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Immune Thrombocytopenic Purpura
Symposium on Oil Helnatologic Hemat%gic Disorders SyrnposiUln
Immune Thrombocytopenic Purpura Charles A. Koller, M.D.*
Immune thrombocytopenic purpura is a hemorrhagic disorder in which thrombocytopenia is associated with increased peripheral de7, 10. 17,20 It is not a single disorder but a syndrome of struction of platelets. 7,10,17,20 different diseases, all of which have in common shortened platelet survival owing to the presence of an antiplatelet antibody. The bone marrow in immune thrombocytopenic purpura has a normal to increased number ofmegakaryocytes, indicative of normal to increased production of platelets. Most cases of immune thrombocytopenic purpura are secondary to an identifiable etiologic agent. The subdivisions of immune thrombocytopenic purpura are shown in Table 1.
General Considerations In an otherwise healthy person without any bleeding manifestations, one must first be suspicious of spurious thrombocytopenia. Before proceeding, it is wise to repeat a low platelet count and then to evaluate the blood film under the microscope, using a film made without anticoagulants. Four or more platelets per high power field is considered adequate. When evaluating a bone marrow aspirate, megakaryocytes are probably adequate if several can be found without much difficulty. A patient with spleen enlarged for any reason can have thrombocytopenia as a result of increased splenic sequestration. Generally speakiIlg, speaking, the larger the spleen, the lower the platelet count. The symptoms of thrombocytopenia are independent of the cause of thrombocytopenia and vary inversely with the platelet count.:lo count.~~;) It is unlikely that a bleeding diathesis will be present with platelet counts above 50,000 to 100,000. Excessive bleeding with stresses, such as trauma or surgery, is possible in the 20,000 to 100,000 range. Spontaneous bleeding, with petechiae and purpura of the skin, epistaxis, bleeding gums, and bleeding from other sites, is common with platelet counts below 20,000 and especially, below 5,000. Finally, given a certain low platelet count, the risk of life-threatening bleeding increases as the patient's age increases."H) increases. Hi ';'Assistant Professor, Division of Hematology and Oncology, Simpson Memorial Research "Assistant Institute, University of Michigan, Ann Arbor, Michigan 64. No. 4, July 1980 Medical Clinics of North America - Vo!. 64,
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Table 1.
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Classification of Immune Thrombocytopenic Purpura
Autoimmune thrombocytopenia, idiopathic or secondary, chronic or acute Neonatal thrombocytopenia, due to transplacental transfer of maternal autoimmune thrombocytopenia Isoimmune neonatal thrombocytopenia Dru g-induced thrombocytopenia Drug-induced Post-transfusion purpura causes Miscellaneous eau ses of immune thrombocytopenia
AUTOIMMUNE THROMBOCYTOPENIC PURPURA Autoimmune thrombocytopenic purpura is frequently referred to as 10 This is a type of immune thromidiopathic thrombocytopenic purpura. 10 bocytopenic purpura characterized by the presence of an autoantibody auto antibody directed against a normal platelet antigen. Autoimmune thrombocytopenic purpura is presently a diagnosis of exclusion. All other possible causes of thrombocytopenia should be considered before placing a patient in this category20 (Table 2). Harrington 21 demonstrated that serum from the majority of patients with autoimmune thrombocytopenic purpura contains an antiplatelet factor by administering serum from a patient with autoimmune thrombocytopenia to himself. He then responded with a dramatic fall in his own platelet count lasting over 5 days. Shulman later showed that this thrombocytopenic factor was an IgG type antibody.42 In order to diagnose autoimmune thrombocytopenic purpura, it would seem to be easier to demonstrate the presence of the antiplatelet antibody directly rather than to rule out a myriad of alternative diag-
Differential Diagrnosis Diagnosis of Thrombocytopenia Caused Predominantly by Enhanced Platelet Destruction
Table 2.
CONGENITAL
Non-Immune
Drug-induced Erythroblastosis fetalis Prematurity Infection Giant cavernous hemangioma
Immune
Drug-induced Isoimmune neonatal thrombocytopenia Neonatal ITP due to maternal auto-ITP Infection
ACQUIRED
Non-Immune
Drug-induced Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura
Immune
Drug·induced Drug-induced Post-transfusion purpura Allergy Sepsis Autoimmune thrombocytopenia, acute or chronic
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noses. However, direct detection the antibody in vitro has been diffi10 The antibody does not fix complement, and assays dependent upon cult. 10 agglutination as an indicator of the presence of antibody have proved unreliable because of the platelet's inherent tendency to aggregate. Numerous techniques that depend upon alteration of the platelet or its function have been developed for the estimation of an antiplatelet antibody in the serum of patients with autoimmune thrombocytopenic 26 All of these tests are more qualitative than quantitative, and purpura. 26 suffer from problems of sensitivity, selectivity, or reproducibility. 16 to assess antiplatelet The quantitative method of Dixon et al. 16 antibody via an indirect antiglobulin consumption technique (Fig. la) considerably improved the capacity to diagnose immune thrombocytopenia and for the first time to correlate the serum and platelet-bound antibody titer with the clinical response to therapy. Subsequently, direct assays were developed, including the radiolabelled Coombs' antiglobulin 14 which depends on the ability of animal anti-human antibodies to test 14 bind to human IgG on platelets (Fig. lb), and the radiolabelled staphylococcal protein A (SPA) test,29 which depends on the property of SPA to avidly bind to the Fc end of IgG (Fig. lc). These direct assays may be available to the clinical laboratory in the near future. Autoimmune thrombocytopenic purpura has acute and chronic presentations,23 with several differences between the two forms (Table 3). Some of these differences probably reflect the wide spectrum of disorders that are included in the immune thrombocytopenic purpura syndrome. However, when one takes into consideration data concerning incidence, prognosis, and results of therapy, it seems reasonable to think of acute autoimmune thrombocytopenic purpura and chronic autoimmune thrombocytopenic purpura as fundamentally different disorders. Acute Autoimmune Thrombocytopenic Purpura
30 ,48 occurs most freAcute autoimmune thrombocytopenic purpura30 quently in children and has a peak age of incidence of 2 to 6 years. It represents over 90 per cent of all childhood cases and about two thirds of all cases of autoimmune thrombocytopenic purpura. There is no sex predilection but there is a seasonal variation, with most cases occurring during the colder months. Eighty per cent of patients have an acute febrile illness, most commonly of viral origin, within 3 weeks of onset of the purpura. Acute autoimmune thrombocytopenic purpura presents with sudden onset of purpura of the skin and mucous membranes, a very marked thrombocytopenia (platelets generally less than 20,000) associated with normal to increased numbers of megakaryocytes in the bone marrow. It almost always runs a self-limited course. 32 The mortality is very low, intracranial bleeding is rare and steroid hormones do not shorten the duration of disease or hasten the restoration of normal 30,, 31, :11, 48 4R platelet counts. 30
Chronic Autoimmune Thrombocytopenic Purpura
25 may be encounChronic autoimmune thrombocytopenic purpura66 ,, 25 tered in persons of all ages, but it is relatively more common in adults. It
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Table 3.
