HEMOLYTIC ANEMIA

HEMOLYTIC ANEMIA

Current Diagnosis

• Anemia accompanied by reticulocytosis without evidence of bleeding or recovery from a nutritional anemia should prompt an evaluation for immune and nonimmune causes of hemolytic anemia.

• Key test results that help confirm the presence of hemolysis include elevated indirect bilirubin and lactate dehydrogenase (LDH) levels, often accompanied by a low haptoglobin level. Examination of the peripheral smear may reveal findings that guide further diagnostic testing.

• The direct antiglobulin test (DAT) can be an important initial test and if positive, would establish the diagnosis of immune-mediated hemolysis. Further testing will distinguish warm-antibody autoimmune hemolytic anemia (AIHA) from cold-antibody AIHA.

• A negative DAT should prompt evaluation for causes of nonimmune hemolysis. Both congenital and acquired red blood cell (RBC) disorders will require further diagnostic testing.

Current Therapy

• Patients with ongoing moderate to severe hemolysis should be treated with folate (folic acid),1 1 mg orally daily.

• RBC transfusion may be used for life-threatening situations. When the DAT is positive, least incompatible units should be used.

• Patients with warm AIHA are best treated with corticosteroids. Patients refractory to steroids or who cannot have their steroids tapered, will require second-line therapy such as splenectomy or rituximab (Rituxan).1

• Those patients with cold-antibody AIHA or paroxysmal cold hemoglobinuria (PCH) should avoid cold exposure; therapies used for warm AIHA are often not successful.

• Splenectomy can benefit selected patients with congenital hemolytic anemia. Vaccinations for Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis should be administered before surgery.

• Acquired causes of nonimmune hemolytic anemia are generally managed by treating the underlying cause or removing the offending agent.

1 Not FDA approved for this  indication.

Hemolysis, the premature destruction of red blood cells (RBC), leads to hemolytic anemia when the bone marrow cannot compensate for RBC loss. A useful classification divides the hemolytic anemias mechanistically into immune or nonimmune causes. Immune- mediated causes include autoimmune hemolytic anemia (AIHA) and alloantibody-induced hemolytic anemia (Box 1). AIHA occurs as a result of antibody production against self-RBC antigens. AIHA can be idiopathic or can occur secondary to drugs, infections, malignancies, or autoimmune disorders. Types of AIHA include warm-antibody AIHA, cold-antibody AIHA, paroxysmal cold hemoglobinuria (PCH), and medication-induced AIHA (see Box 1). Alloantibody-induced hemolytic anemia includes hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. Nonimmune causes of hemolysis can be further classified into congenital disorders with defects in the RBC membrane, enzymes, or hemoglobin, and acquired disorders when, usually, the cause of hemolysis is by extrinsic influences on the RBC. Extrinsic factors causing direct injury to the RBCs include the microangiopathic hemolytic anemias, infections, toxins, and certain systemic illnesses. The one acquired cause of hemolytic anemia where the defect is due to an intrinsic RBC abnormality is paroxysmal nocturnal hemoglobinuria.

Box 1
Classification of Hemolytic Anemia
•   Immune Hemolytic Anemia

•   Warm-antibody autoimmune hemolytic anemia

•   Primary or idiopathic warm-antibody AIHA

•   Secondary warm-antibody AIHA associated with

•   Lymphoproliferative disorders (e.g., Hodgkin Disease, non- Hodgkin lymphoma, chronic lymphocytic leukemia)

•   Rheumatologic or autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis)

•   Cold-antibody autoimmune hemolytic anemia

•   Mediated by cold agglutinins

•   Idiopathic (primary) cold agglutinin disease

•   Secondary cold agglutinin hemolytic anemia associated with

•   Infections (e.g., Mycoplasma pneumonia, infectious mononucleosis)

•   Lymphoproliferative disorders

•   Mediated by cold hemolysins

•   Idiopathic (primary) paroxysmal cold hemoglobinuria (PCH)

•   Secondary PCH associated with

•   Infections (e.g., syphilis, viral infections)

