Clinical Presentation and Management of Hemolytic Anemias

September 3, 2002

The hallmark of hemolysis is shortened red blood cell survival in the peripheral blood. Hemolysis results in anemia only when bone marrow cannot keep up with the rate of red cell destruction. Even though anemia is very commonly observed in most cancer patients, hemolytic anemias are rather rare.

ABSTRACT: The hallmark of hemolysis is shortened red blood cell survival in the peripheral blood. Hemolysis results in anemia only when bone marrow cannot keep up with the rate of red cell destruction. Even though anemia is very commonly observed in most cancer patients, hemolytic anemias are rather rare. Acute or chronic hemolysis, when present can impact on quality of life adversely, especially when bone marrow has limited compensation capacity. The underlying etiologies and pathophysiologies of the varying types of hemolytic anemias differ vastly, and there are numerous disorders causing red blood cell destruction that result in a similar clinical presentation. Careful review of the peripheral blood smear can provide invaluable information in diagnosing the underlying disorder. The majority of the nonhemolytic anemias have a chronic and stable course. In hemolytic disorders, however, the severity of the hemolysis can also create life-threatening emergencies. Management of hemolytic anemias depend on the diagnosis. Thus clinicians often face added pressure to determine the causative disorder rapidly so that timely interventions can be planned. Thus, even though they are not very common, hemolytic anemias remain a big challenge in the practice of hematology and oncology. [ONCOLOGY 16(Suppl 10):163-170, 2002]

In hemolytic disorders,the normal life span of erythrocytes inthe peripheral blood of 120 days is substantially shortened because of red celldestruction. As a compensatory mechanism, there is increased red blood cell (RBC)production by the bone marrow. Under normal conditions, the bone marrow canincrease its capacity for RBC generation severalfold in response to anemia.[1]Shortening of RBC life span does not lead to anemia until a relative bone marrowfailure follows with an inability of the marrow to keep up with the loss.Proportional increases in both destruction and generation of RBCs can result incompensated hemolysis without significant anemia. Some of the earliestobservations of hemolysis have been the visualization of red-pink urine inpatients with such rare conditions as paroxysmal cold hemoglobinuria, marchhemoglobinuria, or paroxysmal nocturnal hemoglobinuria (PNH).

Classification and Pathogenesis

Hemolytic anemias can be categorized as acute or chronic,inherited or acquired, by the site of hemolysis (intravascular or extravascular),or by the location of the abnormality responsible for the hemolysis (intrinsicor extrinsic to the red cell). The distinction between inherited and acquired isprobably the most useful clinically. Most intrinsic defects are inherited, andmost extrinsic ones are acquired. Exceptions to this rule are few and includeparoxysmal nocturnal hemoglobinuria (acquired intrinsic RBC defect), and G6PDdeficiency (inherited intrinsic defect that depends on an extrinsic factor suchas drugs to become evident).

Inherited intrinsic RBC disorders can be due to impairmentsin membrane structure, glycolytic pathway, glutathione metabolism, hemoglobinstructure, or other rare enzyme defects. The acquired hemolytic anemias can bedivided into antibody induced, physical injury related, or due to infection,physical agents, chemical agents, hypophosphatemia and liver disease.

The site of hemolysis may be intravascular, in which case theerythrocyte is destroyed in the circulation, or extravascular, in which case thered cell destruction occurs within macrophages in the spleen, liver, or bonemarrow (see Table 1). Intravascular hemolysis is typically severe and resultsfrom mechanical damage to the red cell due to prosthetic valves, the presence offibrin within the vasculature (microangiopathic hemolytic anemia), or thermalinjury to the erythrocytes from serious burns; infections or toxins, such as Clostridiumperfringens bacteremia, severe falciparum malaria, or certain snake venoms;or complement-mediated damage to red cells, as with paroxysmal nocturnalhemoglobinuria, ABO-incompatible blood transfusions, and cold agglutinins.

Intravascular hemolysis liberates hemoglobin into thebloodstream, where it binds to haptoglobin. The haptoglobin/hemoglobin complexis then removed by the liver. A reduced serum haptoglobin level is one of manyfindings in intravascular hemolysis, but it also occurs in extravascularhemolysis. When the amount of free hemoglobin in the circulation exceeds thebinding capacity of haptoglobin, it makes the plasma pink and is filteredthrough the kidneys. The urine may become red, and proves positive for bloodupon dipstick testing in the absence of erythrocytes on urine microscopy. Therenal tubular cells, which reabsorb some of the hemoglobin and convert it tohemosiderin, are shed into the urine. Iron stains of urinary sedimentdemonstrate the hemosiderin within these renal tubular cells and confirm ongoingor recent intravascular hemolysis, even when hemoglobin has become undetectablein the plasma or urine.

