Issues in the Diagnosis and Management of Thombocytopenic Disorders

1. Issues in the Diagnosis and Management of Thombocytopenic Disorders Alice Ma, M.D. Hematology UNC-CH August 10, 2009

2. Overview • Normal Physiology • Categories of Thrombocytopenias • ITP • TTP • HIT

3. Normal Physiology-Production and Number • Platelets are normally made in the bone marrow from progenitor cells known as megakaryocytes. • Normal platelet lifespan is 10d. Every day, 1/10 of platelet pool is replenished. • Normal platelet count is between 150,000 and 450,000/mm3

4. Platelet Response • Platelets adhere to vessel wall, then aggregate, leading to formation of a platelet plug • Platelets provide phospholipid scaffold for thrombin generation.

5. Thrombocytopenia-How low is too low? • 150,000 - 50,000: no symptoms • No treatment generally required. • 50,000 - 20,000: first symptoms • Generally need to begin therapy • 20,000-10,000: life-threatening • Generally requires hospitalization • <10,000: risk for spontaneous intracranial hemorrhage

6. Thrombocytopenia3 broad categories of causes • Pseudothrombocytopenia • Underproduction • Splenic sequestration • Peripheral Destruction

7. Pseudothrombocytopenia • Platelet clumping is of no clinical significance • No increased risk of bleeding or clotting

8. Thrombocytopenia - Peripheral Destruction • Non-immune mechanisms: • Platelet activation and consumption • e.g. TTP and DIC • Immune Mechanisms: • antibody-mediated platelet destruction • may be primary, secondary, or drug-induced.

9. ITP - Immune/Idiopathic Thrombocytopenic Purpura • Definition: isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia. • Etiology: autoantibodies directed against platelets coat platelet surface. IgG-coated platelets are taken up by RE system. • Incidence: approximately 100 per million; half of these are children. In adults, two peaks: • one are young (<40) with female predominance, • one are older (>60), no gender predominance.

10. ITP - Diagnosis • ITP is a Diagnosis of Exclusion • No laboratory test can diagnose ITP • Need to exclude other causes of thrombocytopenia

11. Evaluation of Patient with Low Platelets • History • Has the patient ever had a normal platelet count? • Carefully review medications, including OTC meds. • Antibiotics, quinine, anti-seizure medications • Ask about other conditions which may be associated with low platelets • Liver Disease/hepatitis • Thyroid Disease - both hypo- and hyper- • Infections: viral, rickettsial • Pregnancy • Ask about other conditions which may be associated with ITP • Lupus, CLL, lymphoma

12. Evaluation of Patient with Low Platelets • Physical • Evaluate for lymphadenopathy and splenomegaly • Look for stigmata of bleeding • Blood blisters and oral petechiae, ie “Wet Purpura” • best harbinger of intracranial hemorrhage • Laboratory Data • Other blood counts should be normal. • Check B12 and folate levels. • Look at peripheral smear to exclude pseudothrombocytopenia, also exclude TTP (especially if anemia also present.) • Send coagulation screens (PT/PTT) to exclude DIC • Send HIV, hepatitis serologies and TSH • Consider doing a bone marrow biopsy • Megakaryocytes should be present.

13. Management of ITPAsymptomatic Adult • If platelet count is >40-50 K, no therapy is required. Check platelet counts at designated intervals. • If platelet count is < 20-30 K, begin therapy with corticosteroids. • Stop all NSAIDS and ASA to improve platelet function.

14. Initial Management of ITPAdult with Symptomatic Purpura • If platelet count is >10, treat with prednisone alone - use 1 mg/kg. • If platelet count <10, treat with prednisone, but also add IVIg 1g/kg/d x 2d. - may require admission • Along with prednisone, add Calcium and Vitamin D to prevent bone loss. • If patient has severe bleeding, may need platelet transfusions.

15. Subsequent Management of ITPAdult with Symptomatic Purpura • Follow platelet counts daily until >20, then can d/c patient with close follow-up • Once platelet count normalizes, commence a slow steroid taper over 6-8 weeks. • 1/3 of adults will have gone into remission. • 2/3 of patients will relapse during or after steroid taper.

16. Management of Relapsed ITP • Once the patient relapses, may need to use steroids to increase the platelet count out of the danger range, but THIS CANNOT SUBSTITUTE FOR DEFINITIVE THERAPY. • Prednisone is now a crutch to support a dangerously low platelet count. • Options now include splenectomy (standard of care) or intermittent treatment with anti-D immune globulin (WinRho®).