•   Lymphoproliferative disorders

•   Mixed cold and warm autoantibodies

•   Primary or idiopathic mixed AIHA

•   Secondary mixed AIHA

•   Associated with rheumatologic diseases, especially SLE

•   Drug-immune hemolytic anemia

•   Hapten or drug-adsorption mechanism

•   Immune complex mechanism

•   Autoantibody mechanism

•   Allo antibody hemolysis

•   Acute transfusion reaction

•   Delayed transfusion reaction

•   Hemolytic disease of the fetus and newborn

•   Nonimmune Hemolytic Anemia

•   Congenital hemolytic anemia

•   Membrane disorders (e.g., hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, hereditary stomatocytosis)

•   Hemoglobinopathies (e.g., sickle cell disease, hemoglobin CC disease, unstable hemoglobins)

•   Enzyme disorders (e.g., G6PD deficiency)

•   Acquired hemolytic anemia

•   Microangiopathic (e.g., TTP, HUS, DIC, malignancy, vasculitis)

•   Infections (e.g., malaria, babesiosis)

•   Toxins (e.g., arsenic, lead, copper, insect or spider or snake bites)

•   Paroxysmal nocturnal hemoglobinuria

•   Other (liver failure, extensive burns)

Pathophysiology

RBCs have a lifespan in the circulation of approximately 120 days. Senescent RBCs are removed from the circulation in the spleen.

Hemolysis takes place either in the spleen or liver (extravascular hemolysis) or within the vasculature (intravascular hemolysis).

Immune Hemolytic Anemias

Immune hemolysis occurs due to antibodies directed against self-RBC antigens (AIHA) or antibodies directed against transfused RBCs.

Autoimmune Hemolytic Anemia Warm AIHA

The antibodies most commonly involved in warm-antibody AIHA are of the IgG type. These IgG antibodies are typically directed against RBC Rh proteins. The antibodies bind RBCs at 37°C, allowing their Fc region to remain exposed. This region is recognized by Fc receptors on the macrophages of the spleen, resulting in fragmentation and ingestion of the antibody-coated RBCs. Partial or complete phagocytosis of the RBC ensures; if partial phagocytosis occurs, spherocytes are formed. Splenomegaly results from entrapment of RBCs in the spleen.

Cold-Antibody AIHA

Cold agglutinins are typically IgM autoantibodies that cause RBC agglutination at temperatures lower than 37°C, with maximal RBC agglutination at temperatures lower than 4°C. Cold agglutinins may occur in response to infection, as is commonly seen with Mycoplasma pneumonia and infectious mononucleosis. The IgM antibody usually reacts with I/i RBC antigen, resulting in complement activation by fixation of antibody to the antigen at low temperatures. Anti-I is characteristic of Mycoplasma pneumonia-induced hemolysis, whereas anti-i is characteristic of infectious mononucleosis

Paroxysmal Cold Hemoglobinuria

The Donath-Landsteiner autoantibody is a biphasic, polyclonal IgG that binds RBCs at cooler temperatures (4°C), activates complement, and results in intravascular hemolysis at warmer temperatures (37°C) due to complement fixation. This autoantibody is able to bind several RBC antigens, although its main target is the P antigen.

Medication AIHA

Medication-induced AIHA results from three proposed mechanisms based on the interactions among medications, RBC membrane antigens, and antibodies. These mechanisms are induced by drug or hapten adsorption, neoantigen formation, and autoantibody binding.

Alloantibody Hemolysis

Alloantibodies can occur in recipients of blood transfusions due to exposure to non–self-RBCs. Acute transfusion reactions are due to preformed antibodies in the recipient which attack donor RBCs leading to complement activation. Intravascular hemolysis occurs, often leading to disseminated intravascular coagulation (DIC) and acute renal failure. Delayed transfusion reactions occur 3 to 21 days after a transfusion due to an anamnestic antibody response from the recipient because of prior exposure to RBCs either through transfusions or pregnancy. The most common antibodies formed are anti-Kidd or directed against RH antigens. Typically, these antibodies are noncomplement binding and cause extravascular hemolysis.

Nonimmune Hemolytic Anemia

Congenital Hemolytic Anemia

The congenital nonimmune hemolytic anemias are caused by mutations affecting the RBC membrane, hemoglobin, or enzymes.

  • Membrane Disorders

The most common RBC membrane disorders are hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis. Each disorder is caused by a defect in one of the cell wall proteins. The nature of the deformity depends upon the exact structural protein defect. Spherocytes (Figure 1), and to a lesser extent, elliptocytes (Figure 2), are not as deformable as the normal biconcave RBCs and are removed from the circulation by macrophages. This extravascular hemolysis typically occurs predominantly within the spleen. Patients with hereditary pyropoikilocytosis are double heterozygotes, usually inheriting two hereditary elliptocytosis mutations, resulting in the production of tiny, fragmented RBCs and severe hemolytic anemia.

FIGURE 1    Hereditary spherocytosis. Peripheral blood film  showing spherocytes.

FIGURE 2    Hereditary elliptocytosis. Peripheral blood film  showing elliptocytes.

  • Hemoglobinopathies

Hemoglobin is composed of four subunits held together by noncovalent forces. A number of mutations affect the forces maintaining this structural integrity and can result in degradation and precipitation of the hemoglobin within the cell. These unstable hemoglobins form precipitates, or Heinz bodies, attach to the membrane, and impair the deformability of the RBC, ultimately leading to removal of the cells within the spleen. Another hemoglobinopathy, and the most common, sickle cell disease, results from the replacement of valine for glutamic acid in the sixth position of the β-globin subunit. Sickle cell disease has a myriad of downstream physiologic effects that ultimately leads to hemolysis of the sickled RBCs (Figure 3).

FIGURE 3    Sickle cell anemia. Peripheral blood smear showing  sickle cells.

  • Enzyme Disorders

The RBC relies on enzymes functioning in two glycolysis pathways to generate energy. Energy is required to maintain the RBC’s biconcave shape as well as the integrity of the enzymes, hemoglobin, and membrane through its 120-day life span. The two metabolic pathways are the anaerobic glycolysis (Embden- Meyerhof) pathway and the aerobic glycolysis (hexose monophosphate) pathway. Enzyme defects in the Embden- Meyerhof pathway are generally associated with chronic hemolysis; enzyme defects in the hexose monophosphate pathway are often associated with episodic hemolysis. The most common defect affects the glucose-6-phosphate dehydrogenase (G6PD) enzyme. This enzyme is responsible for diverting glucose from the Embden-Meyerhof pathway to the hexose monophosphate pathway and for restoring intracellular reduced nicotinamide adenine dinucleotide phosphate, which functions as an antioxidant. Low levels of G6PD activity result in the inability of the cell to defend itself against oxidant stresses; absent levels result in chronic hemolysis.

Acquired Hemolytic Anemia

For the acquired nonimmune hemolytic anemias, hemolysis results from extrinsic forces affecting the RBC. In the microangiopathic hemolytic anemias, RBCs undergo fragmentation due to high sheer forces generated from abnormal vascular surfaces.

Infections can cause hemolysis due to direct invasion of the organism into the RBC (malaria, babesiosis) by release of products that can destabilize the red cell membrane (Clostridia perfringens), or by initiating DIC, resulting in microangiopathic hemolysis.

Certain toxic chemicals and physical agents can cause hemolysis through a variety of mechanisms affecting the RBC membrane or metabolism. These substances include arsenic; lead; copper; and insect, spider, and snake venoms.

Other systemic disease states causing hemolysis include liver failure and extensive burns. In liver failure, the ratio of cholesterol to phospholipid in the red cell membrane is altered, resulting in membrane instability and hemolysis. Patients with extensive burns can present acutely with a brisk hemolytic anemia; the heat from the burns likely causes mechanical and osmotic damage to RBCs.

