H

HAEMODYNAMIC DISORDERS, THROMBOEMBOLIC DISEASE, AND SHOCK

      The health of cells and organs critically depends on an unbroken circulation to deliver oxygen and nutrients and to remove wastes. However, the well-being of tissues also requires normal fluid balance; abnormalities in vascular permeability or hemostasis can result in injury even in the setting of an intact blood supply. This chapter will describe major disturbances involving hemodynamics and the maintenance of blood flow, including edema, hemorrhage, thrombosis, embolism, infarction, and shock. Normal fluid homeostasis encompasses maintenance of vessel wall integrity as well as intravascular pressure and osmolarity within certain physiologic ranges. Changes in vascular volume, pressure, or protein content, or alterations in endothelial function, all affect the net movement of water across the vascular wall. Such water extravasation into the interstitial spaces is called edema and has different manifestations depending on its location. In the lower extremities, edema mainly causes swelling; in the lungs, edema causes water to fill alveoli, leading to difficulty in breathing. Normal fluid homeostasis also means maintaining blood as a liquid until such time as injury necessitates clot formation. Clotting at inappropriate sites (thrombosis) or migration of clots (embolism) obstructs blood flow to tissues and leads to cell death (infarction). Conversely, inability to clot after vascular injury results in hemorrhage; local bleeding can compromise regional tissue perfusion, while more extensive hemorrhage can result in hypotension (shock) and death.

      Some of the failures of fluid homeostasis reflect a primary pathology in a discrete vascular bed (e.g., hemorrhage due to local trauma) or in systemic coagulation (thrombosis due to hypercoagulability disorders); others may represent a secondary manifestation of some other disease process. Thus, pulmonary edema due to increased hydrostatic pressure may be a terminal complication of ischemic or valvular heart disease. Similarly, shock may be the fatal sequela of infection. Overall, disturbances iormal blood flow are major sources of human morbidity and mortality; thrombosis, embolism, and infarction underlie three of the most important causes of pathology in Western society-myocardial infarction, pulmonary embolism, and cerebrovascular accident (stroke). Thus, the hemodynamic disorders described in this chapter are important in a wide spectrum of human disease.

Edema

   Approximately 60% of lean body weight is water; two thirds of this water is intracellular, and the remainder is found in the extracellular space, mostly as interstitial fluid (only about 5% of total body water is in blood plasma). The term edema signifies increased fluid in the interstitial tissue spaces. In addition, depending on the site, fluid collections in the different body cavities are variously designated hydrothorax, hydropericardium, and hydroperitoneum (the last is more commonly called ascites). Anasarca is a severe and generalized edema with profound subcutaneous tissue swelling

Pathophysiologic Categories of Edema

Increased Hydrostatic Pressure

Impaired venous return

Congestive heart failure

Constrictive pericarditis

Ascites (liver cirrhosis)

Venous obstruction or compression

Thrombosis

External pressure (e.g., mass)

Lower extremity inactivity with prolonged dependency

Arteriolar dilation

Heat

Neurohumoral dysregulation

Reduced Plasma Osmotic Pressure (Hypoproteinemia)

Protein-losing glomerulopathies (nephrotic syndrome)

Liver cirrhosis (ascites)

Malnutrition

Protein-losing gastroenteropathy

Lymphatic Obstruction

Inflammatory

Neoplastic

Postsurgical

Postirradiation

Sodium Retention

Excessive salt intake with renal insufficiency

Increased tubular reabsorption of sodium

Renal hypoperfusion

Increased renin-angiotensin-aldosterone secretion

Inflammation

Acute inflammation

Chronic inflammation

Angiogenesis

      In general, the opposing effects of vascular hydrostatic pressure and plasma colloid osmotic pressure are the major factors that govern movement of fluid between vascular and interstitial spaces. Normally the exit of fluid into the interstitium from the arteriolar end of the microcirculation is nearly balanced by inflow at the venular end; a small residuum of excess interstitial fluid is drained by the lymphatics. Either increased capillary pressure or diminished colloid osmotic pressure can result in increased interstitial fluid. As extravascular fluid accumulates, the increased tissue hydrostatic pressure and plasma colloid osmotic pressure eventually achieve a new equilibrium, and water reenters the venules. Any excess interstitial edema fluid is typically removed by lymphatic drainage, ultimately returning to the bloodstream via the thoracic duct .clearly, lymphatic obstruction (e.g., due to scarring or tumor) will also impair fluid drainage and result in edema. Finally, a primary retention of sodium (and its obligatory associated water) in renal disease also leads to edema.

An Oil Red O stain demostrates the fat globules within the pulmonary arterioles. The globules stain reddish-orange. The cumulative effect of many of these gobules throughout the lungs is similar to a large pulmonary embolus, but the onset of dyspnea is usually 2 to 3 days following the initiating event, such as blunt trauma with bone fractures.

 

     Increased Hydrostatic Pressure. Local increases in hydrostatic pressure may result from impaired venous outflow. For example, deep venous thrombosis in the lower extremities leads to edema, which is restricted to the affected leg. Generalized increases in venous pressure, with resulting systemic edema, occur most commonly in congestive heart failure affecting right ventricular cardiac function.

Although increased venous hydrostatic pressure is important, the pathogenesis of cardiac edema is more complex Congestive heart failure is associated with reduced cardiac output and, therefore, reduced renal perfusion. Renal hypoperfusion, in turn, triggers the renin-angiotensin-aldosterone axis, inducing sodium and water retention by the kidneys (secondary aldosteronism). This process is putatively designed to increase intravascular volume and thereby improve cardiac output (via the Frank-Starling law) with restoration of normal renal perfusion. If the failing heart cannot increase cardiac output, however, the extra fluid load results only in increased venous pressure and eventually edema.¹ Unless cardiac output is restored or renal water retention is reduced (e.g., by salt restriction, diuretics, or aldosterone antagonists), a cycle of renal fluid retention and worsening edema ensues. Although discussed here in the context of edema in congestive heart failure, salt restriction, diuretics, and aldosterone antagonists may also be used to manage generalized edema arising from a variety of other causes

 

The capillary loops of this glomerulus contain fat globules in a patient with fat embolism syndrome.

 

    Reduced Plasma Osmotic Pressure. Reduced plasma osmotic pressure can result from excessive loss or reduced synthesis of albumin, the serum protein most responsible for maintaining colloid osmotic pressure. An important cause of albumin loss is the nephrotic syndrome characterized by a leaky glomerular capillary wall and generalized edema. Reduced albumin synthesis occurs in the setting of diffuse liver pathology (e.g., cirrhosis, or as a consequence of protein malnutrition (In each case, reduced plasma osmotic pressure leads to a net movement of fluid into the interstitial tissues and a resultant plasma volume contraction. Predictably, with reduced intravascular volume, renal hypoperfusion with secondary aldosteronism follows. The retained salt and water cannot correct the plasma volume deficit because the primary defect of low serum proteins persists. As with congestive heart failure, edema precipitated by hypoproteinemia is exacerbated by secondary salt and fluid retention.

 

From several days to a week following the event initiating fat embolism syndrome, there may be loss of consciousness from lesions evidenced by the “brain purpura” as shown here. Numerous petechial hemorrhages are produced by fat emboli to the brain, particularly in the white matter. Subsequent to this there can be brain edema with herniation.

 

     Lymphatic Obstruction. Impaired lymphatic drainage and consequent lymphedema is usually localized; it can result from inflammatory or neoplastic obstruction. For example, the parasitic infection filariasis often causes massive lymphatic and lymph node fibrosis in the inguinal region. The resulting edema of the external genitalia and lower limbs is so extreme that it is called elephantiasis. Cancer of the breast may be treated by removal or irradiation (or both) of the breast and the associated axillary lymph nodes. The resection of the lymphatic channels as well as scarring related to the surgery and radiation can result in severe edema of the arm. In carcinoma of the breast, infiltration and obstruction of superficial lymphatics can cause edema of the overlying skin, giving rise to the so-called peau d’orange (orange peel) appearance. Such a finely pitted appearance results from an accentuation of depressions in the skin at the site of hair follicles.