17. Management of Relapsed ITPSplenectomy • Splenectomy is effective in 2/3 of patients, leading to normal platelet counts. • Can be performed via open method or laparoscopically. • Need to vaccinate against encapsulated bacteria 2 weeks before procedure. • May need steroids and/or IVIg before procedure to boost platelet counts preoperatively.

18. Management of Relapsed ITPAnti-D Immune Globulin • Can be used as a substitute for IVIg for maintenance therapy • Especially useful in patients with contraindications to splenectomy. • Coats red cells with IgG and allows red cells to serve as decoy for splenic macrophages. • Patient must be Rh positive. • Not effective after splenectomy. • Designed to cause hemolytic anemia--Hgb may drop as much as 3g/dl. • Intermittent dosing may allow patients to avoid splenectomy.

19. Case 1 • A 19 y.o. female college student presents with a rash over her lower extremities. She had a viral illness 2 weeks ago. She has no other medical problems, and she takes no medications. • Physical examination reveals petechiae over the shins. • Platelet count is 20K.

20. Case 1 • The patient is begun on prednisone at 1 mg/kg. • Seven days later, the patient returns, complaining of acne, insomnia, severe indigestion, and visual hallucinations. The platelet count is 250K. Prednisone dose is tapered over 8 weeks, and the patient remains asymptomatic with normal platelet counts.

21. Case 2 • A 39 y.o. man presents with epistaxis to the ER. He has no medical problems, and he takes no medications. He works as a taxi driver and has no occupational exposures. He is married and has 3 children. • Physical examination is remarkable only for epistaxis and scattered petechiae. • The platelet count is 35K

22. Case 2 • HIV testing is positive, and the patient admits to having numerous unprotected homosexual encounters. The CD4 count is 140, and the patient is started on antiretrovirals. The platelet count slowly rises to normal.

23. Case 3 • A 46 y.o. woman is found to have a platelet count of 20 on routine laboratory testing. She has some easy bruising and gum bleeding, but admits to not flossing. • She has no PMHx, and is on no medications. She works as a school principal. • She is started on 1 mg/kg of prednisone.

24. Case 3 • After 1 week, the platelet count is 180, and the prednisone dose is tapered by 10 mg per week. When she reaches a dose of 10 mg qd, the patient develops severe menstrual bleeding and is noted to have a platelet count of 8k. • She is admitted to the hospital, and is begun on IVIg at 1g/kg IV qd x 2d. The prednisone dose is increased to 60 mg daily. By the third day, the platelet count is 60K.

25. Case 3 • The patient is vaccinated against pneumococcus, meningococccus, and Hemophilus influenzae. • She undergoes laparascopic splenectomy, which is uneventful. The platelet count rises to 600K. She is successfully weaned off steroids.

26. Management of Refractory ITP • One third of patients will have an inadequate response to splenectomy. • Management of these patients involves accepting that they have a chronic, incurable condition. • Target platelet counts should be lower--aim for about 30K or absence of bleeding.

27. Treatment of Refractory ITP • Immunosuppressive agents • Rituximab (anti-CD20) • No RTCs vs splenectomy • 40% effective • May be used before splenectomy • Mycophenolate mofetil • Cyclophosphamide • Adjunct agents • Thrombopoietin Receptor Agonists • Romiplostim • Eltrombopag

28. Drugs Commonly Implicated in Thrombocytopenia • Beta-lactam antibiotics. • Trimethoprim-sulfamethoxazole and other sulfa drugs. • Vancomycin. • Quinine/quinidine. • Heparin. • Abciximab (ReoPro®). • H2 blockers • If a patient’s platelets fall, ALL unnecessary drugs need to be stopped.

29. Case 4 • A 55 y.o. woman presented with bleeding from her nose and mouth and gums. • PMHx - HTN, DM, DJD • Medications - glucotrol, glucophage, HCTZ, quinine for leg cramps • PEx - petechiae over limbs and torso, blood blisters in mouth, epistaxis. • Platelet count 2K

30. Case 4 • Pt admitted to hospital, quinine stopped, patient treated with platelet transfusions and IVIg. • Platelet count rose to normal over the next 5-6 days. • Eight months later, thrombocytopenia recurred, and patient admitted to taking quinine again for recurrent leg cramps.

31. Drug Induced ITP • Usually, removing the offending agent is enough to allow the platelets to rise on their own. • If platelets are severely low, platelet transfusions may be required. • IVIg is particularly helpful in quinine-induced ITP.

