Anaemias: iron-deficiency, vitamin В12 and folic acid deficiency anaemias, hemolytic one

Anaemias: iron-deficiency, vitamin В₁₂ and folic acid ndeficiency anaemias, hemolytic one. Clinical pattern. Differential treatment. nThe role of  a doctor–dentist   in treatment. Prophylaxis

 

 

 

 

Blood nis the only fluid tissue in the body. Blood transports oxygen and nutrients to nbody tissues, and returns waste and carbon dioxide. Blood distributes nearly neverything that is carried from one area in the body to another place withithe body. For instance, hormones are transported from the endocrine organs to ntheir target organs. Blood helps maintain body temperature and normal pH levels nin body tissues. The protective functions of blood include clot formation and nthe prevention of infection.

 

 

Fig. 3. The physiologic regulation of red cell production by tissue noxygen tension.

 

 

Human erythropoietin

 

n

 

 

   

A scanning electron microscope (SEM) image of normal circulating humablood.

 One can see red blood cells, several knobby white blood cells including nlymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.

 

 

From left to right: erythrocyte, thrombocyte, nleukocyte.

 

Anaemia

Anaemia is a pathological condition characterized by ndecreased numb of erythrocytes and/or haemoglobin content in a nblood unit volume due their general deficiency (Gk an not, haemia blood, ni.e. deficient of blood.

Anemia is npresent in adults if the hematocrit is less than 41 % (haemoglobin < 13.5 ng/dL) in males or 37 % (haemoglobin < 12 g/dL) in females.

Anaemia should be differentiated from hydraemia n(abnormally wate d) in which the erythrocyte and haemoglobin are ndeficient as well, but at the expense of their absolute nreduction but due to dilution of blood enal, cardiac nand other oedema. Anaemia should also be differentiated noligohaemia, nwhich is the reduction of the total volume of blood, e.g. nediately after a profuse nhaemorrhage. The total mass of circulating od can be normal in anaemia n(normovolaemia), increased (hyperemia) or decreased (oligohaemia or nhypovolaemia). Thickening of od in persistent vomiting and profuse diarrhoea ncan mask anaemia ause the total amount of plasma decreases and the number of throcytes and haemoglobin in a unit volume of the ncirculating blood can normal or even increased.

 

Clinical syndromes.

Anemic syndrome.

Symptoms of anemia are easy fatigability, tachycardia, palpitations, ntachypnea on exertion, pallor, malaise, weakness, light-headedness, vertigo, nand tinnitus, as well as palpitations, angina, and the symptoms of congestive nfailure.

In the anemic patient, physical examination may demonstrate a forceful nheartbeat, strong peripheral pulses, and a systolic “flow” murmur. nThe skin and mucous membranes may be pale if the hemoglobin is <80 to 100 ng/L (8 to 10 g/dL).

 

Hemoglobin is the most important ncomponent of red blood cells.

 

Sideropenic syndrome.

Cheilosis (fissures at the corners of the mouth), fever and nkoilonychia (spooning of the fingernails) are signs of advanced tissue irodeficiency.

Iron deficiency causes skin and mucosal changes, including a smooth ntongue, brittle nails. Dysphagia because of formation of esophageal webs also noccurs. Many iron-deficient patients develop pica, craving for specific foods, nofteot rich in iron.

 

Neurologic manifestations.

The neurologic manifestations often fail to remit fully on treatment. nThey begin pathologically with demyelination, followed by axonal degeneratioand eventual neuronal death; the final stage, of course, is irreversible. Sites nof involvement include peripheral nerves; the spinal cord, where the posterior nand lateral columns undergo demyelination; and the cerebrum itself. Signs and nsymptoms include numbness and paresthesia in the extremities (the earliest nneurologic manifestations), weakness, and ataxia. There may be sphincter ndisturbances. Reflexes may be diminished or increased. The Romberg and Babinski nsigns may be positive, and position and vibration senses are usually ndiminished. Disturbances of mentation will vary from mild irritability and nforgetfulness to severe dementia or frank psychosis. It should be emphasized nthat neurologic disease may occur in a patient with a normal hematocrit and normal nRBC indexes. Although it has many benefits, folate supplementation of food

The clinical features of cobalamin deficiency involve the blood, the ngastrointestinal tract, and the nervous system.

 

 Gastrointestinal nmanifestations.

The gastrointestinal manifestations reflect the effect of cobalamideficiency on the rapidly proliferating gastrointestinal epithelium. The npatient sometimes complains of a sore tongue, which on inspection will be nsmooth and beefy red. Anorexia with moderate weight loss may also be evident, npossibly accompanied by diarrhea and other gastrointestinal symptoms. These nlatter manifestations may be caused in part by megaloblastosis of the small nintestinal epithelium, which results in malabsorption.

Cytopenic syndrome.

Aplastic anemia can appear with seeming abruptness or have a more ninsidious onset. Bleeding is the most common early symptom; a complaint of days nto weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual nflow, and sometimes petechiae will have beeoticed. With thrombocytopenia, nmassive hemorrhage is unusual, but small amounts of bleeding in the central nnervous system can result in catastrophic intracranial or retinal hemorrhage. nSymptoms of anemia are also frequent, including lassitude, weakness, shortness nof breath, and a pounding sensation in the ears. Infection is an unusual first nsymptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, nanorectal infection, or frank sepsis occur early). A striking feature of naplastic anemia is the restriction of symptoms to the hematologic system, and npatients often feel and look remarkably well despite drastically reduced blood ncounts. Systemic complaints and weight loss should point to other etiologies of npancytopenia. History of drug use, chemical exposure, and preceding viral nillnesses must often be elicited with repeated questioning.

 Hemolytic syndrome.

The hematologic manifestations are almost entirely the result of nanemia, although very rarely purpura may appear, due to thrombocytopenia. nSymptoms of anemia may include weakness, light-headedness, vertigo, and ntinnitus, as well as palpitations, angina, and the symptoms of congestive nfailure. On physical examination, the patient with florid cobalamin deficiency nis pale, with slightly icteric skin and eyes. Elevated bilirubin levels are nrelated to high erythroid cell turnover in the marrow. The pulse is rapid, and nthe heart may be enlarged; auscultation will usually reveal a systolic flow nmurmur.

Hemolytic anemias present in different ways. Some appear suddenly as nan acute, self-limited episode of intravascular or extravascular hemolysis, a npresentation pattern often seen in patients with autoimmune hemolysis or with ninherited defects of the Embden-Myerhof pathway or the glutathione reductase npathway. Patients with inherited disorders of the hemoglobin molecule or red ncell membrane generally have a lifelong clinical history typical of the disease nprocess. Those with chronic hemolytic disease, such as hereditary nspherocytosis, may actually present not with anemia but with a complicatiostemming from the prolonged increase in red cell destruction such as aplastic ncrisis, symptomatic bilirubin gallstones, or splenomegaly.

Classificatioof anemias.

Initial Classification of Anemia  Classifying an anemia according to nthe functional defect in red cell production helps organize the subsequent use nof laboratory studies. The three major classes of anemia are:

1) marrow production defects (hypoproliferation),

2) red cell maturation defects (ineffective erythropoiesis),

3) decreased red cell survival (blood loss/hemolysis).

This functional classification of anemia then guides the selection of nspecific clinical and laboratory studies designed to complete the differential ndiagnosis and to plan appropriate therapy.

 

The classification is shown in Fig. 1.

 

 

Anaemia is often characterized not only by nquantitative changes in the i blood composition, but also nqualitative changes in the structure of erythrocytes and haemoglobin molecules. nThese changes are important for : transport function of blood and ntissue respiration, and can be the cause additional npathological changes in the body. For example, a congenital feet nof erythrocytes in some hereditary haemolytic anaemia may (due to ;ir intense nhaemolysis) cause haemosiderosis of the internal organs, for-ition of pigment stones ithe gall bladder, etc.

Anaemia has a pronounced effect on the vital nactivity of the body, memization causes oxygen hunger of organs and tissues n(hypoxia) and their dystrophy. For example, if the blood haemoglobicontent is halved 3-80 g/1), initial symptoms of myocardial dystrophy ndevelop. If the k emoglobicontent decreases to 50 g/1, the dystrophic changes become onounced. nUnoxidized products of metabolism (lactic acid, in the first stance) naccumulate in the body due to hypoxia. The alkaline reserve of ood decreases. In grave ncases, a tendency to acidosis develops which uses nfurther dystrophy of tissues. Severe anaemias attended by marked sorders in tissue metabolism are incompatible with nlife.

Anaemia of any origin is accompanied by some ncompensatory processes, which npartly remove or lessen its consequences: (1) blood circulation is nintensified, i.e. stroke and minute volumes increase, tachycardia develops, nand the rate of blood flow increases; (2) blood distribution is itered, blood depots ithe liver, spleen, and muscles are activated, and ie blood supply to the peripheral tissues becomes limited at the expense nof le increased blood supply to the nvital organs; (3) oxygen utilization in ssues is intensified and the role of anaerobic processes in tissue nrespiration rcreases (anaerobic nrespiration with glutathione); (4) the erythropoietic unction of bone marrow is stimulated. More tha50 types of anaemia are now differentiated. According  to  their  norigin,  the  following  types  of anaemia are listinguished.

1.   Anaemia due to loss of nblood (acute nand chronic).

2. nAnaemia due to disordered haemopoiesis ideficiency of iron (necessary for the production of haemoglobin), in vitamin B₁₂ ndeficien­cy (necessary for normal erythropoiesis), in inhibitioof the bone marrow by endogenous or exogenous toxicosis, radiation, or by some nunknown factors, nand also in cases where red bone marrow is replaced by other tissue, e.g. myeloma or multiple metastases.

3. nAnaemia due to excessive haemolysis. This ntype of anaemia is sub­divided into: (a) anaemia with prevalent nextravascular (intracorpuscular) haemolysis of erythrocytes imacrophages of the spleen, and, to a lesser extent, in the bone marrow and liver. nThese are anaemia caused by hereditary morphological and functional erythrocyte ndeficiency (spherocytic and ovalocytic anaemia), and auto-immune haemolytic nanaemia. They are all characterized by hyperbilirubinaemia and splenomegaly; (b) anaemia with intravascular, nusually acute haemolysis (in various npoisoning, transfusion of incompatible blood, cold and effort anaemia) attended by release into the plasma of nunbound haemoglobin and by nhaemoglobinuria^, haemosiderosis of the internal organs is observed also ichronic haemolysis (e.g. in Marchiafava-Micheli disease). This classificatiois only conventional because both intracorpuscular and vascular haemolysis can occur in one and the same form of haemolytic anaemia.

Haemolytic anaemia is also often subdivided as nfollows: (a) hereditary (congenital) anaemia, which includes membranopathy of nerythrocytes (associated with abnormality of protein or lipid complexes of nerythrocyte envelope, causnift changes in their shape at I premature ndecomposition; microspherocytic anaemia, ovalocytic ana mia, etc.); enzymopenic anaemia (due to deficiency of various enzyme nsystems of erythrocytes, which npromotes their accelerated decomposition) and haemoglobinopathy in which the structure of haemoglobin or its nsynthesis are disturbed (sickle-cell anaemia, thalassaemia); (b) nacquired anaemia (auto-immune haemolytic and iso-immune anaemia, and also nanaemia caused by Vnechanical injury to nerythrocytes, acquired membranopathies, toxic anaemia, etc.).

