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Home , Gamma globulin, Hemolysis, Methemalbumin, Red cell agglutination

REVIEW

RONALD E. DOMEN, MD Director, and Stem Cell Processing Laboratory, Department of Clinical , Cleveland Clinic; Associate Professor of Pathology, Ohio State University College of Medicine.

An overview of immune hemolytic

MMUNE PROCESSES are an often-unrecog- ABSTRACT nized cause of , although in their presentation, the symptoms are consistent Often patients with immune hemolytic anemias with anemia from any cause. For the primary care physician, the key is to be vigilant to the present with symptoms that are common in signs and symptoms of immune hemolytic ane- anemia of any cause. In the different types of mia, especially in patients at high risk, and to initiate treatment promptly when appropriate. immune , red cells are Although researchers have made remarkable destroyed by processes mediated by . progress in elucidating the destructive process- es at work in the various types of immune This article reviews the pathophysiology, diagnosis, hemolytic anemia, the many different causes and treatment of this group of diseases. mirror the complexity of the human immune system. This article reviews the etiologies of different forms of immune hemolytic anemias, KEY POINTS the tests that help make the diagnosis, and the production can be either idiopathic or due to treatments that are available. diseases (eg, leukemia, lymphoma, infections, autoimmune • HOW RED BLOOD CELLS ARE DESTROYED diseases) or a variety of drugs.

Autoimmune hemolytic anemia was one of the All age groups can be affected, and clinical signs and first autoimmune diseases to be recognized. In symptoms can be quite variable. one of the earliest experiments in this area, per- formed in 1904, Landsteiner and Donath1.2 The type and amount of antibody or antibodies involved, found that the of patients with paroxys- and whether complement fixation occurs, can provide mal cold hemoglobinuria lysed normal red blood valuable information for diagnosis and treatment. cells, a finding that explained the clinical char- acteristics of the disease. However, there was no Corticosteroids, followed by , are the mainstays practical way to detect or characterize immune of therapy for non-drug-related , and other hemolytic anemia until Coombs, Mourant, and Race developed the direct antiglobulin test (the adjunctive therapies are available for refractory cases. DAT or Coombs' test) in 1945.3 There are several immune hemolytic disor- Corticosteroid therapy has generally not shown clinical ders; in all of them, red blood cells are destroyed efficacy in patients with uncomplicated cold agglutinin in processes mediated by antibodies.4-7 autoimmune hemolytic anemia, paroxysmal cold hemoglobinuria, or drug-induced immune hemolysis. Antibody production: Alioimmune or autoimmune Two types of processes can give rise to anti- bodies against red blood cells: alioimmune and