Most hemolytic disorders are extravascular. The causes ofextravascular hemolysis include infections, drugs, or immunologic processes;red cell membrane defects, such as hereditary spherocytosis; erythrocytemetabolic defects, such as deficiencies in pyruvate kinase or G6PD; andhemoglobin structural defects, such as sickle cell anemia or hemoglobin C.

Another classification of hemolytic anemias distinguishesbetween disorders intrinsic to the red cell, generally hereditary, and thoseextrinsic to the red cell, generally acquired. The intrinsic disorders includeabnormal hemoglobins, such as HbS or HbC; enzyme defects, such as deficienciesin G6PD; and membrane abnormalities, such as hereditary spherocytosis orelliptocytosis. The extrinsic abnormalities are immunologic—alloantibodies,such as those associated with ABO incompatibility; autoantibodies, as in warm (IgG)or cold (IgM) antibody hemolytic anemias; drug-induced antibodies; mechanicalfactors, such as trauma from prosthetic valves or fibrin deposition in smallvessels, as in microangiopathic hemolytic anemias; infections and toxins, suchas falciparum malaria or certain snake venoms; and severe hypophosphatemia. See Table 2 for the causes of hemolysis broken down by the site of abnormality.

Clinical Aspects

Chronic CongenitalHemolytic Anemias

Even though there are numerous congenital hemolyticdisorders, their clinical features are very similar. Chronic congenitalhemolytic anemias are usually characterized by anemia, jaundice, periodiccrises, splenomegaly, and black pigment gallstones.[2] Other than during acrisis, symptoms are usually mild to moderate because of compensation by severalorgan systems, including the bone marrow. Chronic symptoms may become severe attimes of crisis. Aplastic crisis can be induced by infection with humanparvovirus type B19 (fifth disease).[3] The presence of the parvovirus-specificIgM antibody in serum is a marker of recent infection. A single infectionresults in lifelong immunity (IgG). The virus infects and inhibits proliferationof erythroid progenitors, only in the bone marrow (very low reticulocyte count).

The clinical picture can also worsen with increased RBCdestruction (splenic crisis) or folate deficiency (megaloblastic crisis). Legulcers can be seen with chronic hemolytic disorders, especially with hereditaryspherocytosis and sickle cell anemia. When hemolysis is severe during growth anddevelopment, as in thalassemia major, marked expansion of the bone marrow maylead to skeletal changes such as tower-shaped skull, thickening of the frontaland parietal bones, dental abnormalities, and other bony distortions.[4]

Acquired Hemolytic Anemias

If hemolytic anemia develops acutely, as in hemolytictransfusion reaction or G6PD deficiency, the symptoms may suggest an acutefebrile illness with skeletal pains, headache, malaise, fever, and chills.[5]Symptoms of shock, renal failure, jaundice, and anemia may be evident in severecases. Usually, however, the symptoms are more gradual and mimic a congenitalhemolytic disease. In other patients, symptoms may be more related to theunderlying disease, such as lupus, lymphoma, and mycoplasma infection.

Laboratory Observations

Laboratory abnormalities seen with hemolysis can be traced toincreased RBC destruction, increased erythropoiesis by the bone marrow, anddisease-specific findings.

When RBCs are destroyed at an accelerated rate, bile pigmentsand carbon monoxide are excreted more than usual. The unconjugated bilirubin iselevated, accounting for more than 80% of the total bilirubin, and is notexcreted in the urine. Total bilirubin usually does not exceed 4 to 5 units withhemolysis.[6] Unlike in liver disease, in patients with hemolysis pruritus isusually absent. Fecal urobilinogen excretion increases as an indicator ofincreased bilirubin metabolism in the liver. When plasma hemoglobin levelsexceed haptoglobin binding capacity, the plasma turns pink and is filtered intothe urine. The urine becomes red and urine iron levels increase. Other thanhemolysis, only in hemochromatosis and nephrotic syndrome can one detectincreased urinary iron levels.[7,8]

In hemolytic anemias the reticulocyte count is elevated; thisis an indicator of accelerated erythropoiesis. Low reticulocyte count isencountered during aplastic crisis despite hemolysis. The mean corpuscularvolume (MCV) may be normal or increased, depending on how many large, immatureerythrocytes have prematurely left the bone marrow in response to the anemia.The serum lactate hydrogenase (LDH) level is increased. Of the LDH isozymes,LDH-2 predominates; in megaloblastic conditions LDH-1 is elevated. LDH valueslack specificity in hemolysis because many other conditions can result in highlevels.

