Overview Normal platelet production and survival Thrombocytopenic bleeding Approach

Overview • • • • • • Normal platelet production and survival Thrombocytopenic bleeding Approach to thrombocytopenia ITP DIC TