic cuff tourniquet during varicose vein surgery reduces perioperative blood loss, operative time, and postoperative bruising without any obvious drawbacks.
Recurrent varicose veins after surgery are acknowledged to be a major problem for patients and society. Traditionally, it was thought that the most common reason for varicose recurrence was failure to perform an adequate saphenofemoral junction dissection (see Figure 6), or to correctly identify the saphenous vein for removal.
Fig.6. In the past, a proper groin dissection consisted of laying out each of the named saphenofemoral junction tributaries and dissecting them back beyond their primary tributaries. Now, this is acknowledged by most to be the
strongest stimulus to neovascularization.
Duplex scans have clarified this situation and instead of technical error, some investigators are convinced that new vessel growth contributes to recurrent varicose veins. In particular, incomplete superficial surgery, at the saphenofemoral and saphenopopliteal junctions, is a less frequent cause of recurrent disease, and neovascular reconnection and persistent abnormal venous function are the major contributors tomdisease recurrence.
PREOPERATIVE PREPARATION
Over the years, much space has been given to clinical examination of the patient with varicose veins. Many clinical tests have been described. Most carry the names of now-dead surgeons who were interested in venous pathophysiology. This august history notwithstanding, the Trendelenburg test, the Schwartz test, the Perthes test, and the Mahorner and Ochsner modifications of the Trendelenburg test essentially are useless in preoperative evaluation of patients today.
The clinical evaluation can be improved by using hand-held Doppler devices. However, preoperative evaluation is best performed by means of duplex scanning and a focused physical examination. Our protocol for duplex mapping of incompetent superficial veins has been published. Although many cite cost considerations as a reason for omitting duplex evaluation, we believe that duplex scanning for venous insufficiency is in fact both simple and cost effective. Duplex mapping defines individual patient anatomy with considerable precision and provides valuable information that supplements the physician’s clinical impression.
Three principal goals must be kept in mind in planning treatment of varicose veins: 1) the varicosities must be permanently removed and the underlying cause of venous hypertension treated; 2) the repair must be done in as cosmetic a fashion as possible; 3) complications must be minimized.
Current practice of treating the source of venous hypertension, the saphenous vein alone either by EVLT or VNUS technology, is inadequate. The patient’s complaint, the varicose veins, must be addressed. This is as important as the physician’s knowledge that the sources of venous hypertension must be addressed.
To speak of permanent removal of varicosities implies that all potential causes of recurrence have been considered and that surgery has been planned so as to address them. There are four principal causes of recurrence of varicose veins, of which three can be dealt with at the time of the primary operation.
One cause of recurrent varicosities is failure to perform the primary operation in a correct fashion. Common errors include missing a duplicated saphenous vein and mistaking an anterolateral or accessory saphenous vein for the greater saphenous vein. Such errors can be eliminated by careful and thorough groin dissection. Accordingly, failure to do a proper groin dissection has long been held to be a second principal cause of recurrent varicose veins. It is now known, however, that such dissection causes neovascularization in the groin, leading to recurrence of varicose veins. A third cause of recurrent varicosities is failure to remove the greater saphenous vein from the circulation. As mentioned earlier, reasons often cited for this failure is the desire to preserve the saphenous vein for subsequent use as an arterial bypass. It is clear, however, that the preserved saphenous vein continues to reflux and continues to elongate and dilate its tributaries. This produces more and larger varicosities. A fourth cause of recurrent varicosities is persistence of venous hypertension through nonsaphenous sources—chiefly, perforating veins with incompetent valves. Muscular contraction generates enormous pressures that are directed against valves in perforating veins. Venous hypertension induces a leukocyte endothelial reaction, which, in turn, incites an infl ammatory response that ultimately destroys the venous valves and weakens the venous wall. The perforating veins most commonly associated with recurrent varicosities are the midthigh perforating vein, the distal thigh perforating vein, the proximal anteromedial calf perforating vein, and the lateral thigh perforating vein, which connects the profunda femoris vein to surface varicosities.
Finally, there is a fi fth cause of recurrent varicosities, which is out of control of the operating surgeon—namely, the genetic tendency to form varicosities through development of localized or generalized vein wall weakness, localized blowouts of venous walls, or stretched, elongated, and floppy venous valves.
SAPHENOUS SURGERY
For varicose vein surgery to be successful, two tasks must be accomplished. The fi rst is ablation of reflux from the deep to the superficial veins, including the saphenofemoral junction, the saphenopopliteal junction, and midthigh varices from the Hunterian perforating vein. Accomplishment of this task is guided by the careful preoperative duplex mapping of major superficial venous reflux.
The second task is removal or destruction of all varicosities present at the time of the surgical intervention. Accomplishment of this task is guided by meticulous marking of all varicose vein clusters. A number of options are available for surgical treatment of varicose veins. Regardless of the specific approach taken, the general technical objectives are the same: 1) ablation of the hydrostatic forces of axial saphenous vein refl ux (see Figure 7) and 2) removal of the hydrodynamic forces of perforator vein outflow.
Fig. 7. Inversion stripping of the saphenous vein was an important step forward in minimizing soft tissue trauma while accomplishing the principal objective of ablating hydrostatic venous hypertension by removing saphenous
reflux. Tearing of the vein during its removal fl awed its performance.
Ankle-to-groin stripping of the saphenous vein has been a dominant treatment of varicose veins over the past 100 years. One argument against routine stripping of the leg (i.e., ankle-to-knee) portion of the saphenous vein is the risk of concomitant saphenous nerve injury. Another argument is that whereas the objective of saphenous vein removal is detachment of perforating veins emanating from the saphenous vein, which are seen in the thigh, the perforating veins in the leg are actually part of the posterior arch vein system rather than the saphenous vein system. This latter argument notwithstanding, preoperative ultrasonography frequently shows that the leg portion of the saphenous vein is in fact directly connected to perforating veins. Therefore, removal of the saphenous vein from ankle to knee should be a consideration in every surgical case.
OPERATIVE TECHNIQUE
The surgical approach taken must be individually tailored to each patient and each limb. Groin-to-knee stripping of the saphenous vein should be considered in every patient requiring surgical intervention. Iearly all patients, this measure is supplemented by removal of the varicose vein clusters via stab avulsion or some form of sclerotherapy.
Preoperative marking, if correctly performed, will have documented the extent of varicose vein clusters and identified the clinical points where control of varices is required. Incisions can then be planned. As a rule, incisions in the groin and at the ankle should be transverse and should be placed within skin lines. In the groin, an oblique variation of the transverse incision may be appropriate. This incision should be placed high enough to permit identification of the saphenofemoral junction.
Generally, throughout the leg and the thigh, the best cosmetic results are obtained with vertical incisions. Transverse incisions are used only in the region of the knee, and oblique incisions are appropriate over the patella when the incisions are placed in skin lines.
A major cause of discomfort and occasional permanent skin pigmentation is subcutaneous extravasation of blood during and after saphenous vein stripping. Such extravasation can be minimized by applying a hemostatic tourniquet after Esmarch exsanguination of the limb. The pressure in the hemostatic tourniquet should be between 250 and
The practice of identifying and carefully dividing each of the tributaries to the saphenofemoral junction has been dominant over the past 50 years. The rationale for this practice has been that it would be inadvisable to leave behind a network of interanastomosing inguinal tributaries. Accordingly, special efforts have been made to draw each of the saphenous tributaries into the groin incision so that when they are placed on traction, their primary and even secondary tributaries can be controlled. The importance of these efforts has been underscored by descriptions of residual inguinal networks as an important cause of varicose vein recurrence. Currently, however, this central practice of varicose vein surgery is under challenge, on the grounds that groin dissection can lead to neovascularization and hence to recurrence of varicosities.
Preoperative duplex studies have already demonstrated incompetent valves in the saphenous system, and a disposable plastic stripper can be introduced from above downward; alternatively, a metal stripper can be employed. Both of these devices can be used to strip the saphenous vein from groin to knee via the inversion technique. This approach should reduce soft tissue trauma in the thigh.
In the groin, the stripper is inserted proximally into the upper end of the divided internal saphenous vein and passed down the main channel through incompetent valves until it can be felt lying distally approximately
Stripping of the saphenous vein has been shown to produce profound distal venous hypertension. This occurs in virtually every operation, even when the limb is elevated. Therefore, after the stripper is placed, one should consider performing the stab avulsion portion of the procedure before the actual stripping maneuver.
Incisions to remove varicose clusters vary according to the size of the vein, the thickness of the vein wall, and the degree to which the vein is adhering to the perivenous tissues. In general, vertical incisions 1 to
Phlebectomy techniques for varicose clusters have been markedly refined by experienced workers in
Once the stab avulsion portion of the procedure is complete, the previously placed stripper is pulled distally to remove the saphenous vein. Although plastic disposable vein strippers and their metallic equivalents were designed to be used with various-sized olives to remove the saphenous vein, in fact, a more efficient technique is simply to tie the vein to the stripper below its tip so that the vessel can then be inverted into itself and removed distally. To decrease oozing into the tract created by stripping, a
Fig. 8 . Adding a hemostatic pack to inversion stripping corrected the principal fl aw in inversion stripping, the tearing of the saphenous vein. The pack acted as an obturator, which insured total vein removal. In most instances, the
pack entered the vein as it was being removed, thus minimizing the soft tissue trauma.
POST-THROMBOTIC SYNDROME
Postthrombotic syndrome (PTS) is a frequent sequel to deep venous thrombosis (DVT). Awareness of this long-term debilitating complication is low among treating physicians whose main focus is the acute embolic complications of DVT. PTS may take years and even decades to fully evolve when the patient is no longer in the care of the original treating physician. Recurrent DVT that may occur years later after the initial event is a known risk factor for the development of PTS. Serial follow up of patients after onset of DVT has provided important new perspectives on many aspects of PTS. After a bout of DVT, only a third of the patients are asymptomatic long term; but the other two thirds have PTS, half of them severe. The direct and indirect costs of this disease that affects all adult age groups is estimated to be enormous, arousing the interest of public health planners.
CLINICAL FEATURES
Major symptoms are limb pain, swelling, and stasis skin changes including ulceration. Recurrent thrombophlebitis and recurrent cellulitis, the latter related to underlying tissue edema, are less well known and less frequent features. Symptoms are present in varying combinations and severity in individual patients. Pain is an important but variable component of the symptom complex. Limb swelling may be described by the patient as severe because it is painful even though only mild pitting is evident on examination. Some patients may not even be aware of limb edema evident to the examiner because it is pain free. Pain is absent in about 20% of patients. In about 10% of patients, pain may be the only symptom without other signs; a diagnosis of PTS may altogether be missed, because the limb looks normal. Severity of pain present may be exaggerated or understated by the patient due to individual variations in pain tolerance and other socioeconomic factors such as work situation; daily or frequent use of nonsteroidal or narcotic dependency for pain relief may not be readily disclosed unless specifically quetioned. Other essential elements of history may not be readily forthcoming as well. For example, previous DVT or severe trauma to the limb may not be volunteered because the remote event years ago had been forgotten or not considered relevant to current complaints. Because of these variables, a detailed comprehensive history-taking with leading questions is essential for proper assessment; clinical features detected on examination should be recorded and graded for severity during initial and follow-up visits for proper assessment of outcome. All components of relevant history and physical examination preloaded on a handheld device is a useful guide to those who see these patients only infrequently. The CEAP classification and Venous Severity Scoring endorsed by the vascular societies can serve as readily usable templates for this purpose. In our own system, we have made some additional enhancements that we find useful. Pain is measured on a visual analogue scale, a simple reliable measure of pain that can be used for outcome assessment as well. Limb swelling is variable throughout the day; limb measurement of swelling should be carried out at the same time of the day to be valid for follow-up assessment. Quality of life (QOL) measurements provide a view of outcome from the patient’s perspective. The degree of disability and social constraint imposed by this disease can be surprising. Many QOL forms (e.g., CIVIQ) are brief enough for routine use.
DIFFERENTIAL DIAGNOSIS
A clinical diagnosis of chronic venous insufficiency is readily apparent from history and physical examination in most cases but other rarer causes with somewhat similar clinical features have to be borne in mind: Periarteritis nodosa, ruptured Baker’s cyst, rheumatoid arthritis, gout, Marjolin’s ulcer, arterio-venous malformations of the calf muscles, adverse drug reactions with limb pain and swelling, acanthoma nigricans, pyoderma, and numerous other dermatological and systemic conditions. As venous insufficiency is common, particularly among the elderly, mixed pathologies that aggravate venous symptoms do occur. Combined arterial/venous insufficiency is not uncommon in the elderly; attention to the arterial component first is usually recommended. Differentiating primary from PTS may not be easy and mixed presentations occur as the following discussion on pathology indicates. Differentiation cannot be made on clinical grounds alone as history and physical findings may be similar including the appearance and size of ulcers. About 30% of DVT are estimated to be silent. In others DVT following trauma or surgery is simply missed as symptoms are submerged by expected postoperative pain—a common occurrence following orthopedic procedures on the hip or knee or for treatment of fractures. Patients with deep valvular insuffi ciency whether primary or post-thrombotic not infrequently present with new onset of acute calf pain and increased swelling in the context of ongoing chronic symptoms. In some, new or recurrent thrombosis is found. In others, no new thrombus is found; the symptoms are presumably due to decompensation of the calf pump from minor injury, low grade cellulitis or other obscure insult that disturbs the equilibrium of the calf pump. A diagnosis of PTS vs primary venous insufficiency is academic from the surgical viewpoint as the approach is the same regardless. But a diagnosis of PTS may have implications for long-term anticoagulation. In many cases, further investigations may provide helpful clarification.
PATHOLOGY
Our current view of PTS pathology is strongly influenced by the work of Strandness and colleagues. Before then, post-thrombotic clinical syndrome had been viewed as primarily related to the development of reflux. In a remarkable series of landmark papers, these authors showed that the dominant pathology was a combination of obstruction and reflux even though isolated obstruction and reflux occurred in some. The location and progression of post-thrombotic reflux followed by serial duplex were unexpected and intriguing. Reflux occurred not only in segments involved by thrombus but also in segments remote from them. Reflux occurred and progressed over time not only in deep venous segments distal to the thrombotic segment but also in segments proximal; in the distal segments, dilatation of the valve station due to cephalad obstruction was not found to be the cause of reflux. The fact that reflux occurs and progresses over time in superfi cial as well as deep valves proximal to the obstructed segment suggests a different (maybe cytokines), as yet poorly understood, mechanism.
Some patients present with femoral valve reflux and thrombosis in the distal femoral popliteal segment or even the calf. This clinical profile could be due to reflux stasis–induced distal thrombosis. Repair of the valve reflux can abate recurrent thrombosis. Similar type of clinical presentation also can result from evolution of de novo reflux above the thrombotic segment as described by Strandness and colleagues. Perivenous and mural fi brosis is a feature of these valves with constriction and foreshortening of the valve station (see Figure 9). The valve cusps themselves are redundant and reflexive apparently as a result of the fibrotic wall changes. The fi brotic valve station is somewhat smaller than the classic primary valve, but the cusps themselves appear normal but redundant and can be repaired like the primary valve using direct repair techniques. A plausible explanation for these features and perhaps for the remote reflux described by Strandness’s group is that perivenous and mural fi brosis may extend beyond the thrombosed segment to involve adjacent segments of preserving valve cusps, but inducing secondary reflux from valve station restriction.
Valves may also escape destruction because the thrombus in the resident segment lyses, but not without inducing fi brotic changes as described.
Fig.
INVESTIGATIONS
A comprehensive set of investigations are necessary for proper management of patients, particularly if invasive or other surgical intervention is contemplated. The aim is to clarify the pathology, identify the sites and nature of pathology, and grade its severity.
Duplex
Duplex is the initial and in many centers the only technique used. It has many deficiencies when used alone in assessment. As a qualitative tool, it can detect local reflux but cannot grade it nor can it adequately provide a measure of the overall severity of refl ux in the limb when multiple segments are involved. Valve closure time (VCT) has received much attention as a quantitative tool in this regard. Though it can identify reflux in a particular segment, VCT has poor correlation with the severity of reflux present. Trivial reflux may be associated with prolonged VCT and conversely high grade reflux may have only slightly prolonged VCT. Peak reflux velocity has a better correlation, but not to a degree that is clinically useable. At present relatively crude indices such as multisegment score (number of refl uxive segments) or the presence of axial reflux are the best measures available. Iliac vein outflow obstruction, an important contributor to PTS, is frequently impervious to duplex.
