American Journal of Hematology 7:87-96 (1979)
Acute Idiopathic Thrombocytopenic Purpura in Children Nancy B. McWilliams and Harold M. Maurer Section of Pediatric Hematology-Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond
Acute idiopathic thrombocytopenic purpura (ITP) characteristically follows a viral illness in preschool children. The exact role of viruses in the pathogenesis of this disorder remains uncertain, but the finding of markedly elevated levels of platelet-associated IgC serves to distinguish it from the chronic form of the disease and permits speculation on the mechanisms of platelet destruction. Although the spleen is important in both antibody production and platelet destruction, bone marrow synthesis of IgC has also been shown to be increased. The clinical course may be alarming, but mortality is low and prognosis excellent. Controversy has surrounded the role of steroids in the management of acute childhood ITP in retrospective studies. Controlled studies, however, indicate that thrombocytopenia is reversed sooner in treated patients. New assays for platelet-associated IgG offer new insights into this disorder and will allow delineation of acute and chronic disease at the time of diagnosis. Key words: platelets, idiopathic thrombocytopenic purpura INTRODUCTION
Idiopathic thrombocytopenic purpura (ITP) has been defined by Wintrobe as thrombocytopenia unassociated with exogenous factors or underlying disease in the presence of normal or increased numbers of megakaryocytes in the bone marrow [ 11. While both acute and chronic forms are seen in children, the acute form, typified by a hstory of previous viral infection, abrupt onset of hemorrhagic manifestations, a benign and relatively short course, usually with complete recovery, is much more common and is the subject of this report. The term “postinfectious ITP” has been proposed by Zuelzer for this syndrome [2].
Received for publication October 20, 1978; accepted May 23, 1979. Address reprint requests to Nancy B. McWilliams, MI>, Medical College of Virginia, Virginia Commonwealth University, MCV Station, Box 121, Richmond, VA 23298.
0361-8609/79/0701-0087$02.00@ 1979 Alan R. Liss, Inc.
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PATHOG ENES IS
Most of the elements of Wintrobe’s diagnostic criteria are widely accepted. It is eminently clear, however, that some “exogenous factor” must ultimately be responsible for the rapid removal of platelets in this disorder. The Role of Viruses
Purpura associated with pestilential fever was known in Hippocrates’ time, and thrombocytopenic purpura has been described during the course of viral illness acquired in utero and postnatally. Some examples include cytomegalovirus [3], herpes simplex [4], rubella [ 5 , 6 ] , coxsackie B [7], mumps [8], varicella [9], rubeola [ l o ] , infectious mononucleosis [I 11, cat scratch fever [ 121, and dengue [ 131. Subclinical thrombocytopenia is well documented within three days of measles vaccination [14, 151 and is reported in young children hospitalized for viral illness [ 161. Proposed mechanisms for thrombocytopenia during acute viral infection include 1) disseminated intravascular coagulation with platelet consumption, 2) platelet agglutination and lysis after surface absorption of virus [ 18, 19],3) incorporation of virus into platelets [20], 4) loss of platelet surface sialic acid from exposure to neuraminidase containing viruses [21], and 5) impaired platelet production from viral infection of megakaryocytes [9, 141. Wlule the effects of viruses on platelets and/or their precursors during active infection are reasonably defined, their exact role in postinfectious thrombocytopenia in children is less so. The very h g h incidence of antecedent viral illness in acute ITP, however, suggests more than a casual relationship between the two events. The Role of Antibodies
There is ample evidence in the literature to support the concept that adult ITP is an autoimmune disease with an antiplatelet antibody as the “exogenous factor” [22-241. Until recently, however, studies in acute ITP directed at antiplatelet antibodies were l i m ited. In 1951 Harrington described a “thrombocytopenic factor” in eight of ten patients with ITP, including one splenectomized child, which promptly produced thrombocytopenia in normals transfused with their blood or plasma [25]. In 1953 the same investigator elaborated on- this factor by further studies on 35 ITP patients, four of whom were children. He demonstrated platelet agglutinins in vitro in about 65%, including one child with chronic ITP and one with an associated autoimmune hemolytic anemia. He concluded that the “thrombocytopenic factor” was probably a platelet antibody [26]. Shulman et a1 elaborated on this factor and found that it was present in the IgG fraction of plasma and could be absorbed by normal platelets [27]. Karpatkin et al later showed that in adults the antibodies were in the IgG3 subclass [28]. Myllyla et al [29] have studied platelet aggregation by rubella antigen-antibody interaction both in children with rubella and in those with postrubella ITP. Their findings indicate that certain small-size antigens (similar to small-size rubella complement fixation antigen) and their antibodies, the titers of which were higher in the postrubella state, interacted to produce platelet aggregation in vitro. They suggested that this interaction might cause platelet damage in vivo. Other techniques for detecting platelet antibody in vitro, not reliant on platelet agglutination have been developed. Two involve the interaction of platelets with sera, plasma, or globulin fractions capable of immune injury with resultant release of platelet factor 3 or ‘‘C-serotonin. By these techniques, 60-65% of adults with ITP were positive for antiplatelet antibody [30,31].
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Detection of serum antibody in adults has been variable. Negative results have been found in some adults with ITP [30,31], and levels do not correlate well with platelet count or response to therapy [23,32]. It has been suggested that this variability may arise because antiplatelet antibodies may have different affinities for the platelet surface [23] . In 1970 Smith et a1 described a method for quantitating IgG associated with cellular elements using competitive binding between a ‘251-labeledFab fragment of IgG and its antibody [33]. This method was later modified by McMillan et a1 for the detection of platelet-associated IgG [34]. A second competitive binding assay introduced b y Dixon quantitates the inhibition of complement-dependent lysis of sheep erythrocytes by platelet-bound IgC, which is inversely proportional to the platelet count 1231. Luiken et al, using the Fab-anti-Fab assay, demonstrated significantly higher levels of platelet-associated IgG in six children with acute ITP than in 3 1 individuals with the chronic form of the disease [35]. In a larger series that included children only, Lightsey et al have recently confirmed this finding [36]. While levels of platelet-associated IgG were higher in all children with ITP than in normals (P < 0.001), those with acute ITP (achievement of normal platelets within six months of diagnosis without subsequent relapse) had even higher levels (P < 0.003) than those with chronic ITP (persistent thrombocytopenia longer than six months from diagnosis). Sequential studies on several children with acute ITP revealed a return to normal of platelet-associated IgG with clinical recovery. In Dixon’s series, using the complement lysis-inhibition assay, one child with post-varicella ITP is described whose bound IgG exceeded that of normals or chronic ITP patients manyfold [23]. It has been proposed that different mechanisms may be involved in the production of thrombocytopenia in chronic and acute ITP in children. In the chronic state antibodycoated platelets are probably removed by the reticuloendothelial system as in adults. In acute ITP however, as mean platelet-associated IgG levels were eight times hgher than the calculated antigen-saturatingquantity of platelet-bound IgG determined from ITP spleen culture studies using McMillan’s method [37], it is speculated that viral infections trigger formation of immune complexes [36]. These immune complexes could be surface absorbed to platelet receptors, making the Fc fragment less available to macrophages, or they could be phagocytized, with resultant platelet alteration and susceptibility to reticuloendothelial removal [36]. Both hypotheses represent a possible light at the end of the tunnel but remain to be proved. The most recently reported technique for detection of platelet-associated IgG is a modification of the direct Coombs’ test using a radiolabeled antiglobulin reagent. With this technique Cines and Schreiber 1381 studied 50 ITP patients, including 19 children. Sixteen of the children and 29 of the 31 adults studied had elevated platelet-associated IgG, but further analysis of the data in children was not reported. Platelet-associated C3 was also elevated in some patients [38], suggesting a role for C3 in the pathogenesis of thrombocytopenia. An indirect Coombs’ modification to study anti-platelet activity in plasma showed a significant overlap with normal controls 1381. The ability to determine platelet-associated IgG in this disease is clearly an important advance. Further studies are needed to assess the value of the assay in predicting an acute or chronic course, at present a retrospective judgment. The Role of the Spleen
Kaznelson is credited with postulating increased splenic platelet destruction in ITP in 1916 after he observed the salutary effect of splenectomy [40]. Harrington in 1953 suggested that the spleen served two purposes in the pathogenesis of ITP: removal of sensitized platelets and production of platelet agglutinin (thrombocytopenic factor) [26].