Apart from the pathogenetic classification, there are classifications based on other principles. Three groups of nanaemia, for example, are distinguished nin accordance with haemoglobin saturation of erythrocytes (by the colour nindex): normochromic (0.8-1.0), hypochromic (less than 0.8) and hyperchromic nanaemia (more than 1.0). The group of hypochromic nanaemia includes iron-deficiency anaemia: chronic (less acute) posthaemorrhagic anaemia, gastrogenic niron-deficiency anaemia, and njuvenile chlorosis. Hyperchromic anaemia is caused by the deficiency of nvitamin B₁₂. This is Addison-Biermer anaemia, bothriocephalus nanaemia, and also achrestic anaemia (due to defective utilization of Vitamin B₁₂). Other anaemias proceed nwithout considerable changes in the colour index of blood and are ntherefore normochromic.

It is very important to assess the regenerative ncapacity of the bone mar­row upon which (to a certain degree) ndepend treatment and prognosis of the diseases. Distinguished are nregenerative anaemia, i.e. anaemia in which the bone marrow npreserves its capacity to produce new erythrocytes; hyporegenerative nanaemia, in which this capacity is impaired; and aregenerative nor aplastic anaemia, in which bone marrow function is ncomV pletely or almost completely lost. The regenerative nfunction of the bone, marrow is assessed by the rate at which the quantity of nreticulocytes in­creases in the peripheral blood and by the nproportion of the erythro- and leucoblastic elements in the sternal punctate. nTheir normal ratio is 1:3 or 1:4, while in regenerative anaemia, in which nerythropoiesis dominates in the compensatory function of the bone nmarrow, this ratio becomes 1:1, 2:1 and even higher. This shift is nabsent in hypo- or aregenerative anaemia, while the reticulo; le content of the nperipheral blood is low.

ACUTE   n POSTHEMORRHAGIC        ANAEMIA

Anaemia caused by an acute blood loss (acute nposthaemorrhagic anaemia) occurs mostly in various injuries nassociated with traumatized large vessels (extrauterine pregnancy, delayed placental detachment nduring labour, etc.). Acute posthaemorrhagic anaemia occurs in diseases that ncan be attended by profuse bleeding, e.g. in gastric and duodenal ulcer, degrading tumour of the stomach, kidneys, or the nlung, in tuberculosis and abscess of the lung, bronchiectasis, varicose dilation of the oesophageal veins iliver cirrhosis, haemor- rhagic diathesis, and especially ihaemophilia. 

Clinical picture. Icases w)th external haemorrhage, the physician can often locate the source nof bleeding at first sight (e.g. in injury). The patient’s grave condition cain these cases be directly attributed to profuse bloefd loss. nHaemorrhage from the internal organs can be manifested by nblood vomiting (unaltered blood originates from the oesophagus; brown blood from nthe stomach), by expectoration of blood (scarlet foaming liquid), by the npresence of blood in faeces (melaena in haemorrhage from the stomach nor the small intestine; dark or scarlet blood originates from the large nintestine, especially from its terminal part) and by blood presence nin the urine (haematuria). It should be remembered that in gastro-intestinal haemorrhage, nthe blood can only be discharged into the environment in a.certain lapse of ntime (with the vomit or excretions). Moreover, haemorrhage ncaused by the rupture of the spleen, liver, or by the internal injury to the nchest can be difficult to establish because blood will ac­cumulate in the abdominal nor pleural cavity.

The first sign of a sudden haemorrhage is the nfeeling of weakness, dizziness, noise in the ears, palpitation of the heart, nnausea, and in rare cases vomiturition. In severe cases with pro-» fuse blood nloss, the patient is in the state of shock (if the bleeding is caused by ainjury) or collapse (if haemorrhage is due to affection of the ninternal organs). The patient’s condition depends not only on the amount of nblood loss, but also on the rate at which blood is lost. In­spectioreveals pronounced and in some cases deadly pallidness; the skin is covered nwith sticky cold sweat, the skin temperature is subnormal. nRespiration is superficial and ac celerated. The pulse is fast, nsmall, and (in severe cases) thready. Arterial pressure (botl systolic nand diastolic) is low. Auscultation of the heart reveals marked tachycardia.

The pathological and compensatory changes in acute blood nloss with benign outcome cai be divided into three stages (or nphases). First oligohaemia develops. It causes a reflex spasm o the nvessels to decrease the volume of the vascular system and to recover blood from nit reserves (depots). For this reason, the blood haemoglobin and nerythrocyte content may re maiormal within the first hours (or even within 1 nor 1.5 days) following the blood loss Tissue fluids are drawn into the nvessels to cause hydraemia in 2 or 3 days: the erythrocyte an haemoglobicontent in unit volume decreases. Signs of marked activation of erythropoiesi appear non the third to seventh day. Anaemia becomes hypochromic in the loss of nconsiderabl amount nof blood due to exhaustion of the iron store.

Treatment. Bleeding should nbe arrested as soon as possible by placing a tourniquet or by tamponade nof the external haemorrhages in wounds. Surgical intervention is indicated icoi tir.uing haemorrhage from the internal organs. Measures to prevent shock or ncollapse shoul alsotre taken. Blood loss should be compensated for nby infusion of whole blood or i substitutes; cardiac and vascular nmedicinal preparations should be administered. Ire preparations nshould be given to patients with profuse blood loss in several days after tl haemorrhage has been arrested.

IRON DEFICIENCY ANAEMIA

Iron deficiency anaemia (anaemia sideropriva gastroenterogenic arises in the deficit of iron which is necessary nfor the production of haemoglobin ierythrocytes. This type of anaemia develops in patien with decreased iron absorption due to resection of nthe stomach (“agastric anaemia”), nremoval of a considerable part of the small intestine, especial of its proximal part, in intestinal diseases nattended by abnormal absor tion, and in the iron deficit in food. The nlatter occurs mostly in childr with nprolonged milk diet and copper deficit. Increased iron demands occ during intense growth of the body. During nestablishment of the menstrt cycle nin young girls (menstrual loss of blood and iron ions) juvenile in deficiency anaemia (juvenile chlorosis) may ndevelop. Chronic haemorrha also causes iron deficiency anaemia.

Repeated (not profuse) loss of blood cause nanaemization due to exhaustion of the ii store which is nnecessary for the production of haemoglobin in erythrocytes. Daily intake irowith food is small, about 11-28 mg, and one fourth of this quantity is only nabsorb This is equivalent to the iron content of 15 ml of blood. nDaily loss of 15 ml (or even sina amount) of blood therefore inevitably exhausts the niron store to cause iron deficie anaemia.

Chronic blood loss and chronic posthaemorrhagic anaemia after many diseases of the internal organs, and in the nfirst instance, of I gastro-intestinal ntract. In most cases these are gastric or duodenal ulc cancer, polyposis of the nstomach and intestine, haemorrhoids, and cert: types of helminthiasis. Chronic posthaemorrhagic anaemia often occurs tumours of the kidneys, cavernous tuberculosis of nthe lungs, and in uterine haemorrhage.

Some other factors promote anaemia. These are mainly nthose factors which can decrease the iron stores of the body. For nexample, patients with secondary gastric hyposecretion and nenteritis develop anaemia sooner and it runs a more severe course ithe presence of even insignificant chronic haemorrhage. Gravity of chronic nposthaemorrhagic anaemia arising in pa­tients with ndegrading tumours of the gastro-intestinal tract, kidney, or the uterus, nis intensified by the toxic effect of the tumour on the haemopoiesis and nby multiple metastases into the bone marrow, etc. Hydrochloric acid of the gastric juice npromotes reduction of trivalent iron to its divalent form, which is easier assimilated. But recent studies show that nhydrochloric acid does not play a decisive role in activation of iroabsorption.

In the absence of adequate iron supply to the body or its utilizatiofrom the store, the synthesis of haemoglobin, myoglobin, and iron-containing enzymes of various cells involved ithe oxidation processes is upset. nThis impairs nutrition of tissues and accounts for the development of many symptoms of the disease. The clinical npicture of iron deficiency anaemia is nexplained by insufficient oxygen transport to tissues due to anaemia on the one hand, and by disordered cell nrespiration on the other.

STAGES OF IRON DEFICIENCY

Iron deficiency anemia is the condition in which there is anemia and nclear evidence of iron deficiency. However, it is worthwhile to consider the nsteps by which iron deficiency occurs.

These can be divided into three stages. The first stage is negative niron balance, in which the demands for (or losses of) iron exceed the body’s nability to absorb iron from the diet. This stage can result from a number of nphysiologic mechanisms including blood loss, pregnancy (in which the demands nfor red cell production by the fetus outstrip the mother’s ability to provide niron), rapid growth spurts in the adolescent, or inadequate dietary irointake. Most commonly, the growth needs of the fetus or rapidly growing child nexceed the individual’s ability to absorb the iroecessary for hemoglobisynthesis from the diet. Blood loss in excess of 10 to 20 mL of red cells per nday is greater than the amount of iron that the gut can absorb from a normal ndiet. Under these circumstances the iron deficit must be made up by mobilizatioof iron from RE storage sites. During this period measurements of iron storesѕsuch as nthe serum ferritin level or the appearance of stainable iron on bone marrow naspirationsѕwill decrease. As long as iron stores are npresent and can be mobilized, the serum iron, total iron-binding capacity n(TIBC), and red cell protoporphyrin levels remain withiormal limits. At this nstage, red cell morphology and indices are normal.

When iron stores become depleted, the serum iron begins to fall. nGradually, the TIBC increases, as do red cell protoporphyrin levels. By ndefinition, marrow iron stores are absent when the serum ferritin level <15 nug/L. As long as the serum iron remains within the normal range, hemoglobisynthesis is unaffected despite the dwindling iron stores. Once the transferrisaturation falls to 15 to 20%, hemoglobin synthesis becomes impaired. This is a nperiod of iron-deficient erythropoiesis. Careful evaluation of the peripheral nblood smear reveals the first appearance of microcytic cells, and if the nlaboratory technology is available, one finds hypochromic reticulocytes icirculation. Gradually, the hemoglobin and hematocrit begin to fall, reflecting niron deficiency anemia. The transferrin saturation at this point is 10 to 15%.

When moderate anemia is present (hemoglobin 10-13 g/dL), the bone nmarrow remains hypoproliferative. With more severe anemia (hemoglobin 7-8 ng/dL), hypochromia and microcytosis become more prominent, misshapen red cells n(poikilocytes) appear on the blood smear as cigar or pencil-shaped forms and ntarget cells, and the erythroid marrow becomes increasingly ineffective. nConsequently, with severe prolonged iron deficiency anemia, erythroid nhyperplasia of the marrow develops rather than hypoproliferation.

 

CAUSES OF IRON DEFICIENCY

Conditions that increase demand for iron, increase iron loss, or ndecrease iron intake, absorption, or use can produce iron deficiency.

 

CLINICAL PRESENTATION OF IRON DEFICIENCY

Certain clinical conditions carry an increased likelihood of irodeficiency. Pregnancy, adolescence, periods of rapid growth, and aintermittent history of blood loss of any kind should alert the clinician to npossible iron deficiency. A cardinal rule is that the appearance of irodeficiency in an adult male means gastrointestinal blood loss until proveotherwise. Signs related to iron deficiency depend upon the severity and nchronicity of the anemia in addition to the usual signs of anemia–fatigue, npallor, and reduced exercise capacity. Cheilosis (fissures at the corners of nthe mouth) and koilonychia (spooning of the fingernails) are signs of advanced ntissue iron deficiency. The diagnosis of iron deficiency is typically based olaboratory results.

 

Slow development (within months, and years) of iron deficiency anaemia naccounts for actuation of the compensatory mechanisms. nMost patients therefore are well adapted to the disease and casatisfactorily stand even significant anaemia.

We shall not discuss patient’s complaints nassociated with the main disease, to which anaemia is secondary n(e.g. the cause of chronic haemorrhage). The specific complaints of anaemic npatieqts will only be emphasized: weakness, dizziness, dyspnoea n(especially exertional), increased fatigue, noise in the ears, and fainting. nMany patients develop various dyspeptic symptoms: decreased appetite, nperverted taste, slight nausea, heaviness in the epigastrium after nmeals, and regurgitation. Diarrhoea is also frequent. nSlight paraesthesia (tinging and pricking) is possible. Excruciating ndysphagia sometimes develops during swallowing dry or solid food in especially severe ncases. This sideropenic dysphagia was first described nby Rossolimo and Bekhterev in 1900-1901. Later this syndrome was described by nPlummer and Vinson. The dysphagia is explained by ex­tension of the atrophic process from the stomach nonto the oesophageal mucosa, and nsometimes by its development in the proximal part of the soft connective-tissue nmembranes and bridges.

Inspection of the patient reveals pallor.

Pallor nof conjunctiva in anaemia

 

 

Pallor nof nail beds in anaemia

 

Certain trophic changes in the skin, its appendages, and nmucosa can be due to the general iron deficit. The skin is dry and sometimes nslightly scaling. The hair is brittle, early grey, and showing the tendency to nfalling. The nails become flat, sometimes nspoon-like, opaque, marked by transverse folds, and brittle (koilonychia). The nmouth angles often have fissures (angular stomatitis), the papillae of the tongue are levelled (atrophic nglossitis). Theteeth lose their luster and quickly decompose despite a nthorough care. If iron preparations are ntaken for a long time, the teeth may blacken due to forma­tion of black iron sulphite (by the reaction of niron with hydrogen sulphide which is liberated by the carious teeth). Purulent ninflammation of the gum mucosa around the tooth necks develops (alveolar npyorrhoea).

Physical examination can reveal a slight indistinct nenlargement of the left ventricle, systolic murmur at the heart apex, nand nun’s murmur over the jugular vein (mostly on the right). nLymph nodes, liver and spleen are not enlarged.

 

The nintra-abdominal physical exemination is shown in video 1  (http://intranet.tdmu.edu.ua/data/teacher/video/fiz_ob/Examination%20Of%20An%20Intra-abdominal%20Lump-(devlto).avi).

 

 

Study of the blood reveals decreased erythrocyte and even more decreased haemoglobin content oflthe blood. The ncolour index is less than 0.85; igrave cases it is 0.6-0.5, and even lower. Microscopy of blood (Plate 30) reveals pallid erythrocytes (hypochromia), nanisocytosis, and poikilocytosis. The average diameter of erythrocytes is less nthaormal (microcytosis). The nnumber of reticulocytes is small. Anaemia is usually at­tended by thrombocytoleukopenia, sometimes nrelative monocytosis, lym­phocytosis, nand eosinopenia. The iron content of the serum is decreased (1.5-2.5 times and more). The percentage of ntransferrin saturation also decreases below 15).

  

Hypochromic nerythrocites

 

Microspherocites

 

n

Ovalocites

 

Reticulocites

 

Erythrocites nin different types of anaemia

Microcytic anemia

 

Peripheral nsmear showing classic spherocytes with loss of central pallor in the nerythrocytes.

 

 

Erythrocytes nin severe iron deficiency.The large area of central pallor (anulocytes) is ntypical. The erythrocytes are flat, small, and appear pale

 

Group nof bone marrow erythroblasts in iron deficiency. The basophilic cytoplasm ncontrasts with the relatively mature nuclei (nuclear-cytoplasmic dissociation)

 

 

Isevere iron deficiency, even the cytoplasm of some mature erythroblasts is nstill basophilic and has indistinct margins

 

A hypoproliferative anemia is typically seen with a low reticulocyte nproduction index together with little or no change in red cell morphology (a nnormocytic, normochromic anemia). Maturation disorders typically have a slight nto moderately elevated reticulocyte production index that is accompanied by neither macrocytic or microcytic red cell indices. Increased red blood cell ndestruction secondary to hemolysis results in an increase in the reticulocyte nproduction index to at least three times normal, provided sufficient iron is navailable for hemoglobin synthesis. Hemorrhagic anemia does not typically nresult in production indices of more than 2.5 times normal because of the nlimitations placed on expansion of the erythroid marrow by iron availability.

Decreased activity of the iron-containing nzyrnes of ntissue respiration provokes (or intensifies) atrophy of the gas. o-intestinal mucosa. The study of gastric juice reveals in most cases nachlorhydria or even achylia; the total amount of the excreted juice is much ndecreased. X-rays reveal levelled folds of the oesophageal and gastric nmucosa. Oesophagoscopy and gastroscopy confirm atrophy of the oesophageal and ngastric mucosa.

 

Serum Iron and Total Iron-Binding Capacity  The nserum iron level represents the amount of circulating iron bound to ntransferrin. The total iron-binding capacity (TIBC) is an indirect measure of nthe circulating transferrin. The normal range for the serum iron is 50 to 150 nug/dL; the normal range for TIBC is 300 to 360 ug/dL. Transferrin saturation, nwhich is normally 25 to 50%, is obtained by the following formula: serum niron x 100 : TIBC. Irodeficiency states are associated with saturation levels below 18%. Ievaluating the serum iron, the clinician should be aware that there is a ndiurnal variation in the value. A transferrin saturation rate of >50% indicates nthat a disproportionate amount of the iron bound to transferrin is being ndelivered to nonerythroid tissues. If this condition persists for an extended ntime, tissue iron overload may occur.

Serum Ferritin. Free iron is toxic to cells, and the body has nestablished an elaborate set of protective mechanisms to bind iron in various ntissue compartments. Within cells, iron is stored complexed to protein as nferritin or hemosiderin. Apoferritin binds to free ferrous iron and stores it nin the ferric state. As ferritin accumulates within cells of the RE system, nprotein aggregates are formed as hemosiderin. Iron in ferritin or hemosiderican be extracted for release by the RE cells although hemosiderin is less nreadily available. Under steady state conditions, the serum ferritin level ncorrelates with total body iron stores; thus, the serum ferritin level is the nmost convenient laboratory test to estimate iron stores. The normal value for nferritin varies according to the age and gender of the individual (Fig. 1). nAdult males have serum ferritin values averaging about 100 ug/L, while adult nfemales have levels averaging 30 ug/L. As iron stores are depleted, the serum nferritin falls to <15 ug/L. Such levels are virtually always diagnostic of nabsent body iron stores.

 

Bone marrow aspirate showing erythroid hyperplasia and many nbinucleated erythroid precursors.

 

 

Irostain reveals absence of iron stores in bone marrow fragments due to severe niron deficiency

 

TREATMENT

 

Iron metabolism

 

The severity and cause of iron deficiency anemia will determine the nappropriate approach to treatment. As an example, symptomatic elderly patients nwith severe iron deficiency anemia and cardiovascular instability may require nred cell transfusions. Younger individuals who have compensated for their nanemia can be treated more conservatively with iron replacement. The foremost nissue for the latter patient is the precise identification of the cause of the niron deficiency.

For the majority of cases of iron deficiency (pregnant women, growing nchildren and adolescents, patients with infrequent episodes of bleeding, and nthose with inadequate dietary intake of iron), oral iron therapy will suffice. nFor patients with unusual blood loss or malabsorption, specific diagnostic ntests and appropriate therapy take priority. Once the diagnosis of irodeficiency anemia and its cause is made, and a therapeutic approach is charted, nthere are three major approaches.

Treatment

Red Cell Transfusion  Transfusion therapy is reserved nfor those individuals who have symptoms of anemia, cardiovascular instability, nand continued and excessive blood loss from whatever source, and those who nrequire immediate intervention. The management of these patients is less nrelated to the iron deficiency than it is to the consequences of the severe nanemia. Not only do transfusions correct the anemia acutely, but the transfused nred cells provide a source of iron for reutilization, assuming they are not nlost through continued bleeding. Transfusion therapy will stabilize the patient nwhile other options are reviewed.

Oral Iron Therapy  In the patient with established irodeficiency anemia who is asymptomatic, treatment with oral iron is usually nadequate. Multiple preparations are available ranging from simple iron salts to ncomplex iron compounds designed for sustained release throughout the small nintestine (Table 105-5). While the various preparations contain different namounts of iron, they are generally all absorbed well and are effective itreatment. Some come with other compounds designed to enhance iron absorption, nsuch as citric acid. It is not clear whether the benefits of such compounds njustify their costs. Typically, for iron replacement therapy up to 300 mg of nelemental iron per day is given, usually as three or four iron tablets (each ncontaining 50 to 65 mg elemental iron) given over the course of the day. nIdeally, oral iron preparations should be taken on an empty stomach, since nfoods may inhibit iron absorption. Some patients with gastric disease or prior ngastric surgery require special treatment with iron solutions, since the nretention capacity of the stomach may be reduced. The retention capacity is nnecessary for dissolving the shell of the iron tablet before the release of niron. A dose of 200 to 300 mg of elemental iron per day should result in the nabsorption of up to 50 mg of iron per day. This supports a red cell productiolevel of two to three times normal in an individual with a normally functioning nmarrow and appropriate erythropoietin stimulus. However, as the hemoglobilevel rises, erythropoietin stimulation decreases, and the amount of iroabsorbed is reduced. The goal of therapy in individuals with iron deficiency nanemia is not only to repair the anemia, but also to provide stores of at least n1/2 to 1 g of iron. Sustained treatment for a period of 6 to 12 months after correction of the anemia will be necessary to achieve this.

Of the complications of oral iron therapy, gastrointestinal distress nis the most prominent and is seen in 15 to 20% of patients. For these patients, nabdominal pain, nausea, vomiting, or constipation often lead to noncompliance. nAlthough small doses of iron or iron preparations with delayed release may help nsomewhat, the gastrointestinal side effects are a major impediment to the neffective treatment of a number of patients.

The response to iron therapy varies, depending upon the erythropoietistimulus and the rate of absorption. Typically, the reticulocyte count should nbegin to increase within 4 to 7 days after initiation of therapy and peak at n11/2 weeks. The absence of a response may be due to poor adsorption, nnoncompliance (which is common), or a confounding diagnosis. If iron deficiency npersists, it may be necessary to switch to parenteral iron therapy.