Venography
Unlike duplex, ascending venography provides a more composite view of venous pathology below the inguinal ligament. Post-thrombotic changes, segmental occlusions, and collateral patterns are readily apparent. The profunda femoris vein is the major natural collateral pathway in femoral stenoses and occlusions. This has an embryologic basis as the profunda femoris is the early axial vein receding to the mature pattern later in embryologic development. A putative profunda-popliteal connection apparently exists as a high resistance embryologic residue; profunda collateral flow can be observed as early as a few hours after onset of acute DVT in venograms. In chronic femoral vein occlusions, the profunda enlarges to the same caliber as the normal femoral vein (see Figure 11). This pattern of complete axial transformation of the profunda femoris vein occurs in about 15% of postthrombotic limbs. Reflux may result from enlargement of the profunda valve station and may be severe with symptoms. Lesser degrees of profunda enlargement can be found in other cases where the femoral vein is not totally occluded but is stenotic.
Because the direction of collateral flow in the profunda is the same as natural fl ow direction in the vessel, it is very efficient. Once fully developed, the profunda fully compensates for the loss of femoral flow with few residual clinical symptoms from outfl ow obstruction. In iliac vein occlusions, collateral flow is mainly through tributaries of the iliac vein itself, requiring reversal of normal flow direction. Collateral flow seems to be less efficient and residual outflow obstruction is present iearly half the cases with iliac occlusions.
These differential patterns of collateral development and function have clinical import. In patients with symptoms of outflow obstruction, iliac vein pathology is likely to be the culprit even if associated femoral vein occlusion is more readily seen on ascending venography. Ascending venography is inadequate for assessment of the iliac vein and the vena cava due to contrast dilution; stenotic lesions may easily be missed.
Fig. 11. Axial transformation of profunda femoral vein through a
large profunda-popliteal connection. The femoral vein is largely occluded
with the distal end seen as a stump.
Transfemoral venography is the procedure of choice for pelvic venous assessment. Exercise femoral venous pressures can be concurrently measured, hich can be helpful in grading severity of outflow obstruction. Descending venography can also be performed at the same time to define the architecture of femoral valves. Descending venography is no longer used for grading reflux due to lack of specificity.
A common pattern in severely post-thrombotic limbs is where the entire outflow appears to occur through the superficial veins with nonvisualization of deep veins giving the appearance of wiped-out deep system. This is invariably an artifact of technique. In most such cases a patent but post-thrombotic deep system with numerous collateral elements can be demonstrated on descending venography (see Figure 12). Presumably, there is a positive gradient across superficial to deep venous connections in these cases that contrast flow preferentially is restricted to the superficial system. The collateral contribution of the superficial system in such cases is negligible. Since the deep system is patent, reconstructive procedures can be planned despite the spurious appearance on ascending venography.
Several authors beginning with Rokitanski have documented the development of a dense perivenous sheath in postthrombotic iliac veins. This prevents or retards the development of collaterals. Surgical attempts have been made to remove the sheath for improving flow. The venographic appearance in such cases is one of diffuse stenosis without collaterals. Iliac vein pathology is easily missed in such cases, especially with ascending venography. With transfemoral venography, the diffuse lesion can be quite evident or subtle requiring measurements of vein diameter, which is seldom practiced. Because of this and other factors cited earlier, the sensitivity of venography in iliac vein pathology is only in the order of 60%.
Fig. 12. Ascending venogram opacifies only superficial network
(right). The deep system appears wiped out. This is often a technical artifact
ample deep venous elements are demonstrated on descending
venography (left).
Intravascular Ultrasound (IVUS)
Intravascular ultrasound is superior to venography in the assessment of post-thrombotic iliac vein and the inferior vena cava. Perivenous and mural fibrosis, stenoses and trabeculae are readily seen. It is invaluable in iliac vein stent placement.
Lymphangiography
About 30% of patients with deep venous insufficiency have lymphographic abnormalities such as pooling and delayed or absent lymphatic transport. Most are thought to be secondary to venous pathology from lymphatic exhaustion or damage. Some may be reversible with correction of venous pathology. Lymphographic information has prognostic value in resolution of leg swelling and affected patients may be adequately forewarned before interventions.
Airplethysmography (APG)
Measurement of ejection fraction and residual volume have been suggested as indirect indices of outflow obstruction. In our own and others’ experience, specifi city and sensitivity have been inconsistent. VFI appears to be a useful measure of reflux.
Ambulatory Venous Pressure Measurement
Ambulatory venous pressure measurement provides a global index of venous function in the limb encompassing multiple components. Post-exercise pressure (% drop) has an inconsistent relationship to the severity of outflow obstruction presumably because of the variability of calf pump efficiency. The recovery time or venous filling time (VFT) has been useful in assessing severity of postthrombotic pathology and reflux. A postoperative VFT of >5 seconds bodes well for a good surgical outcome; a VFT of <5 seconds the opposite. The mean improvement in VFT after successful repairs with good clinical outcome is generally in the order of about 6 ± 4 (SD) seconds. After successful valve repair, postoperative VFT does not reach normal levels in many patients. VFT is influenced not only by reflux but a multiplicity of other factors. Compliance of the conduit below the valve profoundly affects VFT even more than reflux at the valve. Failure to normalize or substantially improve VFT is probably related to the poor venous compliance in post-thrombotic extremities.
Measurement of Outflow Obstruction
Reduced or absent phasicity on duplex examination is often indicative of outflow obstruction at the iliac vein level, the information being qualitative. There are no reliable methods of functionally quantifying and grading outflow obstruction at the present time. Plethysmographic outflow fraction measurement such as with strain gauge technique and APG yield unacceptably high false positives due to compliance changes in the post-thrombotic calf; a reduced outflow fraction (<50%) results from subpar emptying of the venous pool from poor compliance as often as from outflow obstruction per se. And poor compliance may be present without obstruction. A reduced outflow fraction is indicative of post-thrombotic changes, not necessarily obstruction.
Pressure-based tests to detect and grade severity of obstruction such as arm/foot venous pressure differential with reactive hyperemia, exercise femoral venous pressures measurement, and intraoperative femoral vein pressure measurement with papavarine are positive only in about a third of cases. Assessment of outflow obstruction currently rests entirely on morphologic methodology (IVUS) restricted to the iliac vein segment.
TREATMENT
Compression Therapy
Compression therapy is the oldest and until recently the only therapeutic option available to treat PTS. It has been reported anecdotally to be ineffective in PTS but no systematic study has been undertaken. Compression therapy remains the initial approach in chronic venous disease including PTS. Some patients do fail compression therapy despite faithful compliance. Noncompliance, however, is the major cause of compression failure and recurrent symptoms. Noncompliance is high even in cold climates as documented in several community surveys. Longerm supervision or monitoring by health care workers has been advocated to improve compliance. However, noncompliance is high even under supervision. The reasons for noncompliance are many—tightness or fi t (cutting off circulation), warm weather, lack of efficacy, contact dermatitis, recurrent cost and inability to apply stockings due to frailty or arthritis are among the many reasons/excuses cited by patients. But the main underlying reason, often unstated, appears to be the restrictions and negatives of compression regimens in today’s image–conscious world with expectations of an unrestricted lifestyle. Thus compression is a quality of life issue from the patient’s viewpoint. Demands for compliance are unlikely to succeed after previous entreaties have failed and may not be appropriate when therapeutic alternatives have become available. Compression should be viewed not as an end itself, but complementary to the extent patients are willing to use them. Compression should be considered a failure regardless of the cause including noncompliance if symptom relief is not obtained after trial over a reasonable period of time, say three to six months depending on the clinical and socioeconomic situation of the patient. Worsening of symptoms or onset of complications such as recurrent infections during the trial period are also considered failures. Some patients are not candidates for compression therapy at all due to comorbidities (e.g., arthritis, frailty, or arterial compromise) or special work situations. Nonresponders should be offered alternatives, not life-longunna boot regimens as was the case before by necessity, and continues to be so in many parts of the world due to a conservative philosophy of health care delivery.
Saphenous Vein Ablation
There has been traditional advice against saphenous ablation in the presence of deep venous obstruction (secondary varices) to preserve its collateral contribution. The collateral contribution of saphenous vein in the presence of deep venous obstruction is insignificant. Stripping of a refluxive saphenous vein in PTS cases can provide significant symptom benefit by eliminating the reflux component without jeopardizing the limb. Stripping can be easily combined with valve reconstruction in the femoral area. The newer minimally invasive techniques of saphenous ablation are suitable alternatives as well and are easily combined with iliac vein stent placement when indicated
Valvuloplasty
In PTS patients, direct femoral or popliteal valve repair can be performed if the basic valve architecture is preserved. Eriksson stressed the importance of profunda valve repair in post-thrombotic cases due to the frequent presence of collateral reflux. We prefer an external or transmural technique without a venotomy for these cases as they are faster and hence multiple repairs (i.e., femoral and profunda) can be performed in a single sitting; and repairs can be carried out even in constricted or small valve stations. The internal technique is disadvantaged in comparison.
Trancommissural technique, which closes the wide valve angle present at the commissure and simultaneously tightens the lax valve cusps by transmural sutures that can be placed blindly in a reliable fashion. The first step in the procedure is to carry out an adventitial dissection to peel away the fibrous sheath surrounding the valve station. Valve attachment lines should become visible after the dissection. They should be defined in their entirety, which is necessary for placement of transcommissural sutures. Though the sutures are placed blindly, adherence to the technique as described in the original publication will result in technical success of >95%.
Absent or interrupted valve attachment lines invariably indicate cusp dissolution or damage beyond direct repair. In such cases one should proceed forthwith with axillary vein transfer without wasting time on performing a venotomy in a futile search for repairable valve cusps.
Axillary Vein Transfer
Axillary vein transfer is the mainstay of repair in PTS cases when direct valve repair is not feasible due to damage to the valve cusps. Seemingly a simple technique, it is in fact, quite demanding, requiring precise execution. Proctored learning is recommended to achieve consistently good results. The transferred valve should match the size of the native valve station being reconstructed. In most cases, the axillary vein is the preferred donor site to obtain a good size match. In a minority, the proximal brachial vein may also be suitable in size. We approach the axillary-brachial veins through a transverse incision in the armpit along the skin crease; exposure of 5 to
In trabeculated post-thrombotic veins, modifications of the basic technique are necessary. The trabeculae at the site of proximal and distal suture lines are excised (see Figure 13, 14, 15) to create a single lumen at the site for anastamoses.
Fig. 13.
Fig. 14.
Fig. 15.
In a subset of PTS patients both the femoral and profunda femoral veins are severely post-thrombotic with destroyed valve structures. The femoral confluence can be repaired with individual axillary vein transfers or by en bloc transfer of basilic-brachial confluence provided valves are present and size match requirements are satisfied (see Figure 16).
Fig.16.
LYMPHEDEMA
Background
Lymphedema is an abnormal collection of protein-rich fluid in the interstitium due to a defect in the lymphatic drainage network. Lymphedema most commonly affects the extremities, but it can involve the face, genitalia, or trunk. Numerous causes, both primary and secondary iature, have been identified for this condition.
The primary causes are due to abnormalities in the lymphatic system that are present at birth, although not always clinically evident until later in life. The 3 primary categories of lymphedema (due to genetic factors) are congenital lymphedema (Milroy disease), lymphedema praecox (Meige disease), and lymphedema tarda. Primary lymphedema can also be associated with various cutaneous syndromes.
Secondary lymphedema is due to an acquired obstruction or infiltration of the lymphatic system. Secondary lymphedema has a number of causes, which include malignancy, infection, obesity, trauma, congestive heart failure, portal hypertension, and therapeutic intervention. Despite the fact that the underlying etiologies of secondary lymphedema vary, clinical progression is similar and difficult to control.
Lymphedema is a progressive, deforming condition that is both physically and psychologically debilitating.
Angiosarcoma arising in an area of long-standing lymphedema is termed Stewart-Treves syndrome. Most cases of Stewart-Treves syndrome occur in the arm after surgery for breast cancer; however, sometimes angiosarcomas can arise in a chronically lymphedematous leg.
Lymphedema is a notoriously debilitating progressive condition with no known cure. The unfortunate patient faces a lifelong struggle of medical, and sometimes surgical, treatment fraught with potentially lethal complications.
The underlying problem is lymphatic dysfunction, resulting in an abnormal accumulation of interstitial fluid containing high molecular weight proteins. This condition underscores the tremendous importance of a normally functioning lymphatic system, which returns proteins, lipids, and accompanying water from the interstitium to the venous circulatioear the subclavian vein–internal jugular vein junction, bilaterally. The normal and abnormal flow of interstitial fluid through the lymphatic system are demonstrated below.
Fig. 17. The body quadrants of superficial lymph drainage
Fig. 18. (1) Normal lymphatic flow in (a) deep systems and (b) superficial systems. Note the small collateral vessels interconnecting the 2 systems. (2) Lymphedema develops from obstruction, dilation of valves, valvular insufficiency, and subsequent reversal of lymphatic flow.
Pathophysiology
The normal function of the lymphatics is to return proteins, lipids, and water from the interstitium to the intravascular space; 40-50% of serum proteins are transported by this route each day. High hydrostatic pressures in arterial capillaries force proteinaceous fluid into the interstitium, resulting in increased interstitial oncotic pressure that draws in additional water.
Interstitial fluid normally contributes to the nourishment of tissues. About 90% of the fluid returns to the circulation via entry into venous capillaries. The remaining 10% is composed of high molecular weight proteins and their oncotically associated water, which are too large to readily pass through venous capillary walls. This leads to flow into the lymphatic capillaries where pressures are typically subatmospheric and can accommodate the large size of the proteins and their accompanying water. The proteins then travel as lymph through numerous filtering lymph nodes on their way to join the venous circulation.
In a diseased state, the lymphatic transport capacity is reduced. This causes the normal volume of interstitial fluid formation to exceed the rate of lymphatic return, resulting in the stagnation of high molecular weight proteins in the interstitium. It usually occurs after flow has been reduced by 80% or more. The result, as compared to other forms of edema that have much lower concentrations of protein, is high-protein edema, or lymphedema, with protein concentrations of 1.0-5.5 g/mL. This high oncotic pressure in the interstitium favors the accumulation of additional water.
Accumulation of interstitial fluid leads to massive dilatation of the remaining outflow tracts and valvular incompetence that causes reversal of flow from subcutaneous tissues into the dermal plexus. The lymphatic walls undergo fibrosis, and fibrinoid thrombi accumulate within the lumen, obliterating much of the remaining lymph channels. Spontaneous lymphovenous shunts may form. Lymph nodes harden and shrink, losing their normal architecture.
In the interstitium, protein and fluid accumulation initiates a marked inflammatory reaction. Macrophage activity is increased, resulting in destruction of elastic fibers and production of fibrosclerotic tissue. Fibroblasts migrate into the interstitium and deposit collagen. The result of this inflammatory reaction is a change from the initial pitting edema to the brawny nonpitting edema characteristic of lymphedema. Consequently, local immunologic surveillance is suppressed, and chronic infections, as well as malignant degeneration to lymphangiosarcoma, may occur.
The overlying skin becomes thickened and displays the typical peau d’orange (orange skin) appearance of congested dermal lymphatics. The epidermis forms thick scaly deposits of keratinized debris and may display a warty verrucosis. Cracks and furrows often develop and accommodate debris and bacteria, leading to lymphorrhea, the leakage of lymph onto the surface of the skin.
Frequency
A common cause of lymphedema reported in the
Among the primary causes of lymphedema, lymphedema praecox is the most commonly reported.
International
Worldwide, the most common cause of lymphedema is filariasis infection. More than 100 million people are affected in endemic areas worldwide
Mortality/Morbidity
The outcome for persons with lymphedema depends on its chronicity, the complications that result, and the underlying disease state that caused the lymphedema.
The development of angiosarcoma (ie, Stewart-Treves syndrome) in the setting of lymphedema is the most serious complication of secondary lymphedema. The mean survival rate, after treatment, is approximately 24 months. The 5-year survival rate is 10%.
Other complications that increase morbidity are the development of recurrent cellulitis, bacterial or fungal infections, and lymphangioadenitis.
Sex
Primary lymphedema is most common in females. Lymphedema praecox is the most common form and affects
Age
Secondary lymphedema can affect persons of any age group, and its onset is determined by the primary cause. Hereditary (primary) lymphedema can be divided into 3 groups based on the age of onset of clinical lymphedema, as follows.
– Milroy disease is the familial form of lymphedema that usually manifests from birth to age 1 year.
– Lymphedema praecox (ie, Meige disease) occurs from age 1-35 years. It most commonly occurs around menarche.
– Lymphedema tarda manifests after age 35 years
CLINICAL
History
Patients often report that chronic swelling of an extremity preceded lymphedema. Eighty percent of patients present with lower extremity involvement, although the upper extremities, face, genitalia, and trunk can also be involved. The history confirms involvement of a distal extremity initially, with proximal involvement following. Patients with lymphedema often report painless swelling and leg heaviness.
Fevers, chills, and generalized weakness may be reported. Patients may have a history of recurrent episodes of cellulitis, lymphangitis, fissuring, ulcerations, and/or verrucous changes. Patients have a higher prevalence of bacterial and fungal infections.
In primary lymphedema, patients have a congenital defect in the lymphatic system; therefore, the history of onset is more typical of the specific type.
Also more common is for primary lymphedema to be associated with other anomalies and genetic disorders, such as yellow nail syndrome, Turner syndrome, Noonan syndrome, xanthomatosis,2 hemangiomas, neurofibromatosis type 1, distichiasis lymphedema,3,4 Klinefelter syndrome, congenital absence of nails, trisomy 21, trisomy 13, and trisomy 18.
A rare inherited disorder, distichiasis-lymphedema syndrome, is characterized by the presence of extra eyelashes (distichiasis) and swelling of the arms and legs (lymphedema). Swelling of the legs, especially below the knees, and eye irritation are common in people with this disorder. Spinal cysts (epidural) with or without other abnormalities of the spinal column can accompany distichiasis lymphedema. Distichiasis-lymphedema syndrome is inherited as an autosomal dominant genetic trait due to a mutation of the FOX2 gene.
In secondary lymphedema, the associated history should be more evident, based on the primary etiology.
If due to filariasis, the history should include travel or habitation in an endemic area.
Other patients should have a clear history of a neoplasm obstructing the lymphatic system, recurrent episodes of lymphangitis and/or cellulitis, obesity, trauma, or lymphedema resulting after surgery and/or radiation therapy.
A recent history of varicose vein surgery also is reported.
In 2009, Lu et al noted 24 cases of localized lymphedema presenting as solitary large polyps, solid or papillomatous plaques, pedunculated edematous lesions, or tumors that imitated sarcoma. Lesions most commonly occurred on the vulva.
Physical
The earliest symptom of lymphedema is nontender pitting edema of the affected area, most commonly the distal extremities. The face, trunk, and genitalia also may be involved. Radial enlargement of the area occurs over time, which progresses to a nonpitting edema resulting from the development of fibrosis in the subcutaneous fat.
The distal extremities are involved initially, followed by proximal advancement.
Patients have erythema of the affected area and thickening of the skin, which appears as peau d’orange skin and woody edema.
With long-term involvement, ENV develops, which is an area of cobble-stoned, hyperkeratotic, papillomatous plaques most commonly seen on the shins. The plaques of ENV can be covered with a loosely adherent crust, can be weepy or oozing a clear or yellow fluid, and/or can have a foul-smelling odor. The changes of ENV have been described as cobblestone, pebbly, hyperkeratotic, papillomatous, and verrucous.
Fissuring, ulcerations, skin breakdown, and lymphorrhea can also be seen. Lymphorrhea involves the weeping or oozing of clear, yellow, or straw-colored fluids. Superinfection is common and can manifest as impetigo with yellow crusts.
Four cases of cutaneous verruciform xanthomas in association with lymphedema have been cited in the literature. More recent reports have suggested that verruciform xanthomas may be a rare reactive phenomenon found in persons with common cutaneous conditions. Because verruciform xanthoma is considered by some authorities to be a reactive condition, the link between these 2 entities remains unclear at this time.
A positive Stemmer sign (inability to pinch the dorsal aspect of skin between the first and second toes) may be elicited upon examination.
Other associated physical findings specific for the cause of secondary lymphedema and genetic disorders involving lymphedema may be noted upon examination.
Causes
Both primary and secondary lymphedema can have many causes.
Primary lymphedema
Primary lymphedema is divided into 3 main types, which are distinguished by their age of onset. All are caused by a congenital abnormality in the lymphatic system, although these defects may not always be clinically evident until later in life. Additionally, primary lymphedema also can be associated with other cutaneous and genetic disorders not among the 3 main age-based categories.
Congenital lymphedema, also known as Milroy disease, is an autosomal dominant familial disorder of the lymphatic system that manifests at birth to age 1 year. It is often due to anaplastic lymphatic channels. The lower extremity edema is most commonly bilateral, pitting, and nonpainful. This condition may be linked to a mutation that inactivates VEGFR3. It has been associated with cellulitis, prominent veins, intestinal lymphangiectasias, upturned toenails, and hydrocele.
Lymphedema praecox, also known as Meige disease, is the most common form of primary lymphedema. Seventy percent of cases are unilateral, with lower extremity swelling being more common. This type of primary edema is most often due to hypoplastic lymphatic channels. This condition most often manifests clinically around menarche, suggesting that estrogen may play a role in its pathogenesis.
Lymphedema tarda manifests later in life, usually in persons older than 35 years. It is thought to be due to a defect in the lymphatic valves, resulting in incompetent valve function. Whether this defect is congenital or acquired is difficult to determine.
As mentioned, primary lymphedema is also seen in association with other cutaneous and genetic disorders.
Lymphedema-distichiasis syndrome is a form of hereditary early- and late-onset lymphedema associated with distichiasis (double row of eyelashes). Affected persons usually manifest bilateral lower extremity lymphedema by age 8-30 years. Lymphatic vessels are usually larger in affected areas. It is a hereditary condition with an autosomal dominant pattern with variable penetrance. It reportedly is associated with a mutation in FOXC2 transcription factor.5 Other associated anomalies may include vertebral abnormalities, spinal arachnoid cysts, hemangiomas, cleft palate, ptosis, short stature, webbed neck, strabismus, thoracic duct abnormalities, and microphthalmia.
Primary lymphedema has also been associated with yellow nail syndrome. This entity may be associated with recurrent pleural effusions and bronchiectasis.
Other genetic syndromes and cutaneous conditions associated with primary lymphedema are Turner syndrome, Noonan syndrome, Klinefelter syndrome, neurofibromatosis type 1, hemangiomas, xanthomatosis, and congenital absence of nails. One reported case described lymphedema in association with CHARGE (coloboma, heart anomalies, choanal atresia, somatic and mental retardation, genitourinary anomalies, ear abnormalities) syndrome.
Secondary lymphedema
Secondary Lymphedema is caused by an acquired defect in the lymphatic system and is commonly associated with obesity, infection, neoplasm, trauma, or therapeutic modalities.
The most common cause of secondary lymphedema worldwide is filariasis. This is due to a mosquito-borne nematode infection with the parasite Wucheria bancrofti. It commonly occurs in developing countries around the world. This infection results in permanent lymphedema of the limb.
In the developed world, the most common cause of secondary lymphedema is malignancy and treatment.
– It can result from obstruction from metastatic cancer or primary lymphoma or can be secondary to radical lymph node dissection and excision. Although lymphatics are thought to regenerate after transection via surgery, when combined with radiotherapy to the area, the risk of lymphedema increases because of scarring and fibrosis of the tissue.
– The most commonly affected area is the axillary region after mastectomy and radical dissection for breast cancer. Lymphedema can also be seen after regional dissection of pelvic, para-aortic, and neck lymph nodes.
– Other associated neoplastic diseases are Hodgkin lymphoma, metastatic prostate cancer, cervical cancer, breast cancer, and melanoma.
Morbid obesity frequently causes impairment of lymphatic return and commonly results in lymphedema, as shown in the image below.
Fig. 19. Morbidly obese patient with lymphedema.
– Lymphedema is also associated with trauma, varicose vein surgery, congestive heart failure, portal hypertension, and extrinsic pressure, as shown in the image below.
Fig. 20. Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function
– Recurrent episodes of cellulitis or streptococcal lymphangitis have been linked to the development of lymphedema.
Laboratory Studies
Analysis of blood, urine, or tissue is not needed to make the diagnosis of lymphedema. Such tests, however, help to define the underlying causes of lower extremity edema when the etiology is unclear.
– Liver function, BUN/creatinine levels, and urinalysis results should be checked if a renal or hepatic etiology is suspected.
– Specific markers should be checked if a neoplasm is suspected.
– CBC count with differential should be checked if an infectious etiology is being considered.
Imaging Studies
Imaging is not necessary to make the diagnosis, but it can be used to confirm it, to assess the extent of involvement, and to determine therapeutic intervention.
– Lymphangiography is an invasive technique that can be used to evaluate the lymphatic system and its patency. Although it was once thought to be the first-line imaging modality for lymphedema, it is now rarely used because of the potential adverse effects.
– Lymphoscintigraphy is the new criterion standard to assess the lymphatic system. It allows for detailed visualization of the lymphatic channels with minimal risk. The anatomy and the obstructed areas of lymphatic flow can be assessed.
– Ultrasonography can be used to evaluate the lymphatic and venous systems. Volumetric and structural changes are identified within the lymphatic system. Venous abnormalities such as deep vein thrombosis can be excluded based on ultrasonography findings.
– MRI and CT scanning can also be used to evaluate lymphedema. These radiologic tests can be helpful in confirming the diagnosis and monitoring the effects of treatment. They are also recommended when malignancy is suspected.
Other Tests
A biopsy should be performed if the diagnosis is not clinically apparent, if areas of chronic lymphedema look suspicious, or if areas of chronic ulceration exist.
Histologic Findings
Histologic findings include hyperkeratosis with areas of parakeratosis, acanthosis, and diffuse dermal edema with dilated lymphatic spaces. In chronic lymphedema, marked fibrosis and scattered foci of inflammatory infiltrate can be seen.
Medical Care
The goal of therapy is to restore function, to reduce physical and psychologic suffering, and to prevent the development of infection.
- The first-line treatment is complex physical therapy. This therapy is aimed at improving lymphedema with manual lymphatic drainage, massage, and exercise. It advocates the use of compression stockings (at a minimum of
40 mm Hg), multilayer bandaging, or pneumatic pumps. Leg elevation is essential. Appropriate skin care and debridement is also stressed to prevent recurrent cellulitis or lymphangitis. - In secondary lymphedema, the underlying etiology (ie, neoplasm, infection) should also be properly treated to relieve the lymphatic obstruction and to improve lymphedema.
- In cases of recurrent cellulitis or lymphangitis, long-term antibiotic therapy with agents such as penicillins or cephalosporins is sometimes used.
- Filariasis has been treated with diethylcarbamazine and albendazole.
- In cases associated with obesity, weight loss is strongly recommended.
- A few pharmacological therapies have been found to be effective in the treatment of lymphedema.
- The benzopyrones (including coumarin and flavonoids) are a group of drugs that have been found to be successful in treating lymphedema when combined with complex physical therapy. They aid in decreasing excess edematous fluid, softening the limb, decreasing skin temperature, and decreasing the number of secondary infections. The benzopyrones successfully increase the number of macrophages, leading to proteolysis and protein reabsorption. Of note, however, is that hepatotoxicity has been associated with coumarin therapy.
- Case reports have suggested effective treatment of chronic lymphedematous changes (eg, elephantiasis nostra verrucosa [ENV]) with oral and topical retinoids. These therapies are thought to help normalize keratinization and decrease inflammatory and fibrotic changes.
- Topical emollients and keratolytics, such as ammonium lactate, urea, and salicylic acid, have been recommended to improve secondary epidermal changes.
- Diuretics are not effective in treating lymphedema.
Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Moreover, it is rarely indicated as the primary treatment modality. Rather, reserve surgical treatment for those who do not improve with conservative measures or in cases where the extremity is so large that it impairs daily activities and prevents successful conservative management.
Medication
Retinoids
These therapies are thought to help normalize keratinization and decrease inflammatory and fibrotic changes.
Acitretin (Soriatane)
Metabolite of etretinate and related to both retinoic acid and retinol (vitamin A). Mechanism of action unknown; however, thought to exert therapeutic effect by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells.
Tazarotene, topical (Tazorac)
Topical gel 0.1%. Retinoid prodrug whose active metabolite modulates differentiation and proliferation of epithelial tissue; may also have anti-inflammatory and immunomodulatory properties. Ensure skin is dry before applying gel
Anthelmintics
Filaria can cause lymphedema by obstruction.
Albendazole (Albenza, Valbazen)
A benzimidazole carbamate drug that inhibits tubulin polymerization, resulting in degeneration of cytoplasmic microtubules. Decreases ATP production in worm, causing energy depletion, immobilization, and, finally, death. Converted in the liver to its primary metabolite, albendazole sulfoxide. Less than 1% of the primary metabolite excreted in urine. Plasma level is noted to rise significantly (as much as 5-fold) when ingested after high-fat meal. Experience with patients <6 y limited. To avoid inflammatory response in CNS, patient must also be started on anticonvulsants and high-dose glucocorticoids.
Emollients/keratolytics
Ammonium lactate lotion (AmLactin, AmLactin XL, Lac-Hydrin)
Alpha-hydroxy acid; normal constituent of tissues and blood. Believed to act as humectant when applied to skin. This may influence hydration of the stratum corneum. In addition, when applied to skin, may act to decrease corneocyte cohesion. The mechanism by which this is accomplished is not yet known. Used to decrease scaling and pruritus. Found in a variety of topical emollient lotions. Ammonium lactate 5% lotion is available over the counter, and lactic acid 12% cream and lotion are available by prescription.
Urea, topical (Carmol, Keralac, Ureacin)
Promotes hydration and removal of excess keratin in conditions of hyperkeratosis
Indications
Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Moreover, it is rarely indicated as the primary treatment modality. Rather, reserve surgical treatment for those who do not improve with conservative measures or in cases where the extremity is so large that it impairs daily activities and prevents successful conservative management.
Relevant Anatomy
Before embarking on the treatment of lymphedema, a thorough knowledge of the relevant anatomy is essential. Blind-ended lymphatic capillaries arise within the interstitial spaces of the dermal papillae. These unvalved superficial dermal lymphatics drain into interconnected subdermal channels, which parallel the superficial venous system. These subsequently drain into the deeper, epifascial system of valved trunks lined with smooth muscle cells and located just above the deep fascia of the extremity. This system is responsible for the drainage of lymph from the skin and subcutaneous tissues. Valves provide for unidirectional flow towards regional lymph nodes and eventually the venous circulation in the neck. Flow is achieved by variations of tissue pressure through skeletal muscle contractions, pulsatile blood flow, and contractions of the spiral smooth muscle fibers surrounding larger lymphatic channels.
A deeper valved subfascial system of lymphatics is responsible for the drainage of lymph from the fascia, muscles, joints, ligaments, periosteum, and bone. This subfascial system parallels the deep venous system of the extremity. The epifascial and subfascial systems normally function independently, although valved connections do exist in the popliteal, inguinal, antecubital, and axillary regions where lymph nodes form interconnected chains. These connections probably do not function under normal conditions; however, in lymphedema, some reversed flow through perforators from the epifascial to the subfascial system may occur as a mechanism of decompression of the epifascial system. In lymphedema, the derangement is almost always exclusive to the epifascial lymphatic system, with the subfascial system being uninvolved. This is the basis for the surgical approaches to lymphedema, which focus on the epifascial system.
Contraindications
Contraindications to intermittent pneumatic pump compression therapy include congestive heart failure, deep vein thrombosis, and active infection.
Surgical Therapy
Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Moreover, it is rarely indicated as the primary treatment modality. Rather, reserve surgical treatment for those who do not improve with conservative measures or in cases where the extremity is so large that it impairs daily activities and prevents successful conservative management. The goals of surgical therapy are volume reduction to improve function, facilitation of conservative therapy, and prevention of complications. A myriad of surgical procedures have been advocated, reflecting a lack of clear superiority of one procedure over the others. In general, surgical procedures are classified as physiologic or excisional.
Physiologic procedures attempt to improve lymphatic drainage. Multiple techniques have been described, including omental transposition, buried dermal flaps, enteromesenteric bridging, lymphangioplasty, and microvascular lympholymphatic or lymphovenous anastomoses.8 None of these techniques has clearly documented favorable long-term results. Further evaluation is necessary. Moreover, many of these physiologic techniques also include an excisional component, making it difficult to distinguish between the 2 approaches.