    Sodium and Water Retention. Sodium and water retention are clearly contributory factors in several forms of edema; however, salt retention may also be a primary cause of edema. Increased salt, with the obligate accompanying water, causes both increased hydrostatic pressure (owing to expansion of the intravascular fluid volume) and diminished vascular colloid osmotic pressure. Salt (and water) retention may occur with any acute reduction of renal function, including glomerulonephritis and acute renal failure

 

    Morphology. Edema is most easily recognized grossly; microscopically, edema fluid generally manifests only as subtle cell swelling, with clearing and separation of the extracellular matrix elements. Although any organ or tissue in the body may be involved, edema is most commonly encountered in subcutaneous tissues, the lungs, and the brain. Severe, generalized edema is called anasarca

  Subcutaneous edema may have different distributions depending on the cause. It can be diffuse, or it may be relatively more conspicuous at the sites of highest hydrostatic pressures. In the latter case, the edema distribution is typically influenced by gravity and is termed dependent. Edema of the dependent parts of the body (e.g., the legs when standing, the sacrum when recumbent) is a prominent feature of congestive heart failure, particularly of the right ventricle. Edema as a result of renal dysfunction or nephrotic syndrome is generally more severe than cardiac edema and affects all parts of the body equally. It may, however, initially manifest itself in tissues with a loose connective tissue matrix, such as the eyelids; thus, periorbital edema is a characteristic finding in severe renal disease. Finger pressure over substantially edematous subcutaneous tissue displaces the interstitial fluid and leaves a finger-shaped depression, so-called pitting edema

 

    Pulmonary edema is a common clinical problem  most typically seen in the setting of left ventricular failure but also occurring in renal failure, acute respiratory distress syndrome , pulmonary infections, and hypersensitivity reactions. The lungs are two to three times their normal weight, and sectioning reveals frothy, blood-tinged fluid representing a mixture of air, edema fluid, and extravasated red blood cells.

    Edema of the brain may be localized (e.g., owing to abscess or neoplasm) or may be generalized, as in encephalitis, hypertensive crises, or obstruction to the brain’s venous outflow. Trauma may result in local or generalized edema depending on the nature and extent of the injury. With generalized edema, the brain is grossly swollen, with narrowed sulci and distended gyri, showing signs of flattening against the unyielding skull

 

Hyperemia and Congestion

     The terms hyperemia and congestion both indicate a local increased volume of blood in a particular tissue. Hyperemia is an active process resulting from augmented tissue inflow because of arteriolar dilation, as in skeletal muscle during exercise or at sites of inflammation. The affected tissue is redder because of the engorgement of vessels with oxygenated blood. Congestion is a passive process resulting from impaired outflow from a tissue. It may occur systemically, as in cardiac failure, or it may be local, resulting from an isolated venous obstruction. The tissue has a blue-red color (cyanosis), particularly as worsening congestion

leads to accumulation of deoxygenated hemoglobin in the affected tissues

Congestion and edema commonly occur together, primarily since capillary bed congestion can result in edema due to increased fluid transudation. In long-standing congestion, called chronic passive congestion, the stasis of poorly oxygenated blood also causes chronic hypoxia, which can result in parenchymal cell degeneration or death, sometimes with microscopic scarring. Capillary rupture at these sites of chronic congestion may also cause small foci of hemorrhage; breakdown and phagocytosis of the red cell debris can eventually result in small clusters of hemosiderin-laden macrophages

 

Morphology. The cut surfaces of hyperemic or congested tissues are hemorrhagic and wet. Microscopically, acute pulmonary congestion is characterized by alveolar capillaries engorged with blood; there may be associated alveolar septal edema and/or focal intra-alveolar hemorrhage. In chronic pulmonary congestion, the septa are thickened and fibrotic, and the alveolar spaces may contaiumerous hemosiderin-laden macrophages (heart failure cells). In acute hepatic congestion, the central vein and sinusoids are distended with blood, and there may even be central hepatocyte degeneration; the periportal hepatocytes, better oxygenated because of their proximity to hepatic arterioles, experience less severe hypoxia and may only develop fatty change. In chronic passive congestion of the liver, the central regions of the hepatic lobules are grossly red-brown and slightly depressed (owing to a loss of cells) and are accentuated against the surrounding zones of uncongested tan liver (nutmeg liver)

). Microscopically, there is evidence of centrilobular necrosis with loss of hepatocytes dropout and hemorrhage, including hemosiderin-laden macrophages In severe, long-standing hepatic congestion (most commonly associated with heart failure), there may even be grossly evident hepatic fibrosis (cardiac cirrhosis). Because the central portion of the hepatic lobule is the last to receive blood, centrilobular necrosis can also occur whenever there is reduced hepatic blood flow (including shock from any cause); there need not be previous hepatic congestion

 

Hemorrhage

     Hemorrhage generally indicates extravasation of blood due to vessel rupture. As described previously, capillary bleeding can occur under conditions of chronic congestion, and an increased tendency to hemorrhage from usually insignificant injury is seen in a wide variety of clinical disorders collectively called hemorrhagic diatheses However, rupture of a large artery or vein is almost always due to vascular injury, including trauma, atherosclerosis, or inflammatory or neoplastic erosion of the vessel wall. Hemorrhage may be manifested in a variety of patterns, depending on the size, extent, and location of bleeding.

 

ü Hemorrhage may be external or may be enclosed within a tissue; accumulation of blood within tissue is referred to as a hematoma. Hematomas may be relatively insignificant (a bruise) or may be sufficiently large as to be fatal (e.g., a massive retroperitoneal hematoma resulting from rupture of a dissecting aortic aneurysm;

ü Minute 1- to 2-mm hemorrhages into skin, mucous membranes, or serosal surfaces are denoted as petechiae (and are typically associated with locally increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function (as in uremia), or clotting factor deficits.

ü Slightly larger (≥3 mm) hemorrhages are called purpura. These may be associated with many of the same disorders that cause petechiae and may also occur secondary to trauma, vascular inflammation (vasculitis), or increased vascular fragility (e.g., in amyloidosis).

ü Larger (>1 to 2 cm) subcutaneous hematomas (i.e., bruises) are called ecchymoses and are characteristically seen after trauma but may be exacerbated by any of the aforementioned conditions. The erythrocytes in these local hemorrhages are degraded and phagocytosed by macrophages; the hemoglobin (red-blue color) is then enzymatically converted into bilirubin (blue-green color) and eventually into hemosiderin (gold-brown color), accounting for the characteristic

ü color changes in a hematoma.

ü Large accumulations of blood in one or another of the body cavities are called hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis (in joints). Patients with extensive hemorrhage occasionally develop jaundice from the massive breakdown of red cells and systemic release of bilirubin.

The clinical significance of hemorrhage depends on the volume and rate of bleeding. Rapid loss of up to 20% of the blood volume or slow losses of even larger amounts may have little impact in healthy adults; greater losses, however, may result in hemorrhagic (hypovolemic) shock (discussed later). The site of hemorrhage is also important; bleeding that would be trivial in the subcutaneous tissues may cause death if located in the brain because the skull is unyielding and bleeding there can result in increased intracranial pressure and herniation Finally, loss of iron and subsequent iron-deficiency anemia become a consideration in chronic or recurrent external blood loss (e.g., peptic ulcer or menstrual bleeding). In contrast, when red cells are retained, as in hemorrhage into body cavities or tissues, the iron can be reused for hemoglobin synthesis.

 

THROMBOSIS

      Pathogenesis. Three primary influences predispose to thrombus formation, the so-called Virchow triad: (1) endothelial injury; (2) stasis or turbulence of blood flow; and (3) blood hypercoagulability

       Endothelial Injury. This is the dominant influence; endothelial injury by itself can lead to thrombosis. It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors. Thus, thrombus formation within the cardiac chambers (e.g., following endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely due to endothelial injury. Clearly, physical loss of endothelium will lead to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI₂ and PAs. However, it is important to note that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the pro- and antithrombotic effects of endothelium can influence local clotting Thus, dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g., platelet adhesion molecules, tissue factor, PAI) or may synthesize less anticoagulant effectors (e.g., thrombomodulin, PGI₂, t-PA). Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur due to the hemodynamic stresses of hypertension, turbulent flow over scarred valves, or bacterial endotoxins. Even relatively subtle influences, such as homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke may initiate endothelial injury.