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Platelet survival has been determined from the isotope disappearance curve after injection of ”Cr-labeled platelets and is markedly decreased in both adults and children with ITP [41-431, including acute ITP in remission [44]. External scintillation scanning has permitted detection of sites of platelet destruction and correlation with results of splenectomy. Splenic, hepatic, “diffuse ,” and hepatosplenic sites have been reported, with splenic sequestration more frequently observed in patients under the age of 30 [45]. In a series of 34 patients reported by Ries, which included four children, 76% had splenic sequestration, whereas the remainder had splenic and hepatic sequestration. None had only hepatic or “diffuse” sequestration. The results of splenectomy, however, were not significantly different based on platelet sequestration patterns 1461. In spleens removed from ITP patients, histiocytes filled with lipid, presumably from platelet destruction, as well as hstiocytes containing digested platelets, have been described and attest to the increased phagocytic activity [47,48]. In in vitro studies on spleens from ITP patients, McMillan et a1 demonstrated all stages of phagocytosis in splenic macrophages, including platelet attachment to macrophages, both partial and complete engulfment, and platelet degradation [49]. The second role of the spleen, platelet antibody formation, has been determined through studies of McMiIlan in which splenic immunoglobulin synthesis was measured in vitro and found to be five times greater than that of controls [50]. More recently, the spleens of two children with “typical” ITP were studied and were found to have IgG synthesis rates five- and sevenfold greater than normal. That the spleen is not the only site of antibody production is also suggested from the finding of an increased synthesis of IgG in the bone marrow of one of these children [51]. CLINICAL FINDINGS
Although uncertainties remain about the pathogenesis of acute ITP in chddren, the clinical findings are familiar and well described. Acute ITP is well documented under the age of one year but most commonly occurs between two and six years, with a peak age incidence paralleling that of acute lymphoblastic leukemia and the “golden years” of viral infection [ 16,52-561. Boys and girls are equally affected, and Lusher et a1 have reported an increased incidence in white children in their series [ 161. Seasonal incidence is clearly lowest in the summer months [52, 571. In a typical case, the child gives a history of viral illness one to six weeks before, from which he has recovered, when the rapid onset of petechiae and purpura is noted. The degree of skin hemorrhage may vary from a few extra bruises at sites of trauma, especially on the legs, to a florid picture of petechiae and purpura involving neck, trunk, pelvis, and extremities. Epistaxis, palatal petechiae, purpuric lesions of the buccal mucosa, and subconjunctival hemorrhages are not uncommon extradermal bleeding manifestations. Retinal hemorrhage and gastrointestinal and genitourinary bleeding are alarming but uncommon manifestations. Neurologic abnormalities from central nervous system bleeding occur in less than 1% of children with acute ITP [52]. Significant splenomegaly does not occur in acute ITP, and its presence should prompt one to seek a definite etiology. Palpable spleens, however, are recorded in 5-12% of patients [52,54], an incidence similar to that seen in normal children [%].
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LABORATORY FINDINGS
By definition, the platelet count must be less than 100,000/mm3. In our own series of 27 children studied prospectively, platelet counts at diagnosis ranged from 1,000 to 79,000/mm3, with a mean of 20,000 f 4,000 [ 591. Anemia may be present if there has been substantial blood loss, but hemoglobin concentration and leukocyte count are usually normal. Mild eosinophilia of greater than 4% is seen in about 20% of patients [ 161. Lymphocytosis, with atypical forms, may be prominent but is usually appropriate for age and consistent with a recent viral illness. Except for a paucity of platelets, the blood smear is usually normal. The single platelets seen may be large and are considered to be young cells [60]. Bone marrow examination reveals normal or increased numbers of megakaryocytes. Myelopoiesis and erythropoiesis are undisturbed unless complications have induced hyperplasia. The tourniquet test will be positive and the bleeding time prolonged in most children. Prothrombin time, partial thromboplastin time, Coombs’ test, LE prep, and mono spot test are all normal or negative. TREATMENT
Considerable to raging controversy has surrounded the treatment of acute ITP in chldren. The efficacy of corticosteroids in reversing the thrombocytopenia has been examined by a number of authors, but analysis has been retrospective; dose, duration, and timing of treatment have been variable; and patient selection for treatment has been biased. Results have been contradictory [ 16, 52-56]. Lusher, in a retrospective analysis of 236 children with ITP, determined that recovery was “significantly” more rapid in the 201 nontreated patients than in those given steroids [ 161. In our series of 27 children studied prospectively and randomized to receive prednisone, 2 mg/kg per day for three weeks or no therapy, the median time to response (platelets 150,OOO/cu mm) was 21 days in the treated group and 60 days in those receiving no therapy (P = 0.03 Wilcoxin rank sum test) [59] (Table I). These results are simiIar to those of Sartorious [61] in a prospective European collaborative study, and to those of Simons et al in a nonrandomized study [55], and they indicate that early treatment with corticosteroids reverses thrombocytopenia significantly sooner than in those not treated. The short duration of the course was not associated with TABLE I. Prospective Randomized Trial - Steroid vs N o Treatment
Group Treated (13) Control (14)
Agea
5.6 yr 6.3 yr
f
0.9‘
* 1.2‘
aP > 0.05 between groups. bWilcoxin rank sum test P = 0.03. CValueexpressed as Mean i SEM.
