INTRODUCTION
Acquired hemolytic anemias are a group of disorders characterized by hemolysis of red blood cells (RBCs) not due to congenital or inherited disorders of hemoglobin synthesis or of the RBC membrane. Hemolysis of RBCs can take place within the intravascular space or in the extravascular spaces of the spleen and liver and can produce a spectrum of disease from mild, asymptomatic illness to severe hemodynamic compromise leading to critical ED encounters.
Presenting symptoms and signs of hemolytic anemia include those common to anemia in general: weakness, fatigue, dizziness, shortness of breath, dyspnea on exertion, tachycardia, palpitations, chest pain, new or accentuated cardiac murmur, and pallor. RBC destruction generates free hemoglobin that is then broken down into bilirubin. When bilirubin production exceeds the liver’s ability to conjugate it for biliary and fecal excretion, jaundice and darkened urine may develop. Splenic enlargement may promote the storage and extravascular breakdown of RBCs.
The laboratory findings characteristic of acquired hemolytic anemia demonstrate hemolysis of RBCs, hemoglobin breakdown, and compensatory RBC production (Table 237-1). The peripheral blood smear displays abnormal RBC morphology consistent with hemolysis: schistocytes generated by intravascular shearing of RBCs and spherocytes produced by extravascular phagocytosis of RBCs within the liver and spleen.
Purpose | Test | Finding |
---|---|---|
Confirm anemia/blood loss | Hemoglobin Hematocrit | Decreased Decreased |
Confirm compensatory RBC production | Reticulocyte count | Increased |
Confirm hemolysis | Peripheral smear | Schistocytes—intravascular hemolysis, RBCs fragmented by shear mechanism Spherocytes—extravascular hemolysis, RBC phagocytosis by macrophages |
Confirm hemolysis | Lactate dehydrogenase Potassium | Increased, released by RBCs Increased, released by RBCs |
Confirm hemolysis | Haptoglobin Free hemoglobin Hemoglobinuria | Decreased, indicative of intravascular hemolysis Increased, indicative of intravascular hemolysis Present |
Confirm hemoglobin breakdown | Total bilirubin Indirect (unconjugated) bilirubin Urinary urobilinogen | Increased Increased (hepatic conjugation of bilirubin overwhelmed) Increased |
Intravascular hemolysis of RBCs releases hemoglobin into the bloodstream that then binds to haptoglobin and other serum proteins. The hemoglobin–haptoglobin complex travels to the liver for processing, thus decreasing the amount of free haptoglobin in the serum—an important laboratory finding of intravascular hemolysis. Breakdown of RBCs releases lactate dehydrogenase and potassium, leading to elevation of both in serum. With excessive hemoglobin breakdown comes increased bilirubin production that cannot be conjugated by the liver for biliary and fecal excretion. Laboratory findings associated with excess bilirubin production include elevated total bilirubin; elevated indirect or unconjugated bilirubin; and increased urinary urobilinogen, a by-product of bilirubin breakdown formed by the intestine and passed into the urine. Excess free hemoglobin may escape binding by serum haptoglobin as well as reabsorption by the renal tubules, creating hemoglobinuria and darkened urine.
IMMUNE-MEDIATED ACQUIRED HEMOLYTIC ANEMIA
Immune-mediated acquired hemolytic anemia encompasses three main categories: autoimmune, alloimmune, and drug induced.
Individuals with autoimmune hemolytic anemia make antibodies against their own RBCs.1 Diagnosis requires evidence of an antibody on the patient’s RBCs, usually accompanied by an autoantibody in the plasma. The direct antigen test, also known as the direct Coombs test, is performed by combining the patient’s anticoagulated, washed RBCs with anti–immunoglobulin G and anti-C3d (complement) antibodies to detect the presence of immunoglobulin G and/or complement on the RBC surface. A positive direct antigen test consists of the detection of either immunoglobulin G or complement on the RBC surface; it does not require the detection of both.2 A positive direct antigen test is not specific for a diagnosis of autoimmune hemolytic anemia (Table 237-2), nor does the presence of immunoglobulin G and/or complement on a patient’s RBCs indicate the severity of disease; the direct antigen test is, however, a critical confirmatory screen. The indirect Coombs test looks for the presence of autoantibodies in the patient’s serum, testing against a panel of RBCs bearing specific surface antigens. Hemolysis can take place within the vascular space or extravascularly within the liver or spleen.