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TABLE 1 antibodies are efficient at binding and activat- ing complement, both intravascular and Types of immune hemolytic anemia extravascular hemolysis can occur when these antibodies are involved. Autoimmune hemolysis Warm-antibody autoimmune hemolytic anemia Cold-antibody (agglutinin) autoimmune hemolytic anemia Hemopoiesis increases to compensate Mixed warm and cold autoimmune hemolytic anemia for loss Paroxysmal cold hemoglobinuria The normal life span of red blood cells is 100 9 Drug-induced immune hemolysis to 140 days, and under normal, steady-state Immune complex mechanism conditions, the bone marrow produces Drug adsorption (hapten) mechanism approximately 25 mL of mature red cells daily mechanism to replace those that are lost. However, in response to blood loss or increased red blood Alloimmune immune hemolysis cell destruction, the bone marrow can easily Hemolytic disease of the newborn Hemolytic transfusion reaction produce up to 5 times as many red blood cells for sustained periods, and up to 10 times as many for short periods. Therefore, a person can have clinical or laboratory evidence of autoimmune (FIGURE 1). Alloantibodies are pro- increased red cell loss, but as long as the bone duced in response to foreign antigens such as marrow can compensate with increased pro- drugs or allogeneic blood transfusions; autoan- duction, he or she will not have anemia. tibodies react against antigens present on a person's own red cells. Antibodies that react • TYPES OF IMMUNE HEMOLYTIC ANEMIA against antigens common to all red cells are also known as panagglutinins, as they aggluti- The immune hemolytic disorders can he clas- nate all red cells in vitro. sified in several ways (TABLE 1). One distinction is the temperature at which the antibody is Complement activation and fixation most active (ie, their thermal range).8'10 60% to 70% Once an antibody attaches to the red cell "Warm" antibodies are most active at 37°C, of immune membrane, the may or while "cold" antibodies are generally most may not become activated, depending on the active at less than 32°C. Occasionally, mix- hemolysis class or subclass of the antibody involved.4-6.8 tures of warm and cold antibody types are seen 8 11 12 cases IgM, IgA, IgG 1, and IgG3 antibodies can acti- in the same patient. - ' The type and vate the complement system and fix comple- amount of antibody or antibodies involved, are warm ment to red blood cells; lgG2 and and whether complement fixation occurs, can autoimmune IgG4 do not. provide valuable information for diagnosis and treatment. hemolytic Hemolysis: anemia Extravascular or intravascular Warm autoimmune hemolytic anemia Two basic mechanisms explain the immune Warm autoimmune hemolytic anemia occurs destruction of red blood cells. in 1 in 50,000 to 80,000 persons, and accounts Extravascular hemolysis. for 60% to 70% of cases of immune hemoly-

capture and phagocytize red blood cells that sis^-8.^ From 50% to 70% of cases are idio- are coated with antibodies or complement pathic or primary; the remaining 30% to 50% C.3b molecules or both. Red blood cells coat- are associated with underlying diseases present ed with IgG are destroyed primarily in the at the time the patient is first evaluated, such , and IgM-coated cells are destroyed pri- as lymphoproliferative disorders (eg, leukemia, marily in the .4.6 lymphoma, multiple myeloma, Waldenstrom's Intravascular hemolysis occurs when macroglobulinemia), autoimmune disorders complement proteins C5 through C9 attach (eg, systemic erythematosus, rheumatoid to red blood cells, forming pores that allow the arthritis, scleroderma, pernicious anemia), cell contents to leak out. Since IgM and IgA and solid tumors.

90 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUM E 65 • NUMBER 2 FEBRUARY 1998 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. How red blood cells are destroyed in immune hemolytic anemia

Red blood cells RED BLOOD CELLS carry antigens such as Rh on their surface.

^ -f y IMMUNOGLOBULIN ANTIBODIES y- attach to the antigens. Antigens

Antibodies - J a The COMPLEMENT SYSTEM • may become activated and complement molecules may Complement attach to red blood cells if molecules the antibody is an IgM, IgA, IgGI, or lgG3, but not lgG2 or lgG4. / EXTRAVASCULAR HEMOLYSIS LAR HEMOLYSIS begins as macrophages in the occurs if complement proteins C5 liver or spleen capture red through C9 attach to red blood blood cells by attaching to cells and form pores that allow the antibodies or to complement cell contents to leak out. C3b molecules or both, and damage the red blood .

SPHEROCYTES, red blood cells that have assumed a spherical shape due to loss of membrane, are more rigid than normal red blood cells and therefore more easily damaged and destroyed through normal wear and tear. MACROPHAGES may destroy red blood cells by .

