ITP by dr. Mohib Ali
- 1. IDIOPATHIC/IMMUNE THROMBOCYTOPENIC PURPURA (ITP) “Everybody bleeds sometimes, I just bleed more………..” Dr. Mohib Ali
- 2. • A 17 yr old adolescent is brought to the ER by her mother who is concerned that she has bruised easily over the past few days and has had a nose bleed this morning. There are no symptoms of other illness and she is otherwise well. On examination there are generalized petechiae and some bruising mainly affecting the lower limbs. Blood testing reveals a platelet count of 35 * 109, but the platelets are normal size. Hemoglobin is 11.1 g/dl and her white blood cell count is normal. What diagnosis fits best with this clinical picture ? i. Immune thrombocytopenic purpura (ITP) ii. Henoch Schonlein purpura iii. Thrombotic thrombocytopenic purpura (TTP) iv. Hemolytic Uremic Syndrome (HUS) v. Generalized Bone Marrow Suppression
- 3. Platelets • Platelets are released from the megakaryocyte. • The normal blood platelet count is 150,000–450,000/L. • The major regulator of platelet production is the hormone thrombopoietin (TPO), which is synthesized in the liver. • Synthesis is increased with inflammation and specifically by interleukin 6. • A reduction in platelet and megakaryocyte mass increases the level of TPO, which then stimulates platelet production. • Platelets circulate with an average life span of 7 to 10 days.
- 4. • Thrombocytopenia can be broadly classified into five categories based on the mechanism behind reduce platelet count ; – Pseudo or Spurious Thrombocytopenia – Dilutional Thrombocytopenia – Decreased Platelet Production – Increased Platelet Destruction – Altered Distribution of Platelets (Increased Sequestraion)
- 5. Decreased production of platelets Increased destruction of platelets Increased sequestration of platelets Other conditions causing thrombocytopenia Congenital Bone marrow failure(e.g. fanconi anemia, Wiskott-Aldrich syndrome) Immune Thrombocytpenia (including Hep C & HIV related & drug induced) Hypersplenism (e.g. related to cirrhosis, myeloproliferative disorders, lymphoma) Gestational thrombocytopenia Acquired Bone marrow failure (e.g. Aplastic anemia, myelodysplasia) HIT , TMA , DIC , Post transfusion purpura , Hemophagocytosi s Bernard-Soulier syndrome , grey platelet syndrome, May-hegglin anomaly Exposure to chemotherapy, irradiation Neonatal alloimmune thrombocytopenia Psudothrombocytope nia Marrow infiltration (neoplastic, infectious) Von Willebrand disease type2 Nutritional (def. of Mechanical (aortic
- 6. DRUGS THAT ARE STRONGLY ASSOCIATED WITH THROMBOCYTOPENIA
- 7. ANTIBIOTICS AND ANTIVIRALS • Quinine/quinidine • Penicillins • Cephalosporins • Vancomycin • Trimethoprim/sulfamethoxazol e • Sulfonamides/sulfonylureas • Linezolid • Valacyclovir • Ganciclovir • Indinavir CARDIOVASCULAR MEDICATIONS • Abciximab • Tirofiban • Eptifibatide • Salicylates • Digoxin • Furosemide MISCELLANEOUS • Cimetidine • Ranitidine • Famotidine • Valproate • Interferon
- 8. Approach to the Thrombocytopenia Patient • History – Is the patient bleeding ? – Do the sites of bleeding suggest a platelet defect ? – Duration – Is thrombocytopenia acute or chronic ? – Is there a history of medications, alcohol use, or recent transfusion (post transfusion purpura) ? – Are there any symptoms of a secondary illness ? – (neoplasm , infection, autoimmune disease) – Is there a family history of thrmobocytopenia ? – Heparin exposure – recent or within past three months (HIT) ? – Are there any risk factors for HIV infection ? – History of liver disease ?
- 10. Platelet count < 150,000/mcl Hb & WBC count Normal Abnormal Peripheral Smear Bone Marrow Examination Normal RBC morphology; platelets normal or increased in size Fragmented red blood cells Microangiopathic hemolytic anemias (e.g. DIC, TTP) Consider: Drug induced thrombocytopenia Infection induced thrombocytopenia Idiopathic immune thrombocytopenia Congenital thrombocytopenia Platelets clumped: Redraw in Sodium citrate or Heparin
- 11. ITP • Immune thrombocytopenic purpura (ITP; also termed idiopathic thrombocytopenic purpura) is an acquired disorder in which there is immune- mediated destruction of platelets and possibly inhibition of platelet release from the megakaryocyte.