The underlying defect in paroxysmal nocturnal hemoglobinuria is impaired production of a key anchoring cellular membrane protein. Loss of the anchoring protein, glycosylphosphatidylinositol, disrupts a number of cellular proteins including CD59, a protein inhibitor of complement-mediated lysis. Deficiency of CD59 leads to greater sensitivity of RBCs to hemolysis.

Clinical Manifestations

The clinical manifestations of all hemolytic anemias, in large part, depend upon the severity of the anemia and the rapidity of the hemoglobin decline as well as any associated manifestations related to the underlying cause. General symptoms of anemia include weakness, fatigue, lethargy, and palpitations. Physical examination not only includes the typical findings of anemia (pale sclerae and nail beds) but may also reveal icteric sclera and jaundice if the indirect bilirubin is sufficiently increased. Other clinical manifestations of the hemolytic anemias, particularly the congenital nonimmune causes but also seen in AIHA, include splenomegaly, formation of pigmented gallstones with the possibility of cholecystitis, and aplastic crisis due to viral infections. Aplastic crisis results from viral suppression of hematopoiesis. Because RBC survival at baseline is shortened, abrupt cessation of erythropoiesis results in a rapid fall in the hemoglobin level and relatively acute onset of symptomatic anemia.

As noted previously, hemolysis can occur in the intravascular or extravascular space, depending upon the etiology. Clinical manifestations of intravascular hemolysis versus extravascular hemolysis differ. Intravascular hemolysis, as might occur with PCH or an acute transfusion reaction can result in dark or cola-colored urine due to hemoglobinuria. Patients with acute transfusion reactions may also experience fevers and chills as well as flank pain. DIC, hypotension, and renal failure may ensue.

Specific manifestations of certain disorders can occur and may be helpful in establishing the diagnosis. For instance, patients with cold– antibody-mediated AIHA may experience acrocyanosis of their fingers, toes, nose, and ears, especially when exposed to the cold.

Patients with PNH may present with abdominal pain, venous thrombosis, and may have, in addition to the hemolytic anemia, granulocytopenia and thrombocytopenia.

The AIHAs may be associated with other medical conditions. For instance, AIHA may also be associated with other viral or bacterial illnesses, as well as lymphoproliferative or rheumatologic disorders.

Diagnosis

Anemia that is accompanied by reticulocytosis is suggestive of a hemolytic process. Tests that support the presence of hemolysis include an elevated lactate dehydrogenase (LDH) and indirect bilirubin. In general, when hemolytic anemia is suspected due to these findings (reticulocytosis, elevated LDH, and indirect bilirubin), the first test to be performed is the peripheral smear examination.

Abnormalities seen on the peripheral smear examination commonly suggest the cause of the hemolysis and direct further, specialized testing (Table 1).

Table 1

Classification of Nonimmune Hemolytic Anemias

Abbreviations: DIC = disseminated intravascular coagulation; G6PD = glucose-6-phosphate dehydrogenase; HUS = hemolytic-uremic syndrome; TTP = thrombotic thrombocytopenic purpura.

Other tests that may be helpful to confirm the presence of hemolysis include serum haptoglobin, plasma and urinary free hemoglobin, and urinary hemosiderin. Haptoglobin, synthesized by the liver, binds any free hemoglobin in the plasma; the complex is then removed in hepatic parenchymal cells. If the rate of hemolysis exceeds the clearance rate of this complex, the haptoglobin level will be decreased. Haptoglobin is also an acute phase reactant; it can be elevated if there is acute inflammation present. Intravascular hemolysis can result in detection of free hemoglobin in the plasma if the plasma hemoglobin- binding proteins are saturated; urine hemoglobin will be detected if the capacity of renal tubular cells to absorb free hemoglobin is exceeded.

Hemoglobin that is filtered in the kidney is stored in the renal tubular cells and excreted in the form of hemosiderin. As these cells slough into the urine, the hemosiderin can be detected by a Prussian blue stain approximately 5 to 7 days following a hemolytic episode. This test is therefore helpful to detect intravascular hemolysis days after the hemolytic event.