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Cold autoimmune hemolytic anemia Cold autoimmune hemolytic anemia, or cold Partial list agglutinin syndrome, is less common than of drugs associated warm autoimmune hemolytic anemia. with immune hemolysis Classically, this disease occurs after either Immune complex mechanism pneumonia or infec- Acetaminophen tious mononucleosis, but can also be seen as Antihistamines part of several malignant, nonmalignant, and Cefotaxime infectious disorders.8'10'17-20 Ceftriaxone Usually, the antibody is an IgM autoanti- Cephalosporins body against the I blood group system,8'10'21 or 5-Fluorouracil against the Pr or P systems. Nonpathogenic Hydralazine cold agglutinins, typically polyclonal IgM, Hydrochlorothiazide react only at very low temperatures: 0° to Insulin 4°Q8,io,22 l contrast, pathogenic cold agglu- Isoniazid n Melphalan tinins are almost always a monoclonal IgM Probenecid paraprotein (usually of the kappa light chain Quinidine type), and usually react at 30° to 32°C or high- er.8,10,22 Such temperatures can occur in the Streptomycin peripheral circulation under normal circum- Sulfonamides stances, allowing pathogenic IgM—and usual- Tetracycline ly complement as well—to attach to red blood Tolmetin cells. Although the IgM may elute from the red Drug adsorption (hapten) mechanism cell as it rewarms to 37°C, the complement Ampicillin molecules (primarily C3b) remain attached.8 Carbenicillin Then, macrophages in the reticuloendothelial Cephaloridine system, particularly in the liver, bind to and Cephalothin phagocytose the C3b-coated red cells. Cold Methicillin Penicillin Paroxysmal cold hemoglobinuria autoimmune Autoantibody mechanism Historically, paroxysmal cold hemoglobinuria hemolytic Alpha- was associated with congenital or late-stage Ibuprofen syphilis infection, but is now more common in anemia occurs Levodopa children with various viral infections (eg, Mefenamic acid chickenpox, measles, influenza virus, or other after Procainamide upper respiratory infections), or rarely coinci- Thioridazine M pneumoniae dent with a bacterial infection.2'23 pneumonia or The antibodies in paroxysmal cold hemo- globinuria, also termed "biphasic antibodies," mononucleosis are usually IgG against the P The autoantibody in warm autoimmune system.8'22 These antibodies produce positive hemolytic anemia is typically an IgG specifi- results in the Donath-Landsteiner test.2.24 cally active against components of the Rh Like cold agglutinins, biphasic antibodies typ- blood group system, which thus reacts against ically bind to red cells and bind complement all red cells except those that lack Rh antigens at low temperatures and cause hemolysis as (ie, red cells from persons with the rare Rh- the red cells rewarm to 37 °C. However, the null syndrome).8-10 Complement, as well as red cell destruction appears to be more IgA or IgM, may also be present on the red intravascular than extravascular. cell along with IgG, and these combinations may be associated with a more clinically Drug-induced immune hemolytic anemia severe hemolytic anemia. W-'6 Less commonly, Numerous drugs (TABLE 2) can induce immune only IgA or IgM is present. hemolysis. The incidence of drug-induced

