Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Autoimmune hemolytic anemia 1. Warm antibody type Charles A. Horwitz To cite this article: Charles A. Horwitz (1979) Autoimmune hemolytic anemia 1. Warm antibody type, Postgraduate Medicine, 66:2, 167-173, DOI: 10.1080/00325481.1979.11715230 To link to this article: http://dx.doi.org/10.1080/00325481.1979.11715230

Published online: 07 Jul 2016.

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LABORATORY MEDICINE A Series

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Autoimmune hemolytic anemia 1. Warm antibody type Autoimmtme hemolytic anemia, characterized by evidence for autoimmunity against circulating RBCs, cao be classified into primary and secondary forms and warm and cold antibody types. The idiopathie warm type, discussed here, bas a variable clinical presentation and cao be suspected in most cases when a positive direct antihuman globulin test is obtainect. Representative cases illustrate typical laboratory fmdings and treatment protocols in this disorder. Drug-induced and cold antibody types will be discussed in upcoming issues.

Charles A. Horwitz, MD

Hemolytic anemia is usually characterized by accelerated destruction of circulating RBCs and evidence of increased blood production by a responsive bone marrow. Table 1 lists common laboratory findings in hemolytic anemia. In practice, if bleeding or blood loss is excluded, documentation of persistent reticulocytosis without an associated rise in the level of hemoglobin or hematocrit implies a hemolytic process. Autoimmune hemolytic disease or anemia (AIHA) is characterized by an increased rate of destruction of the patient's own RBCs and of normal transfused RBCs. Practical confirmation is obtained by demonstrating evidence of autoimmunity against RBCs, usually by a positive direct antihuman globulin test or by demonstration of circulating autoantibodies against erythrocytes. AIHA can be classified into warm and cold antibody types as weil as into primary and secondary forms. "Primary" refers to idiopathie disease, in which no underlying disease is apparent, white "secondary" refers to a hemolytic pro-

or fatigue and are then found to be anemie. Hepatosplenomegaly is seen in one third to one half of the cases, while lymphadenopathy is only an occasional feature (10%). Jaundice is seen in less than 50% of patients. The hematocrit reflects a variable degree of anemia, and the bone marrow aspirate, a compensatory erythroid hyperplasia. Bilirubin values are often elevated, mainly the unconjugated fraction. When the total bilirubin is greater than 4.0 mgjdl, the conjugated fraction may also be elevated. Serum lactate dehydrogenase (LDH) activity is increased, with isoenzyme studies showing increases in LD H fractions 1 and 2. Levels of other enzymes, such as SGOT and alkaline phosphatase, are usually normal or only slightly elevatedY One of a series of articles on ordering and lntetpretlng laboratory tests Mechanism of erythrocyte dewhlch began ln Apr111978 struction-Immune-mediated fragmentation of erythrocytes and pathic warm antibody type of erythrophagocytosis are important AIHA; other types will be discussed aspects of hemolysis in warm AIHA (figure 1), where complement often in subsequent articles. does not play a major role in the cytologie process. lgG-coated erythOinical and laboratory aspects The onset of idiopathie warm AIHA rocytes interact with phagocytic is insidious, and the clinical picture cells in the reticuloendothelial sysand course vary. Patients often seek tem, leading to fragmentation or medical advice because of malaise "holes" in the cell membranes. The continued

cess appearing in association with underlying disease or as a consequence of drug therapy. The diagnosis of primary, or idiopathie, AIHA should be made with caution, as a small percentage of such patients will eventually manifest an underlying disease. 1 This article considers the idio-

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LABORATORY III!DICINI! CONTINUED

ln wann AIHA, the hematocrit retlects a variable degree of anemia and the bone marrow Mpirate shows a compensatory erythroid hyperp18$ia.

Table 1. Common lebonttory

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flndlngs ln hemolytic anemia Decreased levels of hemoglobin or hematocrW lncreased reticulocyte cou nt* Anhaptoglobinemia • Positive direct antihuman globulin test• Spherocytosis • Erythroid hyperplasia of bone marrow Elevated bilirubin levels, mainly unconjugated Hemoglobinuria or hemosiderinuriat lncreased plasma hemoglobin levelt lncreased fecal or urinary urobilinogen level Associated thrombocytopeniat Decreased in vivo survival of RBCs Poikilocytosis Leukoerythroblastotic reaction *Most useful for diagnosis of warm antibody type of autoimmune hemolytic anemia. tMay or may not be present.

distorted erythrocytes then become spherocytic and are lysed in the spleen. Direct antihuman g/obulin test (DAT)-With most commercially available antihuman globulin serums, at least 300 to 500 lgG molecules per RBC are required for a positive DAT. With polyspecific antiserums, the test is positive in most primary cases of warm AIRA. With monospecific reagents, the "coating substances" can be characterized as IgG alone in 30% to 40% of cases, as

Charles A. Horwitz Dr Horwitz is associate pathologist, Mount Sinai Hospital, and associate professor of laboratory medicine and pathology, University of Minnesota Medical School, Minneapolis.