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ACl1te and Chronic Autoimmune Comparison of Acute Thrombocytopenic r 1'U ra ThTOmbocytopenic Pu PUTi'uTa
Peak incidence Sex ratio Antecedent infection Platelet count Onset of symptoms Hemorrhagic bullae on mucous membranes Duration Spontaneous remission Response to corticosteroids Response to splenectomy
ACUTE
CHRONIC
2-6 years 1 to 1 Common < 20,000 per cu mm Abrupt Common
20-40 years 3 females to 1 male
2-6 weeks 80';; of cases > 80Slc Uncommon Variable
Years Uncommon Common Common
Uncommon cu mm 30-100,000 per Cll c;radual t;radual Uncommon Uncomn10n
occurs much more frequently in women, a ratio of 3 female patients to 1 series, There is no seasonal male patient having been found in most series. variation in its incidence and it is uncommon to elicit a history of previous infection. The onset is insidious, with a long history of easy bruising, prolonged menses, or other relatively mild bleeding manifestations before the diagnosis is made. The platelet count is moderately low, usually 30,000 to 100,000 per cu mm, but there is no significant anemia or leukopenia and no significant splenomegaly. Chronic autoimmune thrombocytopenic purpura remits spontaneously only in a small fraction of cases. More commonly, purpura will wax and wane. At times the patient may be free of petechiae or purpura but the platelet count will remain at one third to one half normal. At other times, bleeding manifestations may become more severe, such as after an infection, after vaccination, or for no apparent reason. The risk of intracranial bleeding is relatively high, with the mortality associated with chronic autoimmune thrombocytopenic purpura on the order of 7 per cent in a series of 147 patients of all ages. 1111 Chronic autoimmune thrombocytopenic purpura is usually idiopathic, but it is also commonly associated with other autoimmune disorders, such as rheumatoid arthritis, vasculitis, glomerulonephritis, or systemic lupus erythematosus. 77 It is also associated with lymphoproliferative disorders such as chronic lymphocytic leukemia. 77 Diagnostic criteria for idiopathic autoimmune thrombocytopenic purpura are shown in Table 4. Table 4. Diagnostic Criteria CriteTia for Idiopathic A1ltoimm1lne Thrombocytopenia ThTOmbocytopenia Pl1TjJ1lra Autoimmune Purpura CLINICAL
LABORATORY
Bleeding or petechiae No splenomegaly No underlying disorder which may cause thrombocytopenia
Thrombocytopenia Normal to increased megakaryocytes in the bone marrow Antiplatelet antibody (if available)
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l'HERAPY THERAPY
ofimmune The severity of immune thrombocytopenic purpura should always be quickly evaluated. A repeat platelet count and evaluation of the bone marrow aspirate for megakaryocytes should be done and every effort should be made to establish a definitive diagnosis 20 (Tables 2 and 4). In the mildest cases without hemorrhagic manifestations, treatment may not even be indicated. In severe cases of chronic autoimmune thrombocytopenic purpura, a treatment regimen must be prescribed quickly. Hospitalization is advised. The principal modes of therapy for chronic autoimmune thrombocytopenic purpura are corticosteroids and splenectomy,6, J7, 25 although other treatments are sometimes indicated. 4. 15. 15. 18 tomY,6.17.25 Corticosteroids Corticosteroids, such as prednisone, can effectively induce remission in most cases of chronic autoimmune thrombocytopenic pur15,25,43 pura. 15 . 25, 43 The mechanism by which they act is unclear. It has been reported that the platelet-bound antibody titer tit er is diminished but the free plasma antiplatelet antibody titer increases following treatment with steroids in some patients. 14, 16 However, there are no data to show that directly, There is also steroids can effect the antigen-antibody reaction directly. evidence that steroids reduce splenic sequestration of lightly sensitized platelets,8 platelets. 8 About 60 per cent of patients will respond to 1 mg of predniday, Another 10 to 20 per cent of patients will respond if2 sone per kg per day. mg per kg per day are given. Above this dose there is little likelihood of response, In the most severe cases, induction of remission should response. probably be attempted at the higher doses in order to optimize the likelihood of response. response, Once a response has been obtained, the dose tapered, 15. 15.25,45 should be tapered. 25. 45 Because of the potentially severe side-effects of long-term administration of corticosteroids, splenectomy should be considered in all patients who must be maintained on high doses of steroids for long periods of time. time, "High doses" and "long periods" have been somewhat arbitrarily defined by various authors, but greater than 15 mg of prednisone daily or greater than 6 weeks duration may be a reasonable cutoff. There is rather good evidence that steroids have no effect on the course of acute autoimmune thrombocytopenic purpura,3J purpura. 31 This is a self-limited disorder with a course of a few days to a few weeks and remission can be expected to occur spontaneously. Many physicians have the clinical impression that purpura are reduced even with the same platelet count if steroids are given in small doses (10 mg prednisone/day). 41 This effect has been ascribed to increased vascular stability, However, the role of even these doses of prednisone in acute stability. controversial. 31 autoimmune thrombocytopenic purpura is controversia1. Splenectomy Splenectomy is the most effective form of treatment for chronic autoimmune thrombocytopenic purpura. 12,38 12. 38 A sustained remission will occur in 60 to 80 per cent of patients after splenectomy, despite the fact
IMMUNE THROMBOCYTOPENIC PURPURA
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that the antiplatelet antibody still circulates. 14. 16 lH A smaller fraction of 10 to 20 per cent will obtain a partial remission, with platelet counts rising but not maintained in the normal range. The remaining 10 to 20 per cent of patients will show no elevation in the platelet count and no improvement in their bleeding diathesis. The platelet count frequently rises immediately after splenectomy and returns to normal 4 to 7 days after surgery. However, some patients have a delayed response to splenectomy with an increase in the platelet count 2 to 4 weeks later. The spleen seems to have two roles in the pathophysiology of autoimmune thrombocytopenic purpura, both supported by clinical and experimental evidence. First, platelets that are coated with low or moderate titers of antibody are selectively trapped in the spleen and destroyed. 8, 33 This explains the rapid response to splenectomy in most patients. Second, the 34 A reduction in spleen is an important site of antibody production. 34 antibody titer best explains the delayed response to splenectomy in some cases. The degree of elevation of the platelet count in the immediate postsplenectomy period appears to have prognostic significance. In a series of 140 patients who had undergone splenectomy, it it was found that 84 per cent of patients whose platelet count rose above 500,000 soon 37 after surgery obtained a complete remission. Only 25 per cent of those remission.:J7 whose platelets rose to the 100,000 to 200,000 range were cured. At present, no test is available to predict in advance which patients will respond. It is important that thrombocytopenic patients without adequate bone marrow megakaryocytes not be considered as possible cases of immune thrombocytopenic purpura; these patients are extremely unlikely to respond to splenectomy. The right time for the physician to prescribe splenectomy in the course of chronic autoimmune thrombocytopenic purpura has been debated. All factors must be taken into consideration such as age of the patient, operative risk, relative contraindications to low or high dose thrombocytopenic purpura steroids, and so forth. Chronic autoimmune' autoimmune'thrombocytopenic is probably best treated by splenectomy, especially if relapse occurs after 4 to 6 weeks of control with steroids. In most patients, it is probably unwise to treat patients with 40 to 100 mg prednisone per day for 6 months or a year in order to try to avoid surgery. The operative mortality of splenectomy in autoimmune thrombocytopenic purpura is less than 1 per cent when done by a suregon who is familiar with the types of problems likely to arise in severely thrombocytopenic patients undergoing surgery. 12, 38 Commonly, patients who respond well to steroids usually have a splenectomy.43 good response to splenectomy. 43 However, there is no strict correlation between the therapeutic effect of these two types of treatment in any individual case. A small fraction of patients will fail splenectomy be44 A liver-spleen scan can cause a small accessory spleen is left behind. 44 sometimes identify these patients, who may benefit by reoperation. In patients in whom splenectomy is unsuccessful in returning the platelet count to normal, the maintenance dose of prednisone necessary to avoid severe thrombocytopenia is usually reduced over pre-splenectomy levels.
