Immune Thrombocytopenic Purpura

1. Immune Thrombocytopenic Purpura David Baer MD April 2009

2. Overview Acquired autoimmune disorder causing thrombocytopenia Etiology is unclear but has been seen often following infections Mild asymptomatic cases often go unrecognized �estimated incidence as high as 1 per 10,000 per yr Among younger patients there is a female predominance More likely self limited in children

3. History � First Descriptions Purpura recognized and named by ancient Greeks Dating to Renaissance many descriptions of cases sounding very much like ITP 1873 Dohrn described simultaneous purpura in a mother and infant Krauss (1883) and Denys (1887) recognized that platelets were diminished during the height of the purpura and increased when the hemorrhages ceased.

4. History � Early Speculations 1915 � Frank - proposed that a toxic substance from the spleen suppressed megakaryocytes 1916 � Kaznelson � first splenectomy 1946 � Dameshek and Miller � megakaryocytes increased but �non-functional� In 1915 Frank proposed that a toxic substance from the spleen suppressed megakaryocytes In 1916 a Kaznelson, a medical student in Prague, persuaded a mentor to perform a splenectomy on a pt with chronic thrombocytopenia � speculated that platelets were destroyed there In 1915 Frank proposed that a toxic substance from the spleen suppressed megakaryocytes In 1916 a Kaznelson, a medical student in Prague, persuaded a mentor to perform a splenectomy on a pt with chronic thrombocytopenia � speculated that platelets were destroyed there

5. Normal Megakaryocyte In 1915 Frank proposed that a toxic substance from the spleen suppressed megakaryocytes In 1916 a Kaznelson, a medical student in Prague, persuaded a mentor to perform a splenectomy on a pt with chronic thrombocytopenia � speculated that platelets were destroyed there In 1915 Frank proposed that a toxic substance from the spleen suppressed megakaryocytes In 1916 a Kaznelson, a medical student in Prague, persuaded a mentor to perform a splenectomy on a pt with chronic thrombocytopenia � speculated that platelets were destroyed there

6. ITP Megakaryocytes In 1915 Frank proposed that a toxic substance from the spleen suppressed megakaryocytes In 1916 a Kaznelson, a medical student in Prague, persuaded a mentor to perform a splenectomy on a pt with chronic thrombocytopenia � speculated that platelets were destroyed there In 1915 Frank proposed that a toxic substance from the spleen suppressed megakaryocytes In 1916 a Kaznelson, a medical student in Prague, persuaded a mentor to perform a splenectomy on a pt with chronic thrombocytopenia � speculated that platelets were destroyed there

7. History � William Harrington

8. Presentation Petechiae, purpura, and easy bruising - very common Epistaxis, gingival bleeding, and menorrhagia -common Overt gastrointestinal bleeding and gross hematuria are rare Intracranial hemorrhage - very rare As opposed to coagulopathies � no muscle hematomas or hemarthroses

9. Diagnosis Clinical diagnosis based on 2 criteria Isolated thrombocytopenia Absence of other causes � infections, drugs, associated illnesses Review the blood smear Bone marrow exam only in atypical cases, the elderly, poor response to therapy, or prior to splenectomy Antiplatelet antibody tests not helpful Check thyroid function tests Pearl � �the patient feels well�

10. History

11. Physical Exam

12. TTP/HUS/DIC TTP - Clinical pentad of throbocytopenia, microangiopathic hemolytic anemia, CNS changes, renal dysfunction, and fevers DIC - Hypofibrinogenemia and increased degredation products

13. SLE or other autoimmune conditions Up to 15% of patients with ITP go on to develop SLE Anti-phospholipid syndrome (�Lupus anticoagulant�) Suspect if there is a history of thrombosis, recurrent miscarriage or prolonged aPTT

14. Pseudothrombocytopenia Platelet clumping � seen with EDTA but not with citrate or heparin � no known consequence

15. Drug Related Quinidine Heparin Many others See http://w3.ouhsc.edu/platelets Thrombocytopenia resolves when drug exposure ceases

16. Hypersplenism Mild to moderate thrombocytopenia due to sequestration Rarely associated with bleeding

17. Myelodysplasia (MDS)

18. Thrombocytopenia with Pregnancy Gestational Thrombocytopenia Asymptomatic, mild thrombocytopenia (platelet count typically >70,000/microL) No past history of thrombocytopenia (except possibly during a previous pregnancy) Occurrence during late gestation Spontaneous resolution following delivery HELLP/Pre-eclampsia Thrombocytopenia associated with red blood cell fragmentation