Initial platelet count/mm3
Medianb time to platelet count 150,000
19,000 f 6,000 23,000 f 5,000
21 days 60 days
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any side-effects except weight gain and a mild cushingoid appearance. Clearly, a careful history of recent exposure to varicella should be taken prior to initiation of treatment. Corticosteroids do not affect platelet production or turnover in ITP, but they have been shown to increase mean platelet life-span, although not to return it to normal [42]. Their principal mode of action appears to be an inhibition of phagocytosis of sensitized platelets without effect on the binding of antibody to platelet or the amount of antibody in the serum [62]. The cause of the impaired clearance of antibody-coated platelets by corticosteroids is not certain, but it may be related to effects on niacrophage IgG or C3 receptors [63] or impairment of granulocyte adherence [64]. Children with ITP should be closely observed for signs of serious bleeding in the hospital, or at home if a responsible adult is present, and activities should be directed to nonhazardous forms of play. Parents or guardians should be warned about the use of aspirin or other agents that interfere with platelet aggregation. Treatment of Life-Threatening Hemorrhage
Splenectomy is recommended for children with life-threatening hemorrhage, which usually is intracranial and occurs less commonly in the gastrointestinal tract. The use of platelet transfusions prior to splenectomy is probably of limited value as the shortest survival curves have been obtained in acute cases [41]. This short survival of normal platelets would indicate that preformed antibody or circulating immune complexes rapidly attach to receptor sites and doom donor cells to the fate of autologous platelets. For the child who continues to bleed from severe thrombocytopenia postsplenectomy, frequent platelet transfusions and aggressive immunosuppressive therapy may be valuable. Lightsey et a1 have reported such a patient to whom they gave dexamethasone, platelet transfusions every one to three hours, and weekly vincristine and cyclophosphamide, with excellent results [65]. A transient response in platelet count and return of plasma antiplatelet antibody t o negative was reported by Novak and Wilimas in a similar splenectomy failure using plasmapheresis and platelet infusions [66]. Plasmapheresis has been successfully used in the management of patients with thrombotic thrombocytopenic purpura [67] as well as those with inhibitors of coagulation factors [68], and it certainly deserves further study in catastrophic ITP complications. Treatment of the Nonresponder
Elective splenectorny should be considered for the 5-10% of children who fail to respond to steroids or to achieve a normal platelet count after 6-12 months. The decision for splenectomy should take into account the age of the child, the degree of thrombocytopenia, the presence o r absence of hemorrhagic symptoms, the risk of overwhelming postsplenectomy sepsis, and the certainty that the child has immune thrombocytopenia. Buchanan et al have recommended the use of homologous platelet survival using 51Crlabeled platelets t o identify patients with nonimmune forms of chronic thrombocytopenia in whom splenectomy would not be beneficial [ 6 9 ] , The preoperative use of steroids and platelet transfusions has not been studied in a controlled fashion, but it is recommended by some authors [ 16,701. Intraoperative bleeding is usually not a problem after the splenic pedicle is clamped. A careful search for accessory spleens and their removal is considered a sine qua non of the procedure. Reports to date indicate that 5 0 4 3 % 153,711 of patients will have a long-term remission after splenectomy. In the remainder, the disease is usually benign [72]. For those
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with persistent symptomatic thrombocytopenia, immunosuppressive therapy with such agents as azathioprine [73], vincristine [74], vinblastine [75] ,or cyclophosphamide [76] has been successful in some patients, including children. An innovative approach to refractory ITP involves the transfusion of vinblastineloaded platelets, aimed at enhancing drug delivery to macrophages. With this technique, complete remissions were attained in 55% and partial remissions in 27% of patients studied [77]. PROGNOSIS
While the dust settles as the debates about therapy continue, one fact remains clear: the prognosis is excellent! Some 40% of children will recover in one month [53], 70% within six months [54], and as many as 92.6% in one year [52]. Late spontaneous remission occurring after one year is reported [56,72], as is recurrent ITP months t o years after complete recovery [54,78]. The availability of assays for platelet-associated IgG will, it is hoped, afford some new answers in this syndrome and will allow delineation of acute and chronic disease on a scientific rather than a temporal basis. ACKNOWLEDGMENTS
The authors would like to thank Mrs. Judy Nevis, Mr. Leslie R. Eaton, and Mrs. Diane Sileo for help in the preparation of this manuscript. REFERENCES 1. Wintrobe MM, Lee GR, Boggs DR, Bithell TC, Athens J N , Foerster J : “Clinical Hematology.” Philadelphia: Lea & Febiger, 1974, p 1075. 2. Zuelzer WW, Lusher JM: Childhood idiopathic thrombocytopenic purpura. Am J Dis Child 131: 360,1977. 3. Emanuel I , Kenny GE: Cytomegalic inclusion disease of infancy. Pediatrics 38:957, 1966. 4. Miller DR, Hanshaw JB, O’Leary DS, Hnilicka JV: Fatal disseminated herpes simplex virus infection and hemorrhage in the neonate. J Pediatr 76:409, 1970. 5. Bayer LW, Sherman FF, Michaels RH, Szeto ILF, Lewis JH: Purpura in congenital and acquired rubella, N Engl J Med 273:1362,1965. 6. Rausen AR, Richter P, Tallal L, Cooper LZ: Hematologic effects of intrauterine rubella. JAMA 109:75,1967. 7. Wright HT Jr, Okuyama K, McAllister RM: An infant fatality associated with Coxsackie B1 virus. J Pediatr 63:428,1963. 8. Fama PG, Paton WB, Bostick MI: Thrombocytopenic purpura complicating mumps. Br Med J 2:1244,1964. 9. Espinoza C, Kuhn C: Viral infection of megakaryocytes in varicella with purpura. Am J Clin Pathol61:203,1974. 10. Hudson JB, Weinstein L, Chang TW: Thrombocytopenic purpura in measles. J Pediatr 48:48, 1956. 11. Radel EG, Schorr JB: Thrombocytopenic purpura with infectious mononucleosis. J Pediatr 63: 4 6 , 1963. 12. Belber JP, Davis AE, Epstein EH: Thrombocytopenic purpura associated with cat-scratch disease. Arch Intern Med 94:321,1954. 13. Weiss HJ, Halstead SB: Studies of hemostasis in Thai hemorrhagic fever. J Pediatr 66:918, 1965. 14. Oski FA, Naiman JL: Effect of live measles vaccine on the platelet count. N Engl J Med 275:352, 1966. 15. Carpentieri U, Haggard ME: Thrombocytopenia and viral diseases. Tex Med 71:81, 1975.
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16. Lusher JM, Iyer R : Idiopathic thrombocytopenic purpura in children. Semin Thromb Hemostas 3:175, 1977. 17. McKay DG, Margaretten W: Disseminated intravascular coagulation in virus diseases. Arch Intern Med 120:129,1967. 18. Terada H, Baldini M, Ebbe S , Madoff MA: Interaction of influenza virus with blood platelets. Blood 28:213,1966. 19. Turpie AGG, Chernesky MA, Larke RPB, Packham MA, Mustard JF: Effect of Newcastle disease virus on human or rabbit platelets. Aggregation and loss of constituents. Lab Invest 28:575, 1973. 20. Jerushalmy Z, Kohn A, DeVries A: Interaction of myxoviruses with human blood platelets in vitro. Proc SOCExp Biol Med 106:462, 1961. 21. Scott S , Reimers HJ, Chernesky MA, Greenberg JP, Kinlough-Rathbone RL, Packham MA, Mustard JF: Effect of viruses on platelet aggregation and platelet survival in rabbits. Blood 52:47, 1978. 22. Dixon R, Rosse W: Platelet antibody in autoimmune thrombocytopenia. Br J Haematol 31:219, 1975. 23. Dixon R, Rosse W, Erbert L: Quantitative determination of antibody in idiopathic thronibocytopenic purpura: Correlation of serum and platelet-bound antibody in clinical response. N Engl J Med 292:230,1975. 24. Mueller-Eckhardt CM: Idiopathic thrombocytopenia purpura (ITP): Clinical and immunologic considerations. Semin Thromb Hemostas 3: 125,1977. 25. Harrington W J , Minnich V, Hollingsworth JW, Moore CV: Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. J Lab Clin Med 38: 1, 1951. 26. Harrington WJ, Sprague CC, Minnich V, Moore CV, Aulvin BS, Dubach R: Immunologic mechanisms in idiopathic and neonatal thrombocytopenic purpura. Ann Intern Med 38:433, 1953. 27. Shulman NR, Marder VJ, Weinrach RS: Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Ann NY Acad Sci 124:499, 1965. 28. Karpatkin S , Schur PM, Strick N, Siskind GW: Heavy chain subclass of human antiplatelet antibodies. Clin Immunol Immunopathol 2:1, 1973. 29. Myllyla G, Vhaeri A, Vesikari T, Penttinen K: Interaction between human blood platelets, viruses, and antibodies. IV Post-rubella thrombocytopenic purpura and platelet aggregation by rubella antigen-antibody interaction. Clin Exp Immunol4:323, 1969. 30. Karpatkin S, Strick N, Karpatkin MB, Siskind GW: Cumulative experience in the detection of antiplatelet antibody in 234 patients with idiopathic thrombocytopenic purpura, systemic lupus erythematosus and other clinical disorders. Am J Med 52:776, 1972. 31. Hirschman RJ, Shulman NR: The use of platelet serotonin release as a sensitive method for detecting anti-platelet antibodies and a plasma anti-platelet factor in patients with idiopathic thrombocytopenic purpura. Br J Haematol 24:793, 1973. 32. Clancy R, Jenkins E, Firkin B: Qualitative platelet abnormalities in idiopathic thrombocytopenic purpura. N Engl J Med 286:622, 1972. 33. Smith RS, Longmire RL, Reid RT, Farr RS: The measurement of immunoglobulin associated with human peripheral lymphocytes. J Immunol 104:367, 1970. 34. McMillan R, Smith RS, Longmire RL, Yelenosky R , Reid RT, Craddock CG: Immunoglobulins associated with human platelets. Blood 37:316, 1971. 35. Luiken GA, McMillan R, Lightsey AL, Gordon P, Zevely S, Shulman I, Gribble JT, Longmire RL: Platelet-associated IgG in immune thrombocytopenic purpura. Blood 50:3 17, 1977. 36. Lightsey AL, Koenig HM, McMillan R, Stone JR: Platelet-associated immunoglobulin G in childhood idiopathic thrombocytopenic purpura. J Pediatr 94:201, 1979. 37. McMiIlan R, Longmire RL, Tavassoli M, Armstrong S, Yelenosky R: Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N Engl J Med 290:249-251, 1974. 38. Cines DB, Schreiber AD: Immune thrombocytopenia. Use of a Coombs’ antiglobin test t o detect IgG and C, on platelets. N Engl J Med 300:106, 1979. 39. Hauch TW, Rosse WF: Platelet-bound complement (C,) in immune thrombocytopenia. Blood 50:1129,1977. 40. Kaznelson P: Verschwinden der hamorrhagischen diathese bei einem falle von “essentieller thrombopenie” (FRANK) nach milexstirpation. Splenogene thromboytische purpura. Wein Klin Wochenschr 29:1451,1916.
