1. IMMUNE PLATELET DESTRUCTION
Autoimmune (ITP)
Childhood
Adult
Drug-induced
Heparin
Quinine, others
Immune complex (infection, etc)
Alloimmune
Post-transfusion purpura
Neonatal purpura

2. ITP Childhood ITP (most < 10 yrs old)
May follow viral infection, vaccination
Peak incidence in fall & winter
~50% receive some treatment
≥75% in remission within 6 mo
Adult ITP
No prodrome
Usually chronic, recurrences common
Spontaneous remission rate about 5%

3. Childhood (acute) ITP
Adult (chronic) ITP

4. Epidemiology (adults)
ITP
Epidemiology (adults)
Prevalence: ~10/100,000
Incidence: ~3/100,000/yr
Bimodal age distribution
Young adults (women > men)
Elderly (men = women)
About 20% have an associated disorder (secondary ITP)

5. Secondary ITP: associated disorders
SLE
Antiphospholipid syndrome
CLL
Large granular lymphocyte syndrome
Autoimmune hemolytic anemia (Evans syndrome)
Common variable immune deficiency
Autoimmune lymphoproliferative disorder (ALPS)
Autoimmune thyroid disease
Sarcoidosis
Carcinomas
Lymphoma
HIV, Hep C infection
H pylori infection (geographic variation)
Following stem cell or organ transplantation
Following vaccination

6. ITP AND H PYLORI
Some patients with ITP and concomitant H pylori infection improve after eradication of infection
Confirm infection via breath test, stool antigen test or endoscopy
Higher response rates in:
Patients from countries with high background rates of infection (Asia, some parts of Europe; response rates low in US)
Patients with less severe thrombocytopenia

7. ITP Pathogenesis
ITP plasma induces thrombocytopenia in normal subjects
Platelet-reactive IgG autoantibodies present in most cases
Often specific for a platelet membrane glycoprotein
Antibody coated platelets cleared by tissue macrophages
Most destruction in spleen (extravascular)
T-cell mediated platelet destruction can occur
Many patients have impaired platelet production
Immune injury to megakaryocytes?
Inadequate TPO response
Increased clearance?
Disrupted link between platelet clearance and TPO production?

8. ITP Pathogenesis - 2 Some antibodies affect platelet function
Interference with platelet function may increase risk of bleeding
Platelet activation by antibodies may decrease bleeding risk but increase risk of thrombosis
ITP patients have an increased risk of thromboembolism (~1.6 x higher)

9. Splenectomy specimen from a patient with chronic ITP
Splenectomy specimen from a patient with chronic ITP. Left: (40x) Activated lymphoid follicles with expanded marginal zone (short arrow), a well-defined dark mantle zone (long arrow), and a germinal center containing activated lymphocytes (arrowhead). Right: (1000x) PAS stain showing histiocytes with phagocytized platelet polysachharides (arrows). Transfusion 2005;45:287

10. Infusion of ITP plasma into a normal person causes dose-dependent thrombocytopenia
Infusion of ITP plasma into normal subject causes dose-dependent thrombocytopenia.

11. Clinical features and diagnosis
ITP
Clinical features and diagnosis
Petechiae, purpura, sometimes mucosal bleeding
Major internal/intracranial bleeding rare
Mortality rate < 5%
Absence of constitutional symptoms or splenomegaly
Other blood counts and coagulation parameters normal
No schistocytes or platelet clumps on blood smear
Marrow shows normal or increased megakaryocytes (optional)
Rule out other causes of thrombocytopenia (HIV, Hepatitis C, etc)

12. The immature platelet fraction reflects rate of platelet production
ITP + iron deficiency
Marrow failure
Higher numbers indicate more rapid production

13. Confirmatory laboratory testing
ITP
Confirmatory laboratory testing
Serum antiplatelet antibody assay (poor specificity)
Test for specific anti-platelet glycoprotein antibodies (more specific, negative in 10-30%)
Confirmatory testing not necessary in most cases