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Serologie specifzcity-Classically, circulating autoantibodi~ from patients with idiopathie warm AIRA react with most types of erythrocytes. Autoantibody specificity is best determined by using eluates from patients' cells rather than serum. Sophisticated studies, performed mainly by Issitt, Vos, and co-workers3•5 using panels of rare RBCs such as Rh null, -D-, U Neg, and Wrb Neg, have, more accurately defined the specificity of autoantibodies in warm AIRA. The autoantibodies can have a simple specificity, such as only anti-c or anti-e, or less commonly, anti-En•, LW, U, or Jka. This pattern is seen in early disFigure 1. Blood smears from patient with warm autoimmune hemolytic anemia show- ease but in no more than 10% to 20% ing (a) spherocytes and (b) erythrophagocyof patients. In the remaining 80% to tosis. 90%, more complex specificities, usually in the Rh system, are enlgG plus complement in 50% of countered; ie, the antibodies can be cases, and as complement alone in classified by their reactivity with 10% to 20% of cases.3 As a general normal Rh (nl), partially deleted Rh rule, complement is not identified on (pdl), or deleted Rh (dl) cells as to RBC samples from patients with anti-nl, anti-pdl, or anti-dl types! early disease; however, following reAutoantibodies may be found lapses and multiple transfusions, it alone, or more commonly, in associis detected along with lgG. The ation with other antibodies. In a DAT is important in establishing study of 87 patients with warm the diagnosis of AIRA, but is not AIRA, Issitt and· co-workers5 found useful in monitoring the effects of autoanti-dl in 62 (in 13 as the sole treatment. autoantibody, and in 49 in combinaIndirect antihuman g/obu/in test tion with others). Thirty-four of the (IAT)-This test is positive in less 62 patients also had a~ti-Wrb, rethan 50% of patients with early dis- cently described as a common autoease but in more than 75% of those antibody in warm AIRA. While with long-standing disease. Patients rare cell panels allow more accurate without circulating autoantibodies, definition of autoantibody specificie, with a negative lAT, generally ity, this information is seldom of respond more rapidly to therapy. practical value. In fact, it may only

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As a general rule, complement is not iclentitied by the direct antiglobUiin test in patients With . .,~y disease; tollowing relapses and multiple transfusions, it is detectecll along with lgQ.

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Table 2. Pertinent cllnlcal and labondory data ln 50-year-old man wlth Idiopathie wann autolmmune hemolytlc anemie treeted wlth prednlsone and then splenectomy

Cele

Clinlcal

Hemoglobln

course

(gm/dl)

Total b111rub1n blns (mg/cl) (mg/dl)

Retlculocyte Haptoglo-

count ('1.)

Oct12

Postural 7.2 hypotension; jaundice(2wk): hepatosplenomegaly: liver biopsy: hemosiderosis

Oct16

6.2

8.1

Oct25

11.1

23.5

Nov4

11.6

9.0

Nov-Apr

Remission (6mo)

>11.0

May

Relapse, with fever, malaise

7.2

9.2

May

Splenectom y

10.3

4.7

Jun

Remission (18mo)t

>11.7

Absent (600

30-40

8.3

9.2

Absent

1.1

243

20

413

20

Well-compensated warm AIHA

20

Exploratory laparotomy: retroperitoneal histiocytic lymphomat

Feb 1972

Fractured femur

6.8·

22.0

Absent

3.3 (0.5 direct)

Jun 1972

Pleural effusion, mass in right lower quadrant of abdomen

7.5·

21.8

Absent

2.3 (0.4 direct)

Preillness data showing prior goodhealth Bone marrow: lymphocytosis (35%), nondiagnostic; peripheral blood smear: spherocytes

•positive direct antihuman globulin test due to lgG coating substance. tFinal diagnosis: malignant lymphoma. histiocytic type, with secondary warm Al HA. Patient died of complications of radiotherapy in late 1972.

complete remission in 20% of cases and steroid-dependent remission in 55% to 60%. In the latter group, low dosage is adequate in 40% to 50% of cases and high dosage is necessary in 10% to 15%. In 15% to 20% of cases, steroids do not produce a response. If no response occurs within three weeks, steroid therapy will be unsuccessful and splenectomy or use of immunosuppressive agents is in-