The serum haptoglobin is commonly diminished. Free hemoglobinin the bloodstream binds to haptoglobin. Haptoglobin/hemoglobin complex is thenremoved by the liver. Haptoglobin is an acute-phase reactant and levels increasein response to inflammation, infection, and malignancy. Haptoglobin levelsdecrease in association with not only intravascular hemolysis but also withextravascular hemolysis (sickle cell anemia, RBC membrane, and enzymedisorders), and intramedullary hemolysis (megaloblastic anemia).[9] One needs tobe aware of nonhemolytic conditions that can result in low haptoglobin levels(liver disease, hereditary haptoglobin deficiency after red cell transfusions),and normalized haptoglobin levels despite hemolysis (acute phase surges) duringwork-up of such patients. Glycosylated hemoglobin levels are also reduced inresponse to hemolysis, and usually reflect hemolysis over the past 4 to 8weeks.[10] Glycosylated hemoglobin levels are not reliable in patients withdiabetes mellitus because of high glucose levels and in patients with anemia dueto bleeding because of hemoglobin loss.

Blood smear is the single most valuable test in defining theunderlying disorder causing hemolysis. Spherocytes are the hallmark ofhereditary spherocytosis, sickle cells of sickle cell anemia, target cells ofthalassemia, schistocytes of RBC fragmentation, erythrophagocytosis of red cellsurface damage by complement-fixing antibodies and infections, autoagglutination of cold agglutinin disease, and elliptocytes of hereditaryelliptocytosis. Morphologic findings of hemolysis can be confirmed on a bloodsmear; this may be very helpful in demonstrating polychromatophilia andnucleated red cells, confirming the early departure of red cells from the bonemarrow. Abnormalities in red cell shape, such as fragments, sickle cells,spherocytes, or bite cells, provide clues regarding etiology that may bediagnostic or at least highly suggestive of the cause. Other suggestive findingsinclude red cell agglutination, indicating IgM-mediated disease; organisms suchas Plasmodium falciparum or Babesia; and erythrophagocytosis, seenespecially with red cell damage from immune mechanisms but also with certaininfections or toxins. The bone marrow usually shows erythroid hyperplasia.

Tests useful in suspected intravascular hemolysis includeevaluation of the plasma and urine for hemoglobin and an iron stain of the urinesediment to detect hemosiderin. For immune-related hemolytic anemia, the Coombstest to demonstrate IgG and complement on the red cell or in the serum, and thecold agglutinin test looking for IgM are indicated. A positive Coombs test(direct antiglobulin test [DAT]) indicates that RBCs are coated with IgG orcomplement, hence an immune etiology for hemolysis. Very rarely a DAT will benegative in immune hemolytic anemia if the amount of globulin on the RBC surfaceis very low.[11]

With suspected hemoglobinopathies, a hemoglobinelectrophoresis is appropriate. An osmotic fragility test may help whenhereditary spherocytosis is suspected.[12] Special stains on blood smear toidentify Heinz body formation (precipitation of hemoglobin to form inclusions)can help identify patients with G6PD deficiency, unstable hemoglobin disease,and thalassemia. Other laboratory evaluations depend on the likely abnormalityand may include searching for rare enzyme defects. The following is a briefreview of some of the major categories of hemolytic disorders.

RBC Membrane Disorders

Hereditary Spherocytosis

Hereditary spherocytosis is a quantitative defect in the RBCmembrane resulting in an aberrant vertical interaction between the skeleton andlipid bilayer. The abnormal red cell membrane is partially digested by themacrophages giving rise to spherocytes, hemolysis, and splenomegaly. Patientshave lifelong hemolysis. Diagnosis is established by peripheral smear findingsand an osmotic fragility test. Patients with symptomatic disease can be treatedwith splenectomy.

