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Treatment options for chronic idiopathic (immune) thrombocytopenic purpura
Treatment Options for Chronic Idiopathic (immune) Thrombocytopenic Purpura Jumes iV. George The goal of treatment for idiopathic (immune) thrombocytopenic purpura (ITP) is to prevent serious bleeding. Traditionally, corticosteroids have been used as first-line therapy followed by splenectomy. Experience with splenectomy over 60 years shows that approximately two thirds of patients achieve normal platelet counts during the initial observation, but that thrombocytopenia often recurs with longer follow-up. We know that long-term use of corticosteroids can lead to significant morbidities; there is no consensus regarding the appropriate timing or indications for splenectomy. To address the issue of appropriate use of splenectomy, we designed a multicenter clinical trial that will randomize patients to either standard care, involving prednisone followed by splenectomy, or to a novel regimen of limited prednisone treatment followed by WinRho SDFTM (Nabi, Boca Raton, FL) (anti-D) therapy to maintain the platelet count in a safe range for 1 year. Anti-D can be administered easily in an outpatient setting with few side effects and can provide predictable, transient increases in platelet count. The hypothesis is that prolonged maintenance therapy with a nontoxic regimen may increase the percentage of patients who will experience a spontaneous remission from thrombocytopenia, thereby avoiding an invasive and permanent surgical procedure, splenectomy, and its potentially life-threatening sequelae. Semin Hematol37(suppll):31-34. Copyright 0 2000 by W.B. Saunders Company.
I
DIOPATHIC (IMMUNE) thrombocytopenit purpura (ITP) has distinct clinical manifestations in children and adults. The goal of treatment in both groups is to prevent serious bleeding. In boys and girls less than 10 years old, the incidence of ITP is equal, the onset is typically abrupt, and the course is typically self-limited. Treatment may be appropriate to increase the platelet count to a safer range until spontaneous recovery occurs. In adults, ITP is typically more indolent in its onset and the course may be persistent, often lasting many years or characterized by recurrent exacerbations of thrombocytopenia. Spontaneous remissions in adults are believed to be infrequent. Although treatment with corticosteroids and other immunosuppressive agents may have a potential for cure, the goal for treatment of adults with ITP is to achieve a safe platelet count with the hope that a spontaneous remission of the disease will eventually occur. Patients with asymptomatic thrombocytopenia and platelet counts above 30 X lO”/L to 50 X 109/L may require no treatment. If initial corticosteroid therapy fails to achieve a sustained remission, splenectomy has usually been the next choice of therapy. The results with splenectomy over 60 years are remarkably consistent, with the achievement of Seminars in Hematology,
normal platelet counts sustained for the duration of observation in two thirds of patients. However, there is strong anecdotal evidence suggesting that longer follow-up reveals that thrombocytopenia will recur in a significant percentage of these patients. There is no consensus regarding the appropriate timing or even indication for splenectomy. Corticosteroids are often used repeatedly, in an attempt to defer splenectomy, until side effects become intolerable. In 1996, the American Society of Hematology (ASH) convened an expert multidisciplinary panel in an attempt to develop practice guidelines for 1TP.l It soon became evident that, in contrast to the situation in other medical disciplines where treatment options are largely determined by the results of large, randomized clinical trials, the available data on ITP are sparse. There has been an extremely wide range of opinions about all aspects of From the University of Oklahoma Health Sciences Center, Oklahoma City, OK. Address repvint requests to James N. George, MD, Hematology-Oncology Section, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190. Copyright 0 2000 by W.B. Saunders Company 003 7-1963lOOl3 701-I 004$10.00/0
Vol 3 7, No 1, Suppl 1 (Jazuary),
2000:
pp 31-34
31
32
James IV. George