Excisional techniques remove the affected tissues, thus reducing the lymphedema load. Some authors advocate suction-assisted removal of subcutaneous tissues, but this technique is difficult because of the extensive subcutaneous fibrosis that is present. Additionally, this approach does not reduce the skin envelope, and the lymphedema often rapidly recurs. Suction-assisted removal of subcutaneous tissue followed by excision of the excess skin envelope has no clear advantage over direct excisional techniques alone.
The Charles procedure is another quite radical excisional technique. This procedure involves the total excision of all skin and subcutaneous tissue from the affected extremity. The underlying fascia is then grafted, using the skin that has been excised. This technique is extreme and is reserved for only the most severe cases. Complications include ulceration, hyperkeratosis, keloid formation, hyperpigmentation, weeping dermatitis, and severe cosmetic deformity.
Van der Walt et al developed a modified Charles procedure in which negative-pressure dressing was employed following debulking surgery, with skin grafting delayed for 5-7 days.9 In a report on 8 patients suffering from severe primary lymphedema who underwent the procedure, the authors reported that the patients experienced no major complications. Minor complications, including operative blood loss and, in 3 patients, the need for additional grafting, did occur.
Staged excision has become the option of choice for many authors. This procedure involves removing only a portion of skin and subcutaneous tissue, followed by primary closure. After approximately 3 months, the procedure is repeated on a different area of the extremity. This procedure is safe, reliable, and demonstrates the most consistent improvement with the lowest incidence of complications.
Preoperative Details
Prior to surgery, appropriate documentation is necessary to evaluate the outcome of treatment. This includes photographic documentation as well as extremity measurements. Ideally, these measurements are of limb volume by water displacement, although some rely on circumferential measurements alone. Obtain measurements and photographs at the same time of day each time, document affected extremities and contralateral extremities, and preferably conduct documentation in the morning after extremity elevation in bed overnight.
Institute strict elevation and pneumatic compression, if available, 24-72 hours prior to surgery. This allows maximum excision to be performed. The extremity must also be free of infection at the time of surgery, and a single dose of preoperative intravenous antibiotic is administered.
Intraoperative Details
After the establishment of appropriate anesthesia, the operative field is sterilized and draped according to surgeon preference.
A pneumatic tourniquet is placed at the root of the extremity and insufflated after the extremity has been exsanguinated.
A longitudinal incision is made along the entire extremity, and skin flaps, 1.0-
Subcutaneous tissue is then excised, taking care not to injure peripheral sensory nerves.
Some authors also excise a strip of deep fascia, but this should not be performed around joints because it may cause instability.
Once the subcutaneous excision is complete, redundant skin is resected. Often, a strip that is 5-
The wound is closed over suction drains.
Postoperative Details
Postoperatively, the extremity is immobilized in a splint and elevated while the patient is placed on strict bed rest.
Antibiotics may be continued until drain removal, according to surgeon preference.
Drains are typically removed at 5-7 days postoperatively, as dictated by a decrease in drain output.
Sutures are removed at 10-14 days and replaced by Steri-Strips.
Measure the patient for a new compression garment when the new dimensions of the extremity have stabilized.
After approximately 10 days, the patient may gradually begin dependency on the extremity with compression bandages or an elastic garment in place.
Follow-up
Once discharged from the hospital, the patient should be seen regularly in the outpatient clinic.
Patients must wear compression garments for 4-6 weeks continuously, and dependency on the involved extremity may be gradually increased at the discretion of the treating physician.
Once healed to physician satisfaction, the patient may return to a normal routine of elevation at night and compression garment therapy during the day.
Follow-up visits should include documentation of circumferential measurement or water displacement of the affected and contralateral extremities as well as photographic documentation.
When staging procedures, allow approximately 3 months between procedures to allow complete healing of the initial operative site.
Complications
Patients with chronic lymphedema for 10 years have a 10% risk of developing lymphangiosarcoma, the most dreaded complication of this disease. Patients with this tumor commonly present with a reddish purple discoloration or nodule that tends to form satellite lesions. It may be confused with Kaposi sarcoma or traumatic ecchymosis. This tumor is highly aggressive, requires radical amputation of the involved extremity, and has a very poor prognosis. The 5-year survival rate is less than 10%, and the average survival following diagnosis is 19 months. This malignant degeneration is most commonly observed in patients with postmastectomy lymphedema (Stewart-Treves syndrome), where incidence is estimated to be 0.5%.
Other complications of lymphedema include recurrent bouts of cellulitis and/or lymphangitis, deep venous thrombosis, severe functional impairment, cosmetic embarrassment, and necessary amputation. Complications following surgery are common and include partial wound separation, seroma, hematoma, skin necrosis, and exacerbation of foot or hand edema.
Outcome and Prognosis
At present, no cure for lymphedema exists. Surgery is palliative at best, and it may be a part of the lifelong therapy patients must endure to manage this disease.
Future and Controversies
A myriad of surgical procedures have been advocated, reflecting a lack of clear superiority of one procedure over the others. Multiple physiological and excisional techniques have been described. None of the physiological techniques has clearly documented favorable long-term results; further evaluation is necessary. Moreover, many of the physiologic techniques also include an excisional component, making it difficult to distinguish between the 2 approaches.
DEEP VENOUS THROMBOSIS
Introduction of acute deep venous thrombosis
Deep venous thrombosis (DVT) most commonly involves the deep veins of the leg or arm, often resulting in potentially life-threatening emboli to the lungs or debilitating venous alular dysfunction and chronic leg swelling. Deep venous thrombosis (DVT) is also one of the most prevalent medical problems today, with an annual incidence of 117 cases per 100,000. Each year in the
Pathophysiology
Over a century ago, Rudolf Virchow described 3 factors that are critically important in the development of venous thrombosis: (1) venous stasis, (2) activation of blood coagulation, and (3) vein damage. Over time, refinements have been made in their description and importance to the development of venous thrombosis. The origin of venous thrombosis is frequently multifactorial, with components of the triad of variable importance in individual patients.
Studies have shown that low flow sites, such as the soleal sinuses, behind venous valve pockets, and at venous confluences, are at most risk for the development of venous thrombi. However, stasis alone is not enough to facilitate the development of venous thrombosis. Experimental ligation of rabbit jugular veins for periods of up to 60 minutes have failed to consistently cause venous thrombosis. Although, patients that are immobilized for long periods of time seem to be at high risk for the development of venous thrombosis, an additional stimulus is required to develop deep venous thrombosis (DVTs).
Mechanical injury to the vein wall appears to provide an added stimulus for venous thrombosis. Hip arthroplasty patients with the associated femoral vein manipulation represent a high-risk group that cannot be explained by just immobilization, with 57% of thrombi originating in the affected femoral vein rather than the usual site of stasis in the calf.6 Endothelial injury can convert the normally antithrombogenic endothelium to become prothrombotic by stimulating the production of tissue factor, von Willebrand factor, and fibronectin.
Genetic mutations within the blood’s coagulation cascade represent those at highest risk for the development of venous thrombosis (See Table 1).
Table 1. Relative Risk for Venous Thrombosis
Primary deficiencies of coagulation inhibitors antithrombin, protein C, and protein S are associated with 5-10% of all thrombotic events. Resistance of procoagulant factors to an intact anticoagulation system has also recently been described with the recognition of factor V Leiden mutation, representing 10-65% of patients with deep venous thrombosis (DVT)
Components of the Virchow triad are of variable importance in individual patients, but the end result is early thrombus interaction with the endothelium. This interaction stimulates local cytokine production and facilitates leukocyte adhesion to the endothelium, both of which promote venous thrombosis. Depending on the relative balance between activated coagulation and thrombolysis, thrombus propagation occurs.
Over time, thrombus organization begins with the infiltration of inflammatory cells into the clot. This results in a fibroelastic intimal thickening at the site of thrombus attachment in most patients and a fibrous synechiae in up to 11%. In many patients, this interaction between vessel wall and thrombus leads to alular dysfunction and overall vein wall fibrosis. Histological examination of vein wall remodeling after venous thrombosis has demonstrated an imbalance in connective tissue matrix regulation and a loss of regulatory venous contractility that contributes to the development of chronic venous insufficiency.
Risk factors
Many factors have been identified as known risk factors for the development of venous thrombosis. The single most powerful risk marker remains a prior history of DVT with up to 25% of acute venous thrombosis occurring in such patients. Pathologically, remnants of previous thrombi are often seen within the specimens of new acute thrombi. However, recurrent thrombosis may actually be the result of primary hypercoagulable states. Abnormalities within the coagulation cascade are the direct result of discrete genetic mutations within the coagulation cascade. Deficiencies of protein C, protein S, or antithrombin III account for approximately 5-10% of all cases of deep venous thrombosis (DVT).
Age has been well studied as an independent risk factor for venous thrombosis development. Although a 30-fold increase in incidence is noted from age 30 to age 80, the effect appears to be multifactorial, with more thrombogenic risk factors occurring in the elderly than in those younger than 40 years. Venous stasis, as seen in immobilized patients and paralyzed limbs, also contributes to the development of venous thrombosis. Autopsy studies parallel the duration of bed rest to the incidence of venous thrombosis, with 15% of patients in those studies dying within 7 days of bedrest to greater than 80% in those dying after 12 weeks.2 Within stroke patients, deep venous thrombosis (DVT) is found in 53% of paralyzed limbs, compared with only 7% on the nonaffected side.
Malignancy is noted in up to 30% of patients with venous thrombosis. The thrombogenic mechanisms involve abnormal coagulation, as evidenced by 90% of cancer patients having some abnormal coagulation factors.18 Chemotherapy may increase the risk of venous thrombosis by affecting the vascular endothelium, coagulation cascades, and tumor cell lysis. The incidence has been shown to increase in those patients undergoing longer courses of therapy for breast cancer, from 4.9% for 12 weeks of treatment to 8.8% for 36 weeks. Additionally, deep venous thrombosis (DVT) complicates 29% of surgical procedures done for malignancy.
Postoperative venous thrombosis varies depending on a multitude of patient factors, including the type of surgery undertaken. Without prophylaxis, general surgery operations typically have an incidence of deep venous thrombosis (DVT) around 20%, while orthopedic hip surgery can occur in up to 50% of patients. Based on radioactive labeled fibrinogen, about half of lower extremity thrombi develop intraoperatively. Perioperative immobilization, coagulation abnormalities, and venous injury all contribute to the development of surgical venous thrombosis.
Other clinical settings commonly reported as risk factors have also been identified and are shown in Table 2, 3
Table 2. Risk Factors for Venous Thromboemobolic Disease
Table 3. Risk Factors for Venous Thromboembolism
Clinical and diagnostic evaluation
The clinical diagnosis of deep venous thrombosis (DVT) is difficult and fraught with uncertainty. The classic signs and symptoms of deep venous thrombosis (DVT) are those associated with obstruction to venous drainage and include pain, tenderness, and unilateral leg swelling. Other associated nonspecific findings are warmth, erythema, a palpable cord, and pain upon passive dorsiflexion of the foot (Homan sign). However, even with patients with classic symptoms, up to 46% have negative venograms. Furthermore, up to 50% of those with image-documented venous thrombosis lack any specific symptom. Deep venous thrombosis (DVT) simply cannot be diagnosed or excluded based on clinical findings; thus, diagnostic tests must be performed whenever the diagnosis of deep venous thrombosis (DVT) is being considered.
When a patient has deep venous thrombosis (DVT), symptoms may be present or absent, unilateral or bilateral, or mild or severe. Thrombus that does not cause a net venous outflow obstruction is often asymptomatic. Thrombus that involves the iliac bifurcation, the pelvic veins, or the vena cava produces leg edema that is usually bilateral rather than unilateral. High partial obstruction often produces mild bilateral edema that is mistaken for the dependent edema of right-sided heart failure, fluid overload, or hepatic or renal insufficiency.
Severe venous congestion produces a clinical appearance that can be indistinguishable from the appearance of cellulitis. Patients with a warm, swollen, tender leg should be evaluated for both cellulitis and deep venous thrombosis (DVT) because patients with primary deep venous thrombosis (DVT) often develop a secondary cellulitis, while patients with primary cellulitis often develop a secondary deep venous thrombosis (DVT). Superficial thrombophlebitis, likewise, is often associated with a clinically inapparent underlying DVT.
If a patient is thought to have pulmonary embolism (PE) or has documented PE, the absence of tenderness, erythema, edema, or a palpable cord upon examination of the lower extremities does not rule out thrombophlebitis, nor does it imply a source other than a leg vein. More than two thirds of patients with proven PE lack any clinically evident phlebitis. Nearly one third of patients with proven PE have no identifiable source of deep venous thrombosis (DVT), despite a thorough investigation. Autopsy studies suggest that even when the source is clinically inapparent, it lies undetected within the deep venous system of the lower extremity and pelvis in 90% of cases.
Vascular Lab and Radiologic Evaluation
Duplex Ultrasound
DUS is now the most commonly performed test for the detection of infrainguinal DVT, both above and below the knee, and has a sensitivity and specificity of >95% in symptomatic patients. DUS combines real-time B-mode ultrasound with pulsed Doppler capability. Color flow imaging is useful in more technically difficult examinations, such as in the evaluation of possible calf vein DVT. This combination offers the ability to noninvasively visualize the venous anatomy, detect occluded and partially occluded venous segments, and demonstrate physiologic flow characteristics using a mobile self-contained device.
In the supine patient, normal lower extremity venous flow is phasic (Fig. 1), decreasing with inspiration in response to increased intra-abdominal pressure with the descent of the diaphragm and then increasing with expiration. When the patient is upright, the decrease in intra-abdominal pressure with expiration cannot overcome the hydrostatic column of pressure existing between the right atrium and the calf. Muscular contractions of the calf, along with the one-way venous valves, are then required to promote venous return to the heart. Flow also can be increased by leg elevation or compression and decreased by sudden elevation of intra-abdominal pressure (Valsalva’s maneuver). In a venous DUS examination performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to Valsalva’s maneuver are all assessed. However, the primary method of detecting DVT with ultrasound is demonstration of the lack of compressibility of the vein with probe pressure on B-mode imaging. Normally, in transverse section, the vein walls should coapt with pressure. Lack of coaptation indicates thrombus.
Fig. 1. Duplex ultrasound scan of a normal femoral vein with phasic flow signals.
The examination begins at the ankle and continues proximally to the groin. Each vein is visualized, and the flow signal is assessed with distal and proximal compression. Lower extremity DVT can be diagnosed by any of the following DUS findings: lack of spontaneous flow (Fig. 2), inability to compress the vein (Fig. 3), absence of color filling of the lumen by color flow DUS, loss of respiratory flow variation, and venous distention. Again, lack of venous compression on B-mode imaging is the primary diagnostic variable. Several studies comparing B-mode ultrasound to venography for the detection of femoropopliteal DVT in patients clinically suspected to have DVT report sensitivities of >91% and specificities of >97%. The ability of DUS to assess isolated calf vein DVT varies greatly, with sensitivities ranging from 50 to 93% and specificities approaching 100%.
Fig. 2. Duplex ultrasound of a femoral vein containing thrombus demonstrating no flow within the femoral vein
Fig. 3. B-mode ultrasound of the femoral vein in cross-section. The femoral vein does not collapse with external compression
Impedance Plethysmography
Impedance plethysmography (IPG) was the primary noninvasive method of diagnosing DVT before the widespread use of DUS but is infrequently used today. IPG is based on the principle that resistance to the flow of electricity between two electrodes, or electrical impedance, occurs as the volume of the extremity changes in response to blood flow. Two pairs of electrodes containing aluminum strips are placed circumferentially around the leg approximately
Iodine 125 Fibrinogen Uptake
Iodine 125 fibrinogen uptake (FUT) is a seldom used technique that involves IV administration of radioactive fibrinogen and monitoring for increased uptake in fibrin clots. An increase of 20% or more in one area of a limb indicates an area of thrombus.23 FUT can detect DVT in the calf, but high background radiation from the pelvis and the urinary tract limits its ability to detect proximal DVT. It also cannot be used in an extremity that has recently undergone surgery or has active inflammation. In a prospective study, FUT had a sensitivity of 73% and specificity of 71% for identification of DVT in a group of symptomatic and asymptomatic patients. Currently, FUT is primarily a research tool of historic interest.
Venography
Venography is the most definitive test for the diagnosis of DVT in both symptomatic and asymptomatic patients. It is the gold standard to which other modalities are compared. This procedure involves placement of a small catheter in the dorsum of the foot and injection of a radiopaque contrast agent. Radiographs are obtained in at least two projections. A positive study result is failure to fill the deep system with passage of the contrast medium into the superficial system or demonstration of discrete filling defects (Fig. 4). A normal study result virtually excludes the presence of DVT. In a study of 160 patients with a normal venogram followed for 3 months, only two patients (1.3%) subsequently developed DVT and no patients experienced symptoms of PE.
Fig. 4. Venogram showing a filling defect in the popliteal vein (arrows).
Venography is not routinely used for the evaluation of lower extremity DVT because of the associated complications discussed previously. Currently, venography is reserved for imaging before operative venous reconstruction and catheter-based therapy. It does, however, remain the procedure of choice in research studies evaluating methods of prophylaxis for DVT.
Laboratory analysis has also been used in aiding the diagnosis of venous thrombosis. D-dimers are degradation products of cross-linked fibrin by plasmin that are detected by diagnostic assays. Although highly sensitive, up to 97%, elevated levels are not specific with rates as low as 35%.27 Many other clinical situations can result in elevated D-dimer levels, including infection, trauma, postoperative states, and malignancy.28 Additional blood work should include coagulation studies to evaluate for a hypercoagulable state, if clinically indicated. A prolonged prothrombin time or activated partial thromboplastin time does not imply a lower risk of new thrombosis. Progression of deep venous thrombosis (DVT) and PE can occur despite full therapeutic anticoagulation in 13% of patients.
Treatment
Once the diagnosis of VTE has been made, antithrombotic therapy should be initiated promptly. If clinical suspicion for VTE is high, it may be prudent to start treatment while the diagnosis is being objectively confirmed. The theoretic goals of VTE treatment are the prevention of mortality and morbidity associated with PE and the prevention of the postphlebitic syndrome. However, the only proven benefit of anticoagulant treatment for DVT is the prevention of death from PE. Treatment regimens may include antithrombotic therapy, vena caval interruption, catheter-directed or systemic thrombolytic therapy, and operative thrombectomy.
Antithrombotic Therapy
Antithrombotic therapy may be initiated with IV or SC unfractionated heparin, SC low molecular weight heparin, or SC fondaparinux (a synthetic pentasaccharide). This initial therapy usually is continued for at least 5 days, while oral vitamin K antagonists are being simultaneously administered. The initial therapy typically is discontinued when the international normalized ratio (INR) is ≥2.0 for 24 hours.
Unfractionated heparin (UFH) binds to antithrombin via a specific 18-saccharide sequence, which increases its activity over 1000-fold. This antithrombin-heparin complex primarily inhibits factor IIa (thrombin) and factor Xa and, to a lesser degree, factors IXa, XIa, and XIIa. In addition, UFH also binds to tissue factor pathway inhibitor, which inhibits the conversion of factor X to Xa, and factor IX to IXa. Finally, UFH catalyzes the inhibition of thrombin by heparin cofactor II via a mechanism that is independent of antithrombin.
UFH therapy is most commonly administered with an initial IV bolus of 80 units/kg or 5000 units. Weight-based UFH dosages have been shown to be more effective than standard fixed boluses in rapidly achieving therapeutic levels. The initial bolus is followed by a continuous IV drip, initially at 18 units/kg per hour or 1300 units per hour. The half-life of IV UFH ranges from 45 to 90 minutes and is dose dependent. The level of antithrombotic therapy should be monitored every 6 hours using the activated partial thromboplastin time (aPTT), with the goal range of 1.5 to 2.5 times control values. This should correspond with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL.
Initial anticoagulation with UFH may be administered SC, although this route is less commonly used. Adjusted-dose therapeutic SC UFH is initiated with 17,500 units, followed by 250 units/kg twice daily, and dosing is adjusted to an aPTT goal range similar to that for IV UFH. Fixed-dose unmonitored SC UFH is started with a bolus of 333 units/kg, followed by 250 units/kg twice daily.
Hemorrhage is the primary complication of UFH therapy. The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of >2 units of packed red blood cells) is approximately 5% in hospitalized patients undergoing UFH therapy (1% in medical patients and 8% in surgical patients).27 For patients with UFH-related bleeding complications, cessation of UFH is required, and anticoagulation may be reversed with protamine sulfate. Protamine sulfate binds to UFH and forms an inactive salt compound. Each milligram of protamine neutralizes 90 to 115 units of heparin, and the dosage should not exceed 50 mg IV over any 10-minute period. Side effects of protamine sulfate include hypotension, pulmonary edema, and anaphylaxis. Patients with prior exposure to protamine-containing insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established. The protamine infusion should be terminated if any side effects occur.
In addition to hemorrhage, heparin also has unique complications. Heparin-induced thrombocytopenia (HIT) results from heparin-associated antiplatelet antibodies (HAAbs) directed against platelet factor 4 complexed with heparin. HIT occurs in 1 to 5% of patients being treated with heparin. In patients with repeat heparin exposure (such as vascular surgery patients), the incidence of HAAb may be as high as 21%.HIT occurs most frequently in the second week of therapy and may lead to disastrous venous or arterial thrombotic complications. Therefore, platelet counts should be monitored periodically in patients receiving continuous heparin therapy. All forms of heparin should be stopped if there is a high clinical suspicion or confirmation of HIT [usually accompanied by an unexplained thrombocytopenia (<100,000/L) or platelet count decrease of 30 to 50%]. Fortunately, direct thrombin inhibitors (recombinant hirudin, argatroban, bivalirudin) now are available as alternative antithrombotic agents (see later). Another complication of prolonged high-dose heparin therapy is osteopenia, which results from impairment of bone formation and enhancement of bone resorption by heparin.
Low molecular weight heparins (LMWHs) are derived from the depolymerization of porcine UFH. Like UFH, LMWHs bind to antithrombin via a specific pentasaccharide sequence to expose an active site for the neutralization of factor Xa. However, LMWHs lack the sufficient number of additional saccharide units (18 or more), which results in less inactivation of thrombin (factor IIa). In comparison to UFH, LMWHs have increased bioavailability (>90% after SC injection), longer half-lives (approximately 4 to 6 hours), and more predictable elimination rates. Weight-based once- or twice-daily SC LMWH injections, for which no monitoring is needed, provide a distinct advantage over continuous IV infusions of UFH for treatment of VTE.
Most patients who receive therapeutic LMWH do not require monitoring. Patients who do require monitoring include those with significant renal insufficiency or failure, pediatric patients, obese patients of >
Numerous well-designed trials comparing SC LMWH with IV and SC UFH for the treatment of DVT have been critically evaluated in several meta-analyses. The more recent studies demonstrate a decrease in thrombotic complications, bleeding, and mortality with LMWHs. LMWHs also are associated with a decreased rate of HAAb formation and HIT (<2%) compared with UFH (at least in prophylactic doses). However, patients with established HIT should not subsequently receive LMWHs due to significant rates of cross reactivity. A major benefit of LMWHs is the ability to treat patients with VTE as outpatients. In a randomized study comparing IV UFH and the LMWH nadroparin calcium, there was no significant difference in recurrent thromboembolism (8.6% for UFH vs. 6.9% for LMWH) or major bleeding complications (2.0% for UFH vs. 0.5% for LMWH). There was a 67% reduction in mean days in the hospital for the LMWH group.
A patient with VTE should meet several criteria before receiving outpatient LMWH therapy. First, the patient should not require hospitalization for any associated conditions. The patient should not require monitoring of the LMWH therapy (which is necessary in patients with severe renal insufficiency, pediatric patients, obese patients, and pregnant patients). The patient should be hemodynamically stable with a low suspicion of PE and have a low bleeding risk. An established outpatient system to administer LMWH and warfarin, as well as to monitor for recurrent VTE and bleeding complications, should be present. In addition, the patient’s symptoms of pain and edema should be controllable at home.
Fondaparinux currently is the only synthetic pentasaccharide that has been approved by the U.S. Food and Drug Administration (FDA) for the initial treatment of DVT and PE. Its five-polysaccharide sequence binds and activates antithrombin, causing specific inhibition of factor Xa. In two large noninferiority trials, fondaparinux was compared with the LMWH enoxaparin for the initial treatment of DVT and with IV UFH for the initial treatment of PE.The rates of recurrent VTE ranged from 3.8 to 5%, with rates of major bleeding of 2 to 2.6%, for all treatment arms. The drug is administered SC once daily with a weight-based dosing protocol: 5 mg, 7.5 mg, or 10 mg for patients weighing <
Direct-thrombin inhibitors (DTIs) include recombinant hirudin, argatroban, and bivalirudin. These antithrombotic agents bind to thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet activation. These actions are independent of antithrombin. The direct thrombin inhibitors should be reserved for (a) patients in whom there is a high clinical suspicion or confirmation of HIT, and (b) patients who have a history of HIT or test positive for heparin-associated antibodies. In patients with established HIT, DTIs should be administered for at least 7 days, or until the platelet count normalizes. Warfarin may then be introduced slowly, overlapping therapy with a DTI for at least 5 days.41 Because bivalirudin is approved primarily for patients with or without HIT who undergo percutaneous coronary intervention, it is not discussed here in further detail.
Commercially available hirudin is manufactured using recombinant DNA technology. It is indicated for the prophylaxis and treatment of patients with HIT. In patients with normal renal function, recombinant hirudin is administered in an IV bolus dose of 0.4 mg/kg, followed by a continuous IV infusion of 0.15 mg/kg per hour. The half-life ranges from 30 to 60 minutes. The aPTT is monitored, starting approximately 4 hours after initiation of therapy, and dosage is adjusted to maintain an aPTT of 1.5 to 2.5 times the laboratory normal value. The less commonly used ecarin clotting time is an alternative method of monitoring. Because recombinant hirudin is eliminated via renal excretion, significant dosage adjustments are required in patients with renal insufficiency.
Argatroban is indicated for the prophylaxis and treatment of thrombosis in HIT. It also is approved for patients with, or at risk for, HIT who undergo percutaneous coronary intervention. Antithrombotic prophylaxis and therapy are initiated with a continuous IV infusion of 2 g/kg per minute, without the need for a bolus. The half-life ranges from 39 to 51 minutes, and the dosage is adjusted to maintain an aPTT of 1.5 to 3 times normal. Large initial boluses and higher rates of continuous infusion are reserved for patients with coronary artery thrombosis and myocardial infarction. In these patients, therapy is monitored using the activated clotting time. Argatroban is metabolized by the liver, and the majority is excreted via the biliary tract. Significant dosage adjustments are needed in patients with hepatic impairment. There is no reversal agent for argatroban.
Vitamin K antagonists, which include warfarin and other coumarin derivatives, are the mainstay of long-term antithrombotic therapy in patients with VTE. Warfarin inhibits the -carboxylation of vitamin K–dependent procoagulants (factors II, VII, IX, X) and anticoagulants (proteins C and S), which results in the formation of less functional proteins. Warfarin usually requires several days to achieve its full effect, because normal circulating coagulation proteins must first undergo their normal degradation. Factors X and II have the longest half-lives, in the range of 36 and 72 hours, respectively. In addition, the steady-state concentration of warfarin is usually not reached for 4 to 5 days.
Warfarin therapy usually is monitored by measuring the INR, calculated using the following equation:
where ISI is the international sensitivity index. The ISI describes the strength of the thromboplastin that is added to activate the extrinsic coagulation pathway. The therapeutic target INR range is usually 2.0 to 3.0, but the response to warfarin is variable and depends on liver function, diet, age, and concomitant medications. In patients receiving anticoagulation therapy without concomitant thrombolysis or venous thrombectomy, the vitamin K antagonist may be started on the same day as the initial parenteral anticoagulant, usually at doses ranging from 5 to 10 mg. Smaller initial doses may be needed in older and malnourished patients, in those with liver disease or congestive heart failure, and in those who have recently undergone major surgery.
The recommended duration of warfarin antithrombotic therapy is increasingly being stratified based on whether the DVT was provoked or unprovoked, whether it was the first or a recurrent episode, where the DVT is located, and whether malignancy is present.
Table 4. Summary of
In contrast to patients with thrombosis related to transient risk factors, patients with idiopathic VTE are much more likely to develop recurrence (rates as high as 40% at 10 years). In this latter group of patients, numerous clinical trials have compared 3 to 6 months of anticoagulation therapy with extended-duration warfarin therapy, both at low intensity (INR of 1.5 to 2.0) and at conventional intensity (INR of 2.0 to 3.0). In patients with idiopathic DVT, extended-duration antithrombotic therapy is associated with a relative reduction in the rate of recurrent VTE by 75% to >90%. In addition, conventional-intensity warfarin reduces the risk even further compared with low-intensity warfarin (0.7 events per 100 person-years vs. 1.9 events per 100 person-years), but the rate of bleeding complications is no different.
In patients with VTE in association with a hypercoagulable condition, the optimal duration of anticoagulation therapy is influenced more by the clinical circumstances at the time of the VTE (idiopathic vs. secondary) than by the actual presence or absence of the more common thrombophilic conditions. In patients with VTE related to malignancy, increasing evidence suggests that longer-term therapy with LMWH (up to 6 months) is associated with a lower VTE recurrence rate than treatment using conventional vitamin K antagonists.
The primary complication of warfarin therapy is hemorrhage, and the risk is related to the magnitude of INR prolongation. Depending on the INR and the presence of bleeding, warfarin anticoagulation may be reversed by (a) omitting or decreasing subsequent dosages, (b) administering oral or parenteral vitamin K, or (c) administering fresh-frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa. Warfarin therapy rarely may be associated with the development of skiecrosis and limb gangrene. These conditions occur more commonly in women (4:1), and the most commonly affected areas are the breast, buttocks, and thighs. This complication, which usually occurs in the first days of therapy, is occasionally, but not exclusively, associated with protein C or S deficiency and malignancy. Patients who require continued anticoagulation may restart low-dose warfarin (2 mg) while receiving concomitant therapeutic heparin. The warfarin dosage is then gradually increased over a 1- to 2-week period.
Systemic and Catheter-Directed Thrombolysis
Patients with extensive proximal DVT may benefit from systemic thrombolysis or catheter-directed thrombolysis, which can potentially reduce acute symptoms more rapidly than anticoagulation alone. These techniques also may decrease the development of postthrombotic syndrome. Several thrombolysis preparations are available, including streptokinase, urokinase, alteplase (recombinant tissue plasminogen activator), reteplase, and tenecteplase. All these agents share the ability to convert plasminogen to plasmin, which leads to the degradation of fibrin. They differ with regard to their half-lives, their potential for inducing fibrinogenolysis (generalized lytic state), their potential for antigenicity, and their FDA-approved indications for use.
Streptokinase is purified from beta-hemolytic Streptococcus and is approved for the treatment of acute myocardial infarction, PE, DVT, arterial thromboembolism, and occluded central lines and arteriovenous shunts. It is not specific for fibrin-bound plasminogen, however, and its use is limited by its significant rates of antigenicity. Fevers and shivering occur in 1 to 4% of patients. Urokinase is derived from humaeonatal kidney cells, grown in tissue culture. Currently, it is only approved for lysis of massive PE or PE associated with unstable hemodynamics. Alteplase, reteplase, and tenecteplase all are recombinant variants of tissue plasminogen activator. Alteplase is indicated for the treatment of acute myocardial infarction, acute ischemic stroke, and acute massive PE. However, it often is used for catheter-directed thrombolysis of DVT. Reteplase and tenecteplase are indicated only for the treatment of acute myocardial infarction.
Systemic thrombolysis was evaluated iumerous older prospective and randomized clinical trials, and its efficacy was summarized in a recent Cochrane Review. In 12 studies involving over 700 patients, systemic thrombolysis was associated with significantly more clot lysis [relative risk (RR) 0.24 to 0.37] and significantly less postthrombotic syndrome (RR 0.66). However, venous function was not significantly improved. In addition, more bleeding complications did occur (RR 1.73), but the incidence appears to have decreased in later studies, probably due to improved patient selection.
In an effort to minimize bleeding complications and increase efficacy, catheter-directed thrombolytic techniques have been developed for the treatment of symptomatic DVT. With catheter-directed therapy, venous access may be achieved through percutaneous catheterization of the ipsilateral popliteal vein, retrograde catheterization through the contralateral femoral vein, or retrograde cannulation from the internal jugular vein. Multi–side-hole infusion catheters, with or without infusion wires, are used to deliver the lytic agent directly into the thrombus.