     Alterations in Normal Blood Flow. Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction as well as by forming countercurrents and local pockets of stasis; stasis is a major factor in the development of venous thrombi.Normal blood flow is laminar such that the platelets flow centrally in the vessel lumen, separated from the endothelium by a slower-moving clear zone of plasma. Stasis and turbulence therefore (1) disrupt laminar flow and bring platelets into contact with the endothelium; (2) prevent dilution of activated clotting factors by fresh flowing blood; (3) retard the inflow of clotting factor inhibitors and permit the build-up of thrombi; and (4) promote endothelial cell activation, predisposing to local thrombosis, leukocyte adhesion, and a variety of other endothelial cell effects

 

Turbulence and stasis clearly contribute to thrombosis in a number of clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM, but are also sources of turbulence. Abnormal aortic and arterial dilations called aneurysms cause local stasis and are favored sites of thrombosis Myocardial infarctions not only have associated endothelial injury, but also have regions of noncontractile myocardium, adding an element of stasis in the formation of mural thrombi. Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for thrombus development. Hyperviscosity syndromes (such as polycythemia; cause small vessel stasis; the deformed red cells in sickle cell anemia cause vascular occlusions, with the resulting stasis predisposing to thrombosis.

he most common sources of embolism are proximal leg deep venous thrombosis (DVTs) or pelvic vein thromboses. Any risk factor for DVT also increases the risk that the venous clot will dislodge and migrate to the lung circulation, which may happen in as many as 15% of all DVTs.[citatioeeded] The conditions are generally regarded as a continuum termed venous thromboembolism (VTE).

 

The development of thrombosis is classically due to a group of causes named Virchow’s triad (alterations in blood flow, factors in the vessel wall and factors affecting the properties of the blood). Often, more than one risk factor is present.

Alterations in blood flow: immobilization (after surgery, injury, pregnancy (also procoagulant), obesity (also procoagulant), cancer (also procoagulant)

Factors in the vessel wall: surgery, catheterizations causing direct injury (“endothelial injury”)

Factors affecting the properties of the blood (procoagulant state):

Estrogen-containing hormonal contraception

Genetic thrombophilia (factor V Leiden, prothrombin mutation G20210A, protein C deficiency, protein S deficiency, antithrombin deficiency, hyperhomocysteinemia and plasminogen/fibrinolysis disorders)

Acquired thrombophilia (antiphospholipid syndrome, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria)

Cancer (due to secretion of pro-coagulants)

Hypercoagulability. Hypercoagulability contributes less frequently to thrombotic states but is nevertheless an important component in the equation. It is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis. The causes of hypercoagulability may be primary (genetic) and secondary (acquired) disorders 

Hypercoagulable States

Primary (Genetic)

Common

Mutation in factor V gene (factor V Leiden)

Mutation in prothrombin gene

Mutation in methyltetrahydrofolate gene

Rare

Antithrombin III deficiency

Protein C deficiency

Protein S deficiency

Very rare

Fibrinolysis defects

Secondary (Acquired)

High risk for thrombosis

Prolonged bed rest or immobilization

Myocardial infarction

Atrial fibrillation

Tissue damage (surgery, fracture, burns)

Cancer

Prosthetic cardiac valves

Disseminated intravascular coagulation

Heparin-induced thrombocytopenia

Antiphospholipid antibody syndrome (lupus anticoagulant syndrome)

Lower risk for thrombosis

Cardiomyopathy

Nephrotic syndrome

Hyperestrogenic states (pregnancy)

Oral contraceptive use

Sickle cell anemia

Smoking

Morphology. Thrombi may develop anywhere in the cardiovascular system: within the cardiac chambers; on valve cusps; or in arteries, veins, or capillaries. They are of variable size and shape, depending on the site of origin and the circumstances leading to their development. Arterial or cardiac thrombi usually begin at a site of endothelial injury (e.g., atherosclerotic plaque) or turbulence (vessel bifurcation); venous thrombi characteristically occur in sites of stasis. An area of attachment to the underlying vessel or heart wall, frequently firmest at the point of origin, is characteristic of all thromboses. Arterial thrombi tend to grow in a retrograde direction from the point of attachment, whereas venous thrombi extend in the direction of blood flow (i.e., toward the heart). The propagating tail may not be well attached and, particularly in veins, is prone to fragmentation, creating an embolus

When formed in the heart or aorta, thrombi may have grossly (and microscopically) apparent laminations, called lines of Zahn; these are produced by alternating pale layers of platelets admixed with some fibrin and darker layers containing more red cells. Lines of Zahn are significant only in that they imply thrombosis at a site of blood flow; in veins or in smaller arteries, the laminations are typically not as apparent, and, in fact, thrombi formed in the sluggish flow of venous blood usually resemble statically coagulated blood (similar to blood clotted in a test tube). Nevertheless, careful evaluation generally reveals irregular, somewhat ill-defined laminations

These are “lines of Zahn” which are the alternating pale pink bands of platelets with fibrin and red bands of RBC’s forming a true thrombus.

 

When arterial thrombi arise in heart chambers or in the aortic lumen, they usually adhere to the wall of the underlying structure and are termed mural thrombi. Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) leads to cardiac mural thrombi , while ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of aortic thrombus formation

       Arterial thrombi are usually occlusive; the most common sites, in descending order, are coronary, cerebral, and femoral arteries. The thrombus is usually superimposed on an atherosclerotic plaque, although other forms of vascular injury (vasculitis, trauma) may be involved. The thrombi are typically firmly adherent to the injured arterial wall and are gray-white and friable, composed of a tangled mesh of platelets, fibrin, erythrocytes, and degenerating leukocytes.

Here is the anterior surface of the heart with the left anterior descending coronary artery opened longitudinally. This is coronary thrombosis, one of the complications of atherosclerosis. The occlusive dark red thrombus is seen within the lumen of the coronary artery. This produces an acute coronary syndrome.

Here is a closer view of the gross appearnace of a coronary thrombosis. The thrombus occludes the lumen and produces ischemia and/or infarction of the myocardium. Atherosclerosis is an ongoing process that takes years to decades for clinically apparent problems to appear.

 

A coronary thrombosis is seen microscopically occluding the remaining small lumen of this coronary artery. Such an acute coronary thrombosis is often the antecedent to acute myocardial infarction.

 

      Venous thrombosis, or phlebothrombosis, is almost invariably occlusive; the thrombus often creates a long cast of the vein lumen. Because these thrombi form in a relatively static environment, they tend to contain more enmeshed erythrocytes and are therefore known as red, or stasis, thrombi. Phlebothrombosis most commonly affects the veins of the lower extremities (90% of cases). Less commonly, venous thrombi may develop in the upper extremities, periprostatic plexus, or the ovarian and periuterine veins; under special circumstances, they may be found in the dural sinuses, the portal vein, or the hepatic vein. At autopsy, postmortem clots may be confused for venous thrombi. Postmortem clots are gelatinous with a dark red dependent portion where red cells have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat; they are usually not attached to the underlying wall. In contrast, red thrombi are firmer, almost always have a point of attachment, and on transection reveal vague strands of pale gray fibrin

       Under special circumstances, thrombi may form on heart valves. Bacterial or fungal blood-borne infections may establish a foothold, leading to valve damage and the development of large thrombotic masses, or vegetations (infective endocarditis; Sterile vegetations can also develop ooninfected valves in patients with hypercoagulable states, so-called nonbacterial thrombotic endocarditis Less commonly, noninfective, verrucous (Libman-Sacks) endocarditis attributable to elevated levels of circulating immune complexes may occur in patients with systemic lupus erythematosus.

Fate of the Thrombus. If a patient survives the immediate effects of a thrombotic vascular obstruction, thrombi undergo some combination of the following four events in the ensuing days to weeks 

• Propagation. The thrombus may accumulate more platelets and fibrin (propagate), eventually leading to vessel obstruction.

• Embolization. Thrombi may dislodge and travel to other sites in the vasculature.