- 12. Clinical Presentation • Excessive bleeding with minor injuries • Spontaneous bleeding from mouth & nose • Unexplainable or spontaneous bruising • Ecchymoses and Petechiae • Hematuria • Menorrhagia • Intracranial bleed • Purpura • Thrombocytopenia
- 14. • Which of the following conditions is not associated with ITP ? i. SLE ii. HIV iii. Tuberculosis iv. CLL v. Hep B & C
- 15. Classification • Primary • Secondary; – Post-Infectious : HIV, HCV, CMV, H.Pylori – Antiphospholipid syndrome – SLE – Autoimmune thrombocytopenia (e.g. Evan’s syndrome) – Lymphoproliferative Disorders : CLL , NHL , HD – Common Variable Immune Deficiency – Drug Induced ITP
- 17. Types of ITP ITP can be divided into acute and chronic forms: Acute ITP • More commonly seen in children • May follow an infection or vaccination • Usually runs a self-limiting course over 1-2 weeks Chronic ITP • More common in young/middle-aged women • Tends to run a relapsing-remitting course
- 18. Features Acute ITP Chronic ITP 1 Age Usually 2 to 6 years 20 to 30 years 2 Sex Any Predominant in female 3 Onset Acute Chronic 4 Previous Infection Common Unusual 5 Platelet Count <20,000/mm3 >20,000/mm3 6 Spontaneous Remission Common Less, <20% 7 Duration 2 to 4 weeks Chronic, months to years
- 19. • In ITP , the autoantibodies are most commonly directed at ? A. Platelet activating factor B. Glycoprotein IIb/IIIa complex C. ATP receptor D. Anti-thrombin III receptor E. ADP Receptor
- 20. Pathophysiology • Increased platelet destruction caused by antiplatelet antibodies Antibodies directed against platelet membrane antigens such as glycoprotein IIb/IIIa The platelets coated with immune complexes bind to Fc portion of macrophages in spleen and other RES and are removed • Lack of compensatory response by megakaryocytes due to suppressive effect of antiplatelet antibodies • So a combination of increased platelet destruction + ineffective megakaryopoiesis
- 21. Diagnosis • Careful and detailed history, clinical examination • CBC • Peripheral Smear • PT , apTT • LFTs , RFTs • Hep B & C Serology • ANA • Antiphospholipid antibodies • IgG levels to rule out CVID • HIV , EBV , CMV Serology • Bone Marrow Examination • Nutrient workup (Iron, B12, folate )
- 22. When to do Bone Marrow Examination • Bone marrow examination can be reserved for older adults (usually >60 years) or • those who have other signs or laboratory abnormalities not explained by ITP, or • in patients who do not respond to initial therapy. • Megakaryocyte abnormalities and hypocellularity or hypercellularity are not characteristic of ITP.
- 24. Desired Platelet Count Ranges Clinical Scenario Platelet Count (/mcL) Prevention of spontaneous mucocutaneous bleeding >10,000-20,000 Insertion of Central Venous Catheters >20,000-50,000 Administration of therapeutic anticoagulation >30,000-50,000 Minor Surgery and selected invasive procedures >50,000-80,000 Major Surgery >80,000-100,000
- 25. Some Facts • ITP was originally described in 1735 by a German physician, Paul Gottlieb Werlhof, and was therefore known as Werlhof’s disease. • In 1916, Paul Kaznelson reported the first successful treatment for ITP after a patient showed a response to splenectomy • Splenectomy was then used as the first-line therapy for ITP until 1950.
- 26. Management
- 27. Initial Treatment Prednisone 1 mg/kg/d for 7-10 days followed by rapid taper Or Dexamethasone 40mg/d orally for 4 days monthly for 6 months IVIG, 1g/kg/d i/v for 2 days Or Anti-D, 75mcg/kg i/v for 1 dose Platelets, if bleeding +/- +/-
- 28. Relapsed or Persistent ITP Prednisone 1 mg/kg/d for 7-10 days followed by rapid taper Or Dexamethasone 40mg/d orally for 4 days monthly for 6 months Rituximab 375mg/m2 i/v weekly for 4 weeks Anti-D 75mcg/kg i/v serially as needed for platelets < 30,000/mcl IVIG, 1g/kg/d i/v for 2 days serially as needed for platelets < 30,000/mcl Thrombopoeiti n Receptor Agonist Romiplostim (s/c) Eltrombopag (orally) Splenectomy (Laparoscopic) or or or and
- 29. Persistent or Worsening ITP Mycophenolate mofetil – Azathioprine/Danazol – Cyclosporine - Chemotherapy Enrollment in Clinical trial – Autologous transplantation Splenectomy (Laparoscopic) Trial of additional agent(s) above
- 30. THERAPY FOR THE INITIAL MANAGEMENT OF IMMUNE THROMBOCYTOPENIC PURPURA
- 31. ORAL PREDNISONE • Effect is dose dependent—approximately 80% of patients respond to 1 mg/kg/day. • Toxicity also increases with dose and duration of treatment and includes glucose intolerance, immunosuppression, osteoporosis, and cataracts. Relapse is typical once therapy is discontinued.
- 32. • Steroids are presumed to reduce the risk of symptoms in ITP patients by: – Reducing antibody production – Reducing reticuloendothelial system phagocytosis of antibody-coated platelets – Improving vascular integrity – Improving platelet production
- 33. INTRAVENOUS IMMUNOGLOBULIN (IVIG) • More rapid than daily prednisone. Administered at a dose of 1 g/kg/day for 2 consecutive days or 0.4g/kg/day for 5 consecutive days. • Response rates are approximately 80%, and effects typically last 2-4 wk. • Toxicity includes headache, allergic reactions, and, rarely, thrombosis.