19. ITP and infection ITP has often been seen after viral infections HIV H pylori Hepatitis C

20. HIV 5-10% incidence prior to effective ART Platelet counts inversely correlate with viral load Responsive to classic ITP therapies: steroids; IVIG; anti-D; splenectomy In addition, very responsive to anti-retroviral therapy

21. H Pylori Initial description 1998 Gasbarrini � 8 of 11 H pylori infected Italian ITP patients showed improvement with treatment of infection Multiple subsequent reports with discrepant results 2009 � Stasi et al systematic review of literature found 25 reports involving at least 15 patients.

22. Response rate to H pylori eradication - Stasi et al 2009

23. H Pylori Stasi et al 2009 Response rates higher in regions with higher prevalence of H pylori � most reports and 2/3 of pts from Japan Responses usually occur 1-2 wks after eradication of H pylori In study with longest follow up (med 43.5 months) only 1 pt (of 23) with a response >7 mos experienced recurrence. In 6 studies 41 uninfected patients received eradication therapy and none responded It has been proposed that CagA-positive strains of H pylori (which are more prevalent in Japan and less prevalent in western countries) produce antigenic mimicry of platelet antigens.

24. Hepatitis C

25. Hepatitis C Thrombocytopenia can be seen in the absence of liver disease or splenomegaly HCV positive patients are less likely to respond to steroids than HCV negative patients. The response to splenectomy is unaffected 50% response of thrombocytopenia to anti viral interferon therapy

26. Management ITP Practice Guideline � American Society of Hematology Available on the ASH website:  www.hematology.org Published in 1996 becoming dated

27. Should the Patient be Hospitalized? ITP Practice Guideline � American Society of Hematology Patients with platelet counts >20,000 should not be hospitalized if they are either asymptomatic or have only minor purpura. Hospitalization is appropriate for patients with platelet counts <20,000 who have significant mucous membrane bleeding.

28. Does the Pt need to be treated? ASH Guideline � �Current evidence is inadequate to state with certainty which groups of patients with ITP can be safely managed without therapy �� Patients with counts >50,000 do not routinely require treatment However, treatment is indicated in patients with platelet counts <20,000 to 30,000, and those with counts <50,000 and significant mucous membrane bleeding (or risk factors for bleeding, such as hypertension, peptic ulcer disease, or a vigorous lifestyle). When ITP symptoms persist after primary treatment (glucocorticoid) and splenectomy, further therapy is recommended in patients with platelet counts <30,000 who have active bleeding.

29. Does the Pt need to be treated? �How I Treat ITP�  Cines DB and Bussel JB. Blood Oct 2005 � In general, immediate therapy is not required for patients with platelet counts between 20 000 and 50 000 X 109/L in the absence of bleeding or predisposing comorbid conditions such as uncontrolled hypertension, active peptic ulcer disease, anticoagulation, recent surgery, or head trauma.�

30. Does the Pt need to be treated? Meta-analysis of 17 studies: Cohen et al. Arch Intern Med 2000;160:1630-1638

31. Does the Pt need to be treated? Decision should probably be individualized Pt age Occupation Lifestyle: sports, travel, reliability, risk of head trauma Pt preferences Likely need for antiplatelet drugs

32. Options for Treatment Steroids IVIG Anti-D Splenectomy Rituximab Thrombopoietin receptor agonists Others: danazol, cyclophosphomide, azathioprine, vincristine, cyclosporine A, dapsone, Campath 1-H, mycophenolate mofetil

33. Steroids First used in 1951

34. Steroids Most authorities consider steroids as first line therapy and advise starting with prednisone 1 mg/kg High dose dexamethasone � maybe more effective in uncontrolled trials � needs confirmation The advisability of adding additional therapies (usually IVIG or anti-D) depends on the urgency of the clinical situation

35. IVIG and anti-D In 1981 Imbach reported that a 12 yo Swiss boy with chronic hemorrhagic ITP had developed lymphocytopenia and hypogammaglobulinemia as a result of steroids and vincristine. When treated with IVIG he had a dramatic response of his platelet count. Imbach later the same year reported similar dramatic responses in a series of 12 children with acute and chronic ITP

36. IVIG and anti-D Anti-D as effective as IVIG in Rh+, non-spelectomized patients; response rate � 70% Anti-D infusion time is 5 - 10 minutes instead of several hours over 2 � 5 days.