14. Is testing for platelet autoantibodies useful
Is testing for platelet autoantibodies useful? Test results & patient outcomes from at UWHC
All testing done at Blood Center of Wisconsin
Patient
Test result
Outcome/diagnosis
M, 66
Positive
Probable ITP (response to IVIG)
M, 83
Negative
Myelodysplasia
F, 38
ITP (response to IVIG)
F, 81
ITP (response to steroids)
F, 57
Viral-induced thrombocytopenia (zoster)
M, 56
Chemotherapy-induced thrombocytopenia (colon CA)
M, 57
Probable aplastic anemia
Drawn 3 days after platelet transfusion

16. ITP IS A RELATIVELY BENIGN DISEASE A PROSPECTIVE STUDY OF ITP IN 245 ADULTS
Overall incidence 1.6/100,000/yr
Median age 56, F:M 1.2:1
12% presented with bleeding, 28% asymptomatic
18% needed no treatment
Only 12% needed splenectomy
63% in remission (plts > 100K) at end of followup period (6-78 mo, median 60)
87% had at least partial remission (plts >30K) and freedom from symptoms
1.6% died from complications of disease or its treatment
Age-specific incidence
This study challenges the notion of ITP as a chronic disease that preferentially affects women. The age of patients was also higher than in many other published series.
Brit J Haematol 2003;122:966

17. 4.5 x higher risk of infection in year 1 1.8 x higher risk years 2-5
3.2 x higher risk of intrancranial bleeding in years 1-5
Increased risk of subsequent hematologic malignancy
Therapy-related (lymphoma) or misdiagnosis (AML, MDS)
This risk not confirmed in other studies
5 year all-cause mortality rate 2.3 x higher
Risk highest in older patients, those with comorbid conditions
Blood 2011; 117:3514

18. Indications for treatment
ITP
Indications for treatment
Platelets < 20-30K
Active bleeding or high bleeding risk, platelets <50K

19. First line treatment options
ITP
First line treatment options
First line treatment options:
Glucocorticoids (daily vs pulse dose)
IVIG
Anti-Rh globulin (WinRho)
Rituximab?
Thrombopoietin receptor agonists?
Hospitalization often not necessary
Splenectomy rarely used as first line Rx

20. Glucocorticoid therapy
ITP
Glucocorticoid therapy
Mechanism of action: Slows platelet destruction, reduces autoantibody production
Prednisone, 1-2 mg/kg/day (single daily dose)
Begin slow taper after 2-4 weeks (if patient responds)
Consider alternative therapy if no response within 3-4 weeks
About 2/3 of patients respond (plts > 50K) within 1 week
Most patients relapse when steroids withdrawn
Advantages: high response rate, outpatient therapy
Disadvantages: steroid toxicity (increases with time and dose), high relapse rate

21. Prednisone attenuates the effect of ITP plasma infusion on platelet count
Prednisone blunts the decrease in platelet count caused by ITP plasma infusion.

22. Intravenous immunoglobulin therapy
ITP
Intravenous immunoglobulin therapy
Possible mechanisms of action:
Slowed platelet consumption by Fc receptor blockade
Accelerated autoantibody catabolism
Reduced autoantibody production
Dose: 0.4 g/kg/d x 5 days (alternative: 1 g/kg/d x 2 days)
About 75% response rate, usually within a few days to a week
Over 75% of responders return to pre-treatment levels within a month
Advantages: rapid acting, low toxicity
Disadvantages: high cost, short duration of benefit, high relapse rate
Indications: Lifethreatening bleeding; pre-operative correction of platelet count, steroids contraindicated or ineffective

23. Second line treatment options
ITP
Second line treatment options
Rituximab
TPO receptor agonists
Romiplostim (Nplate)
Eltrombopag (Promacta)
Splenectomy

24. ITP Splenectomy Sustained remission in 2/3 of patients
Almost all responses occur within 7-10 days of splenectomy
Operative mortality < 1%
Severe intra- and postoperative hemorrhage rare (about 1% of patients)
Laparoscopic splenectomy usually preferable technique
Advantage: High sustained response/cure rate
Disadvantages: Operative risk (mainly older pts with comorbid disease); post-splenectomy sepsis (fatality rate 1/1500 patient-yrs); increased risk of thrombosis & cardiovascular events
Indication: Steroid failure or relapse after steroid Rx (persistent severe thrombocytopenia or significant bleeding)

25. Splenectomy attenuates the effect of ITP plasma infusion on platelet count
More antibody needed to cause thrombocytopenia in asplenic subject.