92 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUM E 65 • NUMBER 2 FEBRUARY 1998 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. immune hemolysis is not known, but is esti- mated at approximately 1 case per million persons.8 Likewise, the incidence of drug- Selected clinical features induced antibody formation or a positive seen in immune hemolysis' DAT without associated hemolysis is also not FEAtURE PREVALENCE known. There are three basic mechanisms of drug- Anemia 85%--95% induced immune hemolytic anemia.18,10,25,26 The immune complex mechanism. Drugs 50%--55% such as quinidine form a complex with plasma Normal or low 10%--55% proteins and IgM, which binds nonspecifical- Hepatomegaly 45% ly to the red cell membrane. The drug adsorption mechanism. IgG 25%--35% antibodies against drugs such as penicillin and Lymphadenopathy 34% cephalosporins become adsorbed onto the red cell membrane. 10%--25% The autoantibody mechanism produces clinical and laboratory features similar to 'Average percentages based on reports in the warm autoimmune hemolytic anemia. literature (includes both primary and secondary cases of autoimmune hemolytic anemia) Methyldopa, levodopa, mefenamic acid, and procainamide are examples of drugs that can stimulate this mechanism. Patients with various combinations of these mechanisms have been reported. A • CLINICAL MANIFESTATIONS potential fourth mechanism, membrane mod- ification or nonimmunologic adsorption The signs and symptoms of immune hemolysis has so far not been shown to cause immune can vary considerably, depending on the hemolysis. rapidity of the hemolysis, the degree of ane- mia, and the presence of any underlying dis- The history Alloimmune hemolysis eases. 16,21,33,34 TABLE 3 lists some of the more may suggest Two situations can give rise to alloimmune common clinical manifestations. Shortness of hemolytic anemia: blood component transfu- breath, fatigue, dizziness, angina, pallor, and an immune sion and hemolytic disease of the new- jaundice may be present in anemia of any cause of born.27-31 In both, red cell alloantibodies are cause and are not unique to immune hemoly- formed after exposure to foreign red cell anti- sis. Some patients may be totally without anemia gens. The alloantibody is usually an IgG with symptoms, with immune hemolysis manifest- optimal reactivity at 37°C against a specific ed solely by laboratory tests. red cell antigen (eg, K, D, Jka).32 Thus, the The history may suggest an immune cause IgG alloantibody binds only to transfused red of anemia. Things to ask about: cells bearing the corresponding antigen. • Immune hemolysis or another immune In hemolytic disease of the newborn, the cytopenia (eg, autoimmune thrombo- mother becomes sensitized to foreign red cell cytopenia). antigens either after fetal red cells gain • Underlying autoimmune disorders (eg, access to her circulation, or after exposure to systemic lupus erythematosus). allogeneic red cells (eg, blood component • Lymphoproliferative disorders (eg, transfusion or sharing of needles in illicit chronic lymphocytic leukemia). drug use). Antibodies to the fetus's blood • Pregnancy complicated by hemolytic then cross the placenta to the fetus. The disease of the newborn. most common alloantibody in this disease is • Transfusions or transfusion reactions. anti-D, but almost any IgG antibody against • Recent viral or bacterial illnesses. any of the dozens of red cell antigens may be • Prescription or nonprescription drug implicated. use.

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Since cold antibodies can cause red cell tive DAT does not always indicate clinically in the cooler, peripheral circula- significant immune hemolysis: a few otherwise tion, a patient with cold antibody autoim- healthy blood donors have a positive DAT at mune hemolytic anemia may have signs and the time of donation. In general, standardized symptoms consistent with acrocyanosis or antihuman reagents for detecting Raynaud's phenomenon.8'9-21 Cold-induced IgM or IgA are not available except in cyanosis and mottling may be evident in the research laboratories. In cases of autoimmune ears, cheeks, fingers, nose, toes, or any region hemolytic anemia due to IgM or IgA, the of the skin exposed to cooler temperatures. DAT is still often positive owing to the pres- Pain and numbness may be present with the ence of complement on the red cell. cyanosis; dry gangrene has been reported in In cases in which the DAT is positive with rare, severe cases. Thus, persons with chronic anti-IgG antihuman globulin, the antibody cold autoimmune hemolytic anemia may have can be eluted off the red cell and its charac- more severe manifestations during winter. teristics further examined.8'10 The eluate can Similarly, cold may precipitate attacks of be tested against reagent red cells of known hemolysis and hemoglobinuria in paroxysmal antigenic phenotype to determine the speci- cold hemoglobinuria. ficity of the IgG antibody (eg, anti-D, anti-e, Unexplained fever is not uncommon in panagglutinating antibody, anti-I cold agglu- immune hemolysis, and is one of the most tinin). An elution study can also provide clin- common findings in hemolytic transfusion ically useful information in cases of known or reactions. Hepatosplenomegaly and lym- suspected red blood cell alloimmunization sec- phadenopathy may be variably present in one ondary to transfusion or pregnancy. third to two thirds of patients. Additional physical findings are not unique to immune Other tests hemolysis but may be important in identifying Determination of the antibody titer and any associated diseases (eg, a lymphoprolifera- optimum temperature of reactivity may pro- tive disorder). vide useful information in cases of cold agglu- tinin autoimmune hemolytic anemia. Unexplained • LABORATORY MANIFESTATIONS A Donath-Landsteiner test should be fever is performed in cases of suspected paroxysmal The direct antiglobulin or Coombs' test cold hemoglobinuria. common in The single most important test for establishing . Routine and auto- immune and characterizing an immune hemolytic mated blood cell counts indicate the degree of process is the direct antiglobulin test (DAT or anemia but are otherwise nonspecific. The hemolysis Coombs' test).4-7.9 Originally developed to be may be elevated used before transfusion to detect red cell because of . alloantibodies to minor blood group antigens The count is usually elevated (eg, Kell, Duffy, Rh) and thus provide an in hemolytic anemia (sometimes as high as increased margin of safety in crossmatching 30%), but it is normal or low in as many as blood, the DAT has proved valuable for other 25% ofcases.34-36 purposes as well, such as detecting, character- The peripheral blood smear may demon- izing, and investigating the red cell autoanti- strate increased spherocytes, polychro- bodies and drug-related antibodies associated matophilia, and occasionally, nucleated red with red cell hemolysis. cells (FIGURE 2).33 The can be The DAT uses standardized preparations high enough to be confused with hereditary of antihuman globulin to detect IgG or com- spherocytosis. Red cell agglutination or plement (the C3d component) coating the formation may be visually and gross- red cell. It can detect as few as 100 to 200 mol- ly evident in cold antibody autoimmune ecules of IgG per red cell,8'10 but in rare cases hemolytic anemia, and may cause problems in of immune hemolysis the DAT can be nega- obtaining accurate hemograms in automated tive if there are fewer than 100 to 150 IgG cell counters. molecules per red cell.8-35 Conversely, a posi- Liver function tests. The serum