37. IVIG and anti-D

38. ASH Guideline � Initial therapy Based on opinion, the panel concluded that glucocorticoid therapy (prednisone, 1 to 2 mg/kg/d) was appropriate initial treatment Based on opinion, the panel concluded that IVIg was appropriate initial treatment only for patients with platelet counts <50,000 who have severe, life-threatening bleeding There was strong disagreement (category E) among the panel about the appropriateness of IVIg as initial therapy for patients with platelet counts <20,000 who are asymptomatic or have only minor purpura, or for patients with risk factors for bleeding, such as hypertension, peptic ulcer disease, or a vigorous lifestyle

39. Emergency Therapy � serious bleeding

40. Chronic ITP Long term prognosis excellent in children with acute ITP In adults 12-25% will require chronic or recurrent therapies (estimates are quite variable) 5% or less will develop �chronic refractory ITP� the failure of any modality to keep the platelet count above 20 000 X 109/L for an appreciable time without unacceptable toxicity

41. Splenectomy For 50 years until the introduction of steroids in the 1950�s, splenectomy was the only therapy for ITP.

42. Splenectomy Predictors of response � younger age found to correlate with response but this finding is not consistent Durability � while there are reports of late relapses, �analysis of 21 case series with follow-up of more than 5 years, suggest that the response to splenectomy is durable.� Toxicity: operative mortality 0.2 � 1%, complications 9 � 13% (? Related to willingness to operate on older patients?); fatal asplenic sepsis 0.73 per 1000 pt yrs

43. Splenectomy �How I treat idiopathic thrombocytopenic purpura (ITP)� Cines and Bussel � Blood Oct 2005 � Splenectomy remains the single best option to convert a patient with ITP into a �nonpatient,� that is, one who is unlikely to need frequent monitoring or intervention, and it minimizes interference with a normal lifestyle.�

44. Rituximab Anti CD20 monoclonal antibody targeting B-cells Many uncontrolled trials showing response rates (Plts > 50K) from 40 � 60%. Time to response is 3-7 weeks. Follow up is short (median in one systematic review 9.5 mos) though one study of unsplenectomized patients found 33% still responding at 2 yrs. Toxicities: Infusion reactions; rare cutaneous, pulmonary and infectious events described (In rare cases fatal), reactivation of hepatitis B

45. Rituximab - Toxicities

46. Rituximab � infectious complications

47. Thrombopoietin Receptor Agonists Thrombopoietin (TPO) a lineage-specific cytokine that stimulates megakaryocyte growth and maturation was discovered in 1994. Recombinant thrombopoietin (rHuTPO) produced a predictable rise in platelet counts in several settings including Chrnic ITP. Development was halted when a 8% of volunteers developed anti-thrombopoietin antibodies and related thrombocytopenia. Marrow fibrosis seen with 2nd generation agents Though not seen, concern for possible increse in thrombosis

48. Romiplastim (Nplate) Thrombopoietin mimetic � �2nd generation agent� Dimer of novel peptide with high affinity for TPO receptor bound to Fc fragment. Stimulates platelet production in healthy volunteers � rise starts at 5 days and peaks at 12. Admnistered subcutaneously biw

49. Romiplastim (Nplate)

50. Eltrombopag (Promacta) Small molecule, non-peptide TPO mimetic Orally available In healthy volunteers platelets rise after 8 days and peak at 16 days.

51. Eltrombopag (Promacta)

52. TPO Mimetics - toxicity Full spectrum and risk of toxicity not evaluable from current short term studies Concerns include Increased bone marrow reticulin � seen with both agents Rebound thrombocytopenia on discontinuation Thrombosis (high risk patients were excluded from existing studies) Tumor growth (in one study in MDS treatment was associtated with an increase in circulating blasts)

53. Role of platelet production  � a new paradigm Pathophysiology of ITP now seen to include both decreased production and increased peripheral destruction (note that patients studied were highly selected; all were from the subset termed �chronic refractory ITP�)

54. Drug costs

55. Conclusion ITP has been recognized since antiquity Effective therapy has been available for almost 100 years Treatments and insights into pathophysiology are continuing to evolve