treatment for ITP. For example, there was a lack of consensus on how long to continue initial corticosteroid treatment before changing to something else. Using the example of a SO-year-old woman with ITP whose platelet count remains less than 10 X lO’/L, 4 of 11 panel members said they would choose another treatment option after 1 week, but there was no agreement about what that other option should be. Only if the platelet count remained at that level for 4 weeks did 10 of 11 panel members say that they would advise switching to something other than corticosteroids. Similarly, there was little agreement regarding the appropriate timing and indications for splenectomy. l The panelists were asked when it would be appropriate to recommend splenectomy if a patient’s platelet count remained less than 10 X 1O”iL. Most said after about 4 to 6 weeks, but one would not recommend splenectomy even after 10 weeks at this platelet count. There appears to be no major long-term toxicity of splenectomy other than the risk for overwhelming sepsis. One of best reports about splenectomy-associated sepsis, by Schilling et al,* reviewed patients who had been splenectomized for hereditary spherocytosis, in some cases for up to 40 years. They found a very low incidence of postsplenectomy overwhelming sepsis, and those are the data that many of us use today. In the 195Os, splenectomy was still considered the first-line therapy for both children and adults with ITP.3 Clearly, this practice has changed dramatically. A review in 1995 by Reid suggests that the frequency of splenectomy among children in the last 10 years is half of what it was in the previous 20 years.* This is attributed to the fact that spontaneous remissions may occur in children if one waits long enough. Several years ago, Andrew et al used anti-D as an option to try to postpone splenectomy in children, for whom there is a much greater motivation to avoid splenectomy than in adults.5 This series included children with chronic ITP and clinically important thrombocytopenia. Most responded (92%) to the initial treatment and most (86%) continued to respond to repeated treatments.5 This proved to
be a practical strategy to postpone splenectomy. Given the variety of treatments for adults with ITP, the uncertainty of timing of splenectomy, the interest of many patients in an option other than splenectomy, and the comorbid conditions of some adults that may increase the operative risk for splenectomy, there was good reason to attempt a similar trial in adults. To address the issue of appropriate use of splenectomy requires an alternative treatment that is free of the side effects of long-term corticosteroids and can be compared with splenectomy in a randomized clinical trial. WinRho SDFTM (Nabi, Boca Raton, FL) (anti-D) is such an agent; it can be administered easily in an outpatient setting with few side effects and can provide predictable, transient increases in the platelet count. 6,7 We developed a multicenter randomized study designed to compare anti-D with routine care, defined as prednisone followed by splenectomy, in adults with a new diagnosis of ITP. This trial will include 70 patients, males and females I 18 years of age who have been documented to have a diagnosis of ITP as defined by the ASH guide1ines.i The objective is to compare anti-D given early in the management, overlapped with prednisone to routine care with prednisone and splenectomy for preventing major bleeding and delaying splenectomy. Initially, our concept was that we would treat patients with prednisone and begin them on anti-D after they failed to respond to initial therapy. We thought that most adults would fail to achieve a durable remission with prednisone alone. However, we were interested in moving anti-D sooner into the management, to give it immediately after diagnosis to see if we could limit the prednisone treatment. Here we begin to merge some of the concepts of adult hematologists with those that are standard in pediatrics. Hematologists treating adult disease think of prednisone as a prescription that is given indefinitely until there is some clinical reason to try something else. In children, more apparent value is attached to limiting prednisone therapy because of the behavioral side effects. The protocol of this new study ultimately has anti-D given at diagnosis, with prednisone
Treatment fir Chronic ITP
given in a pediatric regimen of 2 weeks followed by a rapid taper. The issue then becomes whether a patient can be managed with anti-D to diminish prednisone use. In the standardcare arm, patients also receive 2 weeks of prednisone, then the care continues at the discretion of the treating physician, excluding only the use of anti-D. Indications for splenectomy are explicit and include a new event of major bleeding following randomization or if platelet counts remain less than 3O,OOO/pL after 14 days. After 14 days, continued treatment with prednisone is at the discretion of the physician. Splenectomy is indicated according to predetermined criteria. Entry criteria into this trial include isolated thrombocytopenia with an otherwise normal complete blood count and peripheral blood smear; Rh,(D) positivity; and no clinically apparent associated conditions or other causes of thrombocytopenia, such as human immunodeficiency virus infection, systemic lupus erythematosus, lymphoproliferative disorders, myelodysplasia, drug-induced thrombocytopenia, or congenital or hereditary thrombocytopenia. Exclusion criteria include a hemoglobin level less than 8 g/dL; history of splenectomy, known IgA