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dicated. Blood transfusion-Blood transfusion should be avoided in patients with idiopathie warm AIHA whenever possible. In most of these patients, the anemia is weil compensated, so even if hemoglobin values fall to 5.0 or 6.0 gmfdl, transfusion can be avoided and steroid therapy attempted. Usually, transfusion of donor

cells incompatible with autoantibodies will not cause a frank hemolytic transfusion reaction, since the transfused cells generally sul"Vive as weil as the patient's own cells. Donor cells incompatible with alloantibodies are quite capable of producing significant hemolytic transfusion reactions. Thus, when blood transfusion is unavoidable, an effort should be made to detect alloanticontinued

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Bloocl transfusion should be avoidecl in patients with idiopathie warm AIHA. If this is not possible, an effort should be made to detect allo· antiboclies as weil as autoantiboclies, since the former can cause significant hemolytic transfusion reactions.

bodies as weil as autoantibodies in the patient's serum. Sirice autoantibodies in AIHA are broadly reactive with most donor samples, underlying and potentially life-threatening alloantibodies may be easily "masked." Severa! methods, none entirely satisfactory, are available to detect underlying alloantibodies. The serum often must be absorbed against washed, eluted, enzymetreated, packed cells from the patient to remove ali potent autoantibodies. The absorbed serum can then be retested in the cross-match or against known panel cells to detect residual alloantibodies. This method can be used only if the patient bas not bad a transfusion recently (within three months). 3•7 Representative cases Sequential data from two patients with warm AIHA are presented in tables 2 and 3. In both cases, the hemolytic process was initially suspected after active bleeding was excluded by appropriate laboratory studies and evidence of bone marrow responsiveness was obtained in the form of elevated reticulocyte counts. An autoimmune process was then suggested by strongly positive direct and indirect antiglobulin tests. In the first patient (table 2), hemoglobin levels rose promptly after prednisone therapy was initiated. The remission continued for the next six months, after which relapse occurred and a splenectomy was eventually required. During the next 18 months, a low dosage of

prednisone (6 mg/day) produced clinical remission, with hemoglobin levels greater than 11.7 gmjdl and normal serum haptoglobin levels. The second patient (table 3) presented with an AIHA that was only partially controlled by moderate to high dosages of prednisone. Initially, a search for underlying disease was unsuccessful. The hemolytic process persisted during the next six to nine months despite prednisone therapy (20 to 40 mg/ day). During this period, hemoglobin values varied from 6.8 to 8.3 gmjdl; haptoglobins were depleted; and reticulocyte counts and total bilirubin levels, as weil as LDH activity, remained elevated as part of a well-compensated AIHA. Ten months after onset, the appearance of an abdominal mass and pleural effusion prompted an exploratory laparotomy, which disclosed a retroperitoneal malignant lymphoma of histiocytic type. In retrospect, the inability to control the ongoing hemolytic process with significant amounts of prednisone may have been related to the underlying malignant lymphoma. Summary Diagnosis of the idiopathie warm antibody type of autoimmune hemolytic anemia requires evidence for hemolysis and autoimmunity against RBCs, ie, a positive direct antihuman globulin test. In addition, underlying disease states and drug tberapy must be excluded as causative factors.

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Therapeutic measures are aimed at suppression of autoantibody production and include steroids (usually prednisone in tapering dosage~ splenectomy, and less commonly, immunosuppressive agents. Next rnonth: Drug-induced autoirnrnune hernolytic anemia. Series coordinator: M. Desmond Burke, MD, associate pathologist, Mount Sinaï Hospital, and associate professor of laboratory medicine and pathology, University of Minnesota Medical School, Minneapolis. Address reprint requests to Charles A. Horwitz, MD, Mount Sinaï Hospital, 2215 Park Ave, Minneapolis, MN 55404.

References 1. Swisher SN: Acquired hemolytic anemia due to warm-reacting autoantibodies. In Williams WJ et al (Editors): Textbook of Hematology. New York, McGraw-Hill Book Co, 1977, pp 585-596 2. Pirofsky 8: Clinical aspects of autoimmune hemolytic anemia. Sernin Hematol 13:251-265, 1976 3. Issitt PD: Auto-immune hemolytic anemia. Am J Med Technol40:479-495, 1974 4. Vos GH et al: Specificity and immunoglobulin characteristics of autoantibodies in acquired hemolytic disease. J Immunol 106: 1172-1176, 1971 S.lssitt PD et al: Anti-Wrb and other autoantibodies responsible for positive direct antiglobulin tests in !50 individuals. Br J Haemato166:5-18, 1976 6. Gilliland BC et al: Red cell antibodies in acquired hemolytic anemia with negative antiglobulin serum tests. N Engl J Med 285: 252-256, 1971 7. BeU CA, Stroup M: Autoimmune problems. In: Transfusion With "CrossmatchIncompatible" Blood. Presented by American Association of Blood Banks Committee on Workshops, November 1975, Chicago, Illinois. Washington, DC, American Association of Blood Banks, 1975

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Autoimmune hemolytic anemia. 1. Warm antibody type.

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