• Dissolution. Thrombi may be removed by fibrinolytic activity.

    (organization) and may eventually become recanalized; that is, may reestablish vascular flow, or may be incorporated into a thickened vascular wall.

      Propagation and embolization are discussed further below. As for dissolution, activation of the fibrinolytic pathways can lead to rapid shrinkage and even total lysis of recent thrombi. With older thrombi, extensive fibrin polymerization renders the thrombus substantially more resistant to proteolysis, and lysis is ineffectual. This is important because therapeutic infusions of fibrinolytic agents such as t-PA (e.g., for pulmonary thromboemboli or coronary thrombosis) are likely to be effective for only a short time after thrombi form

       Older thrombi tend to become organized. This refers to the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich thrombus. In time, capillary channels are formed, which may anastomose to create conduits from one end of the thrombus to the other, re-establishing, to a limited extent, the continuity of the original lumen. Although the channels may not successfully restore significant flow to many obstructed vessels, such recanalization can potentially convert the thrombus into a vascularized mass of connective tissue). With time and contraction of the mesenchymal cells (and particularly for smaller thrombi), the connective tissue may be incorporated as a subendothelial swelling of the vessel wall; eventually, only a fibrous lump may remain to mark the original thrombus site. Occasionally, instead of organizing, the center of a thrombus undergoes enzymatic digestion, presumably as a result of the release of lysosomal enzymes from trapped leukocytes and platelets. This is particularly likely in large thrombi within aneurysmal dilations or the cardiac chambers. If bacterial seeding occurs, such a degraded thrombus is an ideal culture medium, resulting, for example, in a so-called mycotic aneurysm 

       Venous Thrombosis (Phlebothrombosis). The great preponderance of venous thrombi occur in either the superficial or the deep veins of the leg. Superficial venous thrombi usually occur in the saphenous system, particularly when there are varicosities. Such thrombi may cause local congestion, and swelling, pain, and tenderness along the course of the involved vein but rarely embolize. Nevertheless, the local edema and impaired venous drainage do predispose the involved overlying skin to infections from slight trauma and to the development of varicose ulcers. Deep thrombi in the larger leg veins at or above the knee (e.g., popliteal, femoral, and iliac veins) are more serious because they may embolize. Although they may cause local pain and distal edema, the venous obstruction may be rapidly offset by collateral bypass channels. Consequently, deep vein thromboses are entirely asymptomatic in approximately 50% of affected patients and are recognized only in retrospect after they have embolized

          Deep venous thrombosis may occur with stasis and in a variety of hypercoagulable states as described earlier Cardiac failure is an obvious reason for stasis in the venous circulation. Trauma, surgery, and burns usually result in reduced physical activity, injury to vessels, release of procoagulant substances from tissues, and/or reduced t-PA activity. Many factors act in concert to predispose to thrombosis in the puerperal and postpartum states. Besides the potential for amniotic fluid infusion into the circulation at the time of delivery, late pregnancy and the postpartum period are also associated with hypercoagulability. Tumor-associated procoagulant release is largely responsible for the increased risk of thromboembolic phenomena seen in disseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome. Regardless of the specific clinical setting, advanced age, bed rest, and immobilization increase the risk of deep venous thrombosis, particularly in those who have inherited susceptibility reduced physical activity diminishes the milking action of muscles in the lower leg and so slows venous return

       Arterial and Cardiac Thrombosis. Atherosclerosis is a major initiator of thromboses, related to the associated abnormal vascular flow and loss of endothelial integrity Cardiac mural thrombi can arise in the setting of myocardial infarction related to dyskinetic contraction of the myocardium as well as damage to the adjacent endocardium Rheumatic heart disease may result in atrial mural thrombi due to mitral valve stenosis, followed by left atrial dilation; concurrent atrial fibrillation augments atrial blood stasis. In addition to the local obstructive consequences, cardiac and arterial (in particular, aortic) mural thrombi can also embolize peripherally. Virtually any tissue may be affected, but the brain, kidneys, and spleen are prime targets because of their large flow volume.

While we clearly understand a number of conditions that predispose to thrombosis, the phenomenon remains somewhat unpredictable. It continues to occur at a distressingly high frequency in healthy, ambulatory individuals without apparent provocation or underlying pathology

 

DISSEMINATED INTRAVASCULAR COAGULATION (DIC)

       DIC is an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases. It is characterized by activation of the coagulation sequence that leads to the formation of microthrombi throughout the microcirculation of the body, often in a quixotically uneven distribution. Sometimes the coagulopathy is localized to a specific organ or tissue. As a consequence of the thrombotic diathesis, there is consumption of platelets, fibrin, and coagulation factors and, secondarily, activation of fibrinolytic mechanisms. Thus, DIC can present with signs and symptoms relating to tissue hypoxia and infarction caused by the myriad microthrombi or as a hemorrhagic disorder related to depletion of the elements required for hemostasis (hence, the term “consumption coagulopathy” is sometimes used to describe DIC). Activation of the fibrinolytic mechanism aggravates the hemorrhagic diathesis

Etiology and Pathogenesis. At the outset, it must be emphasized that DIC is not a primary disease. It is a coagulopathy that occurs in the course of a variety of clinical conditions. In discussing the general mechanisms underlying DIC, it is useful to briefly review the normal process of blood coagulation and clot removal. Clotting can be initiated by either of two pathways: (1) the extrinsic pathway, which is triggered by the release of tissue factor (“tissue thromboplastin”), and (2) the intrinsic pathway, which involves the activation of factor XII by surface contact with collagen or other negatively charged substances. Both pathways, through a series of intermediate steps, result in the generation of thrombin, which in turn converts fibrinogen to fibrin. Once activated at the site of injury, thrombin further augments local fibrin deposition through feedback activation of the intrinsic pathway and inhibition of fibrinolysis. Remarkably, as excess thrombin is swept away in the blood from sites of tissue injury it is converted to an anticoagulant. Upon binding a surface protein called thrombomodulin on intact endothelial cells, thrombin becomes capable of

activating protein C, an inhibitor of the pro-coagulant factors V and VIII. Other important clot-inhibiting factors include the activation of fibrinolysis by plasmin and the clearance of activated clotting factors by the mononuclear phagocyte system and the liver. These and additional checks and balances normally ensure that just enough clotting occurs at the right place and time.From this brief review, it should be clear that DIC could result from pathologic activation of the extrinsic and/or intrinsic pathways of coagulation or impairment of clot-inhibiting influences. Since the latter rarely constitute primary mechanisms of DIC, we focus our attention on the abnormal initiation of clotting

 

Major Disorders Associated with Disseminated Intravascular Coagulation

Obstetric Complications

Abruptio placentae

Retained dead fetus

Septic abortion

Amniotic fluid embolism

Toxemia

Infections

Gram-negative sepsis

Meningococcemia

Rocky Mountain spotted fever

Histoplasmosis

Aspergillosis

Malaria

Neoplasms

Carcinomas of pancreas, prostate, lung, and stomach

Acute promyelocytic leukemia

Massive Tissue Injury

Traumatic

Burns

Extensive surgery

Miscellaneous

 

      Acute intravascular hemolysis, snakebite, giant hemangioma, shock, heat stroke, vasculitis, aortic aneurysm, liver disease

Two major mechanisms trigger DIC: (1) release of tissue factor or thromboplastic substances into the circulation and (2) widespread injury to the endothelial cells. Tissue thromboplastic substances can be derived from a variety of sources, such as the placenta in obstetric complications and the granules of leukemic cells in acute promyelocytic leukemia. Mucus released from certain adenocarcinomas can also act as a thromboplastic substance by directly activating factor X, independent of factor VII. In gram-negative sepsis (an important cause of DIC), bacterial endotoxins cause activated monocytes to release interleukin-1 and TNF, both of which increase the expression of tissue factor on endothelial cell membranes and simultaneously decrease the expression of thrombomodulin.⁷² The net result is a shift in balance toward procoagulation

     Endothelial injury, the other major trigger, can initiate DIC by causing release of tissue factor, promoting platelet aggregation, and activating the intrinsic coagulation pathway. TNF is an extremely important mediator of endothelial cell inflammation and injury in septic shock. In addition to the effects previously mentioned, TNF up-regulates the expression of adhesion molecules on endothelial cells and thus favors adhesion of leukocytes, which in turn damage endothelial cells by releasing oxygen-derived free radicals and preformed proteases. Even subtle endothelial injury can unleash procoagulant activity by enhancing membrane expression of tissue factor. Widespread endothelial injury may be produced by deposition of antigen-antibody complexes (e.g., systemic lupus erythematosus), temperature extremes (e.g., heat stroke, burns), or microorganisms (e.g., meningococci, rickettsiae).