- 34. ANTI-D IMMUNOGLOBULIN • Administered at a dose of 50-75 μg/kg IV. • Response rates are dose dependent but can approach 75-80%. • Hemolysis is a common toxicity. Rarely, hemolysis can be life threatening and can be associated with disseminated intravascular coagulation, renal failure, and end-organ infarction.
- 35. THERAPY FOR THE MANAGEMENT OF REFRACTORY IMMUNE THROMBOCYTOPENIC PURPURA
- 36. ORAL PREDNISONE • Effect is dose dependent and rapidly dissipates after discontinuation of the medication. Some patients can be maintained on a very low and tolerable daily dose (e.g., 5 mg). • Long-term use is associated with infections, diabetes, osteoporosis, avascular necrosis, weight gain, and cataracts.
- 37. ORAL DEXAMETHASONE • Administered at a dose of 40 mg/day for 4 consecutive days. Repeated every 2-4 wk for several months. • Sustained response rates of 29-42% are possible. • Toxicity is similar to that of oral prednisone.
- 38. SPLENECTOMY • Durable (often lifelong), significant responses are seen in 65-70% of patients who undergo this procedure. • Produces lifelong immunosuppression to encapsulated and gram-positive organisms. • American Society of Hematology guidelines recommend waiting until at least 12 months after diagnosis, if possible. • When possible, surgery should be performed using laparoscopic techniques.
- 39. When to vaccinate the patient before & after splenectomy ?
- 40. • Patients should receive pneumococcal, Haemophilus influenza type b, and meningococcal vaccination at least 2 weeks before the procedure. • Post Splenectomy; – Pneumococcal 5 yearly – Meningococcal 3 yearly – Hemophilus Influenza type b 1 yearly
- 41. • RITUXIMAB • Given at a dose of 375 mg/m2/wk IV for a total of 4 wk. Significant responses are seen in 28-44% of patients and typically last for months. • Toxicity includes reactivation of hepatitis B, immunosuppression, and, rarely, progressive multifocal leukoencephalopathy.
- 42. • For selected refractory patients, other immunosuppressives, such as cyclophosphamide, azathioprine, cyclosporine A, mycophenolate mofetil, dapsone, interferon, and etanercept, can be used.
- 43. • THROMBOPOIETIN RECEPTOR AGONISTS • Administered daily (eltrombopag) or weekly (romiplostim). • An effect is typically seen in 2-3 weeks and disappears a few weeks after discontinuation of the medication. • Toxicity from long-term use is not well known but may include excessive thrombosis and bone marrow fibrosis.
- 45. ITP in Pregnancy • The goal of management of pregnancy-associated ITP is a platelet count of 10,000–30,000/mcL in the first trimester, • > 30,000/mcL during the second or third trimester, and • > 50,000/mcL prior to cesarean section or vaginal delivery. • Moderate-dose oral prednisone or intermittent infusions of IVIG are standard.
- 46. ITP with HIV & HCV • For thrombocytopenia associated with HIV or hepatitis C virus, treatment of either infection leads to an amelioration in the platelet count in most cases; • Refractory thrombocytopenia may be treated with infusion of IVIG or anti-D (HIV and hepatitis C virus), splenectomy (HIV), or interferon-alpha or eltrombopag (hepatitis C virus, including eradication). • Treatment with corticosteroids is not recommended in hepatitis C virus infection.
- 47. Response after Initial Treatment (Steroids) • Complete Responders – Platelet count > 100,000 • Partial Responders – Platelet count 50,000-100,000 • Non Responders – Platelet count < 50,000
- 48. New Terminologies in ITP i. Complete Response ii. Partial response iii. No response iv. Loss of complete response v. Loss of response
- 49. • Complete response – A platelet count of >/= 100 * 109/L measured on two occasions more than 7 days apart and the absence of bleeding. • Partial response – A platelet count of >/= 30 * 109/L and a > 2fold increase in platelet count from baseline measured on two occasions more than 7 days apart and the absence of bleeding. • No response – A platelet count of < 30 * 109/L or a < 2 fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on two occasions more than a day apart.
- 50. • Loss of complete response – A platelet count of < 100 * 109/L measured on two occasions more than a day apart and/or the presence of bleeding. • Loss of response – A platelet count of < 30 * 109/L or < 2 fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on two occasions more than a day apart.
- 51. • A 40-year old lady , 3 years post splenectomy for chronic ITP presents with a petechial rash and gum bleeding . Her blood count shows; – WBC of 6.3 *109 /L – Hb of 11.5 g/dL – platlet count of 3*109 /L • What would be the most appropriate next treatment modality provided ? A. Thrombopoietin agonist ( eltrombopag or romiplostim) B. Rituximab C. Cyclosporine D. Mycophenolate mofetil E. All of the above are acceptable, treatment should be patient- centered as regard to choice of the immunosuppressive agent
- 52. Thank You