94 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUM E 65 • NUMBER 2 FEBRUARY 1998 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. (particularly the indirect fraction) and (LD) levels may be elevated as part of the hemolytic process.5 Isoenzyme fractionation of the elevated LD in acute hemolysis may demonstrate increased LDj out of proportion to the LD2 fraction (ie, a "flip" in the LD isoenzyme pattern between LD^ and LD2). TABLE 4 lists some of the common laboratory signs of hemolysis. Examination of the bone marrow is gen- erally helpful only as part of the workup for an underlying lymphoproliferative disorder or other malignant process.

• DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes all causes of hereditary and acquired hemolytic anemia. Disseminated intravascular , thrombotic thrombocytopenic purpura, and the hemolytic-uremic syndrome should be ruled out. Congenital causes of hemolysis (eg, the hemoglobinopathies, hereditary spherocy- tosis) are often eliminated by a careful history and laboratory tests. Red cell enzyme deficien- cy disorders (eg, glucose-6-phosphate dehydro- genase deficiency) should also be considered. More than one hemolytic process may be present at the same time. Examples include a lymphoproliferative disorder with a cold anti- body autoimmune hemolytic anemia and a transfusion-induced alloantibody causing red cell hemolysis; sickle cell anemia with a super- imposed warm antibody autoimmune hemolyt- ic anemia; and glucose-6-phosphate dehydro- genase deficiency and a drug-induced immune hemolytic process. Evan's syndrome is the asso- ciation of autoimmune hemolytic anemia with autoimmune thrombocytopenia.37'38 Consultations with subspecialists in trans- * Of) o fusion medicine and are impor- tant early in the disease for diagnostic and therapeutic reasons.

• TREATMENT FIGURE 2. Abnormalities found on the peripheral smear in immune hemolytic anemia. Top, agglutination, as Corticosteroids occurs in the cold agglutinin syndrome. Middle, rouleaux Immunosuppressive therapy, initially with formation, so called because the clumped red blood cells corticosteroids, is usually the first line of treat- resemble a stack or roll of coins. Bottom, spherocytosis, in ment for autoimmune disorders of the red cell, which red blood cells have assumed a spherical shape due particularly in cases of warm autoimmune to loss of membrane. hemolytic anemia.4.9,39 A total daily dose of