.     The initiating factors in these conditions are often multiple and interrelated. For example, particularly in infections caused by gram-negative bacteria, released endotoxins can activate both the intrinsic and extrinsic pathways by producing endothelial cell injury and release of thromboplastins from inflammatory cells; furthermore, endotoxins inhibit the anticoagulant activity of protein C by suppressing thrombomodulin expression on endothelium. Endothelial cell damage can also be produced directly by meningococci, rickettsiae, and viruses. Antigen-antibody complexes formed during the infection can activate the classical complement pathway, and complement fragments can secondarily activate both platelets and granulocytes. Endotoxins as well as other bacterial products are also capable of directly activating factor XII. In massive trauma, extensive surgery, and severe burns, the major mechanism of DIC is believed to be the release of tissue thromboplastins. In obstetric conditions, thromboplastins derived from the placenta, dead retained fetus, or amniotic fluid may enter the circulation. However, hypoxia, acidosis, and shock, which often coexist with the surgical and obstetric conditions, also cause widespread endothelial injury. Supervening infection can complicate the problems further. Among cancers, acute promyelocytic leukemia and carcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC. These tumors release of a variety of thromboplastic substances, including tissue factors, proteolytic enzymes, mucin, and other undefined tumor products

      The consequences of DIC are twofold. First, there is widespread deposition of fibrin within the microcirculation. This can lead to ischemia of the more severely affected or more vulnerable organs and to a hemolytic anemia resulting from fragmentation of red cells as they squeeze through the narrowed microvasculature (microangiopathic hemolytic anemia). Second, a hemorrhagic diathesis can dominate the clinical picture. This results from consumption of platelets and clotting factors as well as activation of plasminogen. Plasmin caot only cleave fibrin, but also digest factors V and VIII, thereby reducing their concentration further. In addition, fibrinolysis leads to the formation of fibrin degradation products, which inhibit platelet aggregation and fibrin polymerization and have antithrombin activity. All these influences lead to the hemostatic failure seen in DIC 

Morphology. In general, thrombi are found in the following sites in decreasing order of frequency: brain, heart, lungs, kidneys, adrenals, spleen, and liver. However, no tissue is spared, and thrombi are occasionally found in only one or several organs without affecting others. In giant hemangiomas, for example, thrombi are localized to the neoplasm, where they are believed to form due to local stasis and recurrent trauma to fragile blood vessels. The affected kidneys can reveal small thrombi in the glomeruli that may evoke only reactive swelling of endothelial cells or, in severe cases, microinfarcts or even bilateral renal cortical necrosis. Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated with pulmonary edema and fibrin exudation, creating “hyaline membranes” reminiscent of acute respiratory distress syndrome . In the central nervous system, fibrin thrombi can cause microinfarcts, occasionally complicated by simultaneous hemorrhage. Such changes are the basis for the bizarre neurologic signs and symptoms sometimes observed in DIC. The manifestations of DIC in the endocrine glands are of considerable interest. In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex are the likely basis for the massive adrenal hemorrhages seen in Waterhouse-Friderichsen syndrome Similarly, Sheehan postpartum pituitary necrosis is a form of DIC complicating labor and delivery. In toxemia of pregnancy the placenta exhibits widespread microthrombi, providing a plausible explanation for the premature atrophy of the cytotrophoblast and syncytiotrophoblast encountered in this condition

The bleeding manifestations of DIC are not dissimilar to those encountered in the hereditary and acquired disorders affecting the hemostatic mechanisms discussed earlier

 

Embolism

 

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. Almost all emboli represent some part of a dislodged thrombus, hence the commonly used term thromboembolism. Rare forms of emboli include droplets of fat, bubbles of air or nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow, or even foreign bodies such as bullets. However, unless otherwise specified, an embolism should be considered to be thrombotic in origin. Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion. The potential consequence of such thromboembolic events is the ischemic necrosis of distal tissue, known as infarction. Depending on the site of origin, emboli may lodge anywhere in the vascular tree; the clinical outcomes are best understood from the standpoint of whether emboli lodge in the pulmonary or systemic circulations.

 

The capillary loops of this glomerulus contain fat globules in a patient with fat embolism syndrome

 

PULMONARY THROMBOEMBOLISM

Pulmonary embolism has an incidence of 20 to 25 per 100,000 hospitalized patients.  Although the rate of fatal pulmonary emboli (as assessed at autopsy) has declined from 6% to 2% over the last quarter century, pulmonary embolism still causes about 200,000 deaths per year in the United States. In more than 95% of instances, venous emboli originate from deep leg vein thrombi above the level of the knee as described previously. They are carried through progressively larger channels and usually pass through the right side of the heart into the pulmonary vasculature. Depending on the size of the embolus, it may occlude the main pulmonary artery, impact across the bifurcation (saddle embolus), or pass out into the smaller, branching arterioles Frequently, there are multiple emboli, perhaps sequentially or as a shower of smaller emboli from a single large mass; in general, the patient who has had one pulmonary embolus is at high risk of having more. Rarely, an embolus may pass through an interatrial or interventricular defect to gain access to the systemic circulation (paradoxical embolism).

• Most pulmonary emboli (60% to 80%) are clinically silent because they are small. With time, they undergo organization and are incorporated into the vascular wall in some cases, organization of the thromboembolus leaves behind a delicate, bridging fibrous web.

• Sudden death, right heart failure (cor pulmonale), or cardiovascular collapse occurs when 60% or more of the pulmonary circulation is obstructed with emboli.

• Embolic obstruction of medium-sized arteries may result in pulmonary hemorrhage but usually does not cause pulmonary infarction because of the dual blood flow into the area from the bronchial circulation. A similar embolus in the setting of left-sided cardiac failure (i.e., with sluggish bronchial artery flow), however, may result in a large infarct.

• Embolic obstruction of small end-arteriolar pulmonary branches usually does result in associated infarction.

Multiple emboli over time may cause pulmonary hypertension with right heart failure

 

The main pulmonary trunk and pulmonary arteries to the right and to the left lung are seen here opened to reveal a large “saddle” pulmonary thromboembolus. Patients with such an embolus will have a high mortality rate.

 

 

Here is another large pulmonary thromboembolus seen in cross section of this lung. The typical source for such thromboemboli is from large veins in the legs and pelvis.

 

 

 Pulmonary emboli can be classified by size as small, medium, and large. Small ones may be clinically inapparent. Medium-sized ones may not kill the patient, but may lead to pulmonary infarction. Large ones can be life-threatening. Recurrent pulmonary embolization can reduce pulmonary vascular flow and cause pulmonary hypertension.

 

This is the microscopic appearance of a pulmonary embolus (PE) in a major pulmonary artery branch. The layering of the RBC’s and the lighter pink fibrin enmeshing leukocytes and platelets occurred in the vein in which the thrombus originally formed.

 

 

This pulmonary embolus is adherent to the pulmonary arterial wall. If the patient survives, the thromboembolus will organize and, for the most part, be removed.