Hereditary Elliptocytosis

Hereditary elliptocytosis is caused by horizontal defects inthe RBC membrane. It is usually a milder disease than hereditary spherocytosis.

Acanthocytosis

Acanthocytosis is usually seen with chronic liver disease,and is the result of cholesterol accumulation in the red cell membrane.

RBC Metabolic Disorders

Pyruvate Kinase Deficiency

Pyruvate kinase deficiency is a rare hemolytic disordercaused by abnormalities in the glycolytic pathway. Patients usually have chronichemolysis without acute events.

G6PD Deficiency

G6PD deficiency is a more common disorder mostly affectingmales (only rarely females). Hemolysis and anemia occur only under variousstress conditions such as infection, metabolic problems, drugs, and favism.Acute intravascular hemolysis, Heinz body development, and bite cells are thecharacteristics of the disease.

Wilson’s Disease

Wilson’s disease is characterized by neurologic symptoms,hemolysis, hepatomegaly, low ceruloplasmin levels and copper overload. Hemolysisoccurs as a result of inhibition of glycolysis.

Congenital Hemoglobinopathies

Sickle Cell Anemia

Sickle cell anemia, the most common hemoglobinopathy, occurswith the inheritance of a beta gene from each parent. This gene, which encodesthe beta-globin subunit of hemoglobin, is most prevalent in the populations oftropical Africa, but also occurs in people from Mediterranean countries, SaudiArabia, and portions of India.[13] In the United States, the gene is present inabout 8% of blacks and, accordingly, sickle cell anemia (the homozygous state)occurs in about 1 of 625 black infants.[14]

Because of a single substitution of an amino acid in thisgene abnormality, the hemoglobin produced differs from hemoglobin A in having avaline, rather than glutamic acid, in the sixth position from the N terminal ofthe beta chain. This results in beta-globin tetramers that tend to aggregate.The disease is not evident during intrauterine life because beta chain synthesisbegins after birth. When deoxygenated, this abnormal hemoglobin aggregates intolarge fibers that make the red cell rigid and give it the classic sickle cellshape. In addition, damage to the erythrocyte membrane occurs, producingdehydrated, shrunken cells that may permanently sickle. These factors lead tochronic hemolysis.

Sickle cell trait is caused by having one mutated gene andone normal gene. In patients with sickle cell trait, hemoglobin electrophoresisusually reveals about 60% hemoglobin S and 30% hemoglobin A. In the homozygousstate, about 90% is hemoglobin S.

When the deoxygenated, abnormal cells adhere to the vascularendothelium, they can obstruct the circulation, leading to ischemia or necrosisof areas that these vessels supply. Such vascular occlusion accounts for most ofthe clinical features of this disease. One manifestation is painful crises,which commonly last 4 to 5 days and may involve any tissue but especially theskeleton, abdomen, and chest. Involvement of vessels to the bones causesprogressive discomfort, especially in the humerus, tibia, and femur, but alsothe ribs, causing thoracic pain. Sometimes vascular occlusion causes marrownecrosis and the release of fat particles (emboli) that travel to the lung orother areas. Abdominal crises probably arise from infarcts to the mesentery andabdominal organs, including the spleen.

Some acute events can cause sudden worsening of anemia. Inaplastic crises fever occurs and red cell production markedly diminishes,resulting in a rapid decrease in circulating erythrocytes as the chronichemolysis continues. The most common cause is infection with parvovirus B19,which directly damages the erythroid precursors. Patients typically recover in 5to 10 days. A megaloblastic crisis can also develop, in which folate deficiencyfrom inadequate nutrition or concurrent alcoholism decreases erythropoiesis.Bone marrow infarction, chronic renal failure, and iron deficiency can alsocontribute to the degree of anemia.

Early in life, the dorsa of the hands and feet can swell (dactylitis),often accompanied by fever and leukocytosis; the mechanism is probably avascularnecrosis of the bones. Children may also experience episodes of acute splenicsequestration in which red cells abruptly accumulate in the spleen, causingpain, splenic enlargement, and increased anemia. As patients age, the spleenbecomes shrunken, scarred, and nonfunctional because of repeated infarcts, andsequestration no longer occurs.

Another sudden event is the acute chest syndrome,characterized by fever, shortness of breath, chest pain, leukocytosis, andpulmonary infiltrates. Acute chest syndrome is often self-limited, but onoccasion can lead to severe pulmonary failure and death. Several entities cancause this condition, including infections, pulmonary vascular occlusion, andfat emboli. In some cases the chest pain arises from rib infarcts.