32. Case 5 • A 65 y.o. male smoker with a h/o peripheral vascular disease presented to the ER with unstable angina. He was admitted to the hospital and placed on heparin. Platelet count on admission was 450. Cardiac catheterization showed severe 3-vessel coronary disease, and the patient was scheduled for CABG which occurred on hospital day #7. Pre-op platelet count was 200. Post-op platelet count was 90.

33. Case 5 • On hospital day #12, the patient developed acute left leg swelling and a DVT was diagnosed by ultrasound. Platelet count was 150. The patient was started on IV heparin. The next day, he developed a pulseless left leg and had a platelet count of 30. While in vascular radiology, he developed acute chest pain and suffered a cardiac arrest and subsequently died. Autopsy showed occlusion of all of his bypass grafts.

34. Heparin-Induced Thrombocytopenia • Seen in 1-3% of patients treated with heparin • Usually, 7-10 d after heparin started, platelets fall by at least 1/3 to 1/2. • Patients do not have to be thrombocytopenic. • Can occur earlier in patients who have been previously exposed to heparin, even as SQ injections. • Caused by antibodies against the complex of heparin and PF4. These antibodies activate platelets. • Can lead, paradoxically, to THROMBOSIS, in up to half of patients. • More common in patients with vascular disease

35. Alternate Presentations of HIT/T • Small drop in platelet count (especially with skin necrosis) • Earlier onset thrombocytopenia with heparin re-exposure • Delayed-onset thrombocytopenia/ thrombosis after stopping heparin • Thrombosis after heparin exposure

36. HIT/T treatment • IF PLATELETS FALL ON HEPARIN, STOP HEPARIN IMMEDIATELY. • Stop heparin • Stop heparin • Use a different anticoagulant • Lepirudin • Argatroban

37. Case 6 • A 75 y.o.man presented with fever, nausea, vomiting, epigastric pain with radiation to his back. Amylase 12,000, Lipase 3000. Patient treated for pancreatitis. On Hospital day 2, hemoglobin and platelet count both noted to drop. By hospital day 4, Hgb 7, Plts 12. PT/PTT normal. Amylase and lipase nl, LDH 5000, Cre 2.8.

38. TTP - Diagnostic Features (aka “the Pentad”) • Microangiopathic Hemolytic Anemia (MAHA) • Elevated LDH, elevated bilirubin • Schistocytes on the peripheral smear • MUST BE PRESENT • Low platelets - MUST BE PRESENT • Fever • Neurologic Manifestations- headache, sleepiness, confusion, stupor, stroke, coma, seizures • Renal Manifestations- hematuria, proteinuria, elevated BUN/Creatinine • Abdominal Pain - can see elevated lipase/amylase

40. TTP - etiology • May be associated with an antibody against or a deficiency of the protease which cleaves the ultra-high molecular weight multimers of von Willebrand’s factor. These very high molecular weight vWF multimers cause abnormal platelet activation. • Can be induced bydrugs, including ticlopidine, quinine, cyclosporine, tacrolimus, mitomycin C. • Increased incidence with pregnancyor HIV

41. TTP - Course and Prognosis • 95% fatal prior to therapy, now 5% fatal. • Treatment relies on PLASMA EXCHANGE. • Plasma exchange is superior to plasma infusion, but if PLEX is delayed, give FFP. • Remove all inciting agents. • Platelet transfusions contra-indicated. • Multiple case reports of stroke and/or death during or immediately after platelet transfusion. • Can consider giving if life-threatening hemorrhage is present, but avoid routine platelet transfusions. • Secondary measures if no response to plasma exchange include splenectomy, vincristine

42. HUS - Hemolytic Uremic Syndrome • Usually classified along with TTP as “TTP/HUS” • Has fewer neurologic sequelae, more renal manifestations. • Usually precipitated by diarrheal illness, especially E. coli O157:H7 or Shigella • Seen more in pediatric patients, usually has better prognosis. May respond less well to plasma exchange.

43. Wrapup • Platelet count <20 • Usually requires admission • R/O TTP • Stop all meds, if possible • Probably ITP • Send HIV

44. Wrapup • Platelet count b/w 20-50 • R/O TTP • Probably requires treatment • Stop all meds • Send HIV

45. Wrapup • Platelet count b/w 50-100 • Probably does not require treatment • Find old CBCs to see if new or old • Stop all meds, if possible • Careful follow-up to see if platelet count remains stable • If pt is elderly, may be MDS, o/w probably chronic ITP