 

SYSTEMIC THROMBOEMBOLISM

 

       Systemic thromboembolism refers to emboli traveling within the arterial circulation. Most (80%) arise from intracardiac mural thrombi, two thirds of which are associated with left ventricular wall infarcts and another quarter with dilated and fibrillating left atria (e.g., secondary to mitral valve disease;. The remainder originate from aortic aneurysms, thrombi on ulcerated atherosclerotic plaques, or fragmentation of a valvular vegetation with a small fraction due to paradoxical emboli; 10% to 15% of systemic emboli are of unknown origin. In contrast to venous emboli, which tend to lodge primarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites; the point of arrest depends on the source of the thromboembolus and the volume of blood flow through the downstream tissues. The major sites for arteriolar embolization are the lower extremities (75%) and the brain (10%), with the intestines, kidneys, spleen, and upper extremities involved to a lesser extent. The consequences of systemic emboli depend on the extent of collateral vascular supply in the affected tissue, the tissue’s vulnerability to ischemia, and the caliber of the vessel occluded; in general, arterial emboli cause infarction of tissues downstream of the obstructed vessel

 

FAT EMBOLISM

 

       Microscopic fat globules may be found in the circulation after fractures of long bones (which have fatty marrow) or, rarely, in the setting of soft tissue trauma and burns. Presumably the fat is released by marrow or adipose tissue injury and enters the circulation by rupture of the marrow vascular sinusoids or of venules. Although traumatic fat embolism occurs in some 90% of individuals with severe skeletal injuries less than 10% of such patients have any clinical findings. Fat embolism syndrome is characterized by pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia. Symptoms typically begin 1 to 3 days after injury, with sudden onset of tachypnea, dyspnea, and tachycardia. Neurologic symptoms include irritability and restlessness, with progression to delirium or coma. Patients may present with thrombocytopenia, presumably caused by platelets adhering to the myriad fat globules and being removed from the circulation; anemia may result as a consequence of erythrocyte aggregation and hemolysis. A diffuse petechial rash iondependent areas (related to rapid onset of thrombocytopenia) is seen in 20% to 50% of cases and is useful in establishing a diagnosis. In its full-blown form, the syndrome is fatal in up to 10% of cases

 

The rounded clear holes seen in the small pulmonary arterial branch in this section of lung are characteristic for fat embolism. Fat embolism syndrome is most often a consequence of trauma with long bone fractures. It can also be seen with extensive soft tissue trauma, burn injuries, severe fatty liver, and very rarely with orthopedic procedures.

An Oil Red O stain demostrates the fat globules within the pulmonary arterioles. The globules stain reddish-orange. The cumulative effect of many of these gobules throughout the lungs is similar to a large pulmonary embolus, but the onset of dyspnea is usually 2 to 3 days following the initiating event, such as blunt trauma with bone fractures.

 

    The pathogenesis of fat emboli syndrome probably involves both mechanical obstruction and biochemical injury. Microemboli of neutral fat cause occlusion of the pulmonary and cerebral microvasculature, aggravated by local platelet and erythrocyte aggregation; this is further exacerbated by release of free fatty acids from the fat globules, causing local toxic injury to endothelium. Platelet activation and recruitment of granulocytes (with free radical, protease, and eicosanoid release; complete the vascular assault. Because lipids are dissolved out of tissue preparations by the solvents routinely used in paraffin embedding, the microscopic demonstration of fat microglobules (i.e., in the absence of accompanying marrow) typically requires specialized techniques, including frozen sections and fat stains

From several days to a week following the event initiating fat embolism syndrome, there may be loss of consciousness from lesions evidenced by the “brain purpura” as shown here. Numerous petechial hemorrhages are produced by fat emboli to the brain, particularly in the white matter. Subsequent to this there can be brain edema with herniation.

With cerebral fat embolism syndrome, there is loss of consciousness. Note the multitude of petechial hemorrhages here, most in white matter. Cerebral edema and herniation may follow. Overall, few persons with a history of trauma will develop fat embolism, but it is difficult to predict which patients will.

 

AIR EMBOLISM

      Gas bubbles within the circulation can obstruct vascular flow (and cause distal ischemic injury) almost as readily as thrombotic masses can. Air may enter the circulation during obstetric procedures or as a consequence of chest wall injury. Generally, in excess of 100 cc is required to have a clinical effect; the bubbles act like physical obstructions and may coalesce to form frothy masses sufficiently large to occlude major vessels

A particular form of gas embolism, called decompression sickness, occurs when individuals are exposed to sudden changes in atmospheric pressure. Scuba and deep sea divers, underwater construction workers, and individuals in unpressurized aircraft in rapid ascent are all at risk. When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) become dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli

The rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints is responsible for the painful condition called the bends (so named in the 1880s because afflicted individuals characteristically arched their backs in a manner reminiscent of a then popular women’s fashion called the Grecian Bend). Gas emboli may also induce focal ischemia in a number of tissues, including brain and heart. In the lungs, edema, hemorrhages, and focal atelectasis or emphysema may appear, leading to respiratory distress, the so-called chokes. Treatment of gas embolism requires placing the individual in a compression chamber where the barometric pressure may be raised, thus forcing the gas bubbles back into solution. Subsequent slow decompression theoretically permits gradual resorption and exhalation of the gases so that obstructive bubbles do not re-form

 

A more chronic form of decompression sickness is called caisson disease (named for the pressurized vessels used in the construction of the base of the Brooklyn Bridge in New York; workers digging in these vessels suffered both acute and chronic forms of decompression sickness). In caisson disease, persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis; the more common sites are the heads of the femurs, tibia, and humeri

 

AMNIOTIC FLUID EMBOLISM

 

Amniotic fluid embolism is a grave but fortunately uncommon complication of labor and the immediate postpartum period (1 in 50,000 deliveries). It has a mortality rate of 20% to 40%, and as other obstetric complications (e.g., eclampsia, pulmonary embolism) have been better managed, amniotic fluid embolism has become an important cause of maternal mortality. The onset is characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. If the patient survives the initial crisis, pulmonary edema typically develops, along with (in half the patients) DIC, owing to release of thrombogenic substances from amniotic fluid.

 

The underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins. The classic findings are therefore the presence in the pulmonary microcirculation of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract. There is also marked pulmonary edema and changes of diffuse alveolar damage as well as systemic fibrin thrombi indicative of DIC.

 

Infarction

An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage in a particular tissue. Infarction involving different organs is a common and extremely important cause of clinical illness. In the United States, more than half of all deaths are caused by cardiovascular disease, and most of these are attributable to myocardial or cerebral infarction. Pulmonary infarction is a common complication in a number of clinical settings, bowel infarction is frequently fatal, and ischemic necrosis of the extremities (gangrene) is a serious problem in the diabetic population

Nearly 99% of all infarcts result from thrombotic or embolic events, and almost all result from arterial occlusion. Occasionally, infarction may also be caused by other mechanisms, such as local vasospasm, expansion of an atheroma owing to hemorrhage within a plaque, or extrinsic compression of a vessel (e.g., by tumor). Other uncommon causes include twisting of the vessels (e.g., in testicular torsion or bowel volvulus), compression of the blood supply by edema or by entrapment in a hernia sac, or traumatic rupture of the blood supply. Although venous thrombosis may cause infarction, it more often merely induces venous obstruction and congestion. Usually, bypass channels rapidly open after the thrombosis, providing some outflow from the area, which, in turn, improves the arterial inflow. Infarcts caused by venous thrombosis are more likely in organs with a single venous outflow channel, such as the testis and ovary

Morphology. Infarcts are classified on the basis of their color (reflecting the amount of

hemorrhage) and the presence or absence of microbial infection. Therefore, infarcts may be either red (hemorrhagic) or white (anemic) and may be either septic or bland.

