1. DR BINOD KUMAR SINGH Associate Professor, PMCH, Patna CIAP Executive Board Member 2015 NNF State President-2014 IAP State Secretary,Bihar 2010-2011 NNF State Secretary, Bihar 2008-2009 Chief Consultant: Shiv Shishu Hospital K- 208 P C Colony,Hanuman Nagar Patna 800020. Email- drbksingh210@gmail.comdrbksingh210@gmail.com web site :- www.shivshishuhospital.com

3. Etiology - still unknown and Pathogenesis -is complex and possibly depends on - disturbed antigen presentation, -T cell activation and signaling, -disregulated B cell stimulation and antibodies production, -unbalanced activation / suppression of complement.

5. ITP is mediated by IgG autoantibodies. Glycoprotein IIb/IIa, Ib/Ix, Ia/IIa, IV and V... Accelerated clearance through Fcү receptors that are expressed by tissue macrophages.

13.  No symptoms  Mild symptoms: bruising and petechiae,occasional minor epistaxis.  Moderate: more severe skin and mucosal lesions,troublesome epistaxis and menorrhagia.  Severe: bleeding episodes requiring transfusion or hospitalisation, symptoms interfering seriously with quality of life.

14. Diagnosis should be based on o the infection history o clinical features o physical examination o laboratory test

15. The diagnosis of ITP remains one of exclusion. Secondary causes of thrombocytopenia: Infections - DIC, malaria, kala-azar, DHF, Hepatitis B & C, HIV, congenital torch infection, Infections ass. with hemophagocytosis syndrome Medications – valproate, penicillins, heparin,quinine,digoxin Thrombotic microangiopathy : Thrombotic thrombocytopenic purpura, HUS Malignancies : leukemia,lymphoma, neuroblastoma

16. Auto immune or related disorders: SLE, Evans Syndrome,Antiphospholipid syndrome, Neonatal immune thrombocytopenia Immunodeficiency: Wiskott aldrich syndrome,HIV/ AIDS Bone Marrow failure : TAR, Fanconi anemia, Shwachman-diamond syndrome Marrow replacement : Osteopetrosis, Gaucher disease Others : Hypersplenism, Kasabach meritt syndrome

17. o White blood cell count and morphology are normal. o Hemoglobin values are normal unless there has been prolonged bleeding. o PT and PTT are normal, bleeding time would be prolonged, but testing is unnecessary.

18. o Peripheral blood smear: an isolated thrombocytopenia with no other abnormalities, platelet count<100 x10⁹/L,the few circulating platelet may be quite large (megathromocytes).

19.  In adolescents with new onset ITP, an antinuclear antibody test for SLE.  HIV test in at risk population.  Coomb’s test for unexplained anemia or before instituting therapy with IV anti-D.

20. o Measuring antipatelet antibodies o including the measurment of the amount of platelet-associated IgG (PAIgG)and direct assay of specific platelet antibodies. o However, these tests lack both specificity and sensitivity in acute ITP of childhood.

21.  Abnormal WBC count or differential count  Unexplained anemia  Findings on history and physical examination suggestive of BM failure syndrome or malignancy.

22. o Bone marrow:The bone marrow in patient with ITP contains normal or increased numbers of megakaryocytes Indicating that platelet production is normal and that thrombocytopenia results from increased platelet destruction

23. - Those without hemorrhage – is managed on an outpatient basis with minimal investigation, - Short-term therapy in selected cases, - Avoidance of activities that predispose the patient to trauma and - Avoidance of medications that impair platelet function.

24. 1. General Treatment o salicylate- containing medications, antihistamines and nonsteroidal drugs that interfere function and increase the risk of bleeding should be avoided.

25.  Children who have platelet counts >20,000/mm 3 and are asymptomatic or have only minor purpura do not require routine treatment.  Children who have platelet counts < 20,000/mm 3 and significant mucous membrane bleeding and those who have platelet counts < 10,000/mm 3 and minor purpura should receive specific treatment.