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41. Baldini M: Idiopathic thrombocytopenic purpura. N Engl J Med 274:1245,1966. 42. Branehbg I, Weinfield A: Platelet survival and platelet production in idiopathic thrombocytopenic purpura (ITP) before and during treatment with corticosteroids. Scand J Haematol 12:69, 1974. 43. Aster RM, Keene WR: Sites of platelet destruction in idiopathic thrombocytopenic purpura. Br J Haematol 16:61, 1969. 44. &soylu S, Allahverdi H, Lgleli Y , Pirnar A: Platelet survival in childhood idiopathic thrombocytopenic purpura in remission. J Pediatr 89:388, 1976. 45. Najean Y, Ardaillou N: The sequestration site of platelets in idiopathic thrombocytopenic purpura: Its correlation with the results of splenectomy. Br J Haematol 21:153, 1971. 46. Ries CA: Platelet kinetics in autoimmune thrombocytopenia: Relation between splenic platelet sequestration and response t o splenectomy. Ann Intern Med 86: 194, 1977. 47. King FM, Harstock RJ: Histochemical identification of lipid in spleens of patients with idiopathic thrombocytopenic purpura. Am J Clin Pathol49:250, 1963. 48. Firkin BG, Wright R, Miller S, Stokes E: Splenic macrophages in thrombocytopenia. Blood 33:240, 1969. 49. McMillan R, Longmire RL, Tavassoli M, Armstrong S, Yelenosky R: In vitro platelet phagocytosis by splenic leukocytes in idiopathic thrombocytopenic purpura. N Engl J Med 290:249, 1974. 50. McMillan R , Longmire RL, Yelenosky R, Smith RS, Craddock CG: Immunoglobulin synthesis in vitro by splenic tissue in idiopathic thrombocytopenic purpura. N Engl J Med 286:681, 1972. 51. Lightsey AL, McMillan R , Koenig HM, Schanberger JE, Lang JE: In vitro production of plateletbinding IgG in childhood idiopathic thrombocytopenic purpura. J Pediatr 88:414, 1976. 52. Lusher JM, Zuelzer WW: Idiopathic thrombocytopenic purpura in childhood. J Pediatr 68:971, 1966. 53. Benham ES, Taft LI: Idiopathic thrombocytopenic purpura in children: Results of steroid treatment and splenectomy. Aust Paediatr J 8:311, 1972. 54. Lammi AT, Lovric VA: Idiopathic thrombocytopenic purpura: An epidemiologic study. J Pediatr 83:31, 1973. 55. Simons SM, Main CA, Yaish HM, Rutzky J : Idiopathic thrombocytopenic purpura in children. J Pediatr 87:16, 1975. 56. Alexander N, Van Den Bogaert N, Fondy P: Le pronostic et le traitement du purpura thrombocytopenique idiopathique de l’enfant. Arch Fr Pediatr 33:329, 1976. 57. Choi SI, McClure PD: Idiopathic thrombocytopenic purpura in childhood. Can Med Assoc J 97: 562,1967. 58. Vaughan VC, McKay RJ: “Nelson Textbook of Pediatrics.” Philadelphia: WB Saunders Co, 1974, p 1160. 59. McWilliams NB, Maurer HM: Controlled clinical trial of prednisone in childhood ITP. Pediatr Res 11:476, 1917. 60. Murphy S, Oski FA, Naiman JL, Lusch CJ, Goldberg S, Gardner FM: Platelet size and kinetics in hereditary and acquired thrombocytopenia. N Engl J Med 286:500,1972. 61. Sartorious J: Personal communication. 62. Handin RI, Stossel TP: Effect of corticosteroid therapy on the phagocytosis of antibody-coated platelets by human leukocytes. Blood 51:771, 1978. 63. Schreiber AD, Parsons J, McDermott P, Cooper RA: Effect of corticosteroids on the human monocyte IgG and complement receptors. J Clin Invest 56:1189, 1975. 64. MacGregor RR, Spagnuolo PJ, Lentnek AL: Inhibition of granulocyte adherence by ethanol, prednisone and aspirin measured with an assay system. N Engl J Med 291:642, 1974. 65. Lightsey AL, McMiUan R, Koenig HM: Childhood idiopathic thrombocytopenic purpura: Aggressive management of life-threatening complications. JAMA 232:734, 1975. 66. Novak R, Wilimas J: Plasmapheresis in catastrophic complications of idiopathic thrombocytopenic purpura. J Pediatr 92:434, 1978. 67. Byrnes JJ, Mohan K: Treatment of thrombotic thrornbocytopenic purpura with plasma. N Engl J Med 297:1386,1977. 68. Pintado J, Jaswell HJ, Walter-Bowie EJ: Treatment of life-threatening hemorrhage due to acquired factor VIII inhibitor. Blood 46:535,1975. 69. Buchanan GR, Scher CS, Button LN, Nathan DG: Use of homologous platelet survival in the differential diagnosis of chronic thrombocytopenia in childhood. Pediatrics 59:49,1977. 70. Willoughby MLN: “Paediatric Haematology.” Edinburgh: Churchill Livingstone, 1977, p 262.
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71. Ibid. p 263. 72. Ramos MEG, Newman AJ, Gross S: Chronic thrombocytopenia in childhood. J Pediatr 92:584, 1978. 73. Hilgartner MW, Lanzkowsky P, Smith CH: The use of azothioprine in refractory idiopathic thrombocytopenic purpura in children. Acta Paediatr Scand 59:409, 1970. 74. Ahn YS, Harrington WJ, Seelman RC, Eytel CS: Vincristine therapy of idiopathic and secondary thrombocytopenias. N Engl J Med 291:376,1974. 75. Ahn YS, Harrington WJ: Treatment of idiopathic thrombocytopenic purpura. Annu Rev Med 28:299,1977. 76. Verlin M, Laros RK, Penner J: Treatment of refractory thrombocytopenic purpura with cyclophosphamide. Am J Hematol 1:97, 1976. 77. Ahn YS, Byrnes JJ, Harrington WJ, Cayer ML, Smith DS, Brunskill DE, Pall LM: The treatment of idiopathic thrombocytopenia with vinblastine-loaded platelets. N Engl J Med 298: 1101, 1978. 78. Dameshek W, Ebbe S, Greenberg L, Baldini M: Recurrent acute idiopathic thrombocytopenic purpura. N Engl J Med 269:647, 1963.
Acute Idiopathic Thrombocytopenic Purpura in Children Nancy B. McWilliams and Harold M. Maurer Section of Pediatric Hematology-Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond
Acute idiopathic thrombocytopenic purpura (ITP) characteristically follows a viral illness in preschool children. The exact role of viruses in the pathogenesis of this disorder remains uncertain, but the finding of markedly elevated levels of platelet-associated IgC serves to distinguish it from the chronic form of the disease and permits speculation on the mechanisms of platelet destruction. Although the spleen is important in both antibody production and platelet destruction, bone marrow synthesis of IgC has also been shown to be increased. The clinical course may be alarming, but mortality is low and prognosis excellent. Controversy has surrounded the role of steroids in the management of acute childhood ITP in retrospective studies. Controlled studies, however, indicate that thrombocytopenia is reversed sooner in treated patients. New assays for platelet-associated IgG offer new insights into this disorder and will allow delineation of acute and chronic disease at the time of diagnosis. Key words: platelets, idiopathic thrombocytopenic purpura INTRODUCTION
Idiopathic thrombocytopenic purpura (ITP) has been defined by Wintrobe as thrombocytopenia unassociated with exogenous factors or underlying disease in the presence of normal or increased numbers of megakaryocytes in the bone marrow [ 11. While both acute and chronic forms are seen in children, the acute form, typified by a hstory of previous viral infection, abrupt onset of hemorrhagic manifestations, a benign and relatively short course, usually with complete recovery, is much more common and is the subject of this report. The term “postinfectious ITP” has been proposed by Zuelzer for this syndrome [2].
Received for publication October 20, 1978; accepted May 23, 1979. Address reprint requests to Nancy B. McWilliams, MI>, Medical College of Virginia, Virginia Commonwealth University, MCV Station, Box 121, Richmond, VA 23298.
0361-8609/79/0701-0087$02.00@ 1979 Alan R. Liss, Inc.
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PATHOG ENES IS
Most of the elements of Wintrobe’s diagnostic criteria are widely accepted. It is eminently clear, however, that some “exogenous factor” must ultimately be responsible for the rapid removal of platelets in this disorder. The Role of Viruses
Purpura associated with pestilential fever was known in Hippocrates’ time, and thrombocytopenic purpura has been described during the course of viral illness acquired in utero and postnatally. Some examples include cytomegalovirus [3], herpes simplex [4], rubella [ 5 , 6 ] , coxsackie B [7], mumps [8], varicella [9], rubeola [ l o ] , infectious mononucleosis [I 11, cat scratch fever [ 121, and dengue [ 131. Subclinical thrombocytopenia is well documented within three days of measles vaccination [14, 151 and is reported in young children hospitalized for viral illness [ 161. Proposed mechanisms for thrombocytopenia during acute viral infection include 1) disseminated intravascular coagulation with platelet consumption, 2) platelet agglutination and lysis after surface absorption of virus [ 18, 19],3) incorporation of virus into platelets [20], 4) loss of platelet surface sialic acid from exposure to neuraminidase containing viruses [21], and 5) impaired platelet production from viral infection of megakaryocytes [9, 141. Wlule the effects of viruses on platelets and/or their precursors during active infection are reasonably defined, their exact role in postinfectious thrombocytopenia in children is less so. The very h g h incidence of antecedent viral illness in acute ITP, however, suggests more than a casual relationship between the two events. The Role of Antibodies
There is ample evidence in the literature to support the concept that adult ITP is an autoimmune disease with an antiplatelet antibody as the “exogenous factor” [22-241. Until recently, however, studies in acute ITP directed at antiplatelet antibodies were l i m ited. In 1951 Harrington described a “thrombocytopenic factor” in eight of ten patients with ITP, including one splenectomized child, which promptly produced thrombocytopenia in normals transfused with their blood or plasma [25]. In 1953 the same investigator elaborated on- this factor by further studies on 35 ITP patients, four of whom were children. He demonstrated platelet agglutinins in vitro in about 65%, including one child with chronic ITP and one with an associated autoimmune hemolytic anemia. He concluded that the “thrombocytopenic factor” was probably a platelet antibody [26]. Shulman et a1 elaborated on this factor and found that it was present in the IgG fraction of plasma and could be absorbed by normal platelets [27]. Karpatkin et al later showed that in adults the antibodies were in the IgG3 subclass [28]. Myllyla et al [29] have studied platelet aggregation by rubella antigen-antibody interaction both in children with rubella and in those with postrubella ITP. Their findings indicate that certain small-size antigens (similar to small-size rubella complement fixation antigen) and their antibodies, the titers of which were higher in the postrubella state, interacted to produce platelet aggregation in vitro. They suggested that this interaction might cause platelet damage in vivo. Other techniques for detecting platelet antibody in vitro, not reliant on platelet agglutination have been developed. Two involve the interaction of platelets with sera, plasma, or globulin fractions capable of immune injury with resultant release of platelet factor 3 or ‘‘C-serotonin. By these techniques, 60-65% of adults with ITP were positive for antiplatelet antibody [30,31].
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Detection of serum antibody in adults has been variable. Negative results have been found in some adults with ITP [30,31], and levels do not correlate well with platelet count or response to therapy [23,32]. It has been suggested that this variability may arise because antiplatelet antibodies may have different affinities for the platelet surface [23] . In 1970 Smith et a1 described a method for quantitating IgG associated with cellular elements using competitive binding between a ‘251-labeledFab fragment of IgG and its antibody [33]. This method was later modified by McMillan et a1 for the detection of platelet-associated IgG [34]. A second competitive binding assay introduced b y Dixon quantitates the inhibition of complement-dependent lysis of sheep erythrocytes by platelet-bound IgC, which is inversely proportional to the platelet count 1231. Luiken et al, using the Fab-anti-Fab assay, demonstrated significantly higher levels of platelet-associated IgG in six children with acute ITP than in 3 1 individuals with the chronic form of the disease [35]. In a larger series that included children only, Lightsey et al have recently confirmed this finding [36]. While levels of platelet-associated IgG were higher in all children with ITP than in normals (P < 0.001), those with acute ITP (achievement of normal platelets within six months of diagnosis without subsequent relapse) had even higher levels (P < 0.003) than those with chronic ITP (persistent thrombocytopenia longer than six months from diagnosis). Sequential studies on several children with acute ITP revealed a return to normal of platelet-associated IgG with clinical recovery. In Dixon’s series, using the complement lysis-inhibition assay, one child with post-varicella ITP is described whose bound IgG exceeded that of normals or chronic ITP patients manyfold [23]. It has been proposed that different mechanisms may be involved in the production of thrombocytopenia in chronic and acute ITP in children. In the chronic state antibodycoated platelets are probably removed by the reticuloendothelial system as in adults. In acute ITP however, as mean platelet-associated IgG levels were eight times hgher than the calculated antigen-saturatingquantity of platelet-bound IgG determined from ITP spleen culture studies using McMillan’s method [37], it is speculated that viral infections trigger formation of immune complexes [36]. These immune complexes could be surface absorbed to platelet receptors, making the Fc fragment less available to macrophages, or they could be phagocytized, with resultant platelet alteration and susceptibility to reticuloendothelial removal [36]. Both hypotheses represent a possible light at the end of the tunnel but remain to be proved. The most recently reported technique for detection of platelet-associated IgG is a modification of the direct Coombs’ test using a radiolabeled antiglobulin reagent. With this technique Cines and Schreiber 1381 studied 50 ITP patients, including 19 children. Sixteen of the children and 29 of the 31 adults studied had elevated platelet-associated IgG, but further analysis of the data in children was not reported. Platelet-associated C3 was also elevated in some patients [38], suggesting a role for C3 in the pathogenesis of thrombocytopenia. An indirect Coombs’ modification to study anti-platelet activity in plasma showed a significant overlap with normal controls 1381. The ability to determine platelet-associated IgG in this disease is clearly an important advance. Further studies are needed to assess the value of the assay in predicting an acute or chronic course, at present a retrospective judgment. The Role of the Spleen
Kaznelson is credited with postulating increased splenic platelet destruction in ITP in 1916 after he observed the salutary effect of splenectomy [40]. Harrington in 1953 suggested that the spleen served two purposes in the pathogenesis of ITP: removal of sensitized platelets and production of platelet agglutinin (thrombocytopenic factor) [26].
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Platelet survival has been determined from the isotope disappearance curve after injection of ”Cr-labeled platelets and is markedly decreased in both adults and children with ITP [41-431, including acute ITP in remission [44]. External scintillation scanning has permitted detection of sites of platelet destruction and correlation with results of splenectomy. Splenic, hepatic, “diffuse ,” and hepatosplenic sites have been reported, with splenic sequestration more frequently observed in patients under the age of 30 [45]. In a series of 34 patients reported by Ries, which included four children, 76% had splenic sequestration, whereas the remainder had splenic and hepatic sequestration. None had only hepatic or “diffuse” sequestration. The results of splenectomy, however, were not significantly different based on platelet sequestration patterns 1461. In spleens removed from ITP patients, histiocytes filled with lipid, presumably from platelet destruction, as well as hstiocytes containing digested platelets, have been described and attest to the increased phagocytic activity [47,48]. In in vitro studies on spleens from ITP patients, McMillan et a1 demonstrated all stages of phagocytosis in splenic macrophages, including platelet attachment to macrophages, both partial and complete engulfment, and platelet degradation [49]. The second role of the spleen, platelet antibody formation, has been determined through studies of McMiIlan in which splenic immunoglobulin synthesis was measured in vitro and found to be five times greater than that of controls [50]. More recently, the spleens of two children with “typical” ITP were studied and were found to have IgG synthesis rates five- and sevenfold greater than normal. That the spleen is not the only site of antibody production is also suggested from the finding of an increased synthesis of IgG in the bone marrow of one of these children [51]. CLINICAL FINDINGS
Although uncertainties remain about the pathogenesis of acute ITP in chddren, the clinical findings are familiar and well described. Acute ITP is well documented under the age of one year but most commonly occurs between two and six years, with a peak age incidence paralleling that of acute lymphoblastic leukemia and the “golden years” of viral infection [ 16,52-561. Boys and girls are equally affected, and Lusher et a1 have reported an increased incidence in white children in their series [ 161. Seasonal incidence is clearly lowest in the summer months [52, 571. In a typical case, the child gives a history of viral illness one to six weeks before, from which he has recovered, when the rapid onset of petechiae and purpura is noted. The degree of skin hemorrhage may vary from a few extra bruises at sites of trauma, especially on the legs, to a florid picture of petechiae and purpura involving neck, trunk, pelvis, and extremities. Epistaxis, palatal petechiae, purpuric lesions of the buccal mucosa, and subconjunctival hemorrhages are not uncommon extradermal bleeding manifestations. Retinal hemorrhage and gastrointestinal and genitourinary bleeding are alarming but uncommon manifestations. Neurologic abnormalities from central nervous system bleeding occur in less than 1% of children with acute ITP [52]. Significant splenomegaly does not occur in acute ITP, and its presence should prompt one to seek a definite etiology. Palpable spleens, however, are recorded in 5-12% of patients [52,54], an incidence similar to that seen in normal children [%].
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LABORATORY FINDINGS
By definition, the platelet count must be less than 100,000/mm3. In our own series of 27 children studied prospectively, platelet counts at diagnosis ranged from 1,000 to 79,000/mm3, with a mean of 20,000 f 4,000 [ 591. Anemia may be present if there has been substantial blood loss, but hemoglobin concentration and leukocyte count are usually normal. Mild eosinophilia of greater than 4% is seen in about 20% of patients [ 161. Lymphocytosis, with atypical forms, may be prominent but is usually appropriate for age and consistent with a recent viral illness. Except for a paucity of platelets, the blood smear is usually normal. The single platelets seen may be large and are considered to be young cells [60]. Bone marrow examination reveals normal or increased numbers of megakaryocytes. Myelopoiesis and erythropoiesis are undisturbed unless complications have induced hyperplasia. The tourniquet test will be positive and the bleeding time prolonged in most children. Prothrombin time, partial thromboplastin time, Coombs’ test, LE prep, and mono spot test are all normal or negative. TREATMENT
Considerable to raging controversy has surrounded the treatment of acute ITP in chldren. The efficacy of corticosteroids in reversing the thrombocytopenia has been examined by a number of authors, but analysis has been retrospective; dose, duration, and timing of treatment have been variable; and patient selection for treatment has been biased. Results have been contradictory [ 16, 52-56]. Lusher, in a retrospective analysis of 236 children with ITP, determined that recovery was “significantly” more rapid in the 201 nontreated patients than in those given steroids [ 161. In our series of 27 children studied prospectively and randomized to receive prednisone, 2 mg/kg per day for three weeks or no therapy, the median time to response (platelets 150,OOO/cu mm) was 21 days in the treated group and 60 days in those receiving no therapy (P = 0.03 Wilcoxin rank sum test) [59] (Table I). These results are simiIar to those of Sartorious [61] in a prospective European collaborative study, and to those of Simons et al in a nonrandomized study [55], and they indicate that early treatment with corticosteroids reverses thrombocytopenia significantly sooner than in those not treated. The short duration of the course was not associated with TABLE I. Prospective Randomized Trial - Steroid vs N o Treatment
Group Treated (13) Control (14)
Agea
5.6 yr 6.3 yr
f
0.9‘
* 1.2‘
aP > 0.05 between groups. bWilcoxin rank sum test P = 0.03. CValueexpressed as Mean i SEM.
Initial platelet count/mm3
Medianb time to platelet count 150,000
19,000 f 6,000 23,000 f 5,000
21 days 60 days
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any side-effects except weight gain and a mild cushingoid appearance. Clearly, a careful history of recent exposure to varicella should be taken prior to initiation of treatment. Corticosteroids do not affect platelet production or turnover in ITP, but they have been shown to increase mean platelet life-span, although not to return it to normal [42]. Their principal mode of action appears to be an inhibition of phagocytosis of sensitized platelets without effect on the binding of antibody to platelet or the amount of antibody in the serum [62]. The cause of the impaired clearance of antibody-coated platelets by corticosteroids is not certain, but it may be related to effects on niacrophage IgG or C3 receptors [63] or impairment of granulocyte adherence [64]. Children with ITP should be closely observed for signs of serious bleeding in the hospital, or at home if a responsible adult is present, and activities should be directed to nonhazardous forms of play. Parents or guardians should be warned about the use of aspirin or other agents that interfere with platelet aggregation. Treatment of Life-Threatening Hemorrhage
Splenectomy is recommended for children with life-threatening hemorrhage, which usually is intracranial and occurs less commonly in the gastrointestinal tract. The use of platelet transfusions prior to splenectomy is probably of limited value as the shortest survival curves have been obtained in acute cases [41]. This short survival of normal platelets would indicate that preformed antibody or circulating immune complexes rapidly attach to receptor sites and doom donor cells to the fate of autologous platelets. For the child who continues to bleed from severe thrombocytopenia postsplenectomy, frequent platelet transfusions and aggressive immunosuppressive therapy may be valuable. Lightsey et a1 have reported such a patient to whom they gave dexamethasone, platelet transfusions every one to three hours, and weekly vincristine and cyclophosphamide, with excellent results [65]. A transient response in platelet count and return of plasma antiplatelet antibody t o negative was reported by Novak and Wilimas in a similar splenectomy failure using plasmapheresis and platelet infusions [66]. Plasmapheresis has been successfully used in the management of patients with thrombotic thrombocytopenic purpura [67] as well as those with inhibitors of coagulation factors [68], and it certainly deserves further study in catastrophic ITP complications. Treatment of the Nonresponder
Elective splenectorny should be considered for the 5-10% of children who fail to respond to steroids or to achieve a normal platelet count after 6-12 months. The decision for splenectomy should take into account the age of the child, the degree of thrombocytopenia, the presence o r absence of hemorrhagic symptoms, the risk of overwhelming postsplenectomy sepsis, and the certainty that the child has immune thrombocytopenia. Buchanan et al have recommended the use of homologous platelet survival using 51Crlabeled platelets t o identify patients with nonimmune forms of chronic thrombocytopenia in whom splenectomy would not be beneficial [ 6 9 ] , The preoperative use of steroids and platelet transfusions has not been studied in a controlled fashion, but it is recommended by some authors [ 16,701. Intraoperative bleeding is usually not a problem after the splenic pedicle is clamped. A careful search for accessory spleens and their removal is considered a sine qua non of the procedure. Reports to date indicate that 5 0 4 3 % 153,711 of patients will have a long-term remission after splenectomy. In the remainder, the disease is usually benign [72]. For those
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with persistent symptomatic thrombocytopenia, immunosuppressive therapy with such agents as azathioprine [73], vincristine [74], vinblastine [75] ,or cyclophosphamide [76] has been successful in some patients, including children. An innovative approach to refractory ITP involves the transfusion of vinblastineloaded platelets, aimed at enhancing drug delivery to macrophages. With this technique, complete remissions were attained in 55% and partial remissions in 27% of patients studied [77]. PROGNOSIS
While the dust settles as the debates about therapy continue, one fact remains clear: the prognosis is excellent! Some 40% of children will recover in one month [53], 70% within six months [54], and as many as 92.6% in one year [52]. Late spontaneous remission occurring after one year is reported [56,72], as is recurrent ITP months t o years after complete recovery [54,78]. The availability of assays for platelet-associated IgG will, it is hoped, afford some new answers in this syndrome and will allow delineation of acute and chronic disease on a scientific rather than a temporal basis. ACKNOWLEDGMENTS
The authors would like to thank Mrs. Judy Nevis, Mr. Leslie R. Eaton, and Mrs. Diane Sileo for help in the preparation of this manuscript. REFERENCES 1. Wintrobe MM, Lee GR, Boggs DR, Bithell TC, Athens J N , Foerster J : “Clinical Hematology.” Philadelphia: Lea & Febiger, 1974, p 1075. 2. Zuelzer WW, Lusher JM: Childhood idiopathic thrombocytopenic purpura. Am J Dis Child 131: 360,1977. 3. Emanuel I , Kenny GE: Cytomegalic inclusion disease of infancy. Pediatrics 38:957, 1966. 4. Miller DR, Hanshaw JB, O’Leary DS, Hnilicka JV: Fatal disseminated herpes simplex virus infection and hemorrhage in the neonate. J Pediatr 76:409, 1970. 5. Bayer LW, Sherman FF, Michaels RH, Szeto ILF, Lewis JH: Purpura in congenital and acquired rubella, N Engl J Med 273:1362,1965. 6. Rausen AR, Richter P, Tallal L, Cooper LZ: Hematologic effects of intrauterine rubella. JAMA 109:75,1967. 7. Wright HT Jr, Okuyama K, McAllister RM: An infant fatality associated with Coxsackie B1 virus. J Pediatr 63:428,1963. 8. Fama PG, Paton WB, Bostick MI: Thrombocytopenic purpura complicating mumps. Br Med J 2:1244,1964. 9. Espinoza C, Kuhn C: Viral infection of megakaryocytes in varicella with purpura. Am J Clin Pathol61:203,1974. 10. Hudson JB, Weinstein L, Chang TW: Thrombocytopenic purpura in measles. J Pediatr 48:48, 1956. 11. Radel EG, Schorr JB: Thrombocytopenic purpura with infectious mononucleosis. J Pediatr 63: 4 6 , 1963. 12. Belber JP, Davis AE, Epstein EH: Thrombocytopenic purpura associated with cat-scratch disease. Arch Intern Med 94:321,1954. 13. Weiss HJ, Halstead SB: Studies of hemostasis in Thai hemorrhagic fever. J Pediatr 66:918, 1965. 14. Oski FA, Naiman JL: Effect of live measles vaccine on the platelet count. N Engl J Med 275:352, 1966. 15. Carpentieri U, Haggard ME: Thrombocytopenia and viral diseases. Tex Med 71:81, 1975.
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16. Lusher JM, Iyer R : Idiopathic thrombocytopenic purpura in children. Semin Thromb Hemostas 3:175, 1977. 17. McKay DG, Margaretten W: Disseminated intravascular coagulation in virus diseases. Arch Intern Med 120:129,1967. 18. Terada H, Baldini M, Ebbe S , Madoff MA: Interaction of influenza virus with blood platelets. Blood 28:213,1966. 19. Turpie AGG, Chernesky MA, Larke RPB, Packham MA, Mustard JF: Effect of Newcastle disease virus on human or rabbit platelets. Aggregation and loss of constituents. Lab Invest 28:575, 1973. 20. Jerushalmy Z, Kohn A, DeVries A: Interaction of myxoviruses with human blood platelets in vitro. Proc SOCExp Biol Med 106:462, 1961. 21. Scott S , Reimers HJ, Chernesky MA, Greenberg JP, Kinlough-Rathbone RL, Packham MA, Mustard JF: Effect of viruses on platelet aggregation and platelet survival in rabbits. Blood 52:47, 1978. 22. Dixon R, Rosse W: Platelet antibody in autoimmune thrombocytopenia. Br J Haematol 31:219, 1975. 23. Dixon R, Rosse W, Erbert L: Quantitative determination of antibody in idiopathic thronibocytopenic purpura: Correlation of serum and platelet-bound antibody in clinical response. N Engl J Med 292:230,1975. 24. Mueller-Eckhardt CM: Idiopathic thrombocytopenia purpura (ITP): Clinical and immunologic considerations. Semin Thromb Hemostas 3: 125,1977. 25. Harrington W J , Minnich V, Hollingsworth JW, Moore CV: Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. J Lab Clin Med 38: 1, 1951. 26. Harrington WJ, Sprague CC, Minnich V, Moore CV, Aulvin BS, Dubach R: Immunologic mechanisms in idiopathic and neonatal thrombocytopenic purpura. Ann Intern Med 38:433, 1953. 27. Shulman NR, Marder VJ, Weinrach RS: Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Ann NY Acad Sci 124:499, 1965. 28. Karpatkin S , Schur PM, Strick N, Siskind GW: Heavy chain subclass of human antiplatelet antibodies. Clin Immunol Immunopathol 2:1, 1973. 29. Myllyla G, Vhaeri A, Vesikari T, Penttinen K: Interaction between human blood platelets, viruses, and antibodies. IV Post-rubella thrombocytopenic purpura and platelet aggregation by rubella antigen-antibody interaction. Clin Exp Immunol4:323, 1969. 30. Karpatkin S, Strick N, Karpatkin MB, Siskind GW: Cumulative experience in the detection of antiplatelet antibody in 234 patients with idiopathic thrombocytopenic purpura, systemic lupus erythematosus and other clinical disorders. Am J Med 52:776, 1972. 31. Hirschman RJ, Shulman NR: The use of platelet serotonin release as a sensitive method for detecting anti-platelet antibodies and a plasma anti-platelet factor in patients with idiopathic thrombocytopenic purpura. Br J Haematol 24:793, 1973. 32. Clancy R, Jenkins E, Firkin B: Qualitative platelet abnormalities in idiopathic thrombocytopenic purpura. N Engl J Med 286:622, 1972. 33. Smith RS, Longmire RL, Reid RT, Farr RS: The measurement of immunoglobulin associated with human peripheral lymphocytes. J Immunol 104:367, 1970. 34. McMillan R, Smith RS, Longmire RL, Yelenosky R , Reid RT, Craddock CG: Immunoglobulins associated with human platelets. Blood 37:316, 1971. 35. Luiken GA, McMillan R, Lightsey AL, Gordon P, Zevely S, Shulman I, Gribble JT, Longmire RL: Platelet-associated IgG in immune thrombocytopenic purpura. Blood 50:3 17, 1977. 36. Lightsey AL, Koenig HM, McMillan R, Stone JR: Platelet-associated immunoglobulin G in childhood idiopathic thrombocytopenic purpura. J Pediatr 94:201, 1979. 37. McMiIlan R, Longmire RL, Tavassoli M, Armstrong S, Yelenosky R: Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N Engl J Med 290:249-251, 1974. 38. Cines DB, Schreiber AD: Immune thrombocytopenia. Use of a Coombs’ antiglobin test t o detect IgG and C, on platelets. N Engl J Med 300:106, 1979. 39. Hauch TW, Rosse WF: Platelet-bound complement (C,) in immune thrombocytopenia. Blood 50:1129,1977. 40. Kaznelson P: Verschwinden der hamorrhagischen diathese bei einem falle von “essentieller thrombopenie” (FRANK) nach milexstirpation. Splenogene thromboytische purpura. Wein Klin Wochenschr 29:1451,1916.
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41. Baldini M: Idiopathic thrombocytopenic purpura. N Engl J Med 274:1245,1966. 42. Branehbg I, Weinfield A: Platelet survival and platelet production in idiopathic thrombocytopenic purpura (ITP) before and during treatment with corticosteroids. Scand J Haematol 12:69, 1974. 43. Aster RM, Keene WR: Sites of platelet destruction in idiopathic thrombocytopenic purpura. Br J Haematol 16:61, 1969. 44. &soylu S, Allahverdi H, Lgleli Y , Pirnar A: Platelet survival in childhood idiopathic thrombocytopenic purpura in remission. J Pediatr 89:388, 1976. 45. Najean Y, Ardaillou N: The sequestration site of platelets in idiopathic thrombocytopenic purpura: Its correlation with the results of splenectomy. Br J Haematol 21:153, 1971. 46. Ries CA: Platelet kinetics in autoimmune thrombocytopenia: Relation between splenic platelet sequestration and response t o splenectomy. Ann Intern Med 86: 194, 1977. 47. King FM, Harstock RJ: Histochemical identification of lipid in spleens of patients with idiopathic thrombocytopenic purpura. Am J Clin Pathol49:250, 1963. 48. Firkin BG, Wright R, Miller S, Stokes E: Splenic macrophages in thrombocytopenia. Blood 33:240, 1969. 49. McMillan R, Longmire RL, Tavassoli M, Armstrong S, Yelenosky R: In vitro platelet phagocytosis by splenic leukocytes in idiopathic thrombocytopenic purpura. N Engl J Med 290:249, 1974. 50. McMillan R , Longmire RL, Yelenosky R, Smith RS, Craddock CG: Immunoglobulin synthesis in vitro by splenic tissue in idiopathic thrombocytopenic purpura. N Engl J Med 286:681, 1972. 51. Lightsey AL, McMillan R , Koenig HM, Schanberger JE, Lang JE: In vitro production of plateletbinding IgG in childhood idiopathic thrombocytopenic purpura. J Pediatr 88:414, 1976. 52. Lusher JM, Zuelzer WW: Idiopathic thrombocytopenic purpura in childhood. J Pediatr 68:971, 1966. 53. Benham ES, Taft LI: Idiopathic thrombocytopenic purpura in children: Results of steroid treatment and splenectomy. Aust Paediatr J 8:311, 1972. 54. Lammi AT, Lovric VA: Idiopathic thrombocytopenic purpura: An epidemiologic study. J Pediatr 83:31, 1973. 55. Simons SM, Main CA, Yaish HM, Rutzky J : Idiopathic thrombocytopenic purpura in children. J Pediatr 87:16, 1975. 56. Alexander N, Van Den Bogaert N, Fondy P: Le pronostic et le traitement du purpura thrombocytopenique idiopathique de l’enfant. Arch Fr Pediatr 33:329, 1976. 57. Choi SI, McClure PD: Idiopathic thrombocytopenic purpura in childhood. Can Med Assoc J 97: 562,1967. 58. Vaughan VC, McKay RJ: “Nelson Textbook of Pediatrics.” Philadelphia: WB Saunders Co, 1974, p 1160. 59. McWilliams NB, Maurer HM: Controlled clinical trial of prednisone in childhood ITP. Pediatr Res 11:476, 1917. 60. Murphy S, Oski FA, Naiman JL, Lusch CJ, Goldberg S, Gardner FM: Platelet size and kinetics in hereditary and acquired thrombocytopenia. N Engl J Med 286:500,1972. 61. Sartorious J: Personal communication. 62. Handin RI, Stossel TP: Effect of corticosteroid therapy on the phagocytosis of antibody-coated platelets by human leukocytes. Blood 51:771, 1978. 63. Schreiber AD, Parsons J, McDermott P, Cooper RA: Effect of corticosteroids on the human monocyte IgG and complement receptors. J Clin Invest 56:1189, 1975. 64. MacGregor RR, Spagnuolo PJ, Lentnek AL: Inhibition of granulocyte adherence by ethanol, prednisone and aspirin measured with an assay system. N Engl J Med 291:642, 1974. 65. Lightsey AL, McMiUan R, Koenig HM: Childhood idiopathic thrombocytopenic purpura: Aggressive management of life-threatening complications. JAMA 232:734, 1975. 66. Novak R, Wilimas J: Plasmapheresis in catastrophic complications of idiopathic thrombocytopenic purpura. J Pediatr 92:434, 1978. 67. Byrnes JJ, Mohan K: Treatment of thrombotic thrornbocytopenic purpura with plasma. N Engl J Med 297:1386,1977. 68. Pintado J, Jaswell HJ, Walter-Bowie EJ: Treatment of life-threatening hemorrhage due to acquired factor VIII inhibitor. Blood 46:535,1975. 69. Buchanan GR, Scher CS, Button LN, Nathan DG: Use of homologous platelet survival in the differential diagnosis of chronic thrombocytopenia in childhood. Pediatrics 59:49,1977. 70. Willoughby MLN: “Paediatric Haematology.” Edinburgh: Churchill Livingstone, 1977, p 262.
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71. Ibid. p 263. 72. Ramos MEG, Newman AJ, Gross S: Chronic thrombocytopenia in childhood. J Pediatr 92:584, 1978. 73. Hilgartner MW, Lanzkowsky P, Smith CH: The use of azothioprine in refractory idiopathic thrombocytopenic purpura in children. Acta Paediatr Scand 59:409, 1970. 74. Ahn YS, Harrington WJ, Seelman RC, Eytel CS: Vincristine therapy of idiopathic and secondary thrombocytopenias. N Engl J Med 291:376,1974. 75. Ahn YS, Harrington WJ: Treatment of idiopathic thrombocytopenic purpura. Annu Rev Med 28:299,1977. 76. Verlin M, Laros RK, Penner J: Treatment of refractory thrombocytopenic purpura with cyclophosphamide. Am J Hematol 1:97, 1976. 77. Ahn YS, Byrnes JJ, Harrington WJ, Cayer ML, Smith DS, Brunskill DE, Pall LM: The treatment of idiopathic thrombocytopenia with vinblastine-loaded platelets. N Engl J Med 298: 1101, 1978. 78. Dameshek W, Ebbe S, Greenberg L, Baldini M: Recurrent acute idiopathic thrombocytopenic purpura. N Engl J Med 269:647, 1963.
