Immune Thrombocytopenic Purpura: the Doctor’s Dilemma Dr. Pedro A. de Alarcón William H. Albers Professor and Chair Department of Pediatrics UICOMP Adjunct Member SJCRH

Easy bruising and purpura in ITP Key Points This is a photograph of purpura with large ecchymoses and petechiae in a child with acute ITP.

Peripheral blood smear in ITP Key Points This is a photograph of a large platelet in a peripheral blood smear taken from a child with acute ITP.

Diagnostic tests CBC and platelet count Peripheral smear Bone marrow Coombs test Anti-platelet antibodies ANA Coagulation screen Bleeding Time

Epidemiology of ITP in children and adults Key Points There are significant differences in the clinical features of ITP in children compared with adults. These include1-3: Incidence. In children, ITP is estimated to occur in 10 to 40 individuals per 100,000, while in adults it is 66 in 100,000 Occurrence. The peak years for ITP in children are between ages 2 and 4 years. ITP occurs at equal rates in both genders. In adults, ITP appears most frequently in individuals aged 15 to 40 years and in almost three times as many females as males Presentation. ITP tends to be acute in children with symptoms appearing within less than a week, often after an infectious illness such as an upper respiratory tract infection. It is more insidious in adults, with symptoms appearing gradually over more than 2 months Adults and children with ITP similarly show platelet counts below 20,000/L 1. George JN, El-Harake M, Aster RH. Thrombocytopenia due to enhanced platelet destruction by immunologic mechanisms. In: Beulter E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th ed. New York, NY: McGraw-Hill, Inc; 1995:1315-1354. 2. George JN, Raskob GE. Idiopathic thrombocytopenic purpura: a concise summary of the pathophysiology and diagnosis in children and adults. Semin Hematol. 1998;35(suppl):5-8. 3. Blanchette V, Freedman J, Garvey B. Management of chronic immune thrombocytopenic purpura in children and adults. Semin Hematol. 1998; 35(suppl):36-51. Kühn T, et Lancet 2001;358:2122-2125 George JN et al. Williams Hematology.1995: 1315-1354. George JN et al. Semin Hematol. 1998;35(suppl): 5-8. Blanchette V et al. Semin Hematol. 1998; 35(suppl): 36-51.

Age and sex in ITP Kühn T, et Lancet 2001;358:2122-2125

Seasonal variability of ITP Kühn T, et Lancet 2001;358:2122-2125

Mucosal and gum bleeding Intracranial hemorrhage (ICH) Symptoms in ITP Bruising and petechia 100% Epistaxis 25% Splenomegaly 12% Mucosal and gum bleeding 6% GI hemorrhage 5% GU hemorrhage Intracranial hemorrhage (ICH) <1%(2:2190?)

Platelet count at presentation Blanchette VS. Semin Thrombosis Hemostasis 2003;29:605-617

Symptoms that predict a chronic course Age at presentation Length of symptoms prior to presentation Patient’s sex Platelet count

Symptoms that predict a chronic course Study Prognostic symptom Acute ITP Chronic ITP P value Ahmed et al Sex M:F 23:31 5:13 0.4   Prior viral illness 29/36 (81%) 5/13 (38%) 0.01 Walker and Walker Previous symptoms < 2 weeks 122/132 (92%) 16/45 (36%) <0.01  Rosthoj et al Platelet count < 5K 10.5% 19.9% OR 2.12 Imbach et al Age 6.2 (4.3) 7.2 (4.2) 0.043 0.087 Hemorrhage 13% 27% 0.018 Previous viral illness 50% 41.50% 0.29 AJH 2004;77:358 Arch Dis Child 1984;59:316 BJH 2005;130:145 Pediatr Blood Cancer 2006;46:351

Type of hemorrhage Dry purpura Wet purpura

Therapeutic options Steroids Intravenous Gammaglobulin Anti-D Prednisone Dexamethasone Methylprednisolone Intravenous Gammaglobulin Anti-D Observation

Controversy over the treatment of ITP McWilliams NB and Maurer HM “There exists considerable controversy over the treatment of ITP with steroids” Am J Hematol 1979;7:87-96 Bolton-Maggs et al “The art of medicine consist in entertaining the patient until nature cures him” Semin Thrombosis Hemostasis 2001;27:269-75

Therapeutic Guidelines United States George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88(1):3-40. Great Britain Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120(4):574-596. Italy de Mattia D, del Principe D, Del Vecchio GC, Jankovic M, Arrighini A, Giordano P et al. Acute childhood idiopathic thrombocytopenic purpura: AIEOP consensus guidelines for diagnosis and treatment.Associazione Italiana di Ematologia e Oncologia Pediatrica. Haematologica 2000; 85(4):420-424.