Autoimmune hemolytic anemia Hemolytic transfusion reaction, acute or delayed Hemolytic disease of newborn Transplantation Drug-related hemolytic anemia IV immunoglobulin therapy Rh(D) immunoglobulin therapy Antilymphocyte globulin therapy Antithymocyte globulin therapy Sickle cell disease β-Thalassemia Renal disease Multiple myeloma Hodgkin’s disease Systemic lupus erythematosus Human immunodeficiency virus/acquired immunodeficiency syndrome |
Autoimmune hemolytic anemia can be divided into primary and secondary disease; primary, or idiopathic, disease occurs without a known underlying etiology, whereas secondary disease is associated with an underlying disorder.1 Primary disease is more common in women, with peak incidence during the fourth and fifth decades. Many cases initially designated as primary are later found to be associated with lymphoproliferative, autoimmune, or infectious diseases. In children, the disorder is commonly associated with viral or respiratory infections and can cause acute, fulminant hemolysis. Pregnancy can increase the risk of autoantibody development fivefold, but significant RBC destruction is not common. Autoimmune hemolytic anemia is further divided into autoantibody type: warm type, cold type, and mixed type (Table 237-3).1
Warm antibody AIHA: Autoantibodies adhere most strongly to RBCs at 37°C (98.6°F). | 70%–80% of AIHA cases 2:1 female predominance 50% primary (idiopathic) disease 50% secondary disease: lymphoproliferative, autoimmune disease, postinfection (transient) Usually immunoglobulin G (IgG) autoantibody against Rh(D) antigen Hemolysis usually extravascular Steroid responsive: 70%–80% |
Cold antibody AIHA: Autoantibodies adhere most strongly to RBCs at 0–4°C (32–39.2°F). | Cold agglutinin disease: IgM autoantibody against I antigen Primary disease: older females Secondary disease: lymphoproliferative disorders, postinfection (transient) Raynaud’s phenomenon, livedo reticularis, vascular occlusion Attacks precipitated by cold exposure Rarely intravascular hemolysis Not steroid responsive Paroxysmal cold hemoglobinuria: IgG autoantibody against P antigen Primary disease: rare, in adults Secondary disease: usually in children after upper respiratory infection Intravascular hemolysis during cold weather Usually not steroid responsive |
Mixed-type antibody AIHA: Autoantibodies have variable temperature-dependent RBC adherence. | Primary disease: more common in older females Secondary disease: lymphoproliferative and autoimmune disorders Usually chronic course with severe exacerbations Usually steroid responsive |
Warm autoantibody–mediated hemolysis is predominantly extravascular, with antibody-coated RBCs consumed mostly by splenic macrophages and, to a lesser degree, by hepatic macrophages known as Kupffer cells. Partial phagocytosis of the original RBC membrane structure leads to the formation of the more rigid, fragmentation-prone spherocyte. Increased spherocytosis found on peripheral blood smear correlates positively with severity of extravascular hemolysis.
Autoimmune hemolytic anemia is initially treated with high-dose corticosteroids, typically oral at 1 to 2 milligrams/kg per day for 3 to 4 weeks, with improvement expected in 80% to 85% of patients but complete remission in only up to 30% of patients.3
Monoclonal antibodies (e.g., rituximab), immunosuppressive agents (e.g., azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide), or semisynthetic androgens (e.g., danazol) can be used to decrease autoantibody production.3,4 Splenectomy removes both the main site of extravascular hemolysis in IgG-mediated disease and a major site of general autoantibody production. Splenectomy shows clinical benefit in up to 60% of patients, with potential for long-term remission or a complete cure. A serious complication of splenectomy is overwhelming postsplenectomy infection due to sepsis with encapsulated bacteria.5 Such patients should receive regular pneumococcal and meningococcal vaccinations and may benefit from daily penicillin prophylaxis.
Severe hemolysis in cases of warm antibody autoimmune hemolytic anemia may be treated with plasma exchange as a transient stabilizing measure while waiting for steroids or immunosuppressive agents to take effect. IV immunoglobulin has been used as an adjunctive treatment in children who cannot tolerate the side effects of chronic high-dose steroids or immunosuppressive agents.6
For a patient with life-threatening anemia, the goal is to transfuse allogeneic RBCs without producing potentially harmful transfusion reactions. Laboratory personnel must determine whether the patient’s blood contains alloantibodies against RBC antigens, but first, autoantibodies—usually directed against more commonly occurring or higher prevalence RBC antigens, and thus typically panreactive against RBC panels—must be identified and sifted out because the presence of autoantibodies can hide the existence of alloantibodies.7 The testing process can be both labor and time intensive, sometimes requiring 6 hours or longer. Once completed, however, antigen-free, compatible RBC units can then be selected in hopes of providing safe and effective transfusion for the patient. If emergently needed, transfusion of the least incompatible units may be administered slowly and in the smallest amounts necessary with close monitoring.8
Cold autoantibodies lead to clumping or agglutination of RBCs on peripheral smear at cooler temperatures. Cold antibody autoimmune hemolytic anemia is associated with complement fixation on the RBC surface and triggering of the complement cascade. Hemolysis occurs in both the extravascular and intravascular spaces. Instead of splenic macrophages, the hepatic macrophages known as Kupffer cells are responsible for most of the extravascular RBC destruction. The two major cold antibody disorders are cold agglutinin disease and paroxysmal cold hemoglobinuria. Fifty percent of secondary cold antibody cases are associated with lymphoproliferative disorders, with underlying infection as the next leading cause.
