The Treatment of Auto-immune Hemolytic Anemia

The Treatment of Auto~immune Hemolytic Anemia From the Department of Medicine, Tufts University School of Medicine, and New England Center Hospital, Boston, Massachusetts

ROBERT SCHWARTZ, M.D. Assistant Professor of ill edicine; Research A, sociaie, Blood Research ],alioraiory and Assistant Hernatoiogisi

WILLlAM DAMESHEK, M.n., F.A.C.l'. Professor of 1\1 edicine; Chief of H ernai%gy and Senior Physician

AUTO-IMMUNJ'; HEMOLY'l'IC ANEMIA (A. LH.A.) is a disorder in which premature destruction of red blood cells is brought about by antibodies generated by the patient's own antibody forming tissues. It thus differs from iso-immune hemolytic anemia, such as erythroblastosis fetalis or hemolytic transfusion reactions, in which red cdl destruction is caused by antibodies transferred from another individual. A.I.H.A. may be acute, as in the type which occasionally occurs in the convalescent period of viral pneumonia or in infectious mononucleosis; most patients, however, run a chronic or subacute course. The disorder may occur in association with anothcr disease, such as chronic lymphocytic leukemia, lymphosarcoma, systemic lupus erythcml1tosus (S.L.E.) l1nd ulccrative colitis, or it ml1y be completely "idiopl1thic." Not infrequently A.I.H.A. is the initial ml1nifestation of another disease l1nd is followed within months or years by the appearance of chronic lymphoeytie leukemil1 or S.L.E. Rarely, a positive Coombs' test is found in the hemolytic anemia of thrombohemolytic thromboeytopenic purpura, in which thrombocytopenic purpura and neurological disturbances are also present, although not necessarily simultaneously. The antibodies occurring in A.I.H.A. are of two main types: those which react best at 37° C. (warm antibodies) and those which are most Aided by United States Public Health Service Grant E-3091 and Atomic Energy Commission Grant AT( 30-1 )2032.

1323

1324

ROBERT SCHWARTZ, WILLIAM DAMESHEK

active at 4° C. (cold antibodies). The "cold" hem agglutinin type is rare and constitutes less than 10 per cent of all the cases of A.I.H.A. seen in our clinic; it is usually a very chronic disorder occurring in older individuals. The results of therapy in this type of A.I.H.A. are usually poor. The hallmark of A.I.H.A. due to warm auto-antibodies is a positive direct antiglobulin test; the indirect test mayor may not be positive . .Jaundice, splenomegaly and reticulocytosis are regular, but not invariable featureH of the condition, but anemia, positive antiglobulin tests and Hhortened red cell survival time are always found. THERAPY

Before embarking on a program of therapy in a given ease of the disease, every effort should be made to establish the "idiopathic" or "symptomatic" nature of the condition. To be sure, this may be impossible in eases that have either developed very rapidly or are first seen with extremely low hemoglobin values. In the others, a careful preliminary survey to exclude the lymphoproliferative disorders (infectious mononucleosis, chronic lymphocytic leukemia, and lymphosarcoma), carcinoma, dermoid cyst, systemic lupus, and thrombohemolytic thrombocytopenic purpura should be made. Blood Transfusions

The purpose of transfusion therapy in anemia, regardless of its etiology, is to restore the oxygen-carrying capacity of the blood to the point where symptoms of anoxia are relieved. Tolerance of anoxia is highly variable and depends upon the rate of development of anemia, the age of the patient, the rate of oxygen consumption, the state of the small blood vessels and other factors. Chronically anemic children tolerate extreme degrees of anoxia with amazing ease; adults with very slowly developing pernicious anemia may be entirely asymptomatic with hemoglobin levelH of 7 gm. per cent. On the other hand, angina pectoris may develop in older patients with only minor degrees of anemia. Thus, the main guides in transfusion therapy in A.I.H.A. are symptomatology and the ability of the patient to carry on his activities. Although earlier reports indicated "cure" of A.I.H.A. by blood transfusions,4 it is now recognized that this form of treatment is only palliative and that the survival time of transfused red cells is distinctly reduced as compared to the normal. On the other hand, the quiek transfusion of a seriously anemic patient is often essential. Palliation by transfusion should thus depend on the total clinical assessment of the patient, rather than on adherence to hemoglobin or hematocrit levels alone. Certainly, the practice of transfusing a patient "up to normal" is outmoded, wasteful and risky. Since by definition patients with A.I.H.A. have a positive direct anti-

The Treatment of A uta-immune H emolytic A nemia

1325

globulin test, the "minor" cross-match (donor's serum vs. recipient's red cells) always shows an incompatibility when the cross-matching technique employs the antiglobulin test. If, in addition, the indirect antiglobulin test is positive or if auto-agglutinins are present, "direct" cross-matching of blood is impossible. Furthermore, these serologic abnormalities frequently interfere with Rh typing. However, it is almost always possible to type the patient's ABO group correctly. When faced with the problem of transfusing patients with positive antiglobulin tests or autoagglutinins our practice is to administer type-specific Rh-negative blood. Thus, a patient with A.I.H.A. with positive direct and indirect antiglobulin tests who is blood group A receives type A Rh-negative blood. In the rare situation in which even ABO typing is impossible or if the slightest uncertainty exsits about the patient's major blood group, 0, Rh-negative blood is given. The practice of administering the "least incompatible blood" (as determined by the cross-matching procedure) does not seem to have a special advantage. Under special circumstances, the compatibility of blood may be checked by an in vivo cross-match in which small amounts of prospective donor blood (1 to 2 cc.) labeled with Cr51 are injected into the patient; samples are takcn at 15, 30 and 45 minutes. Disappearance of a majority of the labeled cells within minutes indicates incompatibility. We have found that washing of the donor blood is usually unnecessary since abnormal antibodies are not present in the donor blood. On the other hand, there are occasional cases in which the patient reacts against a plasma constituent of transfused blood. In this circumstance, washed red cell transfusions may be highly desirable and even life-saving. If cold hemagglutinins are present, the blood should be warmed to 37° C. in a water bath prior to administration. We prefer to use blood which has not been stored much over seven days, since the survival of red cells diminishes during storage, and since the recipient already has a mechanism which will further shorten the survival of transfused erythrocytes. Packed red cells may be useful in elderly individuals with cardiac or renal disease or in young children in whom the volume of the transfusion is critical. Corticosteroids

The mainstay of therapy in A.I.H.A. is the group of adrenocorticosteroid hormones, which probably act to diminish abnormal antibody production. The administration of adequate doses of these compounds will result in the rapid improvement of the majority of patients with A.I.H.A. due to warm antibodies. On the other hand, hemolytic anemia due to cold auto-antibodies is frequently resistant to corticosteroid therapy or ACTH. In patients with chronic lymphocytic leukemia or lymphosarcoma with A.I.H.A. corticosteroid therapy will result not only

1326

ROBERT SCHWAH'rZ, VVILLIAM DAMESIIEK

in improvement of the hemolytic anemia, but will also cause a rapid reduction in size of the spleen and lymph nodes. In chronic lymphocytic leukemia, the lymphocytosis may persist for several months, despite amelioration of the hemolytic anemia. The lymphocytolytic effect of corticosteroids may be extremely rapid and the development of hyperuricemia with uric acid renal stones is a real hazard; we, therefore, routinely alkalinize the urine of these patients with sodium bicarbonate (3 to 5 gm./day) during the day and Diamox (250-500 mg.) at bedtime. The urine pH is checked at frequent intervals with nitrazine paper; a value above 5.5 should be achieved and maintained. Our usual practice in cases of A.I.H.A. due to warm antibodies is to begin with prednisone in a dosage of 1 to 2 mg./kg./day. This dose is continued for approximately seven to 14 days, at which time signs of hematologic improvement should be evident. There is frequently a very rapid restoration of the general well-being of the patient, even before signs of improvement of the blood appear. The earliest indication of the effects of corticosteroid on the hemolytic process is usually a reduction in reticulocytosis, although at times an increasc in the reticulocyte count occurs initially. Polymorphonuclear leukocytosis, which reflects the hyperactivity of the bone marrow in this condition, is next to disappear. Within seven to ten days the hemoglobin value increases and the degree of bilirubinemia diminishes. \Vhen the hemoglobin value reaches 10 to 11 gm. per cent, the dose of prednisone is reduced at a rate of approximately 12.5 mg./day until a dosage of 15 to 20 mg./day is reached. Thereafter, the lowest dosage of prednisone necessary to maintain the remission (2.5 to 15 mg./day) is ascertained by trial and error. As a rule, long-term maintenance therapy with small doses of prednisone is required; discontinuance of maintenance therapy results in relapse in over 70 per cent of the patients. 2 The criteria of successful therapy are restoration of hemoglobin or hematocrit values to normal and absence of signs of hemolysis, as judged by the size of the spleen, the reticulocyte count, serum bilirubin value and the Cr51 _ tagged RBC survival time. A few patients will continue to show signs of mild hemolysis, even though their hemoglobin values are normal and they are asymptomatic. These patients are considered to have a compensated hemolytic state. In some patients, especially those who have had hemolytic disease for lengthy periods, the spleen size may diminish very slowly or not at all. The effects of corticosteroid therapy on the serologic abnormalities are variable. The serum antibodies, sueh as auto-agglutinins and the indirect antiglobulin test, diminish rapidly, and usually within a month or two they are no longer detectable. However, the erythrocyte-coating antibody responsible for the direet antiglobulin test frequently remains

The Treatment of A uta-immune H emolyt1:C A nem1:a

1327

positive throughout the course of the diH!'ase and in sOllle patients it remains apparently as a permanent "immunologic scar," even though they are otherwise completely well. Experimental evidence indicates that, while the direct antiglohulin test remains positive, the actual amount of erythrocyte coating antibody diminiHhes with therapy.! The hazards and side effects of corticosteroid therapy are well known and must be watched for with partiwlar (:are in patients on long-term maintenance therapy. The presence of peptic ulcer or diabetes does not, as a rule, constitute a strict contraindication to initiating therapy in this serious dis(~ase. Intensive ulcer therapy and a daily cheek of the stool for occult blood are essential if peptic ulcer is a complication; meticulous observation of the blood and urine glucose levels, proper diet and supplementary insulin are needed in diabetic patients. The essential feature in the care of these patients is awareness on the part of the physician. Splenectomy

The indication for splenectomy in A. LH.A. is failure of adequate medical therapy to control the disease. Since the rate of remission with corticosteroids is approximately 90 per cent and the relapse rate following splenectomy for A.I.H.A. is close to 50 per eent ll , every effort should be made to control the disease medieally. The judicious use of transfusions and wrticosteroids will allow the physician ample time to observe the patient and properly assess his response to medieal treatment. "Emergency splenectomy" is surely unwarranted in this condition. By "adequate" therapy is meant that dose of corticosteroid whieh will induee and maintain a remission. In a few eases ACTH in large doses has been sueeessful where eortisone or its synthetie derivatives have failed. Patients who ean be maintained on small doses of prednisone or other steroid eompounds without the appearance of side effects should not undergo splenectomy. Thus, the indications for splenectomy in our clinie are: (1) failure of an adequate trial of cortieosteroids or ACTH to induee a remission, (2) inability to maintain the remission with small (5 to 15 mg./day) doses of corticosteroids, and (3) development of untoward side effeets such as osteoporosis, diabetes and hypertension. Spleneetomy should not be performed in patients with chronic lymphocytic leukemia, widespread lymphosarcoma or other malignaneies exeept in unusual eireumstanees. In the rare cases of A.I.H.A. with uleerative colitis, partial coleetomy rather than splenectomy may cure the hemolytic anemia. Similarly, in the unusual condition in which A.I.H.A. oeeurs with a dermoid cyst of the ovary, removal of the ovarian tumor will result in a cure. Spleneetomy in A.I.H.A. due to eold agglutinins usually fails, probably beeause the prineipal organ which sequesters red blood cells in this condition is the liver.

1328

ROHEH'l' SCHWAHTZ, \VILL[AM DAMI<;SHI"K

The use of body s(:anning radioisotope techniques in hemolytic Htates has been suggested as of value in obtaining information concerning the site of red cell destruction. 3 It has been stated that the spleen: liver ratio, normally 0.8 to 1.2, is increased to more than 2.5 in those patients who respond favorably to splenectomy; how(~ver, when more than one-half of the Cr51 radioactivity is found over the liver, the chance of a sueeessful splenectomy may be small. This method may have its optimal value in cases in which the decision for spleneetomy is difficult. On the other hand, correlation between test results and operative results has thus far been meager, suggesting some caution in interpreting test data. The preparation of patients with A.I.R.A. for splenectomy requires no special maneuvers except careful attention to preoperative and postoperative corticosteroid administration, since all of these patients have been on high-dose steroid therapy. In no instance should corticoHteroid be omitted before, during or directly after operation, even in patient;; who have received the material months previously. At operation the gallbladder should be inspeeted since the incidence of cholelithiasis is high in this condition. Some surgeons prefer to n:move the gallbladder routinely at the time of splenectomy since acute eholecytitis in the immediate postoperative period is not uncommon in this disease. The postsplenectomy blood picture has been well described,9 but what is not generally appreciated is that reappearance of hemolysis (or bleeding) in the splenectomized patient may produce bizarre changes in the blood, including marked normoblastemia and extreme degrees of reticulocytosis and leukocytosis. Other Forms of Therapy, including Antimetabolites

As a rule, patients with A.I.H.A. due to warm auto-tlntibodieH (:an he quickly brought under control with corticosteroids, and small daily maintenance doses of these materials will maintain the remiHsioJl indefinitely. Occasionally, however, patients are seen who are refraetory to even very large doses of prednisone or in whom its administration is contraindicated. In some patients neither eorticosteroids nor splenectomy ameliorates the disease. For these rpasons It variety of other agents have b(~{~n tried in A.T.H.A., parti(:ularly ill th('s~: "hard-core" patients. Alkylating agent;;, such as nitrogen Illu;;tanl and triethylcne melamine (TEM) have been occasionally helpful; however, the results art' unpredictable and erratic and this form of therapy has been more or less abandoned. Radioactive gold has also been tried, but without uniform success. ID In a few eases the administration of heparin has resulted in definite improvement. 5 Its mode of action in this disorder is obscure. Our laboratory has recently explored the possibility of using antimetabolites in this condition, since purine analogues such as 6-mer-

The Treatment of Auto-immune Hemolytic Anemia

1329

captopurinc (6-MP) and thioguanine are capable of suppressing antibody formation. 6, 8 As with the corticosteroids, these agents presumably act against the proliferation of abnormal immunologic ally competent cells, the source of antibody production. Nine of 15 patients treated with these compounds responded favorably; of these 15, ten were corticosteroid "failures," and in five of these, good responses to purine antagonists took place. 7 These drugs are potentially highly toxic and should be used with great caution; meylotoxicity and gastrointestinal side effects arc troublesome. However, in the patient who has failed to respond to corticosteroids and splenectomy, they may be of great value. The usual dosage of 6-MP or thioguanine employed is 2.5 mg./kg./day in divided doses. This dose level is maintained until hematologic improvement ensues; following this, the dose is tapered to a maintenance level of 50 to 100 mg./day. In some patients at least four to six weekH of antimetabolite therapy are required before remission becomes evident; ill most, however, a favorable response appears within two to three weeks. Patients treated with these agents must be followed with meticulous attention to the blood counts, since leukopenia or thrombocytopenia may occur. We have not found that mild leukopenia (4000 to 5000/mm. 3 ) is an indication to interrupt treatment. Lower values are, however, hazardous. A few patients who cannot tolerate 6-MP because of gastrointestinal reactions may be able to take thioguanine without difficulty. SUMMARY

Auto-immune hemolytic anemia, occasionally a temporary disturbance, is almost always chronic, and once begun, continues indefinitely. It may be "idiopathic," but underlying disorders such as chrollic lymphocytic leukemia and systemic lupus may be found. Acute, fulminating cases may require urgent therapy with transfusions and large, even massive doses of corticosteroids. The more indolent cases usually respond to corticosteroids as the sole therapeutic method. Splenectomy, historically the first therapeutic method used in this disease, should be reserved for those cases not responding to all medical measures or developing serious reactions to medications. Recently, we have demonstrated that the 6-mercaptopurine group of antimetabolites may he effective in some cases not responding to the corticosteroids. Thus another "medical" method has been added to our armamentarium, It should be recognized that the long-range prognosis in auto-immune hemolytic anemia should always be "guarded" with various possibilities lurking in the background, Thus, enthusiasm for splenectomy as a method for quick cure must be discounted and operation reserved as a measure of last resort, The past quarter century has surely seen some

1830

ROBERT SCHWAR'rZ, '¥ILLIAM DAMESHEK

dramatic advances both in our knowledge of the disease and its management. REFERENCES 1. Costea, N., Schwartz, R., Constantoulakis, M. and Dameshek, W.: Use of

2. 3. 4. 5. 6. 7. 8. 9. 10. H.

Radioactive Antiglobulin for the Detection of Erythrocyte Sensitization. Blood, in press. Dameshek, W. and Komninos, )/;. D.: Present Status of Treatment of Autoimmune Hemolytic Anemia with ACTH and Cortisone. Blood 11: 648, 1956. Jandl, J. H., Greenberg, M. S., Yonemoto, R H. and Castle, W. B.: Clinical Determination of the Sites of Red Cell Sequestration in Hemolytic Anemias. J. Clin. Invest. 35: 842, 1956. Lederer, M.: Form of Acute Hernolytic Anemia Probably of Infectious Origin. Am. J. M. Sc. 170: 500, 1925. McFarland, W., Galbraith, R. G. and Miale, A. Jr.: Heparin Therapy in Autoimmune Hemolytic Anemia. Blood 15: 741, 1960. Schwartz, R. and Dameshek, W.: Effects of 6-Mercaptopurine on Homograft Reactions. J. Clin. Invest. 39: 952, 1960. Schwartz, R. and Dameshek, VV.: Treatment of Autoimmune Hemolytic Anema with 6-Mercaptopurine and Thioguanine. Blood 19: 4, 1962. Schwartz, R., Eisner, A. and Dameshek, W.: Effect of 6-Mercaptopurine on Primary and Secondary Immune Responses. J. Clin. Invest. 38: 1394, 1959. Singer, K., Miller, E. B. and Dameshek, W.: Hematologic Changes Following Splenectomy in Man. Am. J. M. Sc. 202: 171, 1941. Tocantins, L. M. and Wong, G. C.: Hadioactive Colloidal Gold in the Treatment of Severe Acquired Hemolytic Anemia Refractory to Splenectomy. Progr. in Hematol. 1: 138, 1956. Welch, C. S. and Dameshek, W.: Splenectomy in Blood Dyscrasias. New England J. Med. 242: 601, 1950.

Pratt Clinic-New England Center Hospital 171 Harrison Avenue Boston 11, Massachusetts