The efficacy of catheter-directed urokinase for the treatment of symptomatic lower extremity DVT has been reported in a large multicenter registry. Two hundred twenty-one patients with iliofemoral DVT and 79 patients with femoropopliteal DVT were treated with catheter-directed urokinase for a mean of 53 hours. Complete lysis was seen in 31% of the limbs, 50 to 99% lysis in 52% of the limbs, and <50% lysis in 17%. Overall, 1-year primary patency was 60%. Patency was higher in patients with iliofemoral DVT than in patients with femoropopliteal DVT (64% vs. 47%, P <.01). In addition, patients with acute symptoms (≤10 days) had a greater likelihood of complete lysis (34%) than patients with chronic symptoms (>10 days; 19%). Major bleeding occurred in 11%, but neurologic involvement and mortality were rare (both 0.4%). Adjunctive stent placement to treat residual stenosis and/or short segment occlusion was required in 103 limbs.
One small randomized trial and numerous other retrospective studies have demonstrated similar rates of thrombolysis, with some also showing improved valve preservation and quality of life. Combining thrombolysis with percutaneous thrombus fragmentation and extraction has the added benefit of decreasing the infusion time, the hospital stay, and the overall cost of treatment. These studies, as well as the current ACCP guidelines, suggest that catheter-directed thrombolysis (with adjunctive angioplasty, venous stenting, and pharmacomechanical fragmentation and extraction) may be useful in selected patients with extensive iliofemoral DVT. Patients should have a recent onset of symptoms (<14 days), good functional status, decent life expectancy, and low bleeding risk.
Since the introduction of the Kimray-Greenfield filter in the
Placement of an IVC filter is indicated for patients who develop recurrent DVT (significant propagation of the original thrombus or proximal DVT at a new site) or PE despite adequate anticoagulation therapy and for patients with pulmonary hypertension who experience recurrent PE. In patients who receive IVC filters for these indications, therapeutic anticoagulation should be continued. The duration of anticoagulation is determined by the underlying VTE and not by the presence of the IVC filter itself. Practically speaking, however, many patients who require an IVC filter for recurrent VTE are the same ones who would benefit most from indefinite anticoagulation. The other major indication for placement of an IVC filter is a contraindication to, or complication of, anticoagulation therapy in the presence of an acute proximal DVT. In patients who are not able to receive anticoagulants due to recent surgery or trauma, the clinician should continually reassess if antithrombotic agents may be started safely at a later date. Even some patients who develop anticoagulation-associated bleeding complications may be able to restart therapy at a lower intensity of anticoagulation later in the hospital course. As before, the clinical circumstances surrounding the VTE should determine the duration of anticoagulation.
Placement of permanent IVC filters has been evaluated as an adjunct to routine anticoagulation in patients with proximal DVT. In this study, routine IVC filter placement did not prolong early or late survival in patients with proximal DVT but did decrease the rate of PE (hazard ratio, 0.22; 95% confidence interval, 0.05 to 0.90). An increased rate of recurrent DVT was seen in patients with IVC filters (hazard ratio, 1.87; 95% confidence interval, 1.10 to 3.20). More controversial indications for IVC filter placement include prophylaxis against PE in patients receiving catheter-directed thrombolysis and in high-risk patients without established DVT or PE.
Hypercoagulability States
Certain patients seem to have a tendency to clot spontaneously. So-called hypercoagulability states were long thought to exist, but they were difficult to document except on clinical grounds. Currently, however, these clotting tendencies are better understood, thanks in large part to recognition of the role of antithrombins. If an antithrombin deficiency exists and clotting goes unchecked, activation of a clotting cascade could theoretically progress to clotting throughout the entire vasculature. Another important development was the recognition that deficiencies of certaiatural clot-removing substances in the blood may lead to a clinical thrombotic tendency. Both types of deficiency can be either acquired or congenital.
Screening
When the etiology of a clotting episode is unclear, the family history should be reviewed for evidence of a congenital disorder. Even if the history is negative, the patient should be screened for both acquired and congenital disorders (table 6).
Acquired Clotting Conditions
Screening for acquired clotting conditions [see Table 7] is based on the history, physical examination, and laboratory assessment. The history should include medications, diseases, and surgical procedures or other injuries.Examination may disclose causes of hypercoagulability. Soft tissue injury, for example, is a potent activator of the coagulation system. If the injury is severe enough, it may be capable of causing a severe acquired coagulopathy. The problem is usually obvious, but on occasion, detailed study may be necessary to identify tissue damage or ischemic injury to bowel or extremities. Hypovolemia”especially hypovolemic shock—markedly reduces clotting time: blood from a patient in profound shock may clot instantaneously in the syringe as it is being drawn. The breakdown of red cells in a hemolytic transfusion reaction can cause clotting. Severe infection, especially from gram-negative organisms, is a potent activator of coagulation.
Table 7. Etiology of Acquired Hypercoagulability
Of the acquired hypercoagulability syndromes, Trousseau syndrome is a particularly important condition for surgeons to recognize because it occurs in the surgical population (cancer patients) and must be treated with heparin (it is unresponsive to warfarin). It occurs when an adenocarcinoma secretes a protein recognized by the body as tissue factor, resulting in multiple episodes of venous thromboembolism over time (migratory thrombophlebitis). Simple depletion of vitamin K-dependent factors is ineffective. Patients should receive therapeutic-dose heparin indefinitely or until the cancer is brought into remission.
Laboratory screening may facilitate diagnosis. A complete blood count may document the presence of polycythemia or leukemia. Thrombocythemia may be a manifestation of a hypercoagulable disorder, and thrombocytopenia after the administration of heparin raises the possibility of intravascular platelet aggregation. A prolonged aPTT is suggestive of lupuslike anticoagulant. Increased levels of D-dimers, fibrin degradation products (FDPs), or fibrin monomers in the plasma may reflect low-grade intravascular coagulation.
Congenital Clotting Conditions
Congenital clotting tendencies can result from deficiencies in inhibitors of thrombosis (antithrombin, proteins C and S, and possibly heparin cofactor II), dysfibrinogenemias, or dysfibrinolysis [see Table 8]. Most congenital clotting defects are transmitted as an autosomal dominant trait. A negative family history does not preclude inherited thrombophilia, because the defects have a low penetrance, and fresh mutations may have occurred.
Table 8. Congenital Clotting Disorders
INITIAL LABORATORY ASSESSMENT
Initial evaluation of a patient with an unexplained thrombotic episode should be directed at the most common causes of hypercoagulability. Acquired causes of clotting are more commonly seen by surgeons than congenital causes and therefore must be excluded first. If a clotting disorder is determined to be congenital, a laboratory workup should be undertaken. Several of the relevant assays ”specifically, the functional assaysв”should be performed after the acute phase of the disorder has passed. If they are performed during the acute phase, levels of several antithrombotics (e.g., antithrombin and proteins C and S) will be misleadingly low not because deficiencies of these substances caused the underlying thrombotic process but because they were consumed in that process.
Specific Causes Of Thrombotic Tendency
The most common congenital causes of accelerated clotting are mutations of prothrombin (prothrombin G20210A mutation) and factor V (Leiden mutation, or activated protein C resistance).The prevalence of each of these ranges from 1% to 5% in the general population and may be much higher in specific ethnic subpopulations.1 Each mutation may be identified conclusively by means of polymerase chain reaction (PCR) techniques. Detection of these mutations, unlike assays for antithrombin and proteins C and S, is not dependent on the patient’s current inflammatory state. It must be remembered that the presence of one of these mutations, especially in the heterozygous form, does not imply that it is the sole cause of thrombosis. In many patients, a second precipitating factor must be present for the pathologic genetic thrombotic potential to be manifested.
Prothrombin G20210A Mutation
The prothrombin G20210A mutation is known to involve a single amino acid substitution in the prothrombin gene, but precisely how this increases the risk of venous thromboembolism is unclear. The one apparent manifestation of the mutation is a 15% to 40% increase in circulating prothrombin. Regardless of the mechanism at work, patients who are at least heterozygous for the trait are at two- to sixfold greater risk for venous thromboembolism than those without the mutation.
Resistance to Activated Protein C (Factor V
Resistance of human clotting factors to inactivation by activated protein C is believed to be the most common inherited procoagulant disorder.114 Normally, activated factor V is degraded by activated protein C in the presence of membrane surface as part of normal regulation of thrombosis. Activated protein C resistance is caused by a single substitution mutation in the factor V gene, which is passed in an autosomal dominant fashion. The mutant factor V that results, termed factor V Leiden, is resistant to inactivation by activated protein C and thus has a greater ability to activate thrombin and accelerate clotting.
Two techniques are commonly used to diagnose this disorder. The first is a functional assay that compares a standard aPTT to one performed in the presence of exogenous activated protein C. If the latter aPTT does not exhibit significant prolongation, the patient is probably resistant to activated protein C. The results of this assay must be interpreted with caution if the patient is still in the acute phase of the illness. The second technique, which is more reliable, involves direct detection of the mutation via PCR analysis of DNA.
Antithrombin Deficiency
Antithrombin (once termed antithrombin III) is a 65 kd protein that decelerates the coagulation system by inactivating activated factors—primarily factor Xa and thrombin but also factors XII, XI, and IX. Antithrombin therefore acts as a scavenger of activated clotting factors. Its activity is enhanced 100-fold by the presence of heparans on the endothelial surface and 1,000-fold by administration of exogenous heparin.
Congenital antithrombin deficiency occurs in approximately 0.01% to 0.05% of the general population and 2% to 4% of patients with venous thrombosis. The trait is passed on as an autosomal dominant trait, with the heterozygous genotype being incompatible with life. Antithrombin-deficient patients are at increased risk for thromboembolism when their antithrombin activity falls below 70% of normal.
Patients with congenital antithrombin deficiency frequently present after a stressful event. They usually have DVT but sometimes have PE. If anticoagulation is not contraindicated, the treatment of choice is heparin at a dosage sufficient to raise the aPTT to the desired level, followed by warfarin. If anticoagulation is contraindicated (as it is during the peripartum period), antithrombin concentrate should be given to raise the antithrombin activity to 80% to 120% of normal during the period when anticoagulants cannot be given.
Acquired antithrombin deficiency is a well-recognized entity. In most patients undergoing severe systemic stress, antithrombin levels fall below normal. Patients with classic risk factors for venous thromboembolism tend to have the lowest levels.
Protein C and Protein S Deficiency
Protein C is a 62 kd glycoprotein with a half-life of 6 hours. Because it is vitamin K dependent, a deficiency will develop in the absence of vitamin K. Acquired protein C deficiency is seen in liver disease, malignancy, infection, the postoperative state, and disseminated intravascular coagulation. Protein C deficiency occurs in approximately 4% to 5% of patients younger than 40 to 45 years who present with unexplained venous thrombosis. It is transmitted as an autosomal dominant trait, and the family history is usually positive for a clotting tendency. Protein C levels range from 70% to 164% of normal in patients without a clotting tendency; levels below 70% of normal are associated with a thrombotic tendency. The most appropriate tests for screening are functional assays; there are cases of dysfunctional protein C deficiency in which protein C antigen levels are normal but protein C activity is low, and these would not be detected by the usual immunoassays.
Protein S is a vitamin K-dependent protein that acts as a cofactor for activated protein C by enhancing protein C-induced inactivation of activated factor V. The incidence of protein S deficiency is similar to that of protein C deficiency. It is transmitted as a dominant trait, and the family history is often positive for a thrombotic tendency.
Hyperhomocysteinemia
Although hyperhomocysteinemia is more commonly associated with cardiac disease and arterial thrombosis, it may also be associated with an increased incidence of venous thromboembolism. This association is not as strong as those already discussed. Accordingly, anticoagulation of asymptomatic patients with elevated homocysteine levels is not currently recommended.
Dysfibrinogenemia
More than 100 qualitative abnormalities of fibrinogen (dysfibrinogenemias) have been reported. Dysfibrinogenemias are inherited in an autosomal dominant manner, with most patients being heterozygous. Most patients with dysfibrinogenemia have either no clinical symptoms or symptoms of a bleeding disorder; a minority (about 11%) have clinical features of a recurrent thromboembolic disorder. Congenital dysfibrinogenemias associated with thrombosis account for about 1% of cases of unexplained venous thrombosis occurring in young people. The most commonly observed functional defect in such dysfibrinogenemias is abnormal fibrin monomer polymerization combined with resistance to fibrinolysis. Decreased binding of plasminogen and increased resistance to lysis by plasmin have beeoted.
In addition to a prolonged TT, patients who have dysfibrinogenemia associated with thromboembolism may have a prolonged INR. The diagnosis is confirmed if the reptilase time is also prolonged. Measured with clotting techniques, fibrinogen levels may be slightly or moderately low; measured immunologically, levels may be normal or even increased.
Dysfibrinolysis
Fibrinolysis can be impaired by inherited deficiencies of plasminogen, defective release of t-PA from the vascular endothelium, and high plasma levels of regulatory proteins (e.g., t-PA inhibitors). In addition, factor XII (contact factor) deficiency may induce failure of fibrinolysis activation.
Inherited plasminogen deficiency is probably only rarely responsible for unexplained DVT in young patients. It is transmitted as an autosomal dominant trait. In heterozygous persons with a thrombotic tendency, plasminogen activity is about one half normal (3.9 to 8.4 Вµmol/ml). The euglobulin clot lysis time is prolonged. Functional assays should be carried out, and there should be full transformation of plasminogen into plasmin activators.
The important role of t-PA inhibitors I and II in the regulation of fibrinolysis is well defined.Iormal plasma, t-PA inhibitor I is the primary inhibitor for both t-PA and urokinase. Release of t-PA inhibitor I by platelets results in locally increased concentrations where platelets accumulate. The ensuing local inhibition of fibrinolysis may help stabilize the hemostatic plug. t-PA inhibitor II is present in and secreted by monocytes and macrophages.
Factor XII deficiency is a rare cause of impaired fibrinolysis. Initial contact activation of factor XII not only results in activation of the clotting cascade and of the inflammatory response but also leads to plasmin generation. This intrinsic activation of fibrinolysis requires factor XII, prekallikrein, and high-molecular-weight kininogen. Patients with factor XII deficiencies can be identified by a prolonged aPTT in the absence of clinical bleeding.
In patients with acute iliofemoral DVT, surgical therapy is generally reserved for patients who worsen with anticoagulation therapy and those with phlegmasia cerulea dolens and impending venous gangrene. If the patient has phlegmasia cerulea dolens, a fasciotomy of the calf compartments is first performed. In iliofemoral DVT, a longitudinal venotomy is made in the common femoral vein and a venous balloon embolectomy catheter is passed through the thrombus into the IVC and pulled back several times until no further thrombus can be extracted. The distal thrombus in the leg is removed by manual pressure beginning in the foot. This is accomplished by application of a tight rubber elastic wrap beginning at the foot and extending to the thigh. If the thrombus in the femoral vein is old and cannot be extracted, the vein is ligated. For a thrombus that extends into the IVC, the IVC is exposed transperitoneally and the IVC is controlled below the renal veins. The IVC is opened and the thrombus is removed by gentle massage. An intraoperative completion venogram is obtained to determine if any residual thrombus or stenosis is present. If a residual iliac vein stenosis is present, intraoperative angioplasty and stenting can be performed. In most cases, an arteriovenous fistula is then created by anastomosing the great saphenous vein (GSV) end to side with the superficial femoral artery in an effort to maintain patency of the thrombectomized iliofemoral venous segment. Heparin is administered postoperatively for several days. Warfarin anticoagulation is maintained for at least 6 months after thrombectomy. Complications of iliofemoral thrombectomy include PE in up to 20% of patients and death in <1% of patients.
One study followed 77 limbs for a mean of 8.5 years after thrombectomy for acute iliofemoral DVT. In limbs with successful thrombectomies, valvular competence in the thrombectomized venous segment was 80% at 5 years and 56% at 10 years. More than 90% of patients had minimal or no symptoms of postthrombotic syndrome. There were 12 (16%) early thrombectomy failures. Patients were required to wear compression stockings for at least 1 year after thrombectomy.