 

In the presence of nsome anemias, the body increases production of red blood cells (RBCs), and nsends these cells into the bloodstream before they are mature. These slightly nimmature cells are called reticulocytes, and are characterized by a network of nfilaments and granules. Reticulocytes normally make up 1% of the total RBC ncount, but may exceed levels of 4% when compensating for anemia.

 

Parenteral Iron Therapy  Intramuscular or intravenous irocan be given to patients who are unable to tolerate oral iron, whose needs are nrelatively acute, or who need iron on an ongoing basis, usually due to npersistent gastrointestinal blood loss. Currently, the intravenous route is nused routinely. Parenteral iron use has been rising rapidly in the last several nyears with the recognition that recombinant erythropoietin therapy induces a nlarge demand for ironѕa demand that frequently cannot be met nthrough the physiologic release of iron from RE sources. Concern has beeraised about the safety of parenteral iron-particularly iron dextran. The nserious adverse reaction rate to intravenous iron dextran is 0.7%. Fortunately, nnewer iron complexes are becoming available in the United States that are nlikely to have an even lower rate of adverse effects. The most recently napproved preparation is intravenous iron gluconate (Ferrlecit).

 

VITAMIN B₁₂ (FOLIC ACID) nDEFICIENCY ANAEMIA

Aetiology and pathogenesis. VitamiB₁₂ (folic acid) deficiency anaemia was nfirst described by Addison in 1855. One of its forms was later given the name nof Addison-Biermer anaemia. In 1868, Biermer published a more ndetailed description of the disease, which he called pernicious or malignant nanaemia, because its prognosis was then grave and patients usually ndied in a few months or years after the appearance of the first symptoms.

An important biological effect of vitamin B₁₂ nis activation of folic acid. Like vitamin B., folic acid belongs to substances nincluded in the group of vitamin B. It is contained in leaves oi various nplants, fresh vegetables, beans, liver, and kidneys of animals. Folic acid is ndepositee in the human body mainly in the liver, where it is npresent in inactive state. Vitamin B₁₂ pro motes formation of folic nacid derivatives, folates, which are probably the factor necessary foi haemopoiesis nin the bone marrow. In conditions associated with vitamin B ₂ and nfolate defi ciency, the synthesis of DNA is disordered; this in turcauses disorders in cell division; tin cells become nlarge and qualitatively inadequate. Erythroblasts are affected most severely large ncells of embryonal haemopoiesis, megaloblasts, are found in the bone marrow ninstead o erythroblasts. They are not only larger thaery’hroblasts; they also differ in the structure o their nuclei and nprotoplasm, earlier and more intense saturation with haemoglobin durini their ndifferentiation (at the stage of reticular structure of the nucleus), retarded nmitotic divi sion, and mainly in their inability to grow to normal nerythrocytes. Most megaloblasts ar decomposed in the bone mafrow before they nreach the stage of a nucleated cell. Only a smal quantity of nmegaloblasts are differentiated to anuclear cells (megalocytes) and enter the nblooi vessels. Megalocytes are large!” and more saturated nwith haemoglobin than erythrocytes ar* differ from them nby morphological and functional inadequacy. Megalocytes have no sue! high noxygen-transport capacity as the erythrocytes and are quickly decomposed by nreticuloei¹ dothelial cells: the average life of nmegalocytes is about three times shorter than of erytli rocytes.

The absence of gastromucoprotein in gastric juice n(like achlorhydria which usually attend this disease) nis due to atrophy of the gastric mucosa. Some investigators believe that atroph nof gastric mucosa is not inflammatory in its origin as it was believed nearlier (atrophic gastritii but is a result of congenital ninsufficiency of its glandular apparatus which is manifested wit time. nIn the opinion of other authors, the atrophy of gastric mucosa is caused by nantibodu produced by the patient’s body to the gastric glandular ncells, which can however be slightl altered by toxic effects or ninflammation (auto-immune mechanism).

If the second coenzyme of vitamin B,_2> ndesoxyadenosylcobalamin, is deficient, fs metabolism nbecomes upset with accumulation of methylmalonic acid, whicli is toxic for th nervous system (provokes nfunicular myelosis).

The Addison-Biermer anaemia attacks commonly the aged; the ir cidence namong women is higher than in men.

CLASSIFICATION OF MEGALOBLASTIC ANEMIAS. CAUSES

 

 

 

Clinical picture. The nonset of the disease is insidious. The patient grow weaker, he complains of heart npalpitation, dizziness, and dyspnoe; especially nduring exercise or brisk movements; the work capacity is in paired, the appetite becomes poor; slight nausea nis possible. The first con plaint is noften the burning sensation in the tongue. This is explained by tr  ndevelopment of atrophic glossitis (see below) which usually attends this ndisease. The patient often develops achylic diarrhoea or, on the contrary, npersistent constipations. Dystrophic changes in the nervous system cause skianaesthesia and paraesthesia; the gait is often affected in grave cases: nspastic paresis develops (incomplete spastic paralysis of the lower ex­tremities); nthe knee reflex disappears, the function of the urinary bladder and the rectum ncan also be affected. All these symptoms are known as the funicular myelosis nwhich develops due to the predominant affection of the lateral spinal columns. nSymptoms of the disordered activity of the central nervous system (deranged nsleep, emotional lability, etc.) become apparent. Inspection of the patient nreveals pallor of the skin and mucosa, usually with a yellowish tint due to nincreased decomposition of megalocytes and  formation of bilirubin from the nreleased haemoglobin, and a slight swelling of the face. The patient is not nthin. Quite the reverse: most patients are well fed. The bright-red smooth and nglossy tongue (because of the pronounced atrophy of the papillae) is quite ncharacteristic of the Addison-Biermer anaemia.

 

 This symptom is known as Hunter’s glossitis (W. Hunter was the first to ndescribe this symptom). The mouth mucosa and the posterior wall of the throat nare also atrophied. The tip and edges of the tongue, and also the mouth mucosa ncan be ulcerated. The tendency to caries is often seen in the.teeth.

Pressing or tapping on the nflat and some tubular bones (especially the tibia) is often painful. This is nthe sign of bone marrow hyperplasia. Palpa-_X « tion can reveal a nslight enlargement of the liver and the spleen.

The cardiovascular system is usually involved as well. The left border of n”” the heart is displaced to the left, tachycardia develops, n”anaemic” systolic murmur is heard at the heart apex in 75 per cent nof cases; the nun’s mur­mur is often heard over the jugular veins.The pulse is nsoft and accelerated. Most patients develop hypotension. ECG shows ascertaidecrease in the general voltage, the decreased T wave and the S-T interval.

The gastrointestinal manifestations reflect the effect of cobalamideficiency on the rapidly proliferating gastrointestinal epithelium. The npatient sometimes complains of a sore tongue, which on inspection will be nsmooth and beefy red. Anorexia with moderate weight loss may also be evident, npossibly accompanied by diarrhea and other gastrointestinal symptoms. These nlatter manifestations may be caused in part by megaloblastosis of the small nintestinal epithelium, which results in malabsorption.

The neurologic manifestations often fail to remit fully on treatment. nThey begin pathologically with demyelination, followed by axonal degeneratioand eventual neuronal death; the final stage, of course, is irreversible. Sites nof involvement include peripheral nerves; the spinal cord, where the posterior nand lateral columns undergo demyelination; and the cerebrum itself. Signs and nsymptoms include numbness and paresthesia in the extremities (the earliest nneurologic manifestations), weakness, and ataxia. There may be sphincter ndisturbances. Reflexes may be diminished or increased. The Romberg and Babinski nsigns may be positive, and position and vibration senses are usually ndiminished. Disturbances of mentation will vary from mild irritability and nforgetfulness to severe dementia or frank psychosis. It should be emphasized nthat neurologic disease may occur in a patient with a normal hematocrit and nnormal RBC indexes. Although it has many benefits, folate supplementation of nfood may increase the likelihood of neurologic presentations of cobalamideficiency.

Changes in the gastro-intestinal tract are pronounced. Especially ncharacteristic is atrophy of gastric mucosa which can be revealed by X-ray nexamination, and more distinctly by gastroscopy. The atrophy is often focal, nand the affected sites (mostly in the fundus of the stomach) can be seen as niridescent spots. Atrophy can combine with polyps in the folds of gastric nmucosa and its polypous thickening. It should be remembered that anaemia, nincluding pernicious anaemia, can be a symptom of a malignant tumour in the nstomach. Cancer of the stomach occurs in patients with the Addison-Biermer nanaemia 8 times more frequently than in healthy persons. Patients with this ndisease should therefore be systematically inspected by X-rays (by gastroscopy nwhenever possible). Almost all patients develop achlorhydria.   In  98  per  cent  nof cases it  has the histamine-resistant haracter. The total amount of juice nproduced during the study is usually significantly diminished; the pepsicontent of the juice is very low or it cannot be determined at all (achylia). nUsually achlorhydria develops many years before the first symptoms of anaemia ndevelop.

Elevated temperature is a common symptom of vitamin B₁₂ (folic nacid) deficiency anaemia; the temperature is usually subfebrile.

Blood plasma contains slightly increased amounts of free bilirubin due to nincreased haemolysis of the red cells, especially megalocytes; the plasma irocontent increased to 30-45 mmol/i (170-200 /tg/rnl).

The blood picture is characterized by a sharp decrease in the quantity of nerythrocytes (to 0.80 x 10¹² per l(J) at a comparatively high nhaemoglobin saturation. Despite the decreased total haemoglobin content of the nblood, the colour index remains high (1.2-1.5). Red blood cells dif­fer in size n(anisocytosis), with prevalence of large erythrocytes (macrocytes). Especially nlarge slightly oval and intensely red megalocytes appear (in many cases nmegaloblasts are also seen). The volume of each cell increases. Many nerythrocytes are oval, or they have the shape of a sickle and other shapes n(poikilocytosis). Megalocytes often have remnants of the nucleus or its nenvelope in the form of Jolly bodies ?* Cabot rings. The con­tent of nreticulocytes is not high. The number of reticulocytes sharply in­creases n(reticulocyte crisis) during vitamin B₁₂ therapy to indicate the nbeginning remission. Blood leucocytes decrease mostly at the expense of nneutrophils. Eosinopenia, relative lymphocytosis, and thrombocytopenia are nobserved. Large neutrophils with polysegmented nuclei also occur.

TheQuality of erythroid precursors in a specimen of bone marrow sharply nincreases, by 3—4 times compared with the number of leucopoietic cells (the nproportion ^xbeing reverse in physiological conditions). Megaloblasts nare observed in varying amounts among the erythroid precur­sors; in grave cases nthey are found in prevailing quantity. Both erythropoiesis and leucopoiesis are ndisordered. Megakaryocytes are also large, with a multi-lobed nucleus: nthrombocyte separation is disordered.

 

nMacrocites

 

 

Macrocites

 

Bone nmarrow in megaloblastic anaemia

This image shows a large PMN with nmultiple discretely-identifiable nuclear lobes, usually seen in megaloblastic nanemias. Normal PMN’s have less than or equal to 5 lobes.

 

This picture shows nlarge, dense, oversized, red blood cells (RBCs) that are seen in megaloblastic nanemia. Megaloblastic anemia can occur when there is a deficiency of vitamiB-12.