Cold agglutinin disease is exacerbated by the cold, so more episodes of acute hemolysis are seen during winter.9 Because the peripheral circulation is typically cooler than the central circulation, secondary Raynaud’s phenomenon and vascular occlusion can complicate cold agglutinin disease, leading to acrocyanosis and tissue necrosis/gangrene. Painful discoloration and mottling of the skin consistent with livedo reticularis may be seen.10 Less commonly, cold urticaria and hemorrhagic vesicles may develop.11
Primary cold agglutinin disease causes chronic, recurrent hemolysis in older adults, particularly females, with a peak incidence at age 70 years old. As with all of the idiopathic autoimmune hemolytic anemias, an associated underlying disease process may be discovered well after initial presentation of cold agglutinin disease; in particular, an occult lymphoproliferative disorder may be the source of the aberrant cold autoantibodies.
Secondary cold agglutinin disease may present after infection with Mycoplasma pneumoniae, Epstein-Barr virus, or infectious mononucleosis, adenovirus, cytomegalovirus, influenza, varicella-zoster virus, human immunodeficiency virus, Escherichia coli, Listeria monocytogenes, or Treponema pallidum. Hemolysis typically begins 2 to 3 weeks after the onset of illness, corresponding with peak antibody development against the infectious agent, and resolves about 2 to 3 weeks after resolution of the infectious illness. Many patients with Mycoplasma pneumonia and infectious mononucleosis will have measurable cold agglutinin titers, but far fewer will develop symptoms and signs of hemolytic anemia. Conversely, cold agglutinin disease associated with lymphoproliferative diseases such as chronic lymphocytic leukemia and lymphoma produces high autoantibody levels with the potential for significant hemolysis.
Agglutination of RBCs can confound an automated CBC device; the mean corpuscular volume may be falsely elevated, whereas the hemoglobin registers spuriously low. Holding the blood tube in warm hands may decrease RBC clumping for more reliable CBC results. A CBC with confusing or bizarre results should undergo peripheral smear examination. Peripheral smear findings of cold agglutinin disease include spherocytosis, anisocytosis, poikilocytosis, polychromasia, and agglutination.12 The direct antigen test demonstrates adherence of complement to patient RBCs, but cold autoantibodies are typically washed off the RBCs during the elution process and thus are not identified. Other laboratory findings correspond with those routinely seen in cases of hemolytic anemia, including findings consistent with intravascular hemolysis in some cold agglutinin disease cases (Table 237-1).
An important principle in treating cold agglutinin disease is keeping the extremities and appendages, particularly the nose and ears, warm in cold weather. Patients should take a daily folate supplement for healthy RBC production. Cold agglutinin disease is less likely to respond to steroids, with response rates as low as 35%.9 Splenectomy is less effective in treating cold agglutinin disease because splenic macrophages play a lesser role in IgM-mediated cold antibody disease. Severe hemolysis has been treated successfully with immunosuppressive agents such as chlorambucil, cyclophosphamide, interferon-α, fludarabine, or rituximab.9 Because immunoglobulin M autoantibodies have an intravascular distribution, plasmapheresis may assist by removing autoantibodies from the circulation when combined with immunosuppressive agents.
Infection-related cold antibody disease does not require immunosuppressive therapy because the hemolytic anemia is usually self-limited. RBC transfusion can be performed for patients at risk for significant cardiac or cerebrovascular ischemia, but transfused blood should be infused at 37°C (98.6°F) using a blood warmer. Transfusions should be limited as they may worsen ongoing hemolysis because most cold antibodies act against the I/i group antigens that are found on most donor RBCs. Donor complement in the transfused product also may exacerbate ongoing hemolysis.
Paroxysmal cold hemoglobinuria is caused by a biphasic hemolysin immunoglobulin G autoantibody called the Donath-Landsteiner (D-L) antibody that is directed against the P antigen system found on most RBCs.13 This potent autoantibody binds to RBCs and fixes early complement cascade proteins at low temperatures, whereas terminal complement components adhere and produce intravascular lysis of RBCs at warmer, physiologic temperatures.
Bursts of cold weather–induced intravascular hemolysis lead to bouts of dark urine or hemoglobinuria for which the disease is named. Other presenting symptoms include attacks of high fever, chills, headache, abdominal cramps, nausea and vomiting, diarrhea, and leg and back pain, all exacerbated by cold weather. Cold urticaria may develop as well as extremity paresthesias and Raynaud’s phenomenon.