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Again, acute autoimmune thrombocytopenic purpura in children is usually best treated conservatively.:1O-:12 conservatively.:w-;~~
Other Therapies Although the majority of patients with chronic autoimmune thrombocytopenic purpura can either be cured or have their disease controlled with splenectomy and/or steroids, autoimmune thrombocytopenic purpura refractory to both of these modalities remains a serious problem. Beneficial results have been obtained with immunosuppressive agents and vinca alkaloids in some of these refractory cases. There is a reasonable chance of response to cyclophosphamide (Cytoxan) or azathioprine (Imuran) in refractory cases, 11),40 lti, 40 but higher doses must frequently be used. This increases the likelihood of side-effects such as nausea, diarrhea, leukopenia, or anemia. Immunosuppressive agents have a relatively low therapeutic index. Vincristine, a vinca alkaloid, has recently shown potential in the autoimmune thrombocytopenic purtreatment of refractory cases of autoimmU11e pura.;) pura.' The dose in adults was 2 mg intravenously per week until response occurred, which frequently was a matter of days in successful cases. Subsequently, it was shown that platelets would concentrate vinca alkaloids and some patients, refractory to all other forms of therapy, have responded to infusion of vinblastine-loaded platelets. platelets.'4 The presence of antiplatelet antibodies in the recipient's plasma led to ingestion of the vinca-laden vinca-l~den platelets by macrophages, thus, selectively delivering drug to the cells responsible for the platelet destruction. Unfortunately, no prospective randomized trial is presently underway to speed evaluation of old and new agents on the treatment of refractory chronic autoimmune thrombocytopenic purpura. Other Considerations It is absolutely essential to exclude drug sensitivity, sepsis, and aI?-d disseminated intravascular coagulation since they share the characteristics of low platelet count with normal to increased megakaryocytes 20 In this context, all drugs or chemicals should be in the marrow. 20 suspect, and only those considered absolutely essential continued. Platelet transfusions are usually effective in controlling bleeding in autoimmune thrombocytopenic purpura. 11 However, Ho,vever, their hemostatic effect is significantly reduced by the circulating antiplatelet antibody which shortens their lifespan. Furthermore, platelet transfusions will cause the rise of isoantibodies in the recipient and subsequent transfusions will probably be progressively less effective. Therefore, platelet transfusions in autoimmune thrombocytopenic purpura have only one major indication: To temporarily arrest an acute bleeding episode that threatens the patient's life. The correct amount to transfuse is the amount that will control the bleeding, frequently 6-20 units/day. Platelets are sometimes used to prepare a patient for splenectomy. At the time of splenectomy, it has frequently been noted that the bleeding diathesis is greatly reduced as soon as the splenic artery is clamped (12). Most patients will not need platelets in the pre-op or post-op period. Platelet transfusions should probably be avoided if they are not clearly indicated.
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NEONATAL IMMlJNE IMMUNE THROMBOCYTOPENIC PURPlJRA PURPURA CAUSED AUTOIMMUNE CAlJSED BY MATERNAL AUTOIMMlJNE THROMBOCYTOPENIC PURPURA PlJRPURA In the case of a mother with autoimmune thrombocytopenic purpura who has been cured with splenectomy, one should assume that her fetus will suffer from neonatal immune thrombocytopenic purpura caused by transplacental passage of still circulating antiplatelet antibody. About half of infants at risk are clinically affected. ]9.22 lB."" Under these circumstances, the obstetrician and pediatrician should be aware of this special danger to the fetus and several routes of action should be considered including: A prenatal course of steroids to the mother beginning one steroids;"2 or week prior to delivery in an attempt to treat the fetus with steroids;22 caesarian section in order to reduce the trauma of birth. If the child is born severely thrombocytopenic anyhow, plasma exchange may be necessary to lower the titer of antiplatelet antibody. The role of steroids given to the infant is n.ot not clear, but they should probably be used if thrombocytopenia is unusually severe. The prognosis is favorable, and fetal and neonatal mortality is low. Thrombocytopenia persists for an average of 1 month, although in some cases lasts 4 to 6 months.
ISOIMMUNE NEONATAL PURPURA ISOIMMlJNE Isoimmune antiplatelet antibodies arise when an individual is transfused with another person's platelets. Isoantibodies directed against HLA antigens are frequently responsible for the shortened survival of transfused platelets. In addition, congenital thrombocytopenia due to isoantibody against the PIAl antigen (see post transfusion purpura 39 below) occurs in about 1 in 5000 births. Presumably the P1Al birthsY9 PIAl negative of· the fetus and the resultant mother is sensitized to the PIAl antigen of'the antibody crosses the placenta, causing thrombocytopenia. This disorder is analogous to erythroblastosis fetalis except that fetal platelets rather than red cells provide the antigenic stimulus, and are destroyed. The firstborn child is affected in half the cases, in marked contrast to firstbom erythroblastosis fetalis, with which the firstborn is rarely affected. As opposed to the difficulty of antibody detection in autoimmune thrombocytopenic purpura, antibodies reacting with platelets from the infant and father may be easily detected in maternal serum by agglutination, complement fixation, and antibody consumption techniques. Cord blood itself rarely gives positive results. Because only 2 per cent of the general population lack the PIAl platelet antigen (most often implicated in ppl antigen on maternal-fetal platelet incompatibility), absence of the PIAl the mother's platelets provides presumptive evidence that the neonatal thrombocytopenia is of isoimmune origin. General considerations for therapy of isoimmune neonatal thrombocytopenic purpura are similar to those of neonatal immune thrombocytopenic purpura. Steroids, exchange transfusions, and caesarian secm Platelet transfusions are usually effective in tion have been advocated.: advocated.~m
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this disease and are best obtained by plateletpheresis of the mother, who will be compatible no matter which antigen-antibody system is involved. Care must be taken to wash maternal platelets to avoid administration of more antibody to the infant. A large majority of infants will recover without sequellae after a thrombocytopenic period of two to three weeks. Fatalities are usually a result of intracranial hemorrhage caused by trauma in the birth canal.
POST -TRANSFUSION PURPURA POST-TRANSFUSION Acute life-threatening thrombocytopenic purpura can rarely occur approximately one week following blood transfusion. 2,2. 47 As in most cases of isoimmune neonatal purpura, the antibody is usually directed against the PIAl platelet antigen. This antigen is found in 98 per cent of the population but is almost always absent from platelets in cases of post-transfusion purpura. No experimentally proven theory has adequately explained the destruction of autologous platelets by an isoantibody (an antibody directed against an antigen not present on the patient's own platelets). Also unexplained is the very low incidence of post-transfusion purpura despite the fact that about 1 in 50 blood recipients is mismatched with respect to this antigen. The typical case of post-transfusion purpura occurs in a middle-aged woman one week after a blood transfusion given in the course of elective surgery. Post-transfusion purpura in men and nulliparous women is rare, suggesting that patients are sensitized to the PIAl antigen during a previous exposure (pregnancy). Anti-PIAl antibody can be detected by a variety of tests. Platelet counts are very low, generally less than 10,000 per cm mm. Bleeding into the skin and mucous membranes is usually profuse at the onset. The risk of intracranial hemorrhage is relatively great because: (1) the platelet count is very low, (2) the onset of thrombocytopenia is rapid, and (3) the typical patient is in an older age group. Steroids have no effect in shortening the duration of symptoms. Transfused platelets are ineffective and dangerous because serious transfusion reactions are likely. Plasmapheresis has been successful and is presently the treatment of choice. 22 This modality seems to work by removing antibody or immune complexes.