• Red (hemorrhagic) infarcts occur with venous occlusions (such as in ovarian torsion); in loose tissues (such as lung), which allow blood to collect in the infarcted zone; in tissues with dual circulations (e.g., lung and small intestine), permitting flow of blood from the unobstructed vessel into the necrotic zone (obviously such perfusion is not sufficient to rescue the ischemic tissues); in tissues that were previously congested because of sluggish venous outflow; and when flow is re-established to a site of previous arterial occlusion and necrosis (e.g., following fragmentation of an occlusive embolus or angioplasty of a thrombotic lesion) 

     White (anemic) infarcts occur with arterial occlusions in solid organs with end-arterial circulation (such as heart, spleen, and kidney), where the solidity of the tissue limits the amount of hemorrhage that can seep into the area of ischemic necrosis from adjoining capillary beds

Most infarcts tend to be wedge-shaped, with the occluded vessel at the apex and the periphery of the organ forming the base when the base is a serosal surface, there is often an overlying fibrinous exudate. The lateral margins may be irregular, reflecting the pattern of vascular supply from adjacent vessels. At the outset, all infarcts are poorly defined and slightly hemorrhagic. The margins of both types of infarcts tend to become better defined with time by a narrow rim of hyperemia attributable to inflammation at the edge of the lesion

In solid organs, the extravasated red cells from the limited hemorrhage are lysed. The released hemoglobin remains in the tissue in the form of hemosiderin within macrophages; this can microscopically identify sites of previous infarction but does not grossly impart any significant color to the tissue. White infarcts resulting from arterial occlusions typically become progressively more pale and sharply defined with time By comparison, in spongy organs the hemorrhage is too extensive to permit thelesion ever to become pale Over the course of a few days, it does, however, become more firm and brown, as the extensive bleeding progressively degrades into hemosiderin pigmentThe dominant histologic characteristic of infarction is ischemic coagulative necrosis It is important to recall that if the vascular occlusion has occurred shortly (minutes to hours) before the death of the patient, no demonstrable histologic changes may be evident; if the patient survives even 12 to 18 hours, the only change present may be hemorrhage

An inflammatory response begins to develop along the margins of infarcts within a few hours and is usually well defined within 1 or 2 days. Inflammation at these sites is incited by the necrotic material; given sufficient time, there is gradual degradation of the dead tissue with phagocytosis of the cellular debris by neutrophils and macrophages. Eventually the inflammatory response is followed by a reparative response beginning in the preserved margins In stable or labile tissues, some parenchymal

 

 

  Infarction of the brain can result from thrombosis, though most cases occur following embolization, involving cerebral arteries, often the circle of Willis. Cerebral infarction typically results in liquefactive necrosis, as shown here with beginning cystic resolution of the infarct.

 

An inflammatory response begins to develop along the margins of infarcts within a few hours and is usually well defined within 1 or 2 days. Inflammation at these sites is incited by the necrotic material; given sufficient time, there is gradual degradation of the dead tissue with phagocytosis of the cellular debris by neutrophils and macrophages. Eventually the inflammatory response is followed by a reparative response beginning in the preserved margins In stable or labile tissues, some parenchymal regeneration may occur at the periphery where the underlying stromal architecture has been spared. However, most infarcts are ultimately replaced by scar tissue .The brain is an exception to these generalizations; as with all other causes of cell death, ischemic injury in the central nervous system results in liquefactive necrosis.

 

 

Infarction of many internal organs leads to a “pale” infarct from loss of hte blood supply, resulting in coagulative necrosis. Shown here is a myocardial infarction from occlusion of a major coronary artery, here the left anterior descending artery.

 

Infarction of many internal organs leads to a “pale” infarct with a wedge-shaped gross appearance (conical in 3 dimensions) from occlusion of a branching blood supply. Here are splenic infarcts in a patient with infective endocarditis. Portions of the vegetations have embolized to the spleen. These infarcts are typical of ischemic infarcts: they are based on the capsule, pale, and wedge-shaped. The remaining splenic parenchyma appears dark red.

 

 

Here are petechial hemorrhages seen on the epicardium of the heart. Petechiae (pinpoint hemorrhages) represent bleeding from small vessels and are classically found when a coagulopathy is due to a low platelet count. They can also appear following sudden hypoxia

 

      Septic infarctions may develop when embolization occurs by fragmentation of a bacterial vegetation from a heart valve or when microbes seed an area of necrotic tissue. In these cases, the infarct is converted into an abscess, with a correspondingly greater inflammatory response. The eventual sequence of organization, however, follows the pattern already described

Shock

       Shock, or cardiovascular collapse, is the final common pathway for a number of potentially lethal clinical events, including severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis. Regardless of the underlying pathology, shock gives rise to systemic hypoperfusion caused by reduction either in cardiac output or in the effective circulating blood volume. The end results are hypotension, followed by impaired tissue perfusion and cellular hypoxia. Although the hypoxic and metabolic effects of

hypoperfusion initially cause only reversible cellular injury, persistence of shock eventually causes

irreversible tissue injury and can culminate in the death of the patient

Shock may be grouped into three general categories The mechanisms underlying cardiogenic and hypovolemic shock are fairly straightforward, essentially involving low cardiac output. Septic shock, by comparison, is substantially more complicated and is discussed in further detail below.

• Cardiogenic shock results from myocardial pump failure. This may be caused by intrinsic myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tamponade; or outflow obstruction (e.g., pulmonary embolism).

• Hypovolemic shock results from loss of blood or plasma volume. This may be caused by hemorrhage, fluid loss from severe burns, or trauma.

Septic shock is caused by systemic microbial infection. Most commonly, this occurs in the setting of gram-negative infections (endotoxic shock), but it can also occur with gram-positive and fungal infections.

Less commonly, shock may occur in the setting of anesthetic accident or spinal cord injury (neurogenic shock), owing to loss of vascular tone and peripheral pooling of blood. Anaphylactic shock, initiated by a generalized IgE-mediated hypersensitivity response, is associated with systemic vasodilation and increased vascular permeability. In these instances, widespread vasodilation causes a sudden increase in the vascular bed capacitance, which is not adequately filled by the normal circulating blood volume. Thus, hypotension, tissue hypoperfusion, and cellular anoxia result.

PATHOGENESIS OF SEPTIC SHOCK

 

Three Major Types of Shock

 

Type of Shock

Clinical Examples

Principal Mechanisms

Cardiogenic

 

Myocardial infarction

Failure of myocardial pump owing to intrinsic myocardial damage, extrinsic pressure, or obstruction to outflow

 

Ventricular rupture

 

Arrhythmia

 

Cardiac tamponade

 

Pulmonary embolism

 

Hypovolemic

 

Hemorrhage

Inadequate blood or plasma volume

 

Fluid loss, e.g., vomiting, diarrhea, burns, or trauma

 

Septic

 

Overwhelming microbial infections

Peripheral vasodilation and pooling of blood; endothelial activation/injury; leukocyte-induced damage; disseminated intravascular coagulation; activation of cytokine cascades

 

Endotoxic shock

 

Gram-positive septicemia

 

Fungal sepsis

 

Superantigens

 

     Septic shock, with a 25% to 50% mortality rate, ranks first among the causes of mortality in intensive care units and is estimated to account for over 200,000 deaths annually in the United States. Moreover, the reported incidence of sepsis syndromes has increased dramatically in the past two decades, owing to improved life support for high-risk patients, increasing use of invasive procedures, and growing numbers of immunocompromised hosts (secondary to chemotherapy, immunosuppression, or human immunodeficiency virus infection). Septic shock results from spread and expansion of an initially localized infection (e.g., abscess, peritonitis, pneumonia) into the bloodstream

       Most cases of septic shock (approximately 70%) are caused by endotoxin-producing gram-negative bacilli, hence the term endotoxic shock. Endotoxins are bacterial wall lipopolysaccharides (LPSs) that are released when the cell walls are degraded (e.g., in an inflammatory response). LPS consists of a toxic fatty acid (lipid A) core and a complex polysaccharide coat (including O antigens) unique to each bacterial species. Analogous molecules in the walls of gram-positive bacteria and fungi can also elicit septic shock

All of the cellular and resultant hemodynamic effects of septic shock may be reproduced by injection of LPS alone. Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a cell-surface receptor (called CD14), followed by binding of the LPS to a signal-transducing protein called mammalian Toll-like receptor protein 4 (TLR-4). (Toll is a Drosophila protein involved in fly development; a variety of molecules with homology to Toll [i.e., “Toll-like”] participate in innate immune responses to different microbial components Signals from TLR-4 can then directly activate vascular wall cells and leukocytes or initiate a cascade of cytokine mediators, which propagates the pathologic state. Engagement of TLR-4 on endothelial cells can lead directly to down-regulation of natural anticoagulation mechanisms, including diminished synthesis of tissue factor pathway inhibitor (TFPI) and thrombomodulin. Engagement of the receptor on monocytes and macrophages (even at doses of LPS as minute as 10 picograms/ml) causes profound mononuclear cell activation with the subsequent production of potent effector cytokines such as IL-1 and TNF Presumably, this series of responses helps to isolate organisms and to trigger elements of the innate immune system to efficiently eradicate invading microbes. Unfortunately, depending on the dosage and numbers of macrophages that are activated, the secondary effects of LPS release can also cause severe pathologic changes, including fatal shock.