Central nervous system crises can manifest as stroke,bleeding, or seizures, especially in children, and they tend to recur. Thepredominant cause is occlusion of the major cerebral vessels, but sometimes theyarise from subarachnoid or intracerebral hemorrhage. Priapism can develop inboth pre- and postpubertal males. Episodes are usually short-lived but oftenrecurrent, and occur from stagnation of blood in the corpora cavernosa. Repeatedepisodes may lead to fibrosis and impotence.

With repetitive episodes or chronic ischemia, permanenttissue damage can occur in many other locations. Avascular necrosis of thefemoral head causes persistent pain and abnormal gait, and involvement of thehumeral head typically produces protracted shoulder discomfort. Ischemic ornecrotic bone predisposes to osteomyelitis, especially from Salmonellaspecies. Damage to the kidneys can produce an inability to concentrate the urinenormally (hyposthenuria) and impair excretion of hydrogen ion (renal tubularacidosis). Hematuria may occur, sometimes associated with renal papillarynecrosis, which also predisposes to urinary infections. Sloughing of thepapillae can lead to urinary tract obstruction.

Eye complications include proliferative retinopathy becauseof chronic ischemia, visual loss, and vitreous hemorrhage. Persistent orrecurrent painful ulcers sometimes form over the distal leg, especially abovethe malleoli, usually in adulthood. These ulcers are more common in males thanin females and typically have a deep base with raised margins. Another commonfinding in older patients is bilirubin gallstones, a complication of chronichemolysis.

Sickle cell anemia predisposes patients to infections, notonly because of the presence of ischemic or necrotic tissues but also because ofdecreased splenic function, which impairs antibody production and splenicphagocytosis of organisms. The alternate complement pathway may also be faulty.In childhood the most common serious infections are from Streptococcuspneumoniae.

The anemia is normochromic, normocytic, and associated with ahematocrit typically in the range of 15% to 33%. Mild leukocytosis, withincreased neutrophils, and thrombocytosis are common. The reticulocyte count isusually 10% to 20%. The blood film characteristically demonstrates thecrescent-shaped sickle cells, target cells, polychromasia, basophilic stippling,macrocytosis (due to large immature red cells), and nucleated red cells. Exceptin very young children, Howell-Jolly bodies are usually seen, indicating splenichypofunction from recurrent infarctions and splenic fibrosis. The presence ofmacrocytes, polychromasia in several erythrocytes, and the nucleated red cellsindicate early release of erythrocytes from the bone marrow secondary to asevere anemia.

Vaccinating to prevent infections, optimizing vitamin andiron levels, managing pain during painful crises, and maintaining adequatehydration and oxygen support are the principles of treatment for patients withsickle cell anemia. Exchange transfusion is usually considered in patients withcentral nervous system crisis, acute chest syndrome, embolism, refractorypriapism, ocular events, complicated pregnancy, and pending major medicalprocedures that may induce a severe crisis. Hydroxyurea treatment can reducepain crises, chest syndrome, and transfusion needs.

Hemoglobin C Disease

Hemoglobin C disease is the result of a mutation in the beta-globin.Hemoglobin C occurs commonly in West Africans and in about 2% to 3% ofAfrican-Americans. Patients may be homozygous (CC), heterozygous with normalhemoglobin A (hemoglobin C trait), heterozygous with sickle cells (SC disease),or heterozygous with beta-thalassemia. Red cells containing hemoglobin C areabnormally rigid, and their fragmentation may lead to microspherocytes. Theirlife span is shortened to about 30 to 35 days.

In patients with hemoglobin C trait, anemia is absent. Bloodsmears show increased target cells and sometimes hypochromic, microcyticerythrocytes. Hemoglobin electrophoresis typically demonstrates that 30% to 40%of the hemoglobin is type C and 50% to 60% is type A.

In homozygous (CC) disease, splenomegaly is usually present.Both aplastic crises and cholelithiasis may occur. Mild to moderate hemolyticanemia is present, with hematocrit being about 20% to 30% and reticulocyte counttypically 2% to 6%. The erythrocytes may be microcytic and are usually dense, asdetected in an increased mean corpuscular hemoglobin concentration. Target cellsare abundant, and numerous small, dense, and irregularly shaped red cells arepresent. Crystals of oxygenated hemoglobin C are sometimes visible on peripheralsmears as brick-shaped objects, usually within an erythrocyte otherwise devoidof hemoglobin. Polychromatophilia and nucleated red cells, consistent withhemolysis, may be apparent. On electrophoresis, hemoglobin C predominates, A isabsent, and F is slightly increased.