Survival rates for surgical pulmonary embolectomy have improved over the past 20 years with the addition of cardiopulmonary bypass. Emergency pulmonary embolectomy for acute PE is rarely indicated. Patients with preterminal massive PE (Fig. 5) for whom thrombolysis has failed or who have contraindications to thrombolytics may be candidates for this procedure. Open pulmonary artery embolectomy is performed through a posterolateral thoracotomy with direct visualization of the pulmonary arteries. Mortality rates range between 20 and 40%.
Fig. 5. Autopsy specimen showing a massive pulmonary embolism.
Percutaneous catheter-based techniques for removal of a PE involve mechanical thrombus fragmentation or embolectomy using suction devices. Mechanical clot fragmentation is followed by catheter-directed thrombolysis. Results of catheter-based fragmentation are based on small case series. In a study in which a fragmentation device was used in 10 patients with acute massive PE, fragmentation was successful in 7 patients with a mortality rate of 20%.65 Transvenous catheter pulmonary suction embolectomy has also been performed for acute massive PE with a reported 76% successful extraction rate and a 30-day survival of 70%.66
Prophylaxis
Patients who undergo major general surgical, gynecologic, urologic, and neurosurgical procedures without thromboprophylaxis have a significant incidence of perioperative DVT (15 to 40%). The incidence is even higher with major trauma (40 to 80%), hip and knee replacement surgery (40 to 60%), and spinal cord injury (60 to 80%). The goal of prophylaxis is to reduce the mortality and morbidity associated with VTE. The first manifestation of VTE may be a life-threatening PE (Fig. 6), and as indicated earlier, clinical evaluation to detect DVT before PE is unreliable.
Fig. 6. Pulmonary angiogram showing a pulmonary embolism (arrow).
Effective methods of VTE prophylaxis involve the use of one or more pharmacologic or mechanical modalities. Currently available pharmacologic agents include low-dose UFH, LMWH, synthetic pentasaccharides, and vitamin K antagonists. Mechanical methods include intermittent pneumatic compression (IPC) and graduated compression stockings. Aspirin therapy alone is not adequate for DVT prophylaxis. These prophylaxis methods vary with regard to their efficacy, and the 2008 ACCP Clinical Practice Guidelines stratify their uses according to the patient’s level of risk (Table 6).
Table 6. Thromboembolism Risk and Recommended Thromboprophylaxis in Surgical Patients
Complications
Complications after venous thrombosis can vary from life threatening to chronically debilitating. Pulmonary embolism develops as venous thrombi break off from their location of origin and travel through the right heart and into the pulmonary artery, causing a ventilation perfusion defect and cardiac strain. PE occurs in approximately 10% of patients with acute deep venous thrombosis and can cause up to 10% of in hospital deaths.60,61 However, most patients (up to 75%) are asymptomatic. Traditionally, proximal venous thrombosis are thought to be at highest risk for causing pulmonary emboli; however, the single largest autopsy series ever performed to specifically to look for the source of fatal PE was performed by Havig in 1977, who found that one third of the fatal emboli arose directly from the calf veins.6
PHLEGMASIA ALBA AND CERULEA DOLENS
More than 600,000 cases of venous thromboembolism are estimated to occur each year in the
History of the Procedure
In the 16th century, Fabricius Hildanus first described the clinical syndrome of what is currently called PCD. In 1938, Gregoire made an outstanding description of the condition and used the term PCD to differentiate ischemia-associated massive venous thrombosis from phlegmasia alba dolens, which describes fulminant venous thrombosis without ischemia.1 The exact incidence of these disorders is not well reported.
In 1939, Leriche and Geissendorfer performed the first thrombectomy for cases of PCD.2 Historically, surgical thrombectomy has been the procedure of choice for PCD refractory to medical therapy and in patients with established or impeding gangrene.
Frequency
More than 600,000 cases of venous thromboembolism are estimated to occur annually in the
Etiology
The main causative factor in phlegmasia is massive thrombosis and occlusion of major venous channels with significantly compromised venous outflow. Multiple triggering factors exist. Malignancy is the most common triggering factor and is present in approximately 20-40% of patients with PCD. Other associated risk factors include hypercoagulable syndrome, surgery, trauma, ulcerative colitis, gastroenteritis, heart failure, mitral valve stenosis, vena caval filter insertion, and May-Thurner syndrome (compression of the left iliac vein by the right iliac artery). Pregnancy has often been associated with phlegmasia alba dolens, especially during the third trimester when the uterus is large enough to compress the left common iliac vein against the pelvic rim (ie, milk leg syndrome). Finally, 10% of patients with phlegmasia have no apparent risk factors.
Pathophysiology
In phlegmasia alba dolens, the thrombosis involves only major deep venous channels of the extremity, therefore sparing collateral veins. The venous drainage is decreased but still present; the lack of venous congestion differentiates this entity from PCD.
In PCD, the thrombosis extends to collateral veins, resulting in venous congestions with massive fluid sequestration and more significant edema. Without established gangrene, these phases are reversible if proper measures are taken.
Of PCD cases, 40-60% also have capillary involvement, which results in irreversible venous gangrene that involves the skin, subcutaneous tissue, or muscle. Under these conditions, the hydrostatic pressure in arterial and venous capillaries exceeds the oncotic pressure, causing fluid sequestration in the interstitium. Venous pressure may increase rapidly, as much as 16- to 17-fold within 6 hours. Fluid sequestration may reach 6-
The exact mechanism for the compromised arterial circulation is debatable but may involve shock, increased venous outflow resistance, and collapse of arterioles due to increased interstitial pressure. Vasospasm of the resistance vessels has also been hypothesized but has never been observed experimentally or radiographically.
Presentation
In the lower extremities, left-sided involvement is more common by a 3:1 or 4:1 ratio. Involvement of upper extremities occurs in less than 5% of patients with PCD. Manifestations may be gradual or fulminant. Of PCD cases, 50-60% are preceded by phlegmasia alba dolens, with symptoms of edema, pain, and blanching (alba) without cyanosis. The blanching, which previously was thought to be caused by arterial vasospasm, is caused by subcutaneous edema, without venous congestion.
Patients with PCD present with the clinical triad of edema, agonizing pain, and cyanosis. Massive fluid sequestration may lead to bleb and bullae formation. The pain is constant, usually starting at the femoral triangle and then progressing to the entire extremity. Cyanosis is the pathognomonic finding of PCD, progressing from distal to proximal areas.
When venous gangrene occurs, it has a similar distribution with the cyanosis. Arterial pulses may be present when the venous gangrene is superficial; however, gangrene that involves the muscular compartment may result in increased compartment pressures and a pulse deficit. In addition, the pulses may be difficult to appreciate because of the significant edema. Various degrees of shock may be present because of significant fluid loss.
Indications
Historically, surgical thrombectomy has been the procedure of choice for phlegmasia cerulea dolens (PCD) refractory to medical therapy and for patients with established or impeding gangrene. The standard treatment of phlegmasia and venous gangrene is evolving, but most clinicians attempt endovascular approaches to thrombolysis, if possible.
Relevant Anatomy
The main causative factor in phlegmasia is massive deep venous thrombosis (DVT) and occlusion of major venous channels with significantly compromised venous outflow. In phlegmasia alba dolens, the thrombosis involves only major deep venous channels of the extremity, therefore sparing collateral veins and preserving some venous outflow from the limb. In phlegmasia cerulea dolens (PCD), the thrombosis extends to collateral veins, with complete obstruction of venous outflow, resulting in massive venous congestion and fluid sequestration and more significant edema.
Contraindications
For phlegmasia alba dolens and mild nongangrenous forms of phlegmasia cerulea dolens (PCD), conservative medical treatment, rather than surgical thrombectomy, should be the initial course of therapy. Thrombolysis may be initiated if conservative management does not elicit a response and if the patient has no contraindication to lytic therapy.
Surgical thrombectomy cannot open the small venules that are affected in venous gangrene, and it does not prevent valvular incompetence or postphlebitic syndrome. For these reasons, thrombolysis seems to be an attractive alternative in the management of PCD and venous gangrene.
Imaging Studies
The diagnoses of phlegmasia alba dolens, phlegmasia cerulea dolens (PCD), and venous gangrene are established mainly via clinical criteria with the assistance of contrast venography and duplex ultrasonography.
Although venography is considered the criterion standard for diagnosis, technical difficulties may be encountered in as many as 20-25% of patients. Attempts to perform ascending venography when extensive deep system thrombosis is present may result ionvisualization of the deep system and a nondiagnostic study result. In these cases, descending venography via the contralateral femoral vein or via the upper extremity veins may provide more information about the iliocaval system and proximal extent of the thrombus.
Recent improvements in ultrasonography have made this modality a more reliable and accurate way to assess for proximal deep venous thrombosis (DVT) with less morbidity. In addition, duplex imaging may be repeated as needed to monitor for thrombus propagation. Ultrasonography can also be performed at the bedside in patients who are critically ill or unstable. Ultrasonography is often used to guide the initial venipuncture for diagnostic venography and initiation of thrombolytic therapy.
Magnetic resonance venography (MRV) is an evolving modality of diagnostic imaging. Its principal advantage is its ability to easily reveal the proximal and distal extent of thrombus with a single study. Its principal disadvantage is the inability to image acutely ill patients with hemodynamic instability or motion artifacts due to pain.
Medical Therapy
The standard treatment of phlegmasia and venous gangrene is still evolving. The optimal therapeutic modality remains under debate. So far, the results of treatment have been moderately successful. For phlegmasia alba dolens and mild nongangrenous forms of phlegmasia cerulea dolens (PCD), conservative medical treatment, such as steep limb elevation, anticoagulation with intravenous administration of heparin, and fluid resuscitation, should be the initial course of therapy.
Initiate heparin administration with an intravenous bolus of 80-100 U/kg, followed by a continuous infusion of 15-18 U/kg/h. Frequently monitor the activated partial thromboplastin time (aPTT), with a goal range of 2-2.5 times the laboratory reference range. Frequently monitor platelet counts to allow the early detection of heparin-induced thrombocytopenia.
The purpose of rapid heparin anticoagulation is to decrease the risk of proximal clot propagation or thromboembolism. Heparin does not directly affect limb swelling. The best nonsurgical method to decrease edema is steep leg elevation.
Recent studies have demonstrated that low molecular weight heparins are safe and effective in the treatment of proximal deep venous thrombosis (DVT) and pulmonary embolism (PE); however, no good evidence supports the use of these newer agents in phlegmasia and venous gangrene.
If heparin-induced thrombocytopenia occurs, immediately discontinue the use of heparin and replace it with an alternative anticoagulant. Danaparoid and lepirudin are effective alternative agents; however, heparin-associated antibodies exhibit a 10-19% cross-reactivity with danaparoid. Thus, perform cross-reactivity testing before the initiation of danaparoid in patients with these antibodies. Lepirudin is a direct thrombin inhibitor that does not demonstrate any cross-reactivity. The recommended dosage of lepirudin in patients without renal failure is 0.4 mg/kg as an intravenous bolus followed by a continuous infusion of 0.15 mg/kg/h. Use aPTT to monitor therapy, with a goal range of 2-2.5 times the laboratory reference range.
Continue long-term anticoagulation with warfarin (or other coumarin derivatives) for at least 6 months. Life-long anticoagulation is recommended in patients with hypercoagulable states.
Patients should wear long-term prescription compression stockings with at least 30-
Surgical Therapy
Surgical thrombectomy performed through a femoral venotomy allows instant decompression of the venous hypertension. An intraoperative Trendelenburg position may be used to decrease the risk of PE. Transabdominal cavotomy and thrombectomy is an alternative approach that permits better control of the cava above the thrombus and, thus, provides protection against PE. Procedures that have been performed in an effort to decrease the rethrombosis rate include cross-pubic vein-to-vein reconstruction with polytetrafluoroethylene (PTFE) or the greater saphenous vein (GSV) or the creation of an arteriovenous fistula between the femoral artery and the GSV. These adjuvant procedures may be especially beneficial in cases that involve proximal iliofemoral vein constriction, damage, or external compression.
Concomitant administration of heparin and long-term anticoagulation are mandatory. Regardless, thrombectomy in patients with PCD is associated with a high rate of rethrombosis. Surgical thrombectomy cannot open the small venules that are affected in venous gangrene, and it does not prevent valvular incompetence or postphlebitic syndrome. The incidence of postphlebitic syndrome may be as high as 94% among survivors.
For the above reasons, thrombolysis seems to be an attractive alternative in the management of PCD and venous gangrene. In 1970, Paquet was the first to use thrombolysis for the treatment of PCD.4 Some authors propose catheter-directed thrombolysis directly into the vein with high doses of urokinase or tissue plasminogen activator (t-PA). Other authors support the method of intra-arterial low-dose thrombolysis via the common femoral artery, reasoning that the arterial route delivers the thrombolytic agent to the arterial capillaries and, subsequently, to the venules. The intra-arterial approach seems to be more effective in cases with venous gangrene. Systemic thrombolysis has also been used. Many authors have strongly recommended the insertion of a vena caval filter prior to initiation of thrombolytic therapy. Combine thrombolysis with heparin administration and long-term oral anticoagulation.
Fasciotomy alone or in conjunction with thrombectomy or thrombolysis reduces compartmental pressures; however, it significantly increases morbidity because of the prolonged wound healing and the risk of infection.
Finally, if all efforts fail and amputation is required, delay the procedure as long as possible. Take all precautions to reduce edema, allow venous channels to recanalize, and allow necrotic tissue to demarcate.
Preoperative Details
Patients who require emergent venous thrombectomy should have heparin continued throughout the perioperative period. Banked red blood cells should be available. The proximal extent of the thrombosis must be defined using a combination of venous ultrasonography for infrainguinal veins and retrograde venography of the iliac veins and inferior vena cava using a jugular or contralateral femoral approach. If the thrombosis extends into the iliac veins and vena cava, preparations should be made to control the cava via a right retroperitoneal incision. A high-quality fluoroscopy unit should be available to aid in catheter manipulation and completion venography.
Intraoperative Details
Operative exposure depends on the proximal and distal extent of the thrombus. The involved veins should be controlled proximally and distally prior to venotomy.
Iliac venous thrombectomy should be performed with large-bore thrombectomy balloon catheters (as large as
Infrainguinal extraction of the thrombus is aided by the intraoperative placement of an Esmarch bandage from foot to thigh. Thrombectomy balloon catheters (
Thrombolytic agents may be administered intraoperatively through the posterior tibial veins. t-PA is the most commonly used agent and may be administered intraoperatively.
After the thrombectomy is performed, an arteriovenous fistula should be constructed, connecting the proximal greater saphenous vein or one of its larger tributaries to the superficial femoral artery in an end-to-side fashion.
Completion venography should be performed to exclude the presence of residual thrombus or proximal venous stenosis. If one is present, balloon angioplasty with or without stent placement may be necessary.
When percutaneous endovascular therapy is performed as a single treatment modality, and many centers are now reporting this as a first-line therapy, the popliteal veins are usually accessed with duplex ultrasonography as an aid. Prone positioning is rarely necessary. If extensive thrombus is present, access via the posterior tibial vein is usually successful. A 6-F sheath is usually adequate. An infusion wire is passed through the thrombus just to its proximal extent, often into the vena cava. Infusion is usually performed in the most proximal segment first, usually in the iliac veins.
A common protocol is to infuse tPA (1 mg/hr) through the infusion wire as well as through the sheath for 24 hours, then to change the sheath perfusion to lower dose heparin after 24 hours. The infusion is then performed in the superficial femoral and popliteal vein segments. Clinical improvement is often noted with clearing of the profunda venous segment. Performance of simultaneous percutaneous mechanical thrombectomy is controversial and may not give better results than postprocedure balloon dilation.
Postoperative Details
Intravenous heparin is administered throughout the postoperative period to prolong the aPTT (2-2.5 times the reference range for aPTT). This is continued until the patient is adequately anticoagulated with warfarin or one of the coumarin derivatives (international normalized ratio [INR] range of 2.0-3.0). The optimal duration of oral anticoagulation is not established.
A sequential compression device is also placed, or, at a minimum, an ace bandage is placed for control of edema. Once the edema is at its minimum, the patient may be fitted for a thigh-length compression stocking. Ambulation is encouraged, if the patient is able.
Complications
The incidence of postphlebitic syndrome may be as high as 94% among survivors. Pulmonary embolism is common, and prophylactic placement of an inferior vena cava filter is recommended in most cases. Thrombectomy in patients with phlegmasia cerulea dolens (PCD) is associated with a high rate of rethrombosis. Amputation and death are common.