DRUG-INDUCED IMMUNE THROMBOCYTOPENIC PURPURA A vast number of drugs have been reported to cause thrombo24,;)6 cytopenia on an immunological basis. a3 ,. 24, 36 Any drug a thrombocytopenic patient is taking should be suspected as possible cause of immune thrombocytopenia. Quinine and quinidine together account for most cases, although digitoxin, aspirin, heparin, sulfonamides, and thiazides 24. :16 also account for many.9, 24, 36 Gold salts frequently cause accelerated destruction of platelets, but an immune mechanism is unproven. A
IMMUNE THROMBOCYTOPENIC PURPURA
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careful drug history must be taken in all patients presenting with thrombocytopenia. In addition to the usual medication history, careful inquiry should be made regarding over the counter and home remedies and ingestion of tonics which may contain quinine. In most cases, the patient has been exposed to the offending agent within 3 to 24 hours of the onset of symptoms. The platelet count may be less than 1000 per cu mm and bleeding may be manifest as petechiae, purpura, hemorrhagic bullae of the mucosa, or bleeding from the gastrointestinal or urinary tract. Antibodies to quinine or quinidine can be detected by a number of 13 With other drugs which cause immune thrombotests in most cases. 13 cytopenic purpura, laboratory detection of the antibody is usually negative. An in vivo challenge to confirm the diagnosis should not be attempted unless continuing the drug is absolutely essential for the patient's welfare. As little as 1 JLg ~g rechallenge with certain drugs may cause life-threatening thrombocytopenia. Once induced, sensitivity to drugs causing immune thrombocytopenic purpura persists indefinitely and the patient should never be re-exposed. In the case of drugs such as quinine and quinidine which are rapidly excreted, bleeding symptoms disappear over a period of 3 to 4 days if no further ingestion occurs.
MISCELLANEOUS CAUSES OF IMMUNE THROMBOCYTOPENIC PURPURA It has recently been shown that some cases of thrombocytopenia 27 As the newer associated with sepsis are due to an immune mechanism. 27 tests to evaluate antiplatelet antibody reach the clinic, it is expected that other causes of thrombocytopenia will be found to have an immune 28 basis. 9n.,28
REFERENCES 1. Abraham, T.: Platelet transfusion in idiopathic thrombocytopenic purpura. J.A.M.A., 236:1847, 1976. Immun· 2. Abramson, N., Eisenberg, P. D., and Asher, R. H.: Post transfusion purpura: Immunologic aspects and therapy. New Engl. 1163-1166, 1974. EngL J. Med., 291: 291 :1163-1166, 3. Ackroyd, J. F.: Pathogenesis of thrombocytopenic purpura due to hypersensitivity to Sedormid. Clin. ScL, Sci., 7:249-285, 1949. 4. Ahn, Y., S., Byrnes, J. J., Harrington, W. J., et al.: Treatment of idiopathic thrombothrombo· EngLJ. Med., 298:1101, cytopenic purpura with Vinblastine loaded platelets. New Engl.J. 1978. 5. Ahn, Y. S., Harrington, W. J., Sellman, R. C., et al.: aL: Vincristine therapy of idiopathic and EngL J. Med., 291 :376-380, :376--380, 1974. secondary thrombocytopenias. New Engl. 6. Ahn, Y. S., and Harrington, W. J.: Treatment of idiopathic thrombocytopenic purpura. 28:299--309, 1977. Ann. Rev. Med., 28:299-309, 7. Amaral, B. W.: Immune thrombocytopenic purpura. Postgraduate Med., 61 :197-202, 1977. 8. Aster, R. H., and Keene, W. R.: Sites of platelet destruction in idiopathic thrombocytopenic purpura. Brit. J. Hematol., HematoL, 16:61-73, 1969. 9. Babcock, R. B., Dumper, C. W., and Scharfman, W. B.: Heparin induced thromboEngL J. J. Med., 295:237-241, 1976. cytopenia. New Engl. CLlN. 10. Baldini, M. G.: Idiopathic thrombocytopenic purpura and the ITP syndrome. MED. CLIN. AMER., 56:47-64, 56:47--64,1972. N. AMER., 1972. traitement des purpuras thrombopeniques idiopathiques. Acta 11. Bernard, J.: Evolution et trmtement 31 :163-176,1964. Haemat., 31: 163-176, 1964.
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KOLLER
R" and Zajtchuk, R.: Splenectomy for idiopathic thrombocytopenic 12. Block, G. E., Evans, R., purpura. Arch. Surg., 92:484, 1966. 13. Cimo, P. L., Pisciotta, A. V., Desai, R. G" G., et al.: Detection of drug-dependent antibodies J. Hematol., 2:65-72, 1977. by the 51-Cr 51-Cl' platelet lysis test. Amer. J.Hematol., thrombocytopenia. Use of a Coombs 14. Cines, D. B., and Schreiber, A. D.: Immune throlnbocytopenia. tcst to detect IgG and C;l C" on platelets. New Engl. J. Med., 300: 300:106-111, antiglobulin test 106-111, 1979. 15. Dameshek, W.: Controversy in idiopathic thrombocytopenic purpura. J.A.M.A., 173:1025-1029,1960. 173: 1025-1029, 1960. 16. Dixon, R., Rosse, W., and Ebbert, L.: Quantitative determination of antibody in idiopathic thrombocytopenic purpura. New Engl. J. Med., Med" 292:230-236, 1975. 17. Doan, C. A., Bouronde, Bouroncle, B. A., and Wiseman, B. K.: Idiopathic and secondary thrombocytopenic purpura: Clinical ClinIcal study and evaluation of 381 cases over 28 years. Ann. Intern. Med., 53:861-876, 1960. 18. Finch, S. C., Castro, D., Cooper, M., et al.: Immunosuppressive therapy of chronic idiopathic thrombocytopenic purpura. Amer. J. Med., 56:4-12, 1974. 19. Goodhue, P. A., and Evans, T. S.: Idiopathic thrombocytopenic purpura in pregnancy. Obstet. Gynecol. Surv., 18:671, 1963. Diflerential diagnosis and management of thrombocytopenia. Med. 20. Harrington, W. J.: Differential Times, 99:53-56, 1971. 21. Harrington, W. J., Minnick, V., Hollingsworth, J. W., et al.: Demonstration of a thrombocytopenic factor in the blood of patients with idiopathic thrombocytopenic purpura. J. Lab. Clin. l\1ed., Med., 38:1-10, 1951. thrombocytopenia purpura. Obstet. Gynecol., 22. Heys, R. F.: Steroid therapy for idiopathic throlnbocytopenia 28:532, 28: 532, 1966. 23. Hirsch, E. 0., and Dameshek, W.: Idiopathic thrombocytopenic purpura. Review of 89 cases with particular reference to the differentiation and treatment of acute (self-limited) and chronic types. Arch. Intern. Med., 88:701-728, 1951. H. I., and Nachman, R. G.: Drug purpura. Semin. Hematol., 2:287-311, 24. Horowitz, H.!., 1965. thrombocytopenic 25. Jiji, R. M., Firozvi, T., and Spurling, C. L.: Chronic idiopathic throlnbocytopenic Med., 132:380-383, purpura: Treatment with steroids and splenectomy. Arch. Intern. lVled., 1973. N .. Karpatkin, M. B., et al.: Cumulative experience in the detection 26. Karpatkin, S., Strick, N., of antiplatelet antibody in 234 patients with ITP, SLE and other clinical disorders. Amer. J. Med., 52:776, 1972. 