With hemoglobin C/beta-thalassemia, mild to moderatehemolytic anemia is typical. The blood smear shows microcytosis, hypochromia,target cells, and the small, irregular erythrocytes described above. HemoglobinC crystals may be visible as well. Electrophoresis typically demonstrates 65% to80% hemoglobin C, 20% to 30% hemoglobin A, and 2% to 5% hemoglobin F.

Hemoglobin SC Disease

Although the red cells in hemoglobin SC disease sickle,causing vascular occlusion, this disorder is milder than sickle cell disease,and life expectancy is nearly normal. It occurs in about 1 in 800 black infantsin the United States. Acute painful episodes (crises) are less frequent andtypically shorter than in sickle cell disease. Aseptic necrosis of the humeraland femoral heads, however, may occur. The spleen is usually enlarged and,although susceptible to infarcts, does not become obliterated as in sickle celldisease. Patients with SC disease may suddenly develop the acute splenicsequestration syndrome, especially when at high altitudes: red cells rapidlyaccumulate in the spleen, causing abdominal pain, progressive splenicenlargement with tenderness, and abrupt decreases in hematocrit, sometimesproducing shock.

Patients have a mildly enhanced susceptibility to infections,primarily with Streptococcus pneumoniae and Hemophilus influenzae.Spontaneous abortions are increased, but the leg ulcerations and neurologicalcomplications seen in sickle cell disease are uncommon. Proliferativeretinopathy, however, is more frequent in sickle cell disease than in sicklecell anemia.

The hematocrit typically exceeds 27%, and the red cells areusually normocytic, but denser than normal, with an increased mean corpuscularhemoglobin concentration characteristic of erythrocytes containing hemoglobin C.Target cells are numerous. "Billiard ball" cells, in which a roundmass of hemoglobin appears in the erythrocyte with a clear space separating themass from the red cell membrane, are a characteristic finding. The erythrocytesare often dense and disfigured, sometimes with branching projections, and theymay contain clusters of hemoglobin C crystals of various sizes and shapes, whichcreate straight edges and blunt angles. Sickle cells, boat-shaped cells, andnucleated red cells are other findings. Polychromasia may be present, and inthose with functional asplenia, Howell-Jolly bodies are visible. Hemoglobinelectrophoresis reveals about equal amounts of hemoglobin C and hemoglobin S.

Hemoglobin E Disease

Hemoglobin E disease is the second most prevalenthemoglobinopathy, and it is mostly seen in Southeast Asia. Patients are usuallyasymptomatic with mild anemia, markedly low mean corpuscular volume levels andhigh numbers of target cells.

Thalassemias

Mutations or deletions in one globin gene lead toquantitative deficiency of that chain causing an imbalance between alpha andbeta chains. In alpha-thalassemia, one through four of the four alpha genes aredeleted, the number of genes deleted directly correlates with the severity ofthe disease. When all four alpha genes are deleted neonatal death occurs (hydropsfetalis). In beta-thalassemia, on the other hand, there is no intrauterinedisease because beta chain synthesis begins with birth. Beta-thalassemiapatients can have thalassemia trait, intermedia, or major types depending on thelevel of hemoglobin A synthesis. Further details of laboratory and clinicalaspects of thalassemias are beyond the scope of this review.

Red Cell Fragmentation Syndromes

Shear forces within the cardiovascular system can slice offportions of the circulating red cells.[15] The erythrocytes then seal theirmembranes to form fragmented cells (schistocytes). Injured red cells may appearas triangles, helmet cells, microspherocytes, crescents, or other irregularlyshaped erythrocytes that phagocytes remove prematurely from the circulation. Theamount of red cell destruction may be sufficient to cause intravascularhemolysis, with hemoglobinemia, hemoglobinuria, and the presence of hemosiderinin the urine. The erythrocyte damage can occur in the heart and great vessels orin the microcirculation.