Outcome and Prognosis
Despite all of the therapeutic modalities described above, phlegmasia cerulea dolens (PCD) and venous gangrene still remain life-threatening and limb-threatening conditions with overall mortality rates of 20-40%. Pulmonary embolism (PE) is responsible for 30% of the deaths reported from PCD. Overall, amputation rates of 12-50% have been reported among survivors. The postphlebitic sequelae are apparent in 60-94% of survivors. Strict adherence to the use of long-term compression stockings helps to control chronic edema.
Future and Controversies
Phlegmasia alba dolens, phlegmasia cerulea dolens (PCD), and venous gangrene still remain a challenge to the vascular surgeon. Treatment modalities continue to evolve. Endovascular management may offer hope of successful and more effective management, with less morbidity, than traditional surgery. The role of mechanical thrombectomy, compared with thrombolysis, is unclear. Small numbers of patients and lack of randomized trials preclude clear recommendations.
SUPERIOR VENA CAVA SYNDROME
Introduction
Background
Superior vena cava syndrome (SVCS) is obstruction of blood flow through the superior vena cava (SVC). It is a medical emergency and most often manifests in patients with a malignant disease process within the thorax. A patient with superior vena cava syndrome (SVCS) requires immediate diagnostic evaluation and therapy.
William Hunter first described the syndrome in
Fig. 1. Superior vena cava syndrome (case 1). The patient was a 35-year-old man with a 3-year history of progressive upper-extremity and fascial swelling. The patient had undergone treatment for histoplasmosis in the past. CT scan shows a narrowed superior vena cava with adjacent calcified lymph nodes and posterior soft tissue thickening
Pathophysiology
The superior vena cava (SVC) is the major drainage vessel for venous blood from the head, neck, upper extremities, and upper thorax. It is located in the middle mediastinum and is surrounded by relatively rigid structures such as the sternum, trachea, right bronchus, aorta, pulmonary artery, and the perihilar and paratracheal lymph nodes. It extends from the junction of the right and left innominate veins to the right atrium, a distance of 6-
Obstruction of the superior vena cava (SVC) may be caused by neoplastic invasion of the venous wall associated with intravascular thrombosis or, more simply, by extrinsic pressure of a tumor mass against the relatively fixed thin-walled superior vena cava (SVC). Postmortem examinations reveal that complete superior vena cava (SVC) obstruction is the result of intravascular thrombosis in combination with extrinsic pressure. Incomplete superior vena cava (SVC) obstruction is more often secondary to extrinsic compression without thrombosis. Other causes include compression by intravascular arterial devices. The incidence is on the rise in line with the increased usage of endovascular devices.4
An obstructed superior vena cava (SVC) initiates collateral venous return to the heart from the upper half of the body through 4 principal pathways. The first and most important pathway is the azygous venous system, which includes the azygous vein, the hemiazygous vein, and the connecting intercostal veins. The second pathway is the internal mammary venous system plus tributaries and secondary communications to the superior and inferior epigastric veins. The long thoracic venous system, with its connections to the femoral veins and vertebral veins, provides the third and fourth collateral routes, respectively.
Despite these collateral pathways, venous pressure is almost always elevated in the upper compartment if obstruction of the superior vena cava (SVC) is present. Venous pressure as high as 200-
Frequency
Superior vena cava syndrome (SVCS) develops in 5-10% of patients with a right-sided malignant intrathoracic mass lesion. In 1969, Salsali and Cliffton observed superior vena cava syndrome (SVCS) in 4.2% of 4960 patients with lung cancer; 80% of the tumors inducing superior vena cava syndrome (SVCS) were of the right lung. In 5 large series of small cell lung cancer, 9-19% of patients demonstrated superior vena cava syndrome (SVCS). In 1987, Armstrong and Perez found superior vena cava syndrome (SVCS) in 1.9% of 952 patients with lymphoma.
Mortality/Morbidity
Survival in patients with superior vena cava syndrome (SVCS) depends mainly on the course of the underlying disease. No mortality, per se, results directly from mild venous congestion.
In patients with benign superior vena cava syndrome (SVCS), life expectancy is unchanged.
If superior vena cava syndrome (SVCS) is secondary to a malignant process, patient survival correlates with the histology of the tumor. Patients with signs and symptoms of laryngeal and cerebral edema have the most life-threatening manifestations of this syndrome and are in danger of sudden death. Clinical observations show that approximately 10% of patients with a bronchogenic carcinoma and 45% of patients with lymphoma treated with irradiation live at least 30 months. In contrast, patients with untreated malignant superior vena cava syndrome (SVCS) survive only approximately 30 days.5
Race
The frequency of superior vena cava syndrome (SVCS) in different races depends largely on the frequency of lung cancer and lymphomas in these populations.
Sex
Malignant causes of superior vena cava syndrome (SVCS) are most commonly observed in males because of the high incidence of lung cancer in this population.
In contrast, no sex difference is observed in cases related to benign causes.
Age
Malignant causes of superior vena cava syndrome (SVCS) are predominantly observed in individuals aged 40-60 years.
Benign causes account for most of the cases diagnosed in individuals aged 30-40 years.
Obstruction of the superior vena cava (SVC) in the pediatric age group is rare and has a different etiologic spectrum.
Clinical
History
Early in the clinical course, partial superior vena cava (SVC) obstruction may be asymptomatic, but more often, minor symptoms and signs are overlooked.
As the syndrome advances toward total superior vena cava (SVC) obstruction, the classic symptoms and signs become more obvious.
Dyspnea is the most common symptom and is observed in 63% of patients with superior vena cava syndrome (SVCS).7,10
Other symptoms include facial swelling, head fullness, cough, arm swelling, chest pain, dysphagia, orthopnea, distorted vision, hoarseness, stridor, headache, nasal stuffiness, nausea, pleural effusions, and light-headedness.7,10,11
Physical
The characteristic physical findings of superior vena cava syndrome (SVCS) include venous distension of the neck and chest wall, facial edema, upper extremity edema, mental changes, plethora, cyanosis, papilledema, stupor, and even coma.
Bending forward or lying down may aggravate the symptoms and signs.
Causes
More than 80% of cases of superior vena cava syndrome (SVCS) are caused by malignant mediastinal tumors.12,13,14
Bronchogenic carcinomas account for 75-80% of all these cases, with most of these being small-cell carcinomas.3
Non-Hodgkin lymphoma (especially the large cell type) represents 10-15% of cases.
Causes of superior vena cava syndrome (SVCS) appear similar to the relative incidence of primary lung and mediastinal tumors.
Rare malignant diagnoses include Hodgkin disease, metastatic cancers,15 primary leiomyosarcomas of the mediastinal vessels, and plasmocytomas.16,17,18
Nonmalignant conditions causing superior vena cava syndrome (SVCS) include mediastinal fibrosis; vascular diseases such as aortic aneurysm, vasculitis, and arteriovenous fistulas; infections such as histoplasmosis, tuberculosis, syphilis, and actinomycosis; benign mediastinal tumors such as teratoma, cystic hygroma, thymoma, and dermoid cyst; cardiac causes, such as pericarditis and atrial myxoma; and thrombosis related to the presence of central vein catheters. These account for approximately 22% of the causes of superior vena cava syndrome (SVCS).
Imaging Studies
Patients presenting with overt superior vena cava syndrome (SVCS) may be diagnosed by means of physical examination alone. However, subtle presentations require diagnostic imaging. Chest radiography may reveal a widened mediastinum or a mass in the right side of the chest. Only 16% of the patients studied by Parish and colleagues in 1981 had normal findings on chest radiography.
CT has the advantage of providing more accurate information on the location of the obstruction and may guide attempts at biopsy by mediastinoscopy, bronchoscopy, or percutaneous fine-needle aspiration.
It also provides information on other critical structures such as the bronchi and the vocal cords.
The additional information is necessary because the involvement of these structures requires prompt action for relief of pressure.
MRI has not been sufficiently investigated, but it appears promising.
It has several potential advantages over CT scanning, including the fact that it provides images in several planes of view and allows direct visualization of blood flow. Furthermore, MRI does not require iodinated contrast material. This is especially important when stenting is anticipated.
Disadvantages may include increased scanning time with attendant problems in patient compliance and increased cost.
Invasive contrast venography is the most conclusive diagnostic tool.
It precisely defines the etiology of obstruction.
It is especially important if surgical management is being considered for the obstructed vena cava.
Radionuclide technetium-99m venography is an alternative minimally invasive method of imaging the venous system. Although images obtained by this method are not as well defined as those achieved with contrast venography, they demonstrate potency and flow patterns.
Gallium single-proton emission CT scanning may be of value in select cases.
Procedures
Most patients with superior vena cava syndrome (SVCS) present before the primary diagnosis is established.
Controversy often arises in the treatment of a patient with superior vena cava syndrome (SVCS) in regard to the need for pathologic confirmation of malignancy before the start of therapy.
Treatment without an established diagnosis should be initiated only in patients with rapidly progressive symptoms or those in whom multiple attempts to obtain a tissue diagnosis have been unsuccessful.
Fortunately, relatively noninvasive measures establish the diagnosis in a high percentage of patients with superior vena cava syndrome (SVCS).
Sputum cytologic results are diagnostic in 68% of the cases, whereas biopsy of a palpable supraclavicular node is positive in 87%.
Bronchoscopy has a 60% success rate, while thoracotomy is 100% successful.
Open biopsy is rarely needed for diagnosis. Dosios et al showed that cervical mediastinoscopy and anterior mediastinoscopy are effective in establishing a histiologic diagnosis.
Medical Care
The goals of superior vena cava syndrome (SVCS) management are to relieve symptoms and to attempt cure of the primary malignant process. Only a small percentage of patients with a rapid-onset superior vena cava (SVC) obstruction are at risk for life-threatening complications.
Patients with clinical superior vena cava syndrome (SVCS) often gain significant symptomatic improvement from conservative treatment measures, including elevation of the head of the bed and supplemental oxygen.
Emergency treatment is indicated when brain edema, decreased cardiac output, or upper airway edema is present. Corticosteroids and diuretics are often used to relieve laryngeal or cerebral edema, although documentation of their efficacy is questionable.
Radiotherapy has been advocated as a standard treatment for most patients with superior vena cava syndrome (SVCS). It is used as the initial treatment if a histologic diagnosis cannot be established and the clinical status of the patient is deteriorating; however, recent reviews suggest that superior vena cava syndrome (SVCS) obstruction alone rarely represents an absolute emergency that requires treatment without a specific diagnosis.
The fractionation schedule of radiation usually includes 2-4 large initial fractions of 300-400 cGy, followed by conventional fractionation of 150-200 cGy daily, to a total dose of 3000-5000 cGy. The radiation dose depends on tumor size and radioresponsiveness. The radiation portal should include a 2-cm margin around the tumor.
During irradiation, patients improve clinically before objective signs of tumor shrinkage are evident on chest radiography. Radiation therapy palliates superior vena cava (SVC) obstruction in 70% of patients with lung carcinoma and in more than 95% with lymphoma.
In patients with superior vena cava syndrome (SVCS) secondary to non–small-cell carcinoma of the lung, radiotherapy is the primary treatment. The likelihood of patients benefiting from such therapy is high, but the overall prognosis of these patients is poor.
Chemotherapy may be preferable to radiation for patients with chemosensitive tumors.
In 1983, Maddox and associates reported on 56 patients with small-cell lung cancer who presented with superior vena cava syndrome (SVCS). Correction of superior vena cava syndrome (SVCS) was obtained in 9 (56%) of 16 patients treated with radiation therapy alone, in 23 (100%) of 23 given chemotherapy, and in 5 (83%) of 6 who received combined therapy.27
The most extensive experience in superior vena cava syndrome (SVCS) management secondary to non-Hodgkin lymphoma is reported from the M.D. Anderson cancer center. Patients were treated with chemotherapy alone, chemotherapy combined with radiation therapy, or radiation therapy alone. All patients achieved complete relief of superior vena cava syndrome (SVCS) symptoms within 2 weeks of the institution of any type of treatment. No treatment modality appeared to be superior in achieving clinical improvement.28
When superior vena cava syndrome (SVCS) is due to thrombus around a central venous catheter, patients may be treated with antifibrinolytics (eg, streptokinase, urokinase, recombinant tissue-type plasminogen activator) or anticoagulants (eg, heparin, oral anticoagulants). Removal of the catheter, if possible, is another option, and it should be combined with anticoagulation to avoid embolization.
In a 1988 report, Adelstein et al discuss prophylaxis against embolic events in the presence of a superior vena cava (SVC) obstruction in the management of 25 patients with malignant superior vena cava syndrome (SVCS).
Ten patients were retrospectively reviewed after having been diagnosed clinically without venography and treated without anticoagulation. Five thromboembolic complications occurred, 2 of which proved fatal.
Fifteen patients were prospectively evaluated by means of angiography and then treated with anticoagulants. Angiographic evidence of intraluminal subclavian vein or superior vena cava (SVC) thrombosis was found in 5 of these patients, and no thromboembolic complications occurred.
Of the 20 patients who were ultimately given anticoagulation therapy, 2 had fatal intracranial hemorrhages.
The authors suggested the need for randomized prospective trials if the role of venography and anticoagulation in this syndrome is to be determined.
Surgical Care
Surgical bypass of the superior vena cava (SVC) may be a useful way to palliate symptoms in carefully selected patients.
Indications to proceed with such procedures are much less clear.
For the most part, these are patients with advanced intrathoracic disease amenable only to palliative therapy (ie, after failure of radiation therapy and chemotherapy).
Patients with benign disease appear to be the best candidates for bypass.
Superior vena cava (SVC) stenting can provide rapid symptomatic relief within few days in most patients with superior vena cava syndrome (SVCS).
Superior vena cava (SVC) stenting may provide relief of severe symptoms for patients while the histological diagnosis of the malignancy causing the obstruction is being actively pursued.
Stenting may also be indicated in patients in whom chemotherapy or radiation has failed.
Some literature recommends stenting as a first-line treatment to be performed early in the management of superior vena cava syndrome (SVCS).
Cases of excimer laser removal of pacemaker leads followed by venoplasty and stenting have been reported.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Corticosteroids
These agents reduce swelling in patients with cerebral or laryngeal edema.
Dexamethasone (Decadron, Dexasone)
Important therapeutic agent in a number of malignant diseases. Exerts biologic action predominately by binding to glucocorticoid receptor. For symptomatic management in tumor-associated edema.
Thrombolytics
The potential benefits of thrombolytics for the treatment of pulmonary embolism include fast dissolution of physiologically compromising pulmonary emboli, quickened recovery, prevention of recurrent thrombus formation, and rapid restoration of hemodynamic disturbances. For deep vein thrombosis, lysis of the thrombus can prevent pulmonary embolism and permanent pathologic changes, such as venous valvular dysfunction and postphlebitic syndrome.
Urokinase (Abbokinase)
Converts plasminogen to plasmin, which degrades fibrin clots, fibrinogen, and other plasma proteins.
Anticoagulants
In superior vena cava syndrome (SVCS), these agents are used mainly to prevent pulmonary embolism from superior vena cava (SVC) thrombus.
Heparin
Inhibits thrombosis by inactivating activated factor X and inhibiting conversion of prothrombin to thrombin.
Warfarin (Coumadin)
Inhibits synthesis of vitamin K–dependent coagulation factors (factors II, VII, IX, X).
Further Inpatient Care
Admit the patient to the hospital if symptoms of superior vena cava syndrome (SVCS) are moderate to severe and/or when a patient requires the administration of thrombolytic therapy or anticoagulation.
Further Outpatient Care
Instruct patients to use supportive measures, such as elevation of the head of the bed.
Carefully monitor the patient’s symptoms and the adverse effects of the administered treatment. Patients should notify the physician immediately if any change in symptoms occurs.
Inpatient & Outpatient Medications
Oxygen supplementation may be provided if needed.
Antiemetics may be provided as needed to prevent nausea and vomiting.
For those patients started on steroids, taper steroids slowly, depending on the patient’s condition.
Transfer
Transfer may be required for further diagnostic evaluation and surgical intervention.
Complications
Complications include laryngeal edema, cerebral edema, decreased cardiac output with hypotension, and pulmonary embolism (when an associated thrombus is present).
Prognosis
The survival of patients with superior vena cava syndrome (SVCS) depends mainly on the course of the underlying disease.
Untreated patients and those not responding to treatment survive approximately 30 days.