27. Kelton, J. G., Neame, P. B., Grauldie, J., et al.: Elevated platelet-associated IgG in the thrombocytopenia of septicemia. New Engl. J. Med., 300: 760-764, 1979. 300:760-764, 28. Kim, H. D., and Boggs, D. R.: A syndrome resembling idiopathic thrombocytopenic J. Med., 67:371-377, 1979. purpura in 10 patients with diverse forms of cancer. Amer. J. 29. LoBuglio, A. F.: Personal communication. Luscher. J. IVI., M., Zuelzer, VV. W. W.: Idiopathic thrombocytopenic purpura in childhood. .j. -1. 30. Luscher, Pediat., 68:971, 1966. 31. McClure, P. D.: Idiopathic thrombocytopenic purpura in children: Should corticosteroids be given? Amer. J. Dis. Child., 131 :357-359, 1977. 32. McElfresh, A. E.: Idiopathic thrombocytopenic purpura: To treat or not to treat. J. 87:160-161,1975. Pediat., 87:160-161, 1975. 33. MacMillan, R., Longmire, R. L., Tavassoli, M., et aL: al.: In vitro platelet phagocytosis by splenic leukocytes in idiopathic thrombocytopenic purpura. N evv Engl. J. Med., 290:249290: 249New 251, 1974. 34. MacMillan, R., Longmire, R. L., Yelenosky, R., et al.: Quantitation of platelet binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. New Engl. .J. J. Med., 291 :812-817, 1974. Opin .• 6:24-29, 35. Metz, E. N., and Koller, C. A.: An approach to the bleeding patient. Med. Opin., 1977. Semin. Hematol., I-Iematol., 10: 10:311, 36. Miescher, P. A.: Drug-induced thrombocytopenia. Sen1in. 311, 1973. 37. Najean, Y., and Ardillous, N.: Indication de la splenectomie dans le purpura thrombopenique idiopathique. Presse Med., 79:443, 1971. 38. Orringer, E., Lewis, M., Silverberg, J., et al.: Splenectomy in chronic idiopathic thrombo11 7, 1970. cytopenic purpura. J. Chron. Dis., 23: 117, 39. Pearson, H. A., Shulman, N. R., Murder, V. J., et aL: al.: lsoimmune neonatal thrombo23:154-157,1964. cytopenia purpura. Blood, :23:154-157, 1964. VerJin, M.: Treatment of refractory idiopathic thrombo40. Penner, J. A., Laros, R. K., and Verlin, cytopenic purpura. New Engl. J. Med., 296:2862, 1977. 41. Robson, Robson. H. N., Duthie, J. J. R.: Capillary resistance and adrenocortical activity. Brit. Med. J., 2:971-977, 1950.
IMMUNE THROMBOCYTOPENIC PURPURA
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R S.: Similarities between known antipla42. Shulman, N. R, R., Murder, V., and Weinrock, R. telet antibodies and a factor responsible for thrombocytopenia in idiopathic thromboN.Y. Sei., 124 124:499, cytopenic purpura. Ann. N. Y. Acad. Sci., :499, 1965. a!.: Idiopathic thrombocytopenic purpura: 43. Thompson, R. L., Moore, RA., R. A., Hess, C. E., et al.: Long-term results of treatment and the prognostic significance of response to corticosteroids. Arch. Intern. Med., 1.30:730-738, 1972. 44. Verheyden, C. N.: Accessory splenectomy in the management of recurrent idiopathic thrombocytopenic purpura. Mayo Clin. Proc., 53:442-446, 53 :442-446, 1978. I. S., and Davidson, S.: The treatment of 45. Watson-Williams, F. J., Macpherson, A. 1. idiopathic thrombocytopenic purpura. A review of 93 cases. Lancet, 2:221-227, 1958. 46. Weiss, G. B., Klock, J. C., and Richards, H. B.: Idiopathic thrombocytopenic purpura in the elderly. Lancet, 1 :411-412, 1975. R, Murphy, S., and Gardner, F. H.: Post-transfusion purpura: A report of three 47. Ziegler, Z. R., cases emphasizing emphaSizing the heterogeneity of the syndrome and the superiority of .)ICr "'Cr release 42:1023,1973. for detecting isoantibody. Blood, 42: 1023, 1973. J. Dis. Child., 48. Zuelzer, W. W.: Childhood idiopathic thrombocytopenic purpura. Amer. J. 131 :360-362, 1977.
Simpson Memorial Research Institute 102 0Observatory bservatory Ann Arbor, l\1ichigan Michigan 48109
Immune Thrombocytopenic Purpura Charles A. Koller, M.D.*
Immune thrombocytopenic purpura is a hemorrhagic disorder in which thrombocytopenia is associated with increased peripheral de7, 10. 17,20 It is not a single disorder but a syndrome of struction of platelets. 7,10,17,20 different diseases, all of which have in common shortened platelet survival owing to the presence of an antiplatelet antibody. The bone marrow in immune thrombocytopenic purpura has a normal to increased number ofmegakaryocytes, indicative of normal to increased production of platelets. Most cases of immune thrombocytopenic purpura are secondary to an identifiable etiologic agent. The subdivisions of immune thrombocytopenic purpura are shown in Table 1.
General Considerations In an otherwise healthy person without any bleeding manifestations, one must first be suspicious of spurious thrombocytopenia. Before proceeding, it is wise to repeat a low platelet count and then to evaluate the blood film under the microscope, using a film made without anticoagulants. Four or more platelets per high power field is considered adequate. When evaluating a bone marrow aspirate, megakaryocytes are probably adequate if several can be found without much difficulty. A patient with spleen enlarged for any reason can have thrombocytopenia as a result of increased splenic sequestration. Generally speakiIlg, speaking, the larger the spleen, the lower the platelet count. The symptoms of thrombocytopenia are independent of the cause of thrombocytopenia and vary inversely with the platelet count.:lo count.~~;) It is unlikely that a bleeding diathesis will be present with platelet counts above 50,000 to 100,000. Excessive bleeding with stresses, such as trauma or surgery, is possible in the 20,000 to 100,000 range. Spontaneous bleeding, with petechiae and purpura of the skin, epistaxis, bleeding gums, and bleeding from other sites, is common with platelet counts below 20,000 and especially, below 5,000. Finally, given a certain low platelet count, the risk of life-threatening bleeding increases as the patient's age increases."H) increases. Hi ';'Assistant Professor, Division of Hematology and Oncology, Simpson Memorial Research "Assistant Institute, University of Michigan, Ann Arbor, Michigan 64. No. 4, July 1980 Medical Clinics of North America - Vo!. 64,
761
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Table 1.