26. o Children with active bleeding – IVIG or Rh anti –D immunoglobulin o Corticosteroids should be adm after malignancy is ruled out by BM examination o Prednisolone- 1 to 4 mg/kg/ d for 2 to 4 weeks and then tapered o Dexamethasone – 20 mg/m² over 4 days every three weeks for 4 to 6 courses. o Serious hemorrhage- platelet transfusion + corticosteroid/IVIG/Rh anti- D Immunoglobulin

27. o Prednisolone low dose on alternate day o Combinations of the following options:- - Danazol - vincristine - cyclosporine - azathioprine o Rituximab (Anti-CD 20 monoclonal antibody) o Splenecdomy o Thrombopoietin receptor- binding agents

28. 2. Intravenous immunoglobulin (IVIG). o Mechanisms: o Blocking Fc receptor of the RE(reticulo= endothelium) phagocytes o Preventing them from binding and destroying IgG antibody-coated platelets.

29.  DOSE: 0.8 – 1gm/kg/day for 1-2 days.  It induces rapid rise in platelet count in 95% of patients within 48hrs.

30. o Disadvantages of IVIG:- - it is expensive, -long infusion time of 6 to 8 hours, - allergic reactions, - aseptic meningitis with severe headache in 10% to 30 %, - 50% to 75% have headache,nausea, vomiting or fever.

31. 3. Corticosteroids. Mechanisms: o Reducing capillary fragility o Inhibiting platelets destruction o Have a rapid, dose dependent action that reduce RE destruction of antibody- coated platelets o Also reduces antibody production slowly.

32. o Children with chronic ITP who have mild or recurrent bleeding are sometimes treated with intermittent courses of IVIG or high dose corticosteroids (interavenous methayl prednisolone 20 ∼ 30 mg/kg/d for 3 days ).

33. 4. Intravenous anti –Rh(D) Immunoglobulin for Rh-positive patient. Mechanisms: o Anti-Rh(D) immunoglobulin produces a mild hemolytic anemia that saturates the Fc receptors of the phagocytic elements of the RE system.

34. o Permitting increased survival of antibody coated platelets. o The immediate goal of therapy is to increase the platelet count to a safe level, usually> 20 x 10⁹/L, in the hope of the reducing the risk of severe hamorrhage. o Dose:IV Anti-Rh(D), 50μg to 75μg/kg for 2 days.

35. Merit of Anti Rh(D) immunoglobulin : o less expensive than IVIG but more costly than steroids, o lower rate of allergic side effects(10%) than IVIG and o does not cause aseptic meningitis. Disadvantage : cause mild hemolysis with a transient hemoglobin decrease of 10 to 20%

36.  For children>4yrs with severe ITP and whose symptoms are not controlled with therapy.  When life threatening hemorrhage complicates ITP.  It is associated with risk of infection caused by encapsulated organisms and potential development of pulmonary hypertension in adulthood.

37. 6. Other treatment. o ɑ interferon, danazol (a synthetic androgen), ascorbic acid, cyclosporine, and a variety of immunosuppressive drugs including mycophenolate mofetil,vincristine (VCR), azathioprine,and cyclophosphamide(CTX). o No large study of these agents have been described in children with chronic ITP, and they may have immediate and long-term toxicities. o Adsorption Ab removal has been used with limited success in refractory cases.

38.  A chimeric monoclonal anti B-cell antibody.  Reduces the immune system response.  May be considered for children with ITP who have significant ongoing bleeding.  May be considered as an alternative to splenectomy in children with chronic ITP or who have failed splenectomy.

39. Eltrombopag (Promacta)  Oral thrombopoietin (TPO) receptor agonist.  Interacts with transmembrane domain of human TPO receptor and induces megakaryocyte proliferation and differentiation from bone marrow progenitor cells.  Indicated for thrombocytopenia associated with chronic ITP in patients experiencing inadequate response to corticosteroids, immunoglobulins, or splenectomy.  FDA approved for use in adults, no published data for use in children.

40. Romiplostim (Nplate)  An Fc-peptide fusion protein (peptibody) that increases platelet production through binding and activation of the thrombopoietin (TPO) receptor.  Indicated for chronic ITP in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.  Side effects: headache, joint or muscle pain, dizziness, nausea, vomiting.

41. LifeThreatening Hemorrhage- IVIG +platelet transfusion o May require concomitant Multimodality Therapy o frequently requires Emergency Splenectomy o sometimes necessary Plasmapheresis

42. Spontaneous recovery is the norm o 60 % in 3 months o 80 % in 6 months o 90 % in 9 months The incidence of significiant bleeding- related morbidity and mortality is extremely low o Less than 5 % Of Patients with chronic ITP o 20% will ultimately have spontaneous resolution of their thrombocytopenia.