For the hemolytic anemias, examination of the bone marrow is seldom helpful and generally not necessary in the diagnostic process.

Specialized Testing

Autoimmune Hemolytic Anemia

A polyspecific direct antiglobulin test (DAT), which contains reagents that will detect IgG and C3 antibodies, is performed when AIHA is suspected. If the test is positive, then monospecific DATs are performed using IgG and complement reagents to determine the subtype of AIHA (warm-mediated, cold-mediated, or Donath- Landsteiner). For individuals with warm–antibody-mediated AIHA, the DAT may be positive for IgG only or for both IgG and complement C3.

For individuals with a Donath-Landsteiner antibody, the monospecific DAT is positive for C3 but negative for IgG, because of its dissociation from the RBC surface at warmer temperatures. The presence of a Donath-Landsteiner antibody is confirmed by specialized testing aimed at detecting the temperature dependency of the antibody-mediated hemolysis. Plasma is incubated with normal RBCs and cooled to 4°C. If a Donath-Landsteiner antibody is present, the cold hemolysin in the plasma binds RBCs, but no hemolysis occurs until the sample is rewarmed to 37°C. At 37°C, the sensitized RBCs are hemolyzed by the complement present in plasma. The presence of hemolysis at 37°C following incubation at 4°C, but not at incubation at only 4°C or 37°C,constitutes a positive antibody test result.

For cold–antibody-mediated AIHA, the monospecific DAT is typically positive for complement (C3) and negative for IgG. Further testing is done to determine the thermal range of the antibody’s reactivity, its titer, and its specificity for either the I/i antigen. A diagnosis of cold–antibody-mediated hemolysis is made when the DAT is positive with C3, negative with IgG, and the cold agglutinin titer at 4°C is at least > 256. Other blood tests can be obtained to determine an underlying etiology of the cold-antibody AIHA, such as Mycoplasma and Epstein-Barr virus titers.

For patients in whom an acute transfusion reaction is suspected, an immediate evaluation for evidence of hemolysis must be undertaken, including a DAT and serum antibody screen and plasma and urine hemoglobin as well as haptoglobin. Both a DAT and serum antibody screen will be positive, and free hemoglobin should be detected in the plasma and urine. The haptoglobin will be low or undetectable. A delayed transfusion reaction is often not appreciated but should be suspected when the hemoglobin level falls more quickly than expected following a transfusion. The diagnosis can be made by demonstrating a new serum alloantibody in the recipient of the transfused blood. A urine hemosiderin can also be positive, reflecting hemolysis that occurred several days previously.

Congenital Hemolytic Anemias

The diagnosis of congenital nonimmune hemolytic anemias is often suspected when the anemia is long-standing. A family history of anemia, splenectomy, or gallstones can also be a clue to a congenital process. Peripheral smear examination is often helpful.

The membrane disorders all have findings on the peripheral smear (see Table 1), though these findings are not necessarily specific to the disorder. A specialized test, osmotic gradient ektacytometry, can be used to help in diagnosing these disorders.

For patients with certain enzymopathies, most notably G6PD deficiency, bite cells and blister cells may be seen in the peripheral smear during an acute hemolytic event (Figure 4). A supravital stain, such as crystal violet, brilliant cresyl blue, or methylene blue, can demonstrate Heinz bodies. G6PD deficiency is definitely diagnosed by the finding of low G6PD levels in the red cell; however, levels can be normal during the acute hemolytic event because RBCs with low levels have been removed from the circulation. If the diagnosis is still suspected after obtaining a normal result, a repeat test 2 to 3 months after the acute hemolytic episode should be performed. Most other RBC enzymopathies need to be diagnosed by specialized reference laboratories.

FIGURE 4    Glucose-6-phosphate  dehydrogenase deficiency.

Peripheral blood film showing bite cells and blister  cells.

Hemoglobin electrophoresis should be performed to diagnose a suspected hemoglobinopathy. The most common hemoglobinopathy causing hemolysis, sickle cell anemia, is readily diagnosed by this test. However, other hemoglobinopathies causing hemolysis, specifically the unstable hemoglobins, may be electrophoretically silent. If the diagnosis of an unstable hemoglobinopathy is suspected, a supravital stain can demonstrate Heinz bodies and a heat stability test should be obtained for definitive diagnosis.