26. LAPAROSCOPIC SPLENECTOMY IS THE PROCEDURE OF CHOICE IN ADULT ITP A Systematic Review
66% complete response rate (2632 patients)
No preoperative characteristic consistently predicted response
Type of procedure
Mortality
Complication rate
Open 1%
12.9%
Laparoscopic
0.2%
9.6%
Blood 2004;104:2623

27. Intervention: Rituximab, 375 mg/m2 weekly x 4 doses
Background: Most patients treated for ITP with corticosteroids relapse when steroids are withdrawn. Many patients can be cured by splenectomy, but some are not. Treatments for relapsed and chronic ITP and adults have variable efficacy.
Subjects: 57 adults with chronic ITP, with platelet counts <30K. All had at least 2 prior ITP treatments and 31 had been splenectomized.
Intervention: Rituximab, 375 mg/m2 weekly x 4 doses
Outcome: Overall 54% response rate (32% with plts >150K, 22% with plts K). 89% of complete responders remained in remission a median of 72.5 weeks after treatment. Toxicity was minimal.
Conclusion: Rituximab is a promising treatment for chronic/refractory ITP
The most effective treatment for patients with ITP who relapse after corticosteroid treatment and/or splenectomy has not been established. This paper shows that Rituximab is effective in a majority of these patients, with minimal toxicity.
British Journal of Haematology 2004; 125: 232–239

28. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia
Vivek L. Patel, Matthieu Mahévas, Soo Y. Lee, Roberto Stasi, Susanna Cunningham-Rundles, Bertrand Godeau, Julie Kanter, Ellis Neufeld, Tillmann Taube, Ugo Ramenghi, Shalini Shenoy, Mary J. Ward, Nino Mihatov, Vinay L. Patel, Philippe Bierling, Martin Lesser, Nichola Cooper, and James B. Bussel
26% of children and 21% of adults with ITP who had an intial response (CR or PR) to rituximab remained in remission without further treatment after 5 years
No major toxicity observed
Children did not relapse after 2 years, but adults did
The most effective treatment for patients with ITP who relapse after corticosteroid treatment and/or splenectomy has not been established. This paper shows that Rituximab is effective in a majority of these patients, with minimal toxicity.
Blood 2012;119:5989

29. TPO Receptor Agonists for ITP
Overall response rate 75% or higher
Modest toxicity
Transaminase increases (~10%)
Marrow fibrosis (~10%), asymptomatic
5-6% incidence of thromboembolism
Can switch drugs if intolerant to one
Expense remains a barrier for some patients

30. ROMIPLOSTIM FOR CHRONIC ITP
Patients: 125 patients with chronic ITP (about half had been splenectomized)
Intervention: Random assignment to treatment with romiplostim (AMG 531) or placebo
Endpoint: Durable platelet response (platelets at least 50K during at least 6 of last 8 wks of treatment)
Outcome: 16/42 splenectomized patients had durable response with romiplostim, vs 0/21 with placebo. 25/41 non-splenectomized pts had durable response with romiplostim vs 1/21 with placebo. 20/23 pts on romiplostim stopped or reduced concurrent treatment for ITP, vs 6/16 on placebo.
No significant toxicity from romiplostim
Lancet 2008;371:395

31. Lancet 2008;371:395

32. Responses to oral eltrombopag in ITP
Lancet 2010

33. EMERGENCY TREATMENT OF ITP
Platelet transfusion + high dose steroids
Platelet transfusion + continuous IVIG
rVIIa (risk of thrombosis)
Antifibrinolytics
Emergent splenectomy

34. ITP IN PREGNANCY
Mild cases indistinguishable from gestational thrombocytopenia
Rule out eclampsia, HIV etc
Indications for treatment
platelets < 10K
platelets < 30K in 2nd/3rd trimester, or with bleeding
Treatment of choice is IVIg
corticosteroids may cause gestational diabetes, fetal toxicity
Splenectomy for severe, refractory disease
some increased risk of preterm labor; technically difficult in 3rd trimester
Potential for neonatal thrombocytopenia (approx 15% incidence)
consider fetal blood sampling in selected cases
consider Cesarian delivery if fetal platelets < 20K