Bone marrow morphology is characteristically abnormal. Marked nerythroid hyperplasia is present as a response to defective red blood cell nproduction (ineffective erythropoiesis). Megaloblastic changes in the erythroid nseries include abnormally large cell size and asynchronous maturation of the nnucleus and cytoplasm – ie, cytoplasmic maturation continues while impaired DNA nsynthesis causes retarded nuclear development. In the myeloid series, giant nmetamyelocytes are characteristically seen.

 

Course. If nuntreated, the disease progresses. Before Minot and Murphy proposed their neffective treatment of the disease, patients rarely survived more than 3 years. nAt the terminal period, many patients developed coma (coma perniciosum) with nloss of consciousness, arephlexia, decreased arterial pressure and temperature, nvomiting and involuntary urination.

At the present time the patient recovers from the Addison-Biermer anaemia nif treated properly and if adequate prophylactic measures against relapses of nthe disease are taken.

Treatment.

Defective Release of Cobalamin from Food. Cobalamin in food is tightly nbound to enzymes in meat and is split from these enzymes by hydrochloric acid nand pepsin in the stomach. People older than 70 years are commonly unable to nrelease cobalamin from food sources but retain the ability to absorb ncrystalline B12, the form most commonly found in multivitamins. The exact nincidence of the defect in cobalamin release from food has not been well ndefined; estimates vary from 10 to greater than 50% of those over age 70 years. nOnly a minority of these persons go on to develop frank cobalamin deficiency, nbut many have biochemical changes, including low levels of cobalamin bound to nTC II and elevated homocysteine levels, that augur cobalamin deficiency (see nbelow).

Similarly, patients on drugs that suppress gastric acid production, nsuch as omeprazole, may also fail to release cobalamin from food.

Cobalamin Deficiency  Apart from specific therapy nrelated to the underlying disorder (e.g., antibiotics for intestinal overgrowth nwith bacteria), the mainstay of treatment for cobalamin deficiency is nreplacement therapy. Because the defect is nearly always malabsorption, npatients are generally given parenteral treatment, specifically in the form of nintramuscular cyanocobalamin. Parenteral treatment begins with 1000 ug ncobalamin per week for 8 weeks, followed by 1000 ug cyanocobalamiintramuscularly every month for the rest of the patient’s life. However, ncobalamin deficiency can also be managed very effectively by oral replacement ntherapy with 2 mg crystalline B12 per day.

The response to treatment is gratifying. Shortly after treatment is nbegun, and several days before a hematologic response is evident in the nperipheral blood, the patient will experience an increase in strength and aimproved sense of well-being. Marrow morphology begins to revert toward normal nwithin a few hours after treatment is initiated. Reticulocytosis begins 4 to 5 ndays after therapy is started and peaks at about day 7 (Fig. 107-3), with nsubsequent remission of the anemia over the next several weeks. If a nreticulocytosis does not occur, or if it is less brisk than expected from the nlevel of the hematocrit, a search should be made for other factors contributing nto the anemia (e.g., infection, coexisting iron and/or folate deficiency, or nhypothyroidism). Hypokalemia and salt retention may occur early in the course nof therapy. Thrombocytosis may also be seen.

 

Folate Deficiency  As for cobalamin deficiency, folate ndeficiency is treated by replacement therapy. The usual dose of folate is 1 nmg/d, by mouth, but higher doses (up to 5 mg/d) may be required for folate ndeficiency due to malabsorption. Parenteral folate is rarely necessary. The nhematologic response is similar to that seen after replacement therapy for ncobalamin deficiency, i.e., a brisk reticulocytosis after about 4 days, nfollowed by correction of the anemia over the next 1 to 2 months. The duratioof therapy depends on the basis of the deficiency state. Patients with a ncontinuously increased requirement (such as patients with hemolytic anemia) or nthose with malabsorption or chronic malnutrition should continue to receive noral folic acid indefinitely. In addition, the patient should be encouraged to nmaintain an optimal diet containing adequate amounts of folate.

 

 

Peripheral smear of blood in a patient with pernicious nanemia. Macrocytes are observed and some of the red blood cells show ovalocytosis. nA 6-lobed polymorphonuclear leucocyte is present.

 

Peripheral nsmear showing ovalocytes, macrocytes, and a hypersegmented polymorphonuclear nleukocyte

 

Histologically, nthe megaloblastosis caused by folic acid deficiency cannot be differentiated nfrom that observed with vitamin B-12 deficiency.

 

Serum nmethylmalonic acid and homocysteine levels are also useful in the diagnosis of nmegaloblastic anemias. Both are elevated in cobalamin deficiency, while nelevated levels of homocysteine but not methylmalonic acid are seen in folate ndeficiency. These tests measure tissue vitamin stores and may demonstrate a ndeficiency even when the more traditional but less reliable folate and ncobalamin levels are borderline or eveormal. Patients (particularly older npatients) without anemia and with normal serum cobalamin levels but elevated nlevels of serum methylmalonic acid may develop neuropsychiatric abnormalities. nTreatment of patients with this “subtle” cobalamin deficiency will nusually prevent further deterioration and may result in improvement.

 

 

Bone nmarrow aspirate from a patient with untreated pernicious anemia. Megaloblastic nmaturation of erythroid precursors is shown. Two megaloblasts occupy the center nof the slide with a megaloblastic normoblast above.

 

Aplastic anemia.

The myelodysplastic syndromes. Anemia is present in the majority nof cases, either alone or as part of bi- or pancytopenia; isolated neutropenia nor thrombocytopenia is more unusual. Macrocytosis is common, and the smear may nbe dimorphic with a distinctive population of large red blood cells. Platelets nare also large and lack granules. In functional studies, they may show marked nabnormalities, and patients may have bleeding symptoms despite seemingly nadequate numbers. Neutrophils are hypogranulated; have hyposegmented, ringed, nor abnormally segmented nuclei; and contain Dohle bodies and may be nfunctionally deficient. Circulating myeloblasts usually correlate with marrow nblast numbers, and their quantitation is important for classification and nprognosis. The total white blood cell count is usually normal or low, except ichronic myelomonocytic leukemia. As in aplastic anemia, MDS also can be nassociated with a clonal population of PNH cells.

DEFINITION

Aplastic anemia is pancytopenia with bone marrow hypocellularity. nAcquired aplastic anemia is distinguished from iatrogenic marrow aplasia, the ncommon occurrence of marrow hypocellularity after intensive cytotoxic nchemotherapy for cancer. Aplastic anemia can also be constitutional: the ngenetic disease Fanconi’s anemia, while frequently associated with typical nphysical anomalies and the development of pancytopenia early in life, can also npresent as marrow failure iormal-appearing adults. Acquired aplastic anemia nis often stereotypical in its manifestations, with the abrupt onset of low nblood counts in a previously well young adult; seronegative hepatitis or a ncourse of an incriminated medical drug may precede the onset. The diagnosis ithese instances is uncomplicated. Sometimes blood count depression is moderate nor incomplete, resulting in anemia, leukopenia, and thrombocytopenia in some ncombination. Aplastic anemia is related to both paroxysmal nocturnal nhemoglobinuria (PNH; Chap. 108) and to MDS, and in some cases a clear ndistinction among these disorders may not be possible.

ETIOLOGY

The origins of aplastic anemia have been inferred from several nrecurring clinical associations (Table 8); unfortunately, these relationships nare neither a reliable guide in an individual patient nor necessarily netiologic. In addition, while most cases of aplastic anemia are idiopathic, nlittle other than history separates these cases from those with a presumed netiology such as a drug exposure.

 

 

 

Infections  Hepatitis is the most ncommon preceding infection, and posthepatitis marrow failure accounts for about n5% of etiologic associations in most series. Patients are usually young men who nhave recovered from a mild bout of liver inflammation 1 to 2 months earlier; nthe subsequent pancytopenia is very severe. The hepatitis is almost invariably nseronegative (non-A, non-B, non-C, non-G) and presumably due to a novel, as yet nundiscovered, virus. Fulminant liver failure in childhood can follow nseronegative hepatitis, and marrow failure occurs at a high rate in these npatients as well. Aplastic anemia can rarely follow infectious mononucleosis, nand Epstein-Barr virus has been found in the marrow of a few aplastic anemia patients, nsome without a suggestive preceding history. Parvovirus B19, the cause of ntransient aplastic crisis in hemolytic anemias and of some pure red cell naplasia (see below), does not usually cause generalized bone marrow failure. nBlood count depression is frequent in the course of many viral and bacterial ninfections but is comparatively moderate and resolves with the infection.

Immunologic nDiseases  nAplasia is a major consequence and the cause of death in transfusion-associated ngraft-versus-host disease, which can occur after infusion of unirradiated blood nproducts to an immunodeficient recipient. Aplastic anemia is strongly nassociated with the rare collagen vascular syndrome called eosinophilic nfasciitis, which is characterized by painful induration of subcutaneous ntissues. Pancytopenia with marrow hypoplasia can also occur in systemic lupus nerythematosus.

Pregnancy  Aplastic anemia very nrarely may occur and recur during pregnancy and resolve with delivery or with nspontaneous or induced abortion.

Congenital nDisorders  nFanconi’s anemia, an autosomal recessive disorder, manifests as progressive npancytopenia, increased chromosome fragility, congenital developmental nanomalies, and an increased risk of malignancy. Patients with Fanconi’s anemia ntypically have short stature; cafe au lait spots; and anomalies involving the nthumb, radius, and genitourinary tract. At least seven different genetic ndefects have been defined by complementation analysis. The most common, type A nFanconi’s anemia, is due to a mutation in FANCA. The function of the four ncloned genes so far identified in Fanconi’s anemia remains unknown.

Patients with nShwachman-Diamond syndrome may develop pancreatic insufficiency, malabsorption, nand neutropenia and are at risk of aplastic anemia. Dyskeratosis congenita is nan X-linked disorder characterized by mucous membrane leukoplasia, dystrophic nnails, reticular hyperpigmentation, and the later development of aplastic nanemia in about half of patients. Mutation in the DKC1 (dyskerin) gene has beefound in some cases.

Drug Injury  Extrinsic damage to the nmarrow follows massive physical or chemical insults such as high doses of nradiation and toxic chemicals. For the more common idiosyncratic reaction to nmodest doses of medical drugs, altered drug metabolism has been invoked as a nlikely mechanism. The metabolic pathways of many drugs and chemicals, nespecially if they are polar and have limited water solubility, involve nenzymatic degradation to highly reactive electrophilic compounds; these nintermediates are toxic because of their propensity to bind to cellular nmacromolecules. For example, derivative hydroquinones and quinolones are nresponsible for benzene-induced tissue injury. Excessive generation of toxic nintermediates or failure to detoxify the intermediates may be genetically ndetermined and apparent only on specific drug challenge; the complexity and nspecificity of the pathways imply multiple susceptible loci and would provide nan explanation for the rarity of idiosyncratic drug reactions.