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plicated cold agglutinin autoimmune hemolyt- ic anemia, paroxysmal cold hemoglobinuria, or Laboratory abnormalities drug-induced immune hemolysis.4.9.21 in red cell hemolysis

Hyperbilirubinemia (unconjugated/indirect) Cytotoxic drugs If corticosteroid therapy does not produce a Decreased serum remission or if the patient has a relapse, addi- Decreased serum tional immunosuppressive therapy may be needed. Cytotoxic drugs such as azathioprine Increased serum and cyclophosphamide have been used with Increased serum lactate dehydrogenase some success. In adults, cyclophosphamide 60 mg/m2 or azathioprine 80 mg/m2 per day can Increased (mild) serum aspartate aminotransferase be considered. Some investigators consider Increased serum free () cytotoxic drugs to be a third- or fourth-line 9 Increased urine hemoglobin (hemoglobinuria) treatment option.

Splenectomy In patients with warm autoimmune hemolytic 60 to 100 mg of prednisone produces a clinical anemia who do not respond to corticosteroid response in approximately 80% to 90% of therapy, splenectomy is often the second line patients with warm autoimmune hemolytic of therapy.4'9 However, only patients with IgG anemia. After 2 or 3 days of therapy, the first autoantibody (whose red cells are destroyed indication of a response may be a transient primarily in the spleen) would be expected to increase in the reticulocyte count, followed by benefit from splenectomy. Not all patients increases in the hemoglobin and respond to splenectomy, and those who show levels. The DAT (direct Coombs' test) may an initial response may relapse and require continue to be positive despite improvement additional immunosuppressive therapy. in other clinical and laboratory measures. The need to give pneumococcal Corticosteroids Most patients show a response to corticos- before the splenectomy, as well as the need for are the first teroids within 10 to 14 days, but the response any long-term prophylactic antibiotic therapy, may not be maximal until after 3 weeks of should be assessed in the individual patient. line of therapy.4'9 treatment Patients with life-threatening hemolysis Intravenous immunoglobulin may benefit from larger doses of corticos- A number of studies have examined the effi- for immune teroids, such as 100 to 200 mg of methy[pred- cacy of intravenous immunoglobulin in treat- hemolysis nisolone or an equivalent drug, given intra- ing autoimmune hemolytic anemia, primarily venously in divided doses over 24 hours.9 of the warm antibody type.40-4'' However, the Once the patient has responded to pred- success rate has been variable and not as nisone, the dose can be gradually reduced over encouraging as in other immune disorders. the ensuing weeks and months until the low- Flores et al45 found that 40% of 73 patients est possible dose is achieved. Alternate-day with warm autoimmune hemolytic anemia prednisone therapy should be started as soon responded to high-dose intravenous as clinically feasible after the patient is stable. within 10 clays, and Approximately 20% to 30% of patients that hepatomegaly and a low pretreatment achieve a lasting remission with prednisone hemoglobin level (< 7.0 g/dL) correlated with therapy, 50% continue to require some form of a positive response. Over half of their patients low-dose maintenance prednisone therapy for also received concomitant corticosteroid ther- months, and another 10% to 20% either do apy. These investigators concluded that intra- not respond to prednisone therapy or require venous immunoglobulin was useful as adjunc- unacceptably high doses.9 tive therapy in selected cases of warm autoim- Corticosteroid therapy has generally not mune hemolytic anemia but should not be shown clinical efficacy in patients with uncom- considered standard therapy.