deficiency or anaphylaxis to plasma products; pregnant or nursing women; and prior treatment with anti-D. A major objective of this trial is to describe clinical outcomes of mortality and morbidity from bleeding. A problem with most previous publications on management of ITP is that the total focus is on the short-term outcome of platelet count recovery. The issues of who bleeds or who does not bleed, and whether morbidity of the treatment may actually be greater than the bleeding symptoms of the ITP, are often not addressed. We need to determine whether management of these patients actually improves or at least is equivalent in terms of bleeding and mortality. If it is equivalent at less cost and less surgical risk, then we have achieved an important outcome. Another key issue is that we do not know the natural history of adult ITP. Approximately 85% of children have a spontaneous remission. We see from the ASH guidelines that there is a wide discrepancy of opinion concerning the
33
ultimate outcome of adu1ts.i Our hypothesis is that if splenectomy can be postponed, there may be a reservoir of adult patients who will have a spontaneous remission; a goal of this study is to postpone splenectomy until that may occur. Other objectives of this study include the cost-effectiveness of the anti-D regimen versus the standard-care regimen, whether a lack of response to anti-D predicts the outcome of splenectomy, and what the duration is until splenectomy is required. Patients will be randomized to 1 of 2 groups: either standard care, involving prednisone followed by splenectomy when indicated, or to a novel regimen of limited (2 weeks followed by tapering) prednisone along with anti-D therapy started at diagnosis to maintain the platelet count in a safe range (>30 X 1O’iL) for 1 year. Patients will be stratified according to age and followed for at least 24 months after enrollment. In the first group, prednisone treatment will be standardized at 1 mgikgld as a single daily dose for 14 days from the time of randomization. After this time, continued treatment with prednisone will be at the discretion of the treating physician. In the event of major bleeding, splenectomy or use of intravenous immunoglobulin or platelet transfusions also will be at the discretion of the treating physician. If the platelet count remains less than 30 X 1O”iL at 14 days after randomization, splenectomy will be performed when clinically feasible, but within the next 4 weeks. If the platelet count is greater than 30 X 109/L at 14 days after randomization, the patient will be managed with prednisone and/or splenectomy at the physician’s discretion. All other treatments for ITP will be prohibited until a new event of major bleeding occurs or the patient has undergone splenectomy, according to the predetermined guidelines. In the second group, prednisone treatment will be standardized at 1 mg/kg/d as a single daily dose X 14 from the time of randomization and then tapered over the next 12 days. If the platelet count remains less than 30 X lOgiL at 14 days, prednisone will be continued at 1 mgikgld until the platelet count is greater than 30 X 109/L or the criteria for splenectomy are met. Intravenous anti-D (75 pglkg) will be
34
James N. George
administered for patients whose hemoglobin level is L 10 g/dL; if hemoglobin is 18 g/dL and less than 10 g/dL, the anti-D dose will be 50 pg/kg. Up to 2 more treatments with anti-D will be given at 4-day intervals if the platelet count does not increase to greater than 30 X lO’/L. Splenectomy is then indicated for patients with platelet counts less than 30 X 109/L who have failed to respond to 3 consecutive treatments with anti-D. Our hypothesis is that prolonged maintenance therapy with such a relatively nontoxic regimen will allow the natural history of ITP in adults to be assessed, possibly revealing a substantial number of patients who have a spontaneous remission from their thrombocytopenia. The goals of th e study are to determine the relative effectiveness of these 2 regimens in preventing severe bleeding complications and to determine if maintenance therapy with anti-D can prevent the need for splenectomy by allowing a remission of thrombocytopenia to occur. If splenectomy can be deferred for up to 1 year, more patients may experience spontaneous remission of their ITP. We hypothesize that maintenance therapy with anti-D for 1 year may allow such remissions to occur.
References 1 George
JN,
pathic guideline American 2
Woolf
SH,
Raskob
thrombocytopenic
developed by explicit Society of Hematology.
1996 Schilling
RF:
Estimating
the
splenectomy in hereditary Med 122:187-188, 1995 3
GE,
et al:
purpura:
A
methods Blood risk
for
for The 88:3-40, sepsis
spherocytosis.
Ann
Doan CA, Bouroncle BA, Wiseman BK: and secondary thrombocytopenic purpura: study years.
idiopathic treatment,
Dis Child 72:125-128, Andrew M, Blanchette multicenter study chronic idiopathic anti-D.