Immune-Mediated nInjury  nThe recovery of marrow function in some patients prepared for bone marrow ntransplantation with antilymphocyte globulin (ALG) first suggested that naplastic anemia might be immune-mediated. Consistent with this hypothesis was nthe frequent failure of simple bone marrow transplantation from a syngeneic ntwin, without conditioning cytotoxic chemotherapy, which also argued both nagainst simple stem cell absence as the cause and for the presence of a host nfactor producing marrow failure. Laboratory data support an important role for nthe immune system in aplastic anemia. Blood and bone marrow cells of patients ncan suppress normal hematopoietic progenitor cell growth, and removal of T ncells from aplastic anemia bone marrow improves colony formation in vitro. Increased nnumbers of activated cytotoxic T cells are observed in aplastic anemia patients nand usually decline with successful immunosuppressive therapy; cytokine nmeasurements suggest a predominant TH1 immune response (interferon g, ninterleukin 2, and tumor necrosis factor). Interferon and tumor necrosis factor ninduce Fas expression on CD34 cells, leading to apoptotic cell death; nlocalization of activated T cells to bone marrow and local production of their nsoluble factors are probably important in stem cell destruction.

Early immune nsystem events in aplastic anemia are not well understood. Many different nexogeneous antigens appear capable of initiating a pathologic immune response, nbut at least some of the active T cells recognize true self-antigens. The nrarity of occurrence of aplastic anemia despite common exposures (medical ndrugs, hepatitis virus) suggests that genetically determined features of the nimmune response can convert a normal physiologic response into a sustained nabnormal autoimmune process.

 

CLINICAL FEATURES

History  Aplastic anemia can appear with seeming abruptness or have a nmore insidious onset. Bleeding is the most common early symptom; a complaint of ndays to weeks of easy bruising, oozing from the gums, nose bleeds, heavy nmenstrual flow, and sometimes petechiae will have beeoticed. With nthrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding nin the central nervous system can result in catastrophic intracranial or nretinal hemorrhage. Symptoms of anemia are also frequent, including lassitude, nweakness, shortness of breath, and a pounding sensation in the ears. Infectiois an unusual first symptom in aplastic anemia (unlike in agranulocytosis, nwhere pharyngitis, anorectal infection, or frank sepsis occur early). A striking nfeature of aplastic anemia is the restriction of symptoms to the hematologic nsystem, and patients often feel and look remarkably well despite drastically nreduced blood counts. Systemic complaints and weight loss should point to other netiologies of pancytopenia. History of drug use, chemical exposure, and npreceding viral illnesses must often be elicited with repeated questioning.

Physical Examination  Petechiae and ecchymoses are often present, and nretinal hemorrhages may be present. Pelvic and rectal examinations should be nperformed with great gentleness to avoid trauma; these will often show bleeding nfrom the cervical os and blood in the stool. Pallor of the skin and mucous nmembranes is common except in the most acute cases or those already transfused. nInfection on presentation is unusual but may be present if the patient has beesymptomatic for a few weeks. Lymphadenopathy and splenomegaly are highly natypical of aplastic anemia. Cafe au lait spots and short stature suggest nFanconi’s anemia; peculiar nails, dyskeratosis congenita.

 

Aplastic anemia. Oral leukoplakia in dyskeratosis ncongenita.

 

LABORATORY STUDIES

Blood  The smear shows large erythrocytes and a paucity of nplatelets and granulocytes. Mean corpuscular volume (MCV) is commonly increased. nReticulocytes are absent or few, and lymphocyte numbers may be normal or nreduced. The presence of immature myeloid forms suggests leukemia or MDS; nnucleated red blood cells suggest marrow fibrosis or tumor invasion; abnormal nplatelets suggest either peripheral destruction or MDS.

The smear shows large erythrocytes and a paucity of platelets and ngranulocytes. Mean corpuscular volume (MCV) is commonly increased. nReticulocytes are absent or few, and lymphocyte numbers may be normal or nreduced. The presence of immature myeloid forms suggests leukemia or MDS; nnucleated red blood cells suggest marrow fibrosis or tumor invasion; abnormal nplatelets suggest either peripheral destruction or MDS.

 

 

Bone Marrow  The bone marrow is usually readily naspirated but appears dilute on smear, and the fatty biopsy specimen may be ngrossly pale on withdrawal; a “dry tap” suggests fibrosis or nmyelophthisis. In severe aplasia the smear of the aspirated specimen shows only nred cells, residual lymphocytes, and stromal cells; the biopsy, which should be n>1 cm in length, is superior for determination of cellularity and shows mainly fat under the microscope, with hematopoietic cells occupying, by definition, <25% of the marrow space. In the most serious cases the biopsy is virtually 100% fat. The ncorrelation between marrow cellularity and disease severity is imperfect. Some npatients with moderate disease by blood counts will have empty iliac crest nbiopsies, while “hot spots” of hematopoiesis may be seen in severe ncases. If an iliac crest specimen is inadequate, cells should also be obtained nby aspiration from the sternum. Residual hematopoietic cells should have normal nmorphology, except for mildly megaloblastic erythropoiesis; megakaryocytes are ninvariably greatly reduced and usually absent. Areas adjacent to the spicule nshould be searched for myeloblasts. Granulomas (in cellular specimens) may nindicate an infectious etiology of the marrow failure.

Sternal npuncture, indications and diagnostic able.

Bone marrow nexamination is performed in adults either from sternum or posterior iliac ncrest. Marrow may be simply aspirated or a bone marrow biopsy (trephine) nperformed.

A small namount of bone marrow is removed during a bone marrow aspiration. The procedure nis uncomfortable, but can be tolerated by both children and adults. The marrow ncan be studied to determine the cause of anemia, the presence of leukemia or nother malignancy, or the presence of some “storage diseases” in which nabnormal metabolic products are stored in certain bone marrow cells.

Bone marrow biopsy

Bone marrow smear (microscopic examination)

 

 The latter ncannot be obtained safely from the sternum and increasingly both aspirate and nbiopsy are performed from the posterior iliac crest. A biopsy is superior for nassessing marrow cellularity and infiltration. Bone marrow examination is nperformed under local anaestethesia and can easily be undertaken as aoutpatient procedure. Both aspiration and trephine biopsy can be carried out by nthe same needle but often separate needles are used.

Marrow nexamined not only for its morphological appearances but increasingly cell nmarker studies, karyotyping and molecular biology studies are undertaken as nappropriate for the accurate diagnosis and assessement of malignant disease. nMarrow can also be sent for culture in cases of suspected tuberculosis. The nmain indications for a bone marrow examination are shown in the table

 

Ancillary Studies  Chromosome breakage studies of nperipheral blood using diepoxybutane (DEB) or mitomycin C should be performed non children and younger adults to exclude Fanconi’s anemia. Chromosome studies nof bone marrow cells are often revealing in MDS and should be negative itypical aplastic anemia. Flow cytometric assays have replaced the Ham test for nthe diagnosis of PNH. Serologic studies may show evidence of viral infection, nespecially Epstein-Barr virus and HIV. Posthepatitis aplastic anemia is ntypically seronegative. The spleen size should be determined by scanning if the nphysical examination of the abdomen is unsatisfactory. Magnetic resonance nimaging may be helpful to assess the fat content on a few vertebrae in order to ndistinguish aplasia from MDS.

 

PROGNOSIS

The natural history of severe aplastic anemia is rapid deterioratioand death. Provision first of red blood cell and later platelet transfusions nand effective antibiotics were of some benefit, but few patients showed nspontaneous recovery. The major prognostic determinant is the blood count; nsevere disease is defined by the presence of two of three parameters: absolute nneutrophil count <500/uL, platelet count <20,000/uL, and corrected nreticulocyte count <1% (or absolute reticulocyte count <50,000/uL). nSurvival of patients who fulfill these criteria is about 20% at 1 year after ndiagnosis; patients with very severe disease, defined by an absolute neutrophil ncount <200/uL, fare even more poorly. Treatment has markedly improved nsurvival in this disease.

TREATMENT

Treatment includes therapies that reverse the underlying marrow nfailure and supportive care of the pancytopenic patient. Severe acquired naplastic anemia can be cured by replacement of the absent hematopoietic cells n(and the immune system) by stem cell transplant, or ameliorated by suppressioof the immune system to allow recovery of the patient’s residual bone marrow nfunction. Hematopoietic growth factors have limited usefulness and nglucocorticoids are of no value. Suspect exposures to drugs or chemicals should nbe discontinued; however, spontaneous recovery of severe blood count depressiois rare, and a waiting period before beginning treatment may not be advisable nunless the blood counts are only modestly depressed.

Bone Marrow Transplantation  This is the best ntherapy for the young patient with a fully histocompatible sibling donor. HLA ntyping should be ordered as soon as the diagnosis of aplastic anemia is nestablished in a child or younger adult. In transplant candidates, transfusioof blood from family members should be avoided so as to prevent sensitizatioto histocompatability antigens; while transfusions in general should be nminimized, limited numbers of blood products probably do not seriously affect noutcome.

For allogeneic transplant from fully matched siblings, long-term nsurvival rates for children are about 80%. Transplant morbidity and mortality nare increased among adults, due mainly to the increased risk of chronic ngraft-versus-host disease and serious infections. Graft rejection was historically na major determinant of outcome in bone marrow transplant for aplastic anemia; nhigh rates of primary or secondary graft failure may be related to the npathophysiology of marrow failure as well as to alloimmunization from ntransfusions.

Most patients do not have a suitable sibling donor. Occasionally, a nfull phenotypic match can be found within the family and serve as well. Far nmore available are other alternative donors, either unrelated but nhistocompatible volunteers, or closely but not perfectly matched family nmembers. Survival using alternative donors is about half that of conventional nsibling transplants. These patients will be at risk for late complications, nespecially a higher rate of cancer, if radiation is used as a component of nconditioning. The majority of adults who undergo alternative donor transplants nsuccumb to transplant-related complications.

Immunosuppression  Used alone, ALG or antithymocyte nglobulin (ATG) induces hematologic recovery (independence from transfusion and na leukocyte count adequate to prevent infection) in about 50% of patients. The naddition of cyclosporine to either ALG or ATG has further increased response nrates to about 70 to 80% and especially improved outcomes for children and for nseverely neutropenic patients. Combined treatment is now standard for patients nwith severe disease. Hematologic response strongly correlates with survival. nImprovement in granulocyte number is generally apparent within 2 months of ntreatment. Most recovered patients continue to have some degree of blood count ndepression, the MCV remains elevated, and the bone marrow cellularity returns ntowards normal only very slowly, if at all. Relapse (recurrent pancytopenia) is nfrequent, often occurring as cyclosporine is discontinued; most, but not all, npatients respond to reinstitution of immunosuppression, and some responders nbecome dependent on continued cyclosporine administration. Development of MDS, nwith typical marrow morphologic or cytogenetic abnormalities, occurs in about n15% of treated patients, usually but not invariably associated with a return of npancytopenia, and some patients develop leukemia. Although the laboratory ndiagnosis of PNH can generally be made at the time of presentation of aplastic nanemia by flow cytometry, recovered patients showing frank hemolysis or, less ncommonly, thrombosis should be retested for PNH. Bone marrow examinations nshould be performed annually or if there is an unfavorable change in blood ncounts.

