1. 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

3. 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.

4. 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.

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

6. 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:
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:
George JN et al. Williams Hematology.1995:
George JN et al. Semin Hematol. 1998;35(suppl): 5-8.
Blanchette V et al. Semin Hematol. 1998; 35(suppl):

7. Age and sex in ITP
Kühn T, et Lancet 2001;358:

8. Seasonal variability of ITP
Kühn T, et Lancet 2001;358:

9. 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?)

10. Platelet count at presentation
Blanchette VS. Semin Thrombosis Hemostasis 2003;29:

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

12. 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

13. Type of hemorrhage
Dry purpura
Wet purpura

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

15. 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

16. 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):
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):

17. 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

18. 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:

19. 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:

20. 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:

21. 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:

22. 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
>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:

23. Characteristics of Scandinavian patients with ITP
Rosthoj S, J Pediatr 2003;143:

24. Hemorrhage in relation to platelet count in 501 patients with ITP
Rosthoj S, J Pediatr 2003;143:

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

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

27. Comparison between Observation, Steroids, Anti-D and IVIG

28. Comparación entre IGIV, Anti-D, prednisona y observación

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

30. Compendium of several studies
Bussel JB. Blood 1991;77:
Buchanan GR. Am J Pediatr Hematol Oncol 1984;6:
Ancona KG. J Pediatr Hematol Oncol 2002;24:

31. Geographic differences in the therapy of ITP
Kühn T, et Lancet 2001;358:

32. 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:

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

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

35. 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

36. Rate of recovery of ITP
Roganovic J Pediatr Blood Cancer 2006;47:

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

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

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

40. Questions?