J Pediatr
Bussel JB, Intravenous bocytopenic and
mechanism
1995 VS,
120:522-527,
of
of 20
thrombocytopenic and outcome. Arch Adams
of the treatment thrombocytopenic
Graziano anti-D purpura:
after Intern
Idiopathic Clinical
and evaluation of 381 cases over a period Ann Intern Med 53:861-876, 1960
Reid MM: Chronic purpura: Incidence,
Idio-
practice
M,
et al:
1992
JN, Kimberly RP, et al: treatment of immune thromAnalysis of efficacy, toxicity, effect.
Blood
77:1884-1893,
1991 Scaradavou A, Woo B, Woloski BMR, et al: Intravenous anti-D treatment of immune thrombocytopenit purpura: 89:2689-2700,
A
of childhood purpura with
Experience 1997
in
272
patients.
Blood
I
DIOPATHIC (IMMUNE) thrombocytopenit purpura (ITP) has distinct clinical manifestations in children and adults. The goal of treatment in both groups is to prevent serious bleeding. In boys and girls less than 10 years old, the incidence of ITP is equal, the onset is typically abrupt, and the course is typically self-limited. Treatment may be appropriate to increase the platelet count to a safer range until spontaneous recovery occurs. In adults, ITP is typically more indolent in its onset and the course may be persistent, often lasting many years or characterized by recurrent exacerbations of thrombocytopenia. Spontaneous remissions in adults are believed to be infrequent. Although treatment with corticosteroids and other immunosuppressive agents may have a potential for cure, the goal for treatment of adults with ITP is to achieve a safe platelet count with the hope that a spontaneous remission of the disease will eventually occur. Patients with asymptomatic thrombocytopenia and platelet counts above 30 X lO”/L to 50 X 109/L may require no treatment. If initial corticosteroid therapy fails to achieve a sustained remission, splenectomy has usually been the next choice of therapy. The results with splenectomy over 60 years are remarkably consistent, with the achievement of Seminars in Hematology,
normal platelet counts sustained for the duration of observation in two thirds of patients. However, there is strong anecdotal evidence suggesting that longer follow-up reveals that thrombocytopenia will recur in a significant percentage of these patients. There is no consensus regarding the appropriate timing or even indication for splenectomy. Corticosteroids are often used repeatedly, in an attempt to defer splenectomy, until side effects become intolerable. In 1996, the American Society of Hematology (ASH) convened an expert multidisciplinary panel in an attempt to develop practice guidelines for 1TP.l It soon became evident that, in contrast to the situation in other medical disciplines where treatment options are largely determined by the results of large, randomized clinical trials, the available data on ITP are sparse. There has been an extremely wide range of opinions about all aspects of From the University of Oklahoma Health Sciences Center, Oklahoma City, OK. Address repvint requests to James N. George, MD, Hematology-Oncology Section, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190. Copyright 0 2000 by W.B. Saunders Company 003 7-1963lOOl3 701-I 004$10.00/0
Vol 3 7, No 1, Suppl 1 (Jazuary),
2000:
pp 31-34
31
32
James IV. George
treatment for ITP. For example, there was a lack of consensus on how long to continue initial corticosteroid treatment before changing to something else. Using the example of a SO-year-old woman with ITP whose platelet count remains less than 10 X lO’/L, 4 of 11 panel members said they would choose another treatment option after 1 week, but there was no agreement about what that other option should be. Only if the platelet count remained at that level for 4 weeks did 10 of 11 panel members say that they would advise switching to something other than corticosteroids. Similarly, there was little agreement regarding the appropriate timing and indications for splenectomy. l The panelists were asked when it would be appropriate to recommend splenectomy if a patient’s platelet count remained less than 10 X 1O”iL. Most said after about 4 to 6 weeks, but one would not recommend splenectomy even after 10 weeks at this platelet count. There appears to be no major long-term toxicity of splenectomy other than the risk for overwhelming sepsis. One of best reports about splenectomy-associated sepsis, by Schilling et al,* reviewed patients who had been splenectomized for hereditary spherocytosis, in some cases for up to 40 years. They found a very low incidence of postsplenectomy overwhelming sepsis, and those are the data that many of us use today. In the 195Os, splenectomy was still considered the first-line therapy for both children and adults with ITP.3 Clearly, this practice has changed dramatically. A review in 1995 by Reid suggests that the frequency of splenectomy among children in the last 10 years is half of what it was in the previous 20 years.* This is attributed to the fact that spontaneous remissions may occur in children if one waits long enough. Several years ago, Andrew et al used anti-D as an option to try to postpone splenectomy in children, for whom there is a much greater motivation to avoid splenectomy than in adults.5 This series included children with chronic ITP and clinically important thrombocytopenia. Most responded (92%) to the initial treatment and most (86%) continued to respond to repeated treatments.5 This proved to