A. KOLLER
Classification of Immune Thrombocytopenic Purpura
Autoimmune thrombocytopenia, idiopathic or secondary, chronic or acute Neonatal thrombocytopenia, due to transplacental transfer of maternal autoimmune thrombocytopenia Isoimmune neonatal thrombocytopenia Dru g-induced thrombocytopenia Drug-induced Post-transfusion purpura causes Miscellaneous eau ses of immune thrombocytopenia
AUTOIMMUNE THROMBOCYTOPENIC PURPURA Autoimmune thrombocytopenic purpura is frequently referred to as 10 This is a type of immune thromidiopathic thrombocytopenic purpura. 10 bocytopenic purpura characterized by the presence of an autoantibody auto antibody directed against a normal platelet antigen. Autoimmune thrombocytopenic purpura is presently a diagnosis of exclusion. All other possible causes of thrombocytopenia should be considered before placing a patient in this category20 (Table 2). Harrington 21 demonstrated that serum from the majority of patients with autoimmune thrombocytopenic purpura contains an antiplatelet factor by administering serum from a patient with autoimmune thrombocytopenia to himself. He then responded with a dramatic fall in his own platelet count lasting over 5 days. Shulman later showed that this thrombocytopenic factor was an IgG type antibody.42 In order to diagnose autoimmune thrombocytopenic purpura, it would seem to be easier to demonstrate the presence of the antiplatelet antibody directly rather than to rule out a myriad of alternative diag-
Differential Diagrnosis Diagnosis of Thrombocytopenia Caused Predominantly by Enhanced Platelet Destruction
Table 2.
CONGENITAL
Non-Immune
Drug-induced Erythroblastosis fetalis Prematurity Infection Giant cavernous hemangioma
Immune
Drug-induced Isoimmune neonatal thrombocytopenia Neonatal ITP due to maternal auto-ITP Infection
ACQUIRED
Non-Immune
Drug-induced Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura
Immune
Drug·induced Drug-induced Post-transfusion purpura Allergy Sepsis Autoimmune thrombocytopenia, acute or chronic
IMMUNE THROMBOCYTOPENIC PURPURA
763
noses. However, direct detection the antibody in vitro has been diffi10 The antibody does not fix complement, and assays dependent upon cult. 10 agglutination as an indicator of the presence of antibody have proved unreliable because of the platelet's inherent tendency to aggregate. Numerous techniques that depend upon alteration of the platelet or its function have been developed for the estimation of an antiplatelet antibody in the serum of patients with autoimmune thrombocytopenic 26 All of these tests are more qualitative than quantitative, and purpura. 26 suffer from problems of sensitivity, selectivity, or reproducibility. 16 to assess antiplatelet The quantitative method of Dixon et al. 16 antibody via an indirect antiglobulin consumption technique (Fig. la) considerably improved the capacity to diagnose immune thrombocytopenia and for the first time to correlate the serum and platelet-bound antibody titer with the clinical response to therapy. Subsequently, direct assays were developed, including the radiolabelled Coombs' antiglobulin 14 which depends on the ability of animal anti-human antibodies to test 14 bind to human IgG on platelets (Fig. lb), and the radiolabelled staphylococcal protein A (SPA) test,29 which depends on the property of SPA to avidly bind to the Fc end of IgG (Fig. lc). These direct assays may be available to the clinical laboratory in the near future. Autoimmune thrombocytopenic purpura has acute and chronic presentations,23 with several differences between the two forms (Table 3). Some of these differences probably reflect the wide spectrum of disorders that are included in the immune thrombocytopenic purpura syndrome. However, when one takes into consideration data concerning incidence, prognosis, and results of therapy, it seems reasonable to think of acute autoimmune thrombocytopenic purpura and chronic autoimmune thrombocytopenic purpura as fundamentally different disorders. Acute Autoimmune Thrombocytopenic Purpura
30 ,48 occurs most freAcute autoimmune thrombocytopenic purpura30 quently in children and has a peak age of incidence of 2 to 6 years. It represents over 90 per cent of all childhood cases and about two thirds of all cases of autoimmune thrombocytopenic purpura. There is no sex predilection but there is a seasonal variation, with most cases occurring during the colder months. Eighty per cent of patients have an acute febrile illness, most commonly of viral origin, within 3 weeks of onset of the purpura. Acute autoimmune thrombocytopenic purpura presents with sudden onset of purpura of the skin and mucous membranes, a very marked thrombocytopenia (platelets generally less than 20,000) associated with normal to increased numbers of megakaryocytes in the bone marrow. It almost always runs a self-limited course. 32 The mortality is very low, intracranial bleeding is rare and steroid hormones do not shorten the duration of disease or hasten the restoration of normal 30,, 31, :11, 48 4R platelet counts. 30
Chronic Autoimmune Thrombocytopenic Purpura
25 may be encounChronic autoimmune thrombocytopenic purpura66 ,, 25 tered in persons of all ages, but it is relatively more common in adults. It
764
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Table 3.
A.
KOLLER
ACl1te and Chronic Autoimmune Comparison of Acute Thrombocytopenic r 1'U ra ThTOmbocytopenic Pu PUTi'uTa
Peak incidence Sex ratio Antecedent infection Platelet count Onset of symptoms Hemorrhagic bullae on mucous membranes Duration Spontaneous remission Response to corticosteroids Response to splenectomy
ACUTE
CHRONIC
2-6 years 1 to 1 Common < 20,000 per cu mm Abrupt Common
20-40 years 3 females to 1 male
2-6 weeks 80';; of cases > 80Slc Uncommon Variable
Years Uncommon Common Common
Uncommon cu mm 30-100,000 per Cll c;radual t;radual Uncommon Uncomn10n
occurs much more frequently in women, a ratio of 3 female patients to 1 series, There is no seasonal male patient having been found in most series. variation in its incidence and it is uncommon to elicit a history of previous infection. The onset is insidious, with a long history of easy bruising, prolonged menses, or other relatively mild bleeding manifestations before the diagnosis is made. The platelet count is moderately low, usually 30,000 to 100,000 per cu mm, but there is no significant anemia or leukopenia and no significant splenomegaly. Chronic autoimmune thrombocytopenic purpura remits spontaneously only in a small fraction of cases. More commonly, purpura will wax and wane. At times the patient may be free of petechiae or purpura but the platelet count will remain at one third to one half normal. At other times, bleeding manifestations may become more severe, such as after an infection, after vaccination, or for no apparent reason. The risk of intracranial bleeding is relatively high, with the mortality associated with chronic autoimmune thrombocytopenic purpura on the order of 7 per cent in a series of 147 patients of all ages. 1111 Chronic autoimmune thrombocytopenic purpura is usually idiopathic, but it is also commonly associated with other autoimmune disorders, such as rheumatoid arthritis, vasculitis, glomerulonephritis, or systemic lupus erythematosus. 77 It is also associated with lymphoproliferative disorders such as chronic lymphocytic leukemia. 77 Diagnostic criteria for idiopathic autoimmune thrombocytopenic purpura are shown in Table 4. Table 4. Diagnostic Criteria CriteTia for Idiopathic A1ltoimm1lne Thrombocytopenia ThTOmbocytopenia Pl1TjJ1lra Autoimmune Purpura CLINICAL
LABORATORY
Bleeding or petechiae No splenomegaly No underlying disorder which may cause thrombocytopenia
Thrombocytopenia Normal to increased megakaryocytes in the bone marrow Antiplatelet antibody (if available)
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766
CHARLES
A.