The most common cardiac etiology is the presence of aprosthetic valve, usually a mechanical device in the aortic position, oftenassociated with regurgitation. Occasionally, the abnormality is severe aorticstenosis of a native valve, coarctation of the aorta, or an intracardiac patchmade from artificial material used to correct anomalies such as septal defects.In each of these situations, excessive turbulence damages the erythrocytes. Withchronic mild hemolysis anemia is absent or slight, the red cells are normal orshow some macrocytosis from the presence of immature cells, polychromatophiliais present, and the reticulocyte count is elevated. With more severe hemolysis,erythrocyte fragments appear on the blood smear, the anemia is moderate toprofound, the serum bilirubin and LDH levels rise, haptoglobin decreases, andhemosiderin appears in the urine. With protracted intravascular hemolysis,urinary hemoglobin loss may cause iron deficiency, with hypochromic, microcytic
red cells.

When diseases affecting the small vessels produce fragmentedred cells, the term used is microangiopathic hemolytic anemia. In thesedisorders, endothelial damage or fibrin deposition in the small vessels damagesthe red cells as they traverse the abnormal vasculature. One cause isdisseminated cancer—usually a mucin-producing neoplasm. Especially common isgastric carcinoma, which accounts for about 50% of cases. Most of the othermalignancies producing microangiopathic hemolytic anemia originate from thebreast, lung, and pancreas. About one-third of patients haveleukoerythroblastosis on the blood smear, about one-half have laboratoryevidence of disseminated intravascular coagulation, and about 60% have tumorcells detectable on bone marrow specimens.

Some medications can cause microangiopathic hemolytic anemia,such as mitomycin (Mutamycin) and ticlopidine (Ticlid). The diseaseusually begins several weeks to months after initiation of the drug, renalfailure and thrombocytopenia are common, and laboratory evidence of disseminatedintravascular coagulation is absent. A similar syndrome may occur after solidorgan or bone marrow transplantation, possibly precipitated by the precedingcytotoxic medications and total-body irradiation used in preparation for thetransplant procedure.

Other common causes of microangiopathic hemolytic anemia arethrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, malignanthypertension, disseminated intravascular coagulation, and severe hypertensionduring pregnancy (preeclampsia or eclampsia). Immunologic damage to the vesselsthat occurs in such disorders as systemic lupus erythematosus, Wegener’sgranulomatosis, systemic sclerosis, and microscopic polyangiitis can causemicroangiopathic hemolytic anemia. It also may arise from the abnormalvasculature of a giant hemangioma (Kasabach-Merritt syndrome) or a hepatichemangioendothelioma. Platelets can be markedly diminished as well.

Immune Hemolysis

Warm-Antibody Acquired Autoimmune Hemolytic Anemia

In autoimmune hemolytic anemia (AHA), RBC life span decreasesbecause autoantibodies (usually polyclonal IgG) are optimally active againsterythrocytes at body temperature. These warm antibodies account for about 80% to90% of acquired autoimmune hemolytic anemia, and only about 10% are caused byantibodies maximally active at lower temperatures (cold-reactive autoantibodies).[16]In about one-half of cases, an underlying disorder is present—most commonly alymphoproliferative disease such as chronic lymphocytic leukemia or lymphoma,but also systemic lupus erythematosus, other inflammatory conditions, someinfections (cytomegalovirus), and nonlymphoid malignancies. Certain drugs canalso play a role in the development of these warm antibodies and hemolysis:levodopa (Dopar, Larodopa) and penicillin can cause IgG, and quinidine can causeIgM-type antibodies and AHA.

In warm AHA, IgG coats many red cells with or withoutcomplement. Macrophages in the spleen and Kupffer cells in the liver trap theseerythrocytes, sometimes ingesting them whole. More commonly, they remove aportion of the membrane, and the surviving red cell re-forms as a spherical cellwith a smaller diameter. These spherocytes are seen on peripheral blood smear,which also discloses evidence of polychromatophilia, indicating the release ofimmature red cells from the bone marrow. Erythrocyte fragments, nucleated redcells, and hemophagocytosis by monocytes may also be visible. In addition toanemia, the automated blood count often reveals an increased mean corpuscularhemoglobin concentration, reflecting the presence of the spherocytes. Thereticulocyte count is usually increased, as are the serum indirect bilirubin andLDH levels. Immature white cells occasionally appear on the peripheral smear. InEvans’ syndrome, immune thrombocytopenia is also present.