• At low doses, LPS predominantly serves to activate monocytes and macrophages, with effects intended to enhance their ability to eliminate invading bacteria. LPS can also directly activate complement, which likewise contributes to local bacterial eradication. The mononuclear phagocytes respond to LPS by producing cytokines, mainly TNF, IL-1, IL-6, and chemokines. TNF and IL-1 both act on endothelial cells to stimulate the expression of adhesion molecules and the production of other cytokines and chemokines. Thus, the initial release of LPS results in a circumscribed cytokine cascade doubtless intended to enhance the local acute inflammatory response and improve clearance of the infection.

• With moderately severe infections, and therefore with higher levels of LPS (and a consequent augmentation of the cytokine cascade), cytokine-induced secondary effectors (e.g., nitric oxide; become significant. In addition, systemic effects of the cytokines such as TNF and IL-1 may begin to be seen; these include fever and increased synthesis of acute phase reactants LPS at higher doses also results in diminished endothelial cell production of thrombomodulin and TFPI, tipping the coagulation cascade toward thrombosis.

• Finally, at still higher levels of LPS, the syndrome of septic shock supervenes the same cytokines and secondary mediators, now at high levels, result in:

• Systemic vasodilation (hypotension)

• Diminished myocardial contractility

• Widespread endothelial injury and activation, causing systemic leukocyte adhesion and pulmonary alveolar capillary damage (acute respiratory distress syndrome;

Activation of the coagulation system, culminating in DIC

The hypoperfusion resulting from the combined effects of widespread vasodilation, myocardial pump failure, and DIC induces multiorgan system failure affecting the liver, kidneys, and central nervous system, among others. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies. Of note, mice lacking LPS-binding protein, CD14, or the mammalian TLR-4 are protected against the effects of LPS. Clinical efforts to take advantage of these insights and induce pharmacologic blockade of the same pathways (e.g., soluble CD14 or antibodies to LPS-binding protein) have yet to bear fruit. Antibodies or antagonists to IL-1 or TNF (or their receptors), or pharmacologic inhibitors of various other secondary mediators (e.g., nitric oxide or prostaglandins) have some efficacy in animal models of septic shock, but they have not shown significant clinical benefit in human disease. Indeed such failure of “anti-inflammatory” therapy in human shock has caused some investigators to challenge the model presented hereInstead, it has been argued that in later stages, sepsis is associated with a state of immunosuppression (rather than uncontrolled inflammation). These observations may dictate different forms of therapy, but this remains to be tested.

An interesting group of bacterial proteins called superantigens also cause syndromes similar to septic shock. These include toxic shock syndrome toxin-1, produced by staphylococci and responsible for the toxic shock syndrome. Superantigens are polyclonal T-lymphocyte activators that induce systemic inflammatory cytokine cascades similar to those occurring downstream in septic shock. Their actions can result in a variety of clinical manifestations ranging from a diffuse

rash to vasodilation, hypotension, and death

Stages of Shock. Shock is a progressive disorder that, if uncorrected, leads to death. Unless the insult is massive and rapidly lethal (e.g., a massive hemorrhage from a ruptured aortic aneurysm), shock tends to evolve through three general (albeit somewhat artificial) phases. A brief discussion here can help to integrate the sequential pathophysiologic and clinical events in the progression of shock. These have been documented most clearly in hypovolemic shock but are common to other forms as well:

• An initial nonprogressive phase during which reflex compensatory mechanisms are activated and perfusion of vital organs is maintained

• A progressive stage characterized by tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances, including acidosis

An irreversible stage that sets in after the body has incurred cellular and tissue injury so severe that even if the hemodynamic defects are corrected, survival is not possible

In the early nonprogressive phase of shock, a variety of neurohumoral mechanisms help maintain cardiac output and blood pressure. These include baroreceptor reflexes, release of catecholamines, activation of the renin-angiotensin axis, antidiuretic hormone release, and generalized sympathetic stimulation. The net effect is tachycardia, peripheral vasoconstriction, and renal conservation of fluid. Cutaneous vasoconstriction, for example, is responsible for the characteristic coolness and pallor of skin in well-developed shock (although septic shock may initially cause cutaneous vasodilation and thus present with warm, flushed skin). Coronary and cerebral vessels are less sensitive to this compensatory sympathetic response and thus maintain relatively normal caliber, blood flow, and oxygen delivery to their respective vital organs

If the underlying causes are not corrected, shock passes imperceptibly to the progressive phase, during which there is widespread tissue hypoxia. In the setting of persistent oxygen deficit, intracellular aerobic respiration is replaced by anaerobic glycolysis with excessive production of lactic acid. The resultant metabolic lactic acidosis lowers the tissue pH and blunts the vasomotor response; arterioles dilate, and blood begins to pool in the microcirculation. Peripheral pooling not only worsens the cardiac output, but also puts endothelial cells at risk for developing anoxic injury with subsequent DIC. With widespread tissue hypoxia, vital organs are affected and begin to fail; clinically the patient may become confused, and the urine output declines

Unless there is intervention, the process eventually enters an irreversible stage. Widespread cell injury is reflected in lysosomal enzyme leakage, further aggravating the shock state. Myocardial contractile function worsens in part because of nitric oxide synthesis. If ischemic bowel allows intestinal flora to enter the circulation, endotoxic shock may be superimposed. At this point, the patient has complete renal shutdown owing to acute tubular necrosis and despite heroic measures, the downward clinical spiral almost inevitably culminates in death

Morphology. The cellular and tissue changes induced by shock are essentially those of hypoxic injury since shock is characterized by failure of multiple organ systems, the cellular changes may appear in any tissue. Nevertheless, they are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract subendocardial hemorrhage and/or contraction band necrosis Although the cardiac changes are not diagnostic of shock (they may also be seen in the setting of cardiac reperfusion after irreversible injury, or after administration of catecholamines), they are usually much more extensive in the setting of shock. The kidneys typically exhibit extensive tubular ischemic injury (acute tubular necrosis; therefore oliguria, anuria, and electrolyte disturbances constitute major clinical problems. The lungs are seldom affected in pure hypovolemic shock because they are resistant to hypoxic injury. When shock is caused by bacterial sepsis or trauma, however, changes of diffuse alveolar damage (may appear, the so-called shock lung. The adrenal changes in shock are those seen in all forms of stress; essentially, there is cortical cell lipid depletion. This does not reflect adrenal exhaustion but rather conversion of the relatively inactive vacuolated cells to metabolically active cells that utilize stored lipids for the synthesis of steroids. The gastrointestinal tract may suffer patchy mucosal hemorrhages and necroses, referred to as hemorrhagic enteropathy. The liver may develop fatty change and, with severe perfusion deficits, central hemorrhagic necrosis

The brain may develop so-called ischemic encephalopathy, discussed in The heart may undergo focal or widespread coagulatioecrosis or may exhibitWith the exception of neuronal and myocyte loss, virtually all of these tissue changes may revert to normal if the patient survives. Unfortunately, most patients with irreversible changes owing to severe shock succumb before the tissues can recover

The prognosis varies with the origin of shock and its duration. Thus, 80% to 90% of young, otherwise healthy patients with hypovolemic shock survive with appropriate management, whereas cardiogenic shock associated with extensive myocardial infarction and gram-negative shock carry mortality rates of up to 75%, even with the best care currently available.

 

 

Small fibrin thrombi from widespread activation of the coagulation system with disseminated intravascular coagulopathy (DIC) can be seen in capillary loops in this glomerulus, highlighted by a fibrin stain. Laboratory findings with DIC include decreased platelets, diminished fibrinogen, prolonged prothrombin time, elevated partial thromboplastin time, and elevated D-dimer. Consumption of coagulation factors with generation of fibrin split products, along with platelet consumption, leads to these findings.