KOLLER
l'HERAPY THERAPY
ofimmune The severity of immune thrombocytopenic purpura should always be quickly evaluated. A repeat platelet count and evaluation of the bone marrow aspirate for megakaryocytes should be done and every effort should be made to establish a definitive diagnosis 20 (Tables 2 and 4). In the mildest cases without hemorrhagic manifestations, treatment may not even be indicated. In severe cases of chronic autoimmune thrombocytopenic purpura, a treatment regimen must be prescribed quickly. Hospitalization is advised. The principal modes of therapy for chronic autoimmune thrombocytopenic purpura are corticosteroids and splenectomy,6, J7, 25 although other treatments are sometimes indicated. 4. 15. 15. 18 tomY,6.17.25 Corticosteroids Corticosteroids, such as prednisone, can effectively induce remission in most cases of chronic autoimmune thrombocytopenic pur15,25,43 pura. 15 . 25, 43 The mechanism by which they act is unclear. It has been reported that the platelet-bound antibody titer tit er is diminished but the free plasma antiplatelet antibody titer increases following treatment with steroids in some patients. 14, 16 However, there are no data to show that directly, There is also steroids can effect the antigen-antibody reaction directly. evidence that steroids reduce splenic sequestration of lightly sensitized platelets,8 platelets. 8 About 60 per cent of patients will respond to 1 mg of predniday, Another 10 to 20 per cent of patients will respond if2 sone per kg per day. mg per kg per day are given. Above this dose there is little likelihood of response, In the most severe cases, induction of remission should response. probably be attempted at the higher doses in order to optimize the likelihood of response. response, Once a response has been obtained, the dose tapered, 15. 15.25,45 should be tapered. 25. 45 Because of the potentially severe side-effects of long-term administration of corticosteroids, splenectomy should be considered in all patients who must be maintained on high doses of steroids for long periods of time. time, "High doses" and "long periods" have been somewhat arbitrarily defined by various authors, but greater than 15 mg of prednisone daily or greater than 6 weeks duration may be a reasonable cutoff. There is rather good evidence that steroids have no effect on the course of acute autoimmune thrombocytopenic purpura,3J purpura. 31 This is a self-limited disorder with a course of a few days to a few weeks and remission can be expected to occur spontaneously. Many physicians have the clinical impression that purpura are reduced even with the same platelet count if steroids are given in small doses (10 mg prednisone/day). 41 This effect has been ascribed to increased vascular stability, However, the role of even these doses of prednisone in acute stability. controversial. 31 autoimmune thrombocytopenic purpura is controversia1. Splenectomy Splenectomy is the most effective form of treatment for chronic autoimmune thrombocytopenic purpura. 12,38 12. 38 A sustained remission will occur in 60 to 80 per cent of patients after splenectomy, despite the fact
IMMUNE THROMBOCYTOPENIC PURPURA
767
that the antiplatelet antibody still circulates. 14. 16 lH A smaller fraction of 10 to 20 per cent will obtain a partial remission, with platelet counts rising but not maintained in the normal range. The remaining 10 to 20 per cent of patients will show no elevation in the platelet count and no improvement in their bleeding diathesis. The platelet count frequently rises immediately after splenectomy and returns to normal 4 to 7 days after surgery. However, some patients have a delayed response to splenectomy with an increase in the platelet count 2 to 4 weeks later. The spleen seems to have two roles in the pathophysiology of autoimmune thrombocytopenic purpura, both supported by clinical and experimental evidence. First, platelets that are coated with low or moderate titers of antibody are selectively trapped in the spleen and destroyed. 8, 33 This explains the rapid response to splenectomy in most patients. Second, the 34 A reduction in spleen is an important site of antibody production. 34 antibody titer best explains the delayed response to splenectomy in some cases. The degree of elevation of the platelet count in the immediate postsplenectomy period appears to have prognostic significance. In a series of 140 patients who had undergone splenectomy, it it was found that 84 per cent of patients whose platelet count rose above 500,000 soon 37 after surgery obtained a complete remission. Only 25 per cent of those remission.:J7 whose platelets rose to the 100,000 to 200,000 range were cured. At present, no test is available to predict in advance which patients will respond. It is important that thrombocytopenic patients without adequate bone marrow megakaryocytes not be considered as possible cases of immune thrombocytopenic purpura; these patients are extremely unlikely to respond to splenectomy. The right time for the physician to prescribe splenectomy in the course of chronic autoimmune thrombocytopenic purpura has been debated. All factors must be taken into consideration such as age of the patient, operative risk, relative contraindications to low or high dose thrombocytopenic purpura steroids, and so forth. Chronic autoimmune' autoimmune'thrombocytopenic is probably best treated by splenectomy, especially if relapse occurs after 4 to 6 weeks of control with steroids. In most patients, it is probably unwise to treat patients with 40 to 100 mg prednisone per day for 6 months or a year in order to try to avoid surgery. The operative mortality of splenectomy in autoimmune thrombocytopenic purpura is less than 1 per cent when done by a suregon who is familiar with the types of problems likely to arise in severely thrombocytopenic patients undergoing surgery. 12, 38 Commonly, patients who respond well to steroids usually have a splenectomy.43 good response to splenectomy. 43 However, there is no strict correlation between the therapeutic effect of these two types of treatment in any individual case. A small fraction of patients will fail splenectomy be44 A liver-spleen scan can cause a small accessory spleen is left behind. 44 sometimes identify these patients, who may benefit by reoperation. In patients in whom splenectomy is unsuccessful in returning the platelet count to normal, the maintenance dose of prednisone necessary to avoid severe thrombocytopenia is usually reduced over pre-splenectomy levels.
768
CHARLES
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KOLLER
Again, acute autoimmune thrombocytopenic purpura in children is usually best treated conservatively.:1O-:12 conservatively.:w-;~~
Other Therapies Although the majority of patients with chronic autoimmune thrombocytopenic purpura can either be cured or have their disease controlled with splenectomy and/or steroids, autoimmune thrombocytopenic purpura refractory to both of these modalities remains a serious problem. Beneficial results have been obtained with immunosuppressive agents and vinca alkaloids in some of these refractory cases. There is a reasonable chance of response to cyclophosphamide (Cytoxan) or azathioprine (Imuran) in refractory cases, 11),40 lti, 40 but higher doses must frequently be used. This increases the likelihood of side-effects such as nausea, diarrhea, leukopenia, or anemia. Immunosuppressive agents have a relatively low therapeutic index. Vincristine, a vinca alkaloid, has recently shown potential in the autoimmune thrombocytopenic purtreatment of refractory cases of autoimmU11e pura.;) pura.' The dose in adults was 2 mg intravenously per week until response occurred, which frequently was a matter of days in successful cases. Subsequently, it was shown that platelets would concentrate vinca alkaloids and some patients, refractory to all other forms of therapy, have responded to infusion of vinblastine-loaded platelets. platelets.'4 The presence of antiplatelet antibodies in the recipient's plasma led to ingestion of the vinca-laden vinca-l~den platelets by macrophages, thus, selectively delivering drug to the cells responsible for the platelet destruction. Unfortunately, no prospective randomized trial is presently underway to speed evaluation of old and new agents on the treatment of refractory chronic autoimmune thrombocytopenic purpura. Other Considerations It is absolutely essential to exclude drug sensitivity, sepsis, and aI?-d disseminated intravascular coagulation since they share the characteristics of low platelet count with normal to increased megakaryocytes 20 In this context, all drugs or chemicals should be in the marrow. 20 suspect, and only those considered absolutely essential continued. Platelet transfusions are usually effective in controlling bleeding in autoimmune thrombocytopenic purpura. 11 However, Ho,vever, their hemostatic effect is significantly reduced by the circulating antiplatelet antibody which shortens their lifespan. Furthermore, platelet transfusions will cause the rise of isoantibodies in the recipient and subsequent transfusions will probably be progressively less effective. Therefore, platelet transfusions in autoimmune thrombocytopenic purpura have only one major indication: To temporarily arrest an acute bleeding episode that threatens the patient's life. The correct amount to transfuse is the amount that will control the bleeding, frequently 6-20 units/day. Platelets are sometimes used to prepare a patient for splenectomy. At the time of splenectomy, it has frequently been noted that the bleeding diathesis is greatly reduced as soon as the splenic artery is clamped (12). Most patients will not need platelets in the pre-op or post-op period. Platelet transfusions should probably be avoided if they are not clearly indicated.
IMMUNE THROMBOCYTOPENIC PURPURA
769
NEONATAL IMMlJNE IMMUNE THROMBOCYTOPENIC PURPlJRA PURPURA CAUSED AUTOIMMUNE CAlJSED BY MATERNAL AUTOIMMlJNE THROMBOCYTOPENIC PURPURA PlJRPURA In the case of a mother with autoimmune thrombocytopenic purpura who has been cured with splenectomy, one should assume that her fetus will suffer from neonatal immune thrombocytopenic purpura caused by transplacental passage of still circulating antiplatelet antibody. About half of infants at risk are clinically affected. ]9.22 lB."" Under these circumstances, the obstetrician and pediatrician should be aware of this special danger to the fetus and several routes of action should be considered including: A prenatal course of steroids to the mother beginning one steroids;"2 or week prior to delivery in an attempt to treat the fetus with steroids;22 caesarian section in order to reduce the trauma of birth. If the child is born severely thrombocytopenic anyhow, plasma exchange may be necessary to lower the titer of antiplatelet antibody. The role of steroids given to the infant is n.ot not clear, but they should probably be used if thrombocytopenia is unusually severe. The prognosis is favorable, and fetal and neonatal mortality is low. Thrombocytopenia persists for an average of 1 month, although in some cases lasts 4 to 6 months.
ISOIMMUNE NEONATAL PURPURA ISOIMMlJNE Isoimmune antiplatelet antibodies arise when an individual is transfused with another person's platelets. Isoantibodies directed against HLA antigens are frequently responsible for the shortened survival of transfused platelets. In addition, congenital thrombocytopenia due to isoantibody against the PIAl antigen (see post transfusion purpura 39 below) occurs in about 1 in 5000 births. Presumably the P1Al birthsY9 PIAl negative of· the fetus and the resultant mother is sensitized to the PIAl antigen of'the antibody crosses the placenta, causing thrombocytopenia. This disorder is analogous to erythroblastosis fetalis except that fetal platelets rather than red cells provide the antigenic stimulus, and are destroyed. The firstborn child is affected in half the cases, in marked contrast to firstbom erythroblastosis fetalis, with which the firstborn is rarely affected. As opposed to the difficulty of antibody detection in autoimmune thrombocytopenic purpura, antibodies reacting with platelets from the infant and father may be easily detected in maternal serum by agglutination, complement fixation, and antibody consumption techniques. Cord blood itself rarely gives positive results. Because only 2 per cent of the general population lack the PIAl platelet antigen (most often implicated in ppl antigen on maternal-fetal platelet incompatibility), absence of the PIAl the mother's platelets provides presumptive evidence that the neonatal thrombocytopenia is of isoimmune origin. General considerations for therapy of isoimmune neonatal thrombocytopenic purpura are similar to those of neonatal immune thrombocytopenic purpura. Steroids, exchange transfusions, and caesarian secm Platelet transfusions are usually effective in tion have been advocated.: advocated.~m
770
CHARLES
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KOLLER
this disease and are best obtained by plateletpheresis of the mother, who will be compatible no matter which antigen-antibody system is involved. Care must be taken to wash maternal platelets to avoid administration of more antibody to the infant. A large majority of infants will recover without sequellae after a thrombocytopenic period of two to three weeks. Fatalities are usually a result of intracranial hemorrhage caused by trauma in the birth canal.
POST -TRANSFUSION PURPURA POST-TRANSFUSION Acute life-threatening thrombocytopenic purpura can rarely occur approximately one week following blood transfusion. 2,2. 47 As in most cases of isoimmune neonatal purpura, the antibody is usually directed against the PIAl platelet antigen. This antigen is found in 98 per cent of the population but is almost always absent from platelets in cases of post-transfusion purpura. No experimentally proven theory has adequately explained the destruction of autologous platelets by an isoantibody (an antibody directed against an antigen not present on the patient's own platelets). Also unexplained is the very low incidence of post-transfusion purpura despite the fact that about 1 in 50 blood recipients is mismatched with respect to this antigen. The typical case of post-transfusion purpura occurs in a middle-aged woman one week after a blood transfusion given in the course of elective surgery. Post-transfusion purpura in men and nulliparous women is rare, suggesting that patients are sensitized to the PIAl antigen during a previous exposure (pregnancy). Anti-PIAl antibody can be detected by a variety of tests. Platelet counts are very low, generally less than 10,000 per cm mm. Bleeding into the skin and mucous membranes is usually profuse at the onset. The risk of intracranial hemorrhage is relatively great because: (1) the platelet count is very low, (2) the onset of thrombocytopenia is rapid, and (3) the typical patient is in an older age group. Steroids have no effect in shortening the duration of symptoms. Transfused platelets are ineffective and dangerous because serious transfusion reactions are likely. Plasmapheresis has been successful and is presently the treatment of choice. 22 This modality seems to work by removing antibody or immune complexes.
DRUG-INDUCED IMMUNE THROMBOCYTOPENIC PURPURA A vast number of drugs have been reported to cause thrombo24,;)6 cytopenia on an immunological basis. a3 ,. 24, 36 Any drug a thrombocytopenic patient is taking should be suspected as possible cause of immune thrombocytopenia. Quinine and quinidine together account for most cases, although digitoxin, aspirin, heparin, sulfonamides, and thiazides 24. :16 also account for many.9, 24, 36 Gold salts frequently cause accelerated destruction of platelets, but an immune mechanism is unproven. A
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careful drug history must be taken in all patients presenting with thrombocytopenia. In addition to the usual medication history, careful inquiry should be made regarding over the counter and home remedies and ingestion of tonics which may contain quinine. In most cases, the patient has been exposed to the offending agent within 3 to 24 hours of the onset of symptoms. The platelet count may be less than 1000 per cu mm and bleeding may be manifest as petechiae, purpura, hemorrhagic bullae of the mucosa, or bleeding from the gastrointestinal or urinary tract. Antibodies to quinine or quinidine can be detected by a number of 13 With other drugs which cause immune thrombotests in most cases. 13 cytopenic purpura, laboratory detection of the antibody is usually negative. An in vivo challenge to confirm the diagnosis should not be attempted unless continuing the drug is absolutely essential for the patient's welfare. As little as 1 JLg ~g rechallenge with certain drugs may cause life-threatening thrombocytopenia. Once induced, sensitivity to drugs causing immune thrombocytopenic purpura persists indefinitely and the patient should never be re-exposed. In the case of drugs such as quinine and quinidine which are rapidly excreted, bleeding symptoms disappear over a period of 3 to 4 days if no further ingestion occurs.
MISCELLANEOUS CAUSES OF IMMUNE THROMBOCYTOPENIC PURPURA It has recently been shown that some cases of thrombocytopenia 27 As the newer associated with sepsis are due to an immune mechanism. 27 tests to evaluate antiplatelet antibody reach the clinic, it is expected that other causes of thrombocytopenia will be found to have an immune 28 basis. 9n.,28
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Simpson Memorial Research Institute 102 0Observatory bservatory Ann Arbor, l\1ichigan Michigan 48109