The direct antiglobulin test detects the presence ofantibodies and complement on erythrocytes by using a reagent that containsantibodies directed against human immunoglobulin and complement components(primarily C3). This test is nearly always positive in warm AHA, but when IgG ispresent in very small quantities, other diagnostic techniques may be necessaryto detect them. Autoantibodies unattached to erythrocytes may be present in theserum and are detectable by incubating the patient’s serum or plasma withnormal red cells, to which the antibodies then attach. These erythrocytes arethen tested for the presence of autoantibodies with the Coombs reagent. This isthe indirect antiglobulin or Coombs test.

Treatment of AHA will depend on the underlying etiology ifone can be identified. Patients with warm AHA usually respond to prednisone. Inpatients who are refractory to prednisone, intravenous immunoglobulin, danazol,plasma exchange, splenectomy, and cyclophosphamide (Cytoxan, Neosar) can beconsidered as other options. Recently, the CD20 antibody rituximab (Rituxan) hasbeen found to be effective in AHA associated with lymphoproliferative disorders.

Cold Agglutinin Disease

Cold agglutinins are IgM antibodies that bind red cells atcold temperatures. They may be polyclonal or monoclonal. Nearly all healthypeople have low titers of clinically insignificant polyclonal cold agglutinins.Cold AHA can be idiopathic or secondary (infection, lymphoma).[17] In certaininfections, transient, high titers of polyclonal cold agglutinins appear,causing the abrupt onset of an anemia that is short-lived, but occasionallysevere. Cold agglutinin disease is mediated by a complement-fixing monoclonalIgM antibody either in an acute (mycoplasma or Epstein-Barr virus infection) orchronic setting (lymphoproliferative disorders).

Infectious mononucleosis (IgG or IgM) and infections with Mycoplasmapneumoniae (IgM) are the two most common causes; the target of theantibodies in the former is typically the i antigen found on the red cellmembrane of fetal erythrocytes, while that in the latter is the I antigen foundon adult erythrocytes. Hemolysis is usually intravascular and in the liver.Agglutination is seen when blood is cooled. Splenomegaly is rare.

The chronic form of cold agglutinin disease typically occursin older adults, and many have an underlying B-cell neoplasm, such asWaldenstrom’s macroglobulinemia, chronic lymphocytic leukemia, or non-Hodgkin’slymphoma. Exposure to cold may precipitate attacks of acrocyanosis created byagglutination of erythrocytes in cool peripheral areas such as the fingers,toes, nose, and earlobes. It may also cause worsening anemia as thetemperature-dependent IgM antibody activates the complement pathway on the redcell membrane, producing intravascular hemolysis, sometimes with sufficienthemoglobinuria to cause acute renal failure. Ordinarily, however, the anemia ismild and stable for the following reasons: (1) the antibody binds toerythrocytes only at temperatures below normal body temperatures; (2) hepaticmacrophages do not avidly phagocytize red cells coated with Cd3, the usualcomplement component on the membrane; and (3) the serum Cd3 inactivator systemdegrades Cd3 into components even less tempting to the macrophages. Hemolysis incold AHA is usually refractory to steroids or splenectomy. Plasmapheresis orchemotherapy may be necessary to control the hemolysis in severe cases.

General Therapeutic Considerations

Appropriate management of hemolytic anemia depends on thespecific diagnosis. Thus, initial efforts should focus on reaching a diagnosisrapidly along with supportive care measures. Supportive care measures shouldinvolve measures to avoid shock and fluid/electrolyte imbalance, and measures toensure adequate renal and cardiovascular function. Risks and benefits of bloodtransfusion should be carefully determined, since transfused blood may worsenthe hemolysis and promote end-organ damage.

Appropriate blood-banking procedures are invaluable inmanaging patients with hemolytic anemia. Because the spleen is often a majorsite of RBC destruction, splenectomy may bring relief. This is especially truein patients with RBC membrane disorders, enzyme deficiencies, immunohemolyticanemias, and some unstable hemoglobin disorders. Patients with splenomegalyrespond better to splenectomy than those patients without a palpable spleen.Steroids can be very effective in immunohemolytic anemias. In patients withchronic hemolysis, folic acid supplementation can prevent megaloblastic crisis.

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3. Owren PA: Congenital hemolytic jaundice. The pathogenesisof the hemolytic crisis. Blood 3:231, 1948.

4. Tanaka KR, Paglia DE: Pyruvate kinase deficiency. SeminHematol 8:367, 1971.

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