96 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUM E 65 • NUMBER 2 FEBRUARY 1998 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. Other investigators40'46 suggested that tions with transfusion-associated alloimmune intravenous immunoglobulin may have hemolysis are acute renal failure and dissemi- greater efficacy in cases of autoimmune nated intravascular coagulation. Treatment is hemolytic anemia secondary to lymphoprolif- primarily supportive. The efficacy of corticos- erative disorders, or when used in combina- teroids or intravenous immunoglobulin in such tion with plasma exchange. Of note: one of cases has not been validated and cannot be rec- the side effects of intravenous immunoglobu- ommended as standard therapy. Additional lin therapy can be hemolysis.47-49 reviews on the treatment of hemolytic transfu- sion reactions should also be consulted.27"29 Folic acid Prevention and treatment of hemolytic Folic acid (1 mg per day) is usually recom- disease of the newborn are beyond the scope mended as long as there is ongoing hemolysis, of this review, and the interested reader is because this nutrient is necessary for red blood referred to excellent reviews elsewhere.7'9.30'31 cell maturation. Transfusion Alternate therapy for refractory cases Consultation with a Cyclosporine shows promise in autoim- specialist is extremely important in hemoly- mune hemolytic anemia refractory to conven- sis. Finding compatible blood for patients tional therapy, or when an alternative to with autoimmune hemolytic anemia can splenectomy is being considered, according to often be difficult and challenging.58-60 The several papers, mostly case reports.50-52 The antibody in patients with warm autoimmune dosage was usually 4 to 6 mg/kg/day by mouth, hemolytic anemia typically demonstrates and side effects were minimal. activity against all red cells (except Rh-null Plasma exchange has been used in a few red cells); therefore, all crossmatches will be cases, often as an adjunct to other therapies in "incompatible." Transfused red cells will also refractory cases.53~55 become coated with antibody and undergo Vincristine, danazol, and other therapies immune hemolysis at the same rate as the have been used in small numbers of refractory patient's own red cells.60 Thus, the beneficial cases.9'46'56'57 effect of transfusion in immune hemolysis Matching will be temporary. blood for Treating specific hemolytic diseases There is always a risk of an acute or Underlying diseases and infections associated delayed hemolytic transfusion reaction after autoimmune with autoimmune hemolytic anemia or parox- any transfusion, and an immune hemolytic ysmal cold hemoglobinuria should be treated, process may make such reactions more diffi- hemolytic and any drugs implicated or proven as a cause cult to detect and prevent. However, in anemia for the patient's immune hemolysis should be patients clearly in need of transfusion because stopped.46 of cardiovascular, central nervous system, or patients is In , avoiding cold pulmonary decompensation, red cells should difficult ambient temperatures is often all that is nec- not be withheld, even if crossmatch compati- 55 56 essary to provide symptomatic relief.9-21'46 In bility cannot be confirmed or guaranteed. ' addition, in hospitalized patients, intravenous Other important supportive measures in such solutions may need to be warmed before infu- patients include maintenance of blood vol- sion. Corticosteroids and splenectomy have ume with intravenous fluids and volume not generally been shown to be effective in expanders, oxygen therapy, and maintenance patients with cold antibody autoimmune of renal function. hemolytic anemia. Although transfusion can precipitate Transfusion reactions. When treating warm-antibody autoimmune hemolytic ane- proven or suspected alloimmune hemolysis sec- mia in otherwise-normal patients, it is less ondary to transfusion it is critical to discontin- clear whether transfusion alone increases the ue the transfusion, as there is a direct relation- severity of autoimmune hemolytic anemia in ship between morbidity and mortality and patients who already have ongoing immune alloimmune hemolysis. The primary complica- hemolysis.59-61