Most patients with aplastic anemia lack a suitable marrow donor and nimmunosuppression is the treatment of choice. Long-term survival is equivalent nwith transplantation and immunosuppression. However, successful transplant ncures marrow failure, while patients who recover adequate blood counts after nimmunosuppression remain at risk of relapse and malignant evolution. Because of nthe excellent results in children, allogeneic transplant should always be nperformed in the pediatric population if a suitable sibling donor is available. nIncreasing age and the severity of neutropenia are the most important factors nweighing in the decision between transplant and immunosuppression in adults who nhave a matched family donor: older patients do better with ATG and ncyclosporine, while transplant is preferred if granulocytopenia is profound. nSome reluctant patients may be treated by immunosuppression followed by ntransplant for failure to recover blood counts or occurrence of late ncomplications.

Outcomes following both transplant and immunosuppression have improved nwith time. High doses of cyclophosphamide, without stem cell rescue, have beereported to produce durable hematologic recovery, without relapse or evolutioto MDS, but this treatment can produce sustained severe neutropenia and nresponse is often delayed. Novel immunosuppressive drugs such as mycophenolate nmofetil may further improve outcome.

 

Hemolythic anaemias

Red blood cells (RBC) normally survive 90 to 120 days in the ncirculation. The life span of RBC may be shortened in a number of disorders, noften resulting in anemia if the bone marrow is not able to replenish nadequately the prematurely destroyed RBC. The disorders associated with nhemolytic anemias are generally identified by the abnormality that brings about nthe premature destruction of the RBC.

In all patients with hemolytic anemia, a careful history and physical nexamination provide important clues to the diagnosis. The patient may complaiof fatigue and other symptoms of anemia. Less commonly, jaundice and evered-brown urine (hemoglobinuria) are reported. A complete drug and toxin exposure nhistory and the family history often provide crucial information. The physical nexamination may show jaundice of skin and mucosae. Splenomegaly is encountered nin a variety of hemolytic anemias. A wide array of other historic and physical nfindings is associated with specific hemolytic anemias (see below).

 

Polychromasia.

 

Laboratory tests may be used initially to demonstrate the presence of nhemolysis and define its cause. An elevated reticulocyte count in the patient nwith anemia is the most useful indicator of hemolysis, reflecting erythroid nhyperplasia of the bone marrow; biopsy of the bone marrow is often unnecessary. nReticulocytes are also elevated in patients with active blood loss, those with nmyelophthisis, and those who are recovering from suppression of erythropoiesis. nWhile the findings on the peripheral blood smear alone are rarely npathognomonic, they may provide important clues to the presence of hemolysis nand to diagnosis.

 

Spherocytes. One arrow points to a nspherocyte; the other, to a normal RBC with a central pallor.

 

RBC may be prematurely removed from the circulation by macrophages, nparticularly those of the spleen and liver (extravascular lysis), or, less commonly, nby disruption of their membranes during their circulation (intravascular nhemolysis). Both mechanisms result in increased heme catabolism and enhanced nformation of unconjugated bilirubin, which is normally conjugated by the liver nand excreted. The plasma level of unconjugated bilirubin may be high enough to nproduce readily apparent jaundice (detectable usually when serum bilirubin is n>34 umol/L or 2 mg/dL). The unconjugated (indirect) bilirubin level can be nfurther elevated by a commonly encountered defect in conjugation of bilirubi(Gilbert’s syndrome). In patients with hemolysis, the level of unconjugated nbilirubiever exceeds 70 to 85 umol/L (4 to 5 mg/dL), unless liver functiois impaired.

In the absence of tissue damage in other organs, serum enzyme levels ncan be useful in the diagnosis and monitoring of patients with hemolysis. nLactate dehydrogenase (LDH), particularly LDH-2, is elevated by accelerated RBC ndestruction. Serum AST (SGOT) may be somewhat elevated, whereas ALT (SGPT) is nnot.

Haptoglobin is an a globulin that is present in high concentratio(~1.0 g/L) in the plasma (and serum). It binds specifically and tightly to the nglobin in hemoglobin. The hemoglobin-haptoglobin complex is cleared withiminutes by the mononuclear phagocyte system. Thus patients with significant nhemolysis, either intravascular or extravascular, have low or absent levels of nserum haptoglobin. The fact that haptoglobin synthesis is decreased in patients nwith hepatocellular disease and increased in inflammatory states must be nconsidered in the interpretation of serum haptoglobin.

 

Schistocytes (thrombotic nthrombocytopenic purpura).

 

Intravascular hemolysis (which is uncommon) results in the release of nhemoglobin into the plasma. In these cases, plasma hemoglobin is increased iproportion to the degree of hemolysis. Plasma hemoglobin may be falsely nelevated due to lysis of RBC in vitro. If the haptoglobin-binding capacity of nthe plasma is exceeded, free hemoglobin passes through renal glomeruli. This nfiltered hemoglobin is reabsorbed by the proximal tubule, where it is ncatabolized in situ, and the heme iron is incorporated into storage proteins n(ferritin and hemosiderin). The presence of hemosiderin in the urine, detected nby staining the sediment with Prussian blue, indicates that a significant namount of circulating free hemoglobin has been filtered by the kidneys. nHemosiderin appears 3 to 4 days after the onset of hemoglobinuria and may npersist for weeks after its cessation. When the absorptive capacity of the ntubular cells is exceeded, hemoglobinuria ensues. Hemoglobinuria indicates nsevere intravascular hemolysis. Hemoglobinuria must be distinguished from nhematuria (in which case RBC are seen on urine examination) and from myoglobidue to rhabdomyolysis; in all three cases, the urine is positive with the nbenzidine reaction, commonly used in analysis of urine. The distinction betweehemoglobinuria and myoglobinuria can best be made by specific tests that exploit nimmunologic differences or differences in solubility. After centrifugation of nan anticoagulated blood specimen, the plasma of patients with hemoglobinuria nhas a reddish-brown color, whereas that of patients with myoglobinuria is nnormal in color. Because of its higher molecular weight, hemoglobin has lower nglomerular permeability than myoglobin and is less rapidly cleared by the nkidneys.

 

CLASSIFICATION

The hemolytic anemias can be grouped in three different ways, shown iTable 108-3. The cause of accelerated RBC destruction can be regarded as

1) a molecular defect (hemoglobinopathy or enzymopathy) inside the red ncell,

2) an abnormality in membrane structure and function,

3) an environmental factor such as mechanical trauma or aautoantibody.

 

 

 

 

In intracorpuscular types of hemolysis, the patient’s RBC have aabnormally short life span in a normal recipient (with a compatible blood ntype), while compatible normal RBC survive normally in the patient. The nopposite is true in extracorpuscular types of hemolysis. Finally, hemolytic ndisorders can be classified as either inherited or acquired.

In contrast to anemias associated with an inappropriately low nreticulocyte production index, blood loss or hemolysis is associated with red ncell production indices of >2.5 times normal. nThe stimulated erythropoiesis is reflected in the blood smear by the appearance nof increased numbers of polychromatophilic macrocytes. A marrow examination is nrarely indicated if the reticulocyte production index is increased nappropriately. The red cell indices are typically normocytic or slightly macrocytic, nreflecting the increased number of reticulocytes. Acute blood loss is not nassociated with an increased reticulocyte production index because of the time nrequired to increase EPO production and, subsequently, marrow proliferation. nSubacute blood loss may be associated with modest reticulocytosis because irois lost along with the red cells. Anemia from chronic blood loss more oftepresents as iron deficiency than with the picture of increased red cell nproduction.

Hemolytic disease, while dramatic, is among the least common forms of nanemia. The ability to sustain a high reticulocyte production index reflects nthe ability of the erythroid marrow to compensate for hemolysis and the nefficient recycling of iron from the destroyed red cells to support new hemoglobisynthesis. The level of response will depend on the severity of the anemia and nthe nature of the underlying disease process.

Hemolytic anemias present in different ways. Some appear suddenly as nan acute, self-limited episode of intravascular or extravascular hemolysis, a npresentation pattern often seen in patients with autoimmune hemolysis or with ninherited defects of the Embden-Myerhof pathway or the glutathione reductase npathway. Patients with inherited disorders of the hemoglobin molecule or red cell nmembrane generally have a lifelong clinical history typical of the disease nprocess. Those with chronic hemolytic disease, such as hereditary nspherocytosis, may actually present not with anemia but with a complicatiostemming from the prolonged increase in red cell destruction such as aplastic ncrisis, symptomatic bilirubin gallstones, or splenomegaly.

 

Hereditary spherocytosis  This ncondition is characterized by spherical RBC due to a molecular defect in one of nthe proteins in the cytoskeleton of the RBC membrane, leading to a loss of nmembrane and hence decreased ratio of surface area to volume and consequently nspherocytosis. This disorder usually has an autosomal dominant inheritance npattern and an incidence of approximately 1:1000 to 1:4500. In ~20% of npatients, the absence of hematologic abnormalities in family members suggests neither autosomal recessive inheritance or a spontaneous mutation. The disorder nis sometimes clinically apparent in early infancy but often escapes detectiountil adult life.

 

 

Peripheral smear showing classic spherocytes with loss of ncentral pallor in the erythrocytes.

 

Bllod cells of different shane (drepanocytes n0 circle cell (left)

 

 

Bllod cells of different shape (drepanocytes n0 tear drop)

 

Bllod cells of different shane (echinocyre n(left), stomatocyte

 

 

Bllod cells of different shane (shistocyte n(left), acanthocyte

 

 

CLINICAL MANIFESTATIONS  The major nclinical features of hereditary spherocytosis are anemia, splenomegaly, and njaundice. The prominence of jaundice accounts for the disorder’s prior ndesignation as “congenital hemolytic jaundice” and is due to aincreased concentration of unconjugated (indirect-reacting) bilirubin iplasma. Jaundice may be intermittent and tends to be less pronounced in early nchildhood. Because of the increased bile pigment production, pigmented ngallstones are common, even in childhood. Compensatory erythroid hyperplasia of nthe bone marrow occurs, with the extension of red marrow into the midshafts of nlong bones and occasionally with extramedullary erythropoiesis, at times nleading to the formation of paravertebral masses visible on chest x-ray. nBecause the bone marrow’s capacity to increase erythropoiesis by six- to neightfold exceeds the usual rate of hemolysis, anemia is usually mild or nmoderate and may even be absent in an otherwise healthy individual. nCompensation may be temporarily interrupted by episodes of relative erythroid nhypoplasia precipitated by infections, particularly parvovirus, trauma, nsurgery, and pregnancy. Splenomegaly is very common. The hemolytic rate may nincrease transiently during systemic infections, which induce further splenic nenlargement. Chronic leg ulcers, similar to those observed in sickle cell nanemia, occur occasionally.

The characteristic erythrocyte abnormality is the spherocyte. The meacorpuscular volume (MCV) is usually normal or slightly decreased, and the meacorpuscular hemoglobin concentration (MCHC) is increased to 350 to 400 g/L. nSpheroidicity may be quantitatively assessed by measurement of the osmotic nfragility of the RBC on exposure to hypoosmotic solutions causing a net influx nof water. Because spherocytes have a decreased surface area per unit volume, nthey are able to take in less water and hence lyse at a higher concentration of nsaline thaormal cells. On microscopic examination, spherocytes are usually ndetected as small cells without central pallor. They will ordinarily not ninfluence the osmotic fragility test unless they constitute more than 1 or 2% nof the total cell population. The autohemolysis test, which measures the amount nof spontaneous hemolysis occurring after 48 h of sterile incubation, is also nuseful.