Controversies over the treatment of ITP Non-randomized studies Simons SM prednisone 1975 Dunn NL prednisone 1984 Lusher JM observation 1984 Bussel JB anti-D 1991 Gereige RS IGIV, pred 2000 Dickerhoff R observation 2000 Newman GC anti-D 2001 Duru F IGIV or Methylpred 2002 Beck CE corticosteroids vs. IGIV 2005 Randomized studies Sartorious JA 1984 Prednisone vs. observation Buchanan GR 1984 Imbach P 1985 IGIV vs. Prednisone Bellucci S 1988 High vs. low prednisone Blanchette VS 1993 IGIV, prednisone, observa Hord JD 1993 IGIV vs. steroids Blachette VS 1994 IGIV, anti-D, prednisone Ancona KG 2002 Methylprednisolone vs. IGIV El Alfy MS 2006 Anti-D vs. Low dose IGIV

Intravenous Gammaglobulin (n=19) Randomized study of the treatment of ITP with either IVIG, prednisone or observation Intravenous Gammaglobulin (n=19) Days Prednisone (n=18) Observation (n=16) Time with platelet count <20K 1 (1-20) 2 (1-11) 4 (1-132) Time to obtain a platelet count of >50K 2 (1-34) 4 (2-13) 16 (2-132) Blanchette VS. J Pediatr 1993;123:989-995

Treatment of ITP: the Italian Collaborative Group Study (ICGS) Patient characteristics at the start of the ICGS of ITP No. of eligible patients 158 Non-evaluable patients 20 Evaluable patients 138 Patients treated with IVIG right away 11 Age 5.8 (3.5) Sex M:F 77:61 Antecedent viral illness 85 Non-specific 56 Measles Rubella 7 Chicken Pox Vaccine 2 Mononucleosis Mori PG. Pediatr Hematol Oncol 1988;5:169-178

Study design of the ICGS for ITP Observation period (10 days) Therapy with IVIG Therapy with prednisone Only patients with a platelet count of < 50K receive the next phase of therapy Mori PG. Pediatr Hematol Oncol 1988;5:169-178

Results in 127 patients Results of the study through the different phases of therapy Phase of therapy n=registered patients n (%) patients that recovered permanently n (%) patients that went on to the next phase Observation 127 65 (51.18) 62 (48.81) IVIG 62 36 (58.06) 24 (38.7) Steroids 24 10 (41.66) 4 Lost to follow up after IVIG=2 Failure to respond after prednisone =2 Mori PG. Pediatr Hematol Oncol 1988;5:169-178

Clinical course of 55 patients that did not receive constant high dose prednisone Characteristics of patients with ITP Group I Group II Group III Patients (n=55) 37 13 5 Platelet count at diagnosis <10.000 10.000-20.000 >20.000 Mucosal hemorrhage (n=15) 10 Patients receiving a 3 day course of prednisone (n=3) 3 1 Remission (n=48) 32 12 4 In < 6 weeks (n=29) 20 6 In 6 weeks to 6 months (n=19) Chronic ITP at 6 months (n=7) Remission 6-12 months (n=3) Remission > 12 months (n=1) No remission (n=3) 2 Duration of ITP 3 years; 8 months 7 years Dickerhoff R. J Pediatr 2000;137:629-632

Characteristics of Scandinavian patients with ITP Rosthoj S, J Pediatr 2003;143:302-307

Hemorrhage in relation to platelet count in 501 patients with ITP Rosthoj S, J Pediatr 2003;143:302-307

Stabilization of platelet count in patients with ITP acute (ס) or chronic (●) Rosthoj S, J Pediatr 2003;143:302-307

Steroids vs. Observation in 84 patients with ITP Simons SM. J Pediatr 1975;87:16-22

Comparison between Observation, Steroids, Anti-D and IVIG

Comparación entre IGIV, Anti-D, prednisona y observación

Randomized study of prednisone vs. placebo in 27 children Buchanan GR. Am J Pediatr Hematol Oncol 1984;6:355-361

Compendium of several studies Bussel JB. Blood 1991;77:1884-1893 Buchanan GR. Am J Pediatr Hematol Oncol 1984;6:355-361 Ancona KG. J Pediatr Hematol Oncol 2002;24:540-544

Geographic differences in the therapy of ITP Kühn T, et Lancet 2001;358:2122-2125

Controversy in ITP therapy “Whether you believe that children with ITP should be treated with medication, or like myself, you believe that observation therapy is best for most patients, the evidence we have is not sufficient to provide guidelines. The choices of therapy are multiple: (1) high-dose, standard-dose, or low-dose corticosteroid; (2) low-dose, high-dose, two-day, or one-day IVIG; (3) low-dose or high-dose anti-D therapy; and (4) observation of all patients with ITP or for evidence of dry purpura. It is only through prospective studies that determine the true risks of ITP, like the study of Rosthøj et al, that we will be able to resolve the controversy and define the patients at risk for significant hemorrhage who require pharmacologic therapy and the patients at low risk who will be better served by observational therapy alone” J Pediatr 2003;143:287-289

Percent of children with ITP with a persistent platelet count of < 20,000 platelets Blanchette VS. Semin Thrombosis Hemostasis 2003;29:605-617

Percent of children with platelet counts < 10 determined at 6 and 12 months of follow-up Imbach P. Pediatr Blood Cancer 2006;46:351-356

Differential gene expression in ITP You can find genes differentially expressed in ITP vs. normal: 176/24,473 Sood R, Pediatr Blood Cancer 2006;47:675–677

Rate of recovery of ITP Roganovic J Pediatr Blood Cancer 2006;47:662-664

Platelet count in patients (n=299) with and without hemorrhage between 7 and 12 months from diagnosis Imbach P. Pediatr Blood Cancer 2006;46:351-356

Treatment of Chronic ITP Splenectomy IVIG Anti-D Prednisone Methylprednisolone Vincristine Cyclosporine Dapsone Interferon Rituximab Apheresis

Suggested reading Buchanan GR Pediatr Blood Cancer 2006;47:681-684 O’Brien SH Pediatr Blood Cancer 2007;48:173-180 Belletrutti M J Pediatr Hematol Oncol 2007;29:95-100 Tarantino M Semin Hematol 2006;43 (S3-7):S11-S17

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