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98 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUM E 65 • NUMBER 2 FEBRUARY 1998 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. 43. Van Rhee F, Abela M. Coombs negative haemolytic anaemia responding to intravenous immunoglobulins in a patient with myelodysplastic syndrome. Clin Lab Haematol 1991; 13:99-101. 44. Ratko TA, Burnett DA, Foulke GE, Matuszewski KA, Sacher RA, and the University Hospital Consortium Expert Panel for off-label use of polyvalent intravenously administered immunoglobulin preparations. Recommendations for off- label use of polyvalent intravenously administered immunoglobulin preparations. JAMA 1995; 273:1865-1870. 45. Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol 1993; 44:237-242. The Cleveland Clinic Journal of Medicine uses 46. Collins PW, Mewland AC. Treatment modalities of autoim- the AMA's database of physician names and addresses. mune blood disorders. Sem Hematol 1992; 29:64-74. (All physicians are included in the AMA database, not 47. Brox AG, Cournoyer D, Sternbach M, Spurll G. Hemolytic just members of the AMA.) Only the AMA can update anemia following intravenous administra- tion. Am J Med 1987; 82:633-635. this data, and will accept a change-of-address notice only 48. Ryan ME, Webster ML, Statler JD. Adverse effects of intra- from you. venous immunoglobulin therapy. Clin Pediatr 1996; 35:23-31. Be sure your primary specialty and type of practice also are 49. Misbah SK, Chapel HM. Adverse effects of intravenous up-to-date on AMA records. This information is impor- immunoglobulin. Drug Safety 1993; 9:254-262. tant in determining who receives the Cleveland Clinic 50. Emilia G, Messora C, Longo G, Bertesi M. Long-term sal- Journal of Medicine. vage treatment by cyclosporin in refractory autoimmune haematological disorders. Br J Haematol 1996; If you have ever notified the AMA that you did not want 93:341-344. to receive mail, you will not receive the Cleveland Clinic 51. Hershko C, Sonnenblick M, Ashkenazi J. Control of steroid- Journal of Medicine. You can reverse that directive by noti- resistant autoimmune haemolytic anaemia by cyclosporine. fying the AMA. Please note that a change of address with Br J Haematol 1990; 76:436-437. the AMA will redirect all medically related mailings to the 52. Rackoff WR, Manno CS. Treatment of refractory Evans syn- drome with alternate-day cyclosporine and prednisone. new location. Am J Ped Hematol Oncol 1994; 16:156-159. 53. von Keyserlimgk H, Meyer-Sabellek W, Arntz R, Haller H. FOR FASTER SERVICE Plasma exchange treatment in autoimmune hemolytic ane- mia of the warm antibody type with renal failure. Vox • PHONE 312-464-5192 Sang 1987; 52:298-300. • FAX 312-464-5827 54. Hughes P, Toogood A. Plasma exchange as a necessary pre- • E-MAIL [email protected] requisite for the induction of remission by human immunoglobulin in auto-immune haemolytic anaemia. or send a recent mailing label along with Acta Haematol 1994; 91:166-169. new information to: 55. Silva V, Seder RH, Weintraub LR. Synchronization of plas- ma exchange and cyclophosphamide in severe and refrac- AMA tory autoimmune hemolytic anemia. J Clin 1994; DEPARTMENT OF DATA SERVICES 9:120-123. 515 North State Street 56. Pignon JM, Poirson E, Rochant H. Danazol in autoimmune haemolytic anaemia. Br J Haematol 1993; 83:343-345. Chicago, IL 60610 57. Fest T, de Wazieres B, Lamy B, Maskani M, Vuitton D, Dupond JL. Successful response to alpha-interferon 2b in a I NEW INFORMATION refractory IgM autoagglutinin-mediated hemolytic anemia. Ann Hematol 1994; 69:147-149. 58. Rosenfield RE, Jagathambal. Transfusion therapy for NAME autoimmune hemolytic anemia. Sem Hematol 1976; 13:311-321. 59. Salama A, Berghofer H, Mueller-Eckhardt C. Red blood cell STREET ADDRESS transfusion in warm-type autoimmune haemolytic anemia. Lancet 1992; 340:1515-1517. 60. Jefferies LC. Transfusion therapy in autoimmune hemolytic SB anemia. Hematol Oncol Clin NA 1994; 8:1087-1104. HCITY 61. Chan D, Poole GD, Binney M, Hamon MD, Copplestone JA, Prentice AG. Severe intravascular hemolysis due to autoan- tibodies stimulated by . Immunohematol 1996; 12:80-83.

ADDRESS: Ronald E. Domen, MD, Section of Transfusion Medicine, L-20, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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