 

 

Peripheral smear that shows evidence of nhereditary pyropoikilocytosis.

 

Heinz body (Glucose-6-Phosphate nDehydrogenase Deficiency)

 

Sickle cell anemia is an inherited nblood disease in which the red blood cells produce abnormal pigment n(hemoglobin). The abnormal hemoglobin causes deformity of the red blood cells ninto crescent or sickle-shapes, as seen in this photomicrograph.

 

Elliptocytosis is a hereditary ndisorder of the red blood cells (RBCs). In this condition, the RBCs assume aelliptical shape, rather than the typical round shape.

 

Spherocytosis is a hereditary ndisorder of the red blood cells (RBCs), which may be associated with a mild nanemia. Typically, the affected RBCs are small, spherically shaped, and lack nthe light centers seen iormal, round RBCs.

 

Sickle cell anemia is an inherited ndisorder in which abnormal hemoglobin (the red pigment inside red blood cells) nis produced. The abnormal hemoglobin causes red blood cells to assume a sickle nshape, like the ones seen in this photomicrograph.

 

Red blood cells (RBCs) are normally nround. In ovalocytosis, the cells are oval. Other conditions that produce nabnormally shaped RBCs include spherocytosis and eliptocytosis.

 

These crescent or sickle-shaped red nblood cells (RBCs) are present with Sickle cell anemia, and stand out clearly nagainst the normal round RBCs. These abnormally shaped cells may become nentangled and block blood flow in the small blood vessels (capillaries).

 

This photomicrograph of red blood ncells (RBCs) shows both sickle-shaped and pappenheimer bodies.

 

These abnormal red blood cells (RBCs) nresemble targets. These cells are seen in association with some forms of nanemia, and following the removal of the spleen (splenectomy).

 

 

Peripheral nsmear showing multiple inclusion bodies inside the red blood cells.

 

This bone marrow film at 400X magnification demonstrates a ncomplete absence of hemopoietic cells. Most of the identifiable cells are nlymphocytes or plasma cells. Photographed by U. Woermann, MD, Division of nInstructional Media, Institute for Medical Education, University of Bern, Switzerland.

 

TREATMENT

Splenectomy reliably corrects the anemia, although the RBC defect and nits consequent morphology persist. The operative risk is low. RBC survival nafter splenectomy is normal or nearly so; if it is not, an accessory spleen or nanother diagnosis should be sought. Because of the potential for gallstones and nfor episodes of bone marrow hypoplasia or hemolytic crises, splenectomy should nbe performed in symptomatic individuals; cholecystectomy should not be nperformed without splenectomy, as intrahepatic gallstones may result. nSplenectomy in children should be postponed until age 4, if possible, to nminimize the risk of severe infections with gram-positive encapsulated norganisms. Polyvalent pneumococcal vaccine should be administered at least 2 nweeks before splenectomy. In patients with severe hemolysis, folic acid (1 nmg/d) should be administered prophylactically.

 

ACQUIRED HEMOLYTIC ANEMIAS

In most patients with acquired hemolytic anemia, RBC are made normally nbut are prematurely destroyed because of damage acquired in the circulation. n(The exceptions are rare disorders characterized by acquired dysplasia of the ncells of the bone marrow and the production of structurally and functionally nabnormal RBC.) The damage that occurs may be mediated by antibodies or toxins nor may be due to abnormalities in the circulation, including an overactive nmononuclear phagocyte system or traumatic lysis by natural or artificial nimpediments to circulation. The acquired hemolytic anemias can be classified ninto five categories (Table 4).

 

Hypersplenism  The spleen is particularly efficient in trapping and ndestroying RBC that have minimal defects. This unique ability of the spleen to nfilter mildly damaged RBC results from its unusual vascular anatomy. Almost all nthe blood circulating through the spleen flows rapidly from arterioles in the nwhite pulp to sinuses in the spleen’s red pulp and then into the venous system. nIn contrast, a small portion of splenic blood flow (normally 1 to 2%) passes ninto the “marginal zone” of the lymphatic white pulp. Although the ncells that occupy this zone are not phagocytic, they serve as a mechanical nfilter that hinders the progress of severely damaged blood cells. As RBC leave nthis zone and enter the red pulp, they flow into narrow cords, rich imacrophages, that end blindly but communicate with sinuses through small nopenings between the lining cells of the sinuses. These openings, averaging 3 num in diameter, test the ability of RBC (4.5 um in diameter) to undergo a ndeformation. RBC that cannot re-enter the vascular sinuses are engulfed by nphagocytic cells and destroyed.

The normal spleen retains reticulocytes for 1 to 2 days but otherwise nposes no threat to normal RBC until they become senescent. However, in the face nof splenomegaly, increased destruction of the cells of the blood, including the nRBC, may take place due to pooling of the blood in a relatively nutrient-poor nenvironment full of phagocytic cells. When splenic sequestration causes ncytopenia, hypersplenism is diagnosed. In infiltrative diseases of the spleen, nsubstantial splenomegaly may exist with no apparent hemolysis; inflammatory and ncongestive splenomegaly is commonly associated with modest shortening of RBC nsurvival time, along with more marked granulocytopenia and thrombocytopenia. nPatients with cytopenia(s) sufficient to produce symptoms generally benefit nfrom splenectomy.

Immunologic nCauses of Hemolysis  Immune hemolysis in the adult is usually induced by IgG or nIgM antibodies with specificity for antigens associated with the patient’s RBC n(often called “autoantibodies”) (Table 4); rarely, transfused RBC may nbe hemolyzed by alloantibodies directed against foreign antigens on those ncells.

The Coombs nantiglobulin test is the major tool for diagnosing autoimmune hemolysis. This ntest relies on the ability of antibodies specific for immunoglobulins n(especially IgG) or complement components (especially C3) to agglutinate RBC nwhen these proteins are present on the RBC. The direct Coombs test measures the nability of anti-IgG or anti-C3 antisera to agglutinate the patient’s RBC. The npresence or absence of IgG and/or C3 may help define the origin of the immune nhemolytic anemia (Table 4). Rarely, neither IgG nor complement may be found othe RBC of the patient (Coombs-negative immune hemolytic anemia).

Antibodies to nparticular RBC antigens in the serum of the patient can be detected by reacting nthe serum with normal RBC bearing the antigen. IgM antibodies (usually cold-reacting) nmay be detected by agglutination of normal or fetal RBC. IgG antibodies may be ndetected by the indirect Coombs test, in which the serum of the patient is nincubated with normal RBC and antibody is detected with anti-IgG, as in the ndirect Coombs test.

“Warm” nantibodies  Antibodies that react with protein antigens are nearly always IgG nand react at body temperature; occasionally, they are IgA and rarely IgM. nHemolysis due to autologous antibodies is called autoimmune hemolytic (or nimmunohemolytic) anemia, warm antibody type.

 

CLINICAL MANIFESTATIONS  Immunohemolytic anemia of the nwarm antibody type is induced by IgG antibody and occurs at all ages, but it is nmore common in adults, particularly women. In approximately one-fourth of npatients this disorder occurs as a complication of an underlying disease naffecting the immune system, especially lymphoid neoplasms; collagen vascular ndiseases, especially systemic lupus erythematosus (SLE); and congenital nimmunodeficiency diseases (Table 5). In the initial evaluation of the patient, ndrugs that are known to cause immunohemolytic anemia must be ruled out (see nbelow). The presentation and course of IgG immunohemolytic anemia are quite nvariable. In its mildest form, the only manifestation is a positive direct Coombs ntest. In this instance, insufficient antibody is present on the RBC surface to npermit the reticuloendothelial system to recognize the cell as abnormal.

Most symptomatic patients have a moderate to severe anemia [hemoglobilevels 60 to 100 g/L and reticulocyte counts 10 to 30% (200 to 600 ґ n103/uL)], spherocytosis (Plate V-8), and splenomegaly.

Severe immunhemolytic anemia presents with fulminant hemolysis nassociated with hemoglobinemia, hemoglobinuria, and shock; this syndrome may be nrapidly fatal unless aggressively treated.

The direct Coombs test is positive in 98% of patients; usually IgG is ndetected with or without C3. Rarely, the cells may be agglutinated by the nantibody, causing difficulty in analysis by flow cytometry.

Immune thrombocytopenia also may be present (Evans’s syndrome), a ndisorder in which separate antibodies are directed against platelets and RBC. nOccasionally, venous thrombosis occurs.

 

TREATMENT

Patients having a mild degree of hemolysis usually do not require ntherapy. In those with clinically significant hemolysis, initial therapy nconsists of glucocorticoids (e.g., prednisone, 1.0 mg/kg per day). A rise ihemoglobin is frequently noted within 3 or 4 days and occurs in most patients nwithin 1 to 2 weeks. Prednisone is continued until the hemoglobin level has nrisen to normal values, and thereafter it is tapered rapidly to about 20 mg/d, nthen slowly over the course of several months. An algorithm for this tapering nprocess is given in Fig. 108-4. For chronic therapy with prednisone, alternate-day nadministration is preferred. More than 75% of patients achieve an initial nsignificant and sustained reduction in hemolysis; however, in half these npatients the disease recurs, either during glucocorticoid tapering or after its ncessation. Glucocorticoids have two modes of action: an immediate effect due to ninhibition of the clearance of IgG-coated RBC by the mononuclear phagocyte nsystem and a later effect due to inhibition of antibody synthesis. Splenectomy nis recommended for patients who cannot tolerate or fail to respond to nglucocorticoid therapy.

Patients who have been refractory to glucocorticoid therapy and to nsplenectomy are treated with immunosuppressive drugs such as azathioprine and ncyclophosphamide. A success rate of ~50% has been reported with each. nIntravenous gamma globulin may cause rapid cessation of hemolysis; however, it nis not nearly as effective in this disorder as in immune thrombocytopenia.

Patients with severe anemia may require blood transfusions. Because nthe antibody in this disease is usually a “panagglutinin,” reacting nwith nearly all normal donor cells, cross-matching is impossible. The goal iselecting blood for transfusion is to avoid administering RBC with antigens to nwhich the patient may have alloantibodies. A common procedure is to adsorb the npanagglutinin present in the patient’s serum with the patient’s own RBC from nwhich antibody has been previously eluted. Serum cleared of autoantibody cathen be tested for the presence of alloantibody to donor blood groups. nABO-compatible RBC matched in this fashion are administered slowly, with nwatchfulness for signs of an immediate-type hemolytic transfusion reaction.

 

PROGNOSIS

 In most patients, hemolysis is controlled by glucocorticoid therapy nalone, by splenectomy, or by a combination. Fatalities occur among three rare nsubsets of patients:

 (1) those with overwhelming hemolysis who die from anemia;

(2) those whose host defenses are impaired by glucocorticoids, nsplenectomy, and/or immunosuppressive agents;

(3) those with major thrombotic events coincident with active nhemolysis.