Acquired Nonimmune Hemolytic Anemias

The diagnosis of acquired causes of nonimmune hemolytic anemias is suspected when a hemolytic anemia is new in onset and previous hemoglobin levels have been normal. A notable exception to this general premise is in G6PD-deficient patients presenting with new anemia due to oxidant stresses. Even though the anemia appears to be acquired, the key feature to recognize is the clinical context, which usually includes an infection or a precipitating event of a new drug.

The peripheral smear is usually very helpful in diagnosing the acquired causes of nonimmune hemolytic anemias. Microangiopathic changes found in thrombotic thrombocytopenia purpura (TTP), hemolytic-uremic syndrome (HUS), DIC, disseminated cancer, and heart valve hemolysis include schistocytes and RBC fragments. The ability to recognize these microangiopathic changes can be crucial, particularly in the diagnosis of conditions such as TTP and HUS, both of which require urgent management (Figure 5). The peripheral smear can also be diagnostic of certain infections (malaria, babesiosis). Other acquired causes are generally diagnosed by the clinical setting.

FIGURE 5    Microangiopathic hemolytic anemia. Peripheral blood  film showing schistocytes and red blood cell  fragments.

The diagnosis of paroxysmal nocturnal hemoglobinuria is made by flow cytometry using peripheral blood cells or bone marrow aspirate and the demonstration of deficiency of hematopoietic cell proteins normally linked to the anchoring glycosylphosphatidylinositol protein.

Differential Diagnosis

The differential diagnosis of the hemolytic anemias includes the reticulocytosis that can be seen with correction of anemia due to replacement of a deficiency (iron, folate, vitamin B12) or recovery from bleeding.

Treatment

Immune Hemolytic Anemias

Autoimmune Hemolytic Anemias

The goal of AIHA treatment is to minimize or eliminate hemolysis. Some mild cases may not require medical intervention.

Warm-Antibody Hemolytic Anemia

For those patients with moderate to severe warm-antibody AIHA, corticosteroids are the treatment of choice. Approximately 80% of patients have a rapid response to corticosteroids, typically within 1 week after starting therapy. However, most responses are not sustained. The majority of adult patients receive high-dose oral prednisone 1 mg/kg/day during the initial phase of treatment.

Intravenous methylprednisolone (Solu-Medrol) may also be used at daily doses of 100 to 200 mg.2 In the pediatric population, prednisone is given at doses ranging from 2 to 6 mg/kg/day.2 These high doses in adults and children are commonly maintained for approximately 2 weeks.

Once the hematocrit has increased, the dose should be decreased and subsequently tapered at a slow rate over several months. Patients who require more than 10 to 15 mg of prednisone daily to keep an adequate hematocrit or those who did not respond to the corticosteroids will need second-line treatment. Splenectomy is a second-line treatment for those who are surgical candidates. More than 50% of splenectomized patients have a partial or complete response. Patients who are candidates for splenectomy should receive immunizations against encapsulated organisms at least 2 weeks before the procedure. Rituximab (Rituxan),1 a monoclonal antibody directed against CD20 antigen on the surface of B lymphocytes, is another choice for second-line treatment. Rituximab, given at a dose of 375 mg/m2 weekly for 4 weeks, results in an overall response rate of 82% with many sustained responses. Recently described is the use of a lower dose of rituximab, 100 mg, weekly for 4 weeks. For cases refractory to steroids, splenectomy and rituximab may respond to other immunosuppressive therapies such as cyclophosphamide (Cytoxan), azathioprine (Imuran),1 or cyclosporine (Neoral).1

Cold-Antibody AIHA

The best-described regimen has been cyclophosphamide 50 mg/kg/day for 4 days. Other treatment options that have been used with some success include danazol (Danocrine)1 and plasmapheresis. High-dose intravenous immune globulin (Gammagard)1 may be effective in some cases, but the response is short-lived (1–4 weeks).