be a practical strategy to postpone splenectomy. Given the variety of treatments for adults with ITP, the uncertainty of timing of splenectomy, the interest of many patients in an option other than splenectomy, and the comorbid conditions of some adults that may increase the operative risk for splenectomy, there was good reason to attempt a similar trial in adults. To address the issue of appropriate use of splenectomy requires an alternative treatment that is free of the side effects of long-term corticosteroids and can be compared with splenectomy in a randomized clinical trial. WinRho SDFTM (Nabi, Boca Raton, FL) (anti-D) is such an agent; it can be administered easily in an outpatient setting with few side effects and can provide predictable, transient increases in the platelet count. 6,7 We developed a multicenter randomized study designed to compare anti-D with routine care, defined as prednisone followed by splenectomy, in adults with a new diagnosis of ITP. This trial will include 70 patients, males and females I 18 years of age who have been documented to have a diagnosis of ITP as defined by the ASH guide1ines.i The objective is to compare anti-D given early in the management, overlapped with prednisone to routine care with prednisone and splenectomy for preventing major bleeding and delaying splenectomy. Initially, our concept was that we would treat patients with prednisone and begin them on anti-D after they failed to respond to initial therapy. We thought that most adults would fail to achieve a durable remission with prednisone alone. However, we were interested in moving anti-D sooner into the management, to give it immediately after diagnosis to see if we could limit the prednisone treatment. Here we begin to merge some of the concepts of adult hematologists with those that are standard in pediatrics. Hematologists treating adult disease think of prednisone as a prescription that is given indefinitely until there is some clinical reason to try something else. In children, more apparent value is attached to limiting prednisone therapy because of the behavioral side effects. The protocol of this new study ultimately has anti-D given at diagnosis, with prednisone
Treatment fir Chronic ITP
given in a pediatric regimen of 2 weeks followed by a rapid taper. The issue then becomes whether a patient can be managed with anti-D to diminish prednisone use. In the standardcare arm, patients also receive 2 weeks of prednisone, then the care continues at the discretion of the treating physician, excluding only the use of anti-D. Indications for splenectomy are explicit and include a new event of major bleeding following randomization or if platelet counts remain less than 3O,OOO/pL after 14 days. After 14 days, continued treatment with prednisone is at the discretion of the physician. Splenectomy is indicated according to predetermined criteria. Entry criteria into this trial include isolated thrombocytopenia with an otherwise normal complete blood count and peripheral blood smear; Rh,(D) positivity; and no clinically apparent associated conditions or other causes of thrombocytopenia, such as human immunodeficiency virus infection, systemic lupus erythematosus, lymphoproliferative disorders, myelodysplasia, drug-induced thrombocytopenia, or congenital or hereditary thrombocytopenia. Exclusion criteria include a hemoglobin level less than 8 g/dL; history of splenectomy, known IgA deficiency or anaphylaxis to plasma products; pregnant or nursing women; and prior treatment with anti-D. A major objective of this trial is to describe clinical outcomes of mortality and morbidity from bleeding. A problem with most previous publications on management of ITP is that the total focus is on the short-term outcome of platelet count recovery. The issues of who bleeds or who does not bleed, and whether morbidity of the treatment may actually be greater than the bleeding symptoms of the ITP, are often not addressed. We need to determine whether management of these patients actually improves or at least is equivalent in terms of bleeding and mortality. If it is equivalent at less cost and less surgical risk, then we have achieved an important outcome. Another key issue is that we do not know the natural history of adult ITP. Approximately 85% of children have a spontaneous remission. We see from the ASH guidelines that there is a wide discrepancy of opinion concerning the