In children, symptoms are usually mild and self-limited. A general approach is to avoid cold exposure. Supportive care to control the underlying disorder is recommended. RBC transfusions warmed to 37°C may be given for life-threatening situations, and the least incompatible unit should be used. For severe anemia, a trial of cytotoxic drugs such as cyclophosphamide1 or chlorambucil (Leukeran)1 may be used to decrease the cold agglutinin titer and the rate of hemolysis. Other alternatives that have been used with some success include rituximab1 and interferon alfa-2b (Intron-A).1 Plasmapheresis may be used to reduce or eliminate IgM antibodies. However, because its effect is not long-standing, it is used only in the acute setting. Eculizumab (Soliris),1 an antibody to complement component 5 approved for use in paroxysmal nocturnal hemoglobinuria, has been reported to be successful in eliminating hemolysis in a patient with refractory cold agglutinin disease.

Treatment with corticosteroids alone or in combination is generally not effective. In addition, splenectomy is not effective, because the liver is the predominant site of hemolysis.

Paroxysmal Cold Hemoglobinuria

For PCH, the mainstay of treatment is supportive care and avoidance of cold exposure. Warmed RBCs may be administered in cases of life- threatening hemolysis or symptomatic anemia. Most cases are self- limited; in the event PCH persists, measures used to treat AIHA can be employed.

Alloantibody Hemolysis

A suspected acute transfusion represents a true medical emergency. The transfusion must be stopped; intravenous access is maintained to provide fluids. All efforts to support the patient’s blood pressure and urine output must be employed. For individuals with a delayed transfusion reaction, treatment is generally not necessary, although a transfusion may be needed to correct the anemia if symptoms due to the anemia develop.

Nonimmune Hemolytic Anemia

Congenital Hemolytic Anemias

For patients who have congenital hemolytic anemias and moderate to severe hemolysis, folate (folic acid)1 replacement is recommended.

Other treatments are more directed at the specific issues that can arise during the patient’s lifetime. Because pigmented gallstone formation is common, cholecystectomy may be necessary. Splenectomy, to decrease the rate of hemolysis and improve the lifespan of circulating RBCs, may be recommended for patients who have moderate to severe ongoing hemolysis resulting in symptomatic anemia.

Vaccinations for Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis should be administered before the splenectomy is performed. Patients with G6PD deficiency need to avoid oxidant drugs such as dapsone, primaquine, sulfamethoxazole (Gantanol), and other sulfa-based drugs. Parvovirus B19 infection in patients with congenital hemolytic anemias resulting in suppression of bone marrow erythropoiesis can manifest as aplastic crisis characterized by an abrupt fall in the hemoglobin. RBC transfusions may be necessary until bone marrow production recovers and erythropoiesis resumes.

Acquired Hemolytic Anemias

For patients with acquired causes of nonimmune hemolytic anemias, therapy is generally supportive, with RBC transfusions as clinically indicated, in addition to therapy directed at the underlying cause of the anemia. For example, infections should be treated appropriately; the underlying cause of DIC or HUS needs to be managed. For TTP and HUS, the initial management consists of emergent plasmapheresis. Exposure to any offending toxins needs to be eliminated; potentially, directed therapy to reduce toxin levels will be required. Specific therapy for paroxysmal nocturnal hemoglobinuria is now available; eculizumab, a humanized monoclonal antibody that inhibits the complement cascade, is used to reduce hemolysis and the need for RBC transfusions.

Monitoring

Patients with hemolytic anemia require frequent monitoring with periodic hemoglobin checks. Patients presenting with worsening anemia should have a reticulocyte count check; a decreased reticulocyte count should prompt an evaluation for reversible causes of anemia (e.g., folate, vitamin B12, or iron deficiency) as well as monitoring for further decline in the hemoglobin. Patients with longstanding hemolysis should have periodic monitoring for cholelithiasis with abdominal ultrasounds.

2  Not available in the United  States.

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