33
ultimate outcome of adu1ts.i Our hypothesis is that if splenectomy can be postponed, there may be a reservoir of adult patients who will have a spontaneous remission; a goal of this study is to postpone splenectomy until that may occur. Other objectives of this study include the cost-effectiveness of the anti-D regimen versus the standard-care regimen, whether a lack of response to anti-D predicts the outcome of splenectomy, and what the duration is until splenectomy is required. Patients will be randomized to 1 of 2 groups: either standard care, involving prednisone followed by splenectomy when indicated, or to a novel regimen of limited (2 weeks followed by tapering) prednisone along with anti-D therapy started at diagnosis to maintain the platelet count in a safe range (>30 X 1O’iL) for 1 year. Patients will be stratified according to age and followed for at least 24 months after enrollment. In the first group, prednisone treatment will be standardized at 1 mgikgld as a single daily dose for 14 days from the time of randomization. After this time, continued treatment with prednisone will be at the discretion of the treating physician. In the event of major bleeding, splenectomy or use of intravenous immunoglobulin or platelet transfusions also will be at the discretion of the treating physician. If the platelet count remains less than 30 X 1O”iL at 14 days after randomization, splenectomy will be performed when clinically feasible, but within the next 4 weeks. If the platelet count is greater than 30 X 109/L at 14 days after randomization, the patient will be managed with prednisone and/or splenectomy at the physician’s discretion. All other treatments for ITP will be prohibited until a new event of major bleeding occurs or the patient has undergone splenectomy, according to the predetermined guidelines. In the second group, prednisone treatment will be standardized at 1 mg/kg/d as a single daily dose X 14 from the time of randomization and then tapered over the next 12 days. If the platelet count remains less than 30 X lOgiL at 14 days, prednisone will be continued at 1 mgikgld until the platelet count is greater than 30 X 109/L or the criteria for splenectomy are met. Intravenous anti-D (75 pglkg) will be
34
James N. George
administered for patients whose hemoglobin level is L 10 g/dL; if hemoglobin is 18 g/dL and less than 10 g/dL, the anti-D dose will be 50 pg/kg. Up to 2 more treatments with anti-D will be given at 4-day intervals if the platelet count does not increase to greater than 30 X lO’/L. Splenectomy is then indicated for patients with platelet counts less than 30 X 109/L who have failed to respond to 3 consecutive treatments with anti-D. Our hypothesis is that prolonged maintenance therapy with such a relatively nontoxic regimen will allow the natural history of ITP in adults to be assessed, possibly revealing a substantial number of patients who have a spontaneous remission from their thrombocytopenia. The goals of th e study are to determine the relative effectiveness of these 2 regimens in preventing severe bleeding complications and to determine if maintenance therapy with anti-D can prevent the need for splenectomy by allowing a remission of thrombocytopenia to occur. If splenectomy can be deferred for up to 1 year, more patients may experience spontaneous remission of their ITP. We hypothesize that maintenance therapy with anti-D for 1 year may allow such remissions to occur.
References 1 George
JN,
pathic guideline American 2
Woolf
SH,
Raskob
thrombocytopenic
developed by explicit Society of Hematology.
1996 Schilling
RF:
Estimating
the
splenectomy in hereditary Med 122:187-188, 1995 3
GE,
et al:
purpura:
A
methods Blood risk
for
for The 88:3-40, sepsis
spherocytosis.
Ann
Doan CA, Bouroncle BA, Wiseman BK: and secondary thrombocytopenic purpura: study years.
idiopathic treatment,
Dis Child 72:125-128, Andrew M, Blanchette multicenter study chronic idiopathic anti-D.
J Pediatr
Bussel JB, Intravenous bocytopenic and
mechanism
1995 VS,
120:522-527,
of
of 20
thrombocytopenic and outcome. Arch Adams
of the treatment thrombocytopenic
Graziano anti-D purpura:
after Intern
Idiopathic Clinical
and evaluation of 381 cases over a period Ann Intern Med 53:861-876, 1960
Reid MM: Chronic purpura: Incidence,
Idio-
practice
M,
et al:
1992
JN, Kimberly RP, et al: treatment of immune thromAnalysis of efficacy, toxicity, effect.
Blood
77:1884-1893,
1991 Scaradavou A, Woo B, Woloski BMR, et al: Intravenous anti-D treatment of immune thrombocytopenit purpura: 89:2689-2700,
A
of childhood purpura with
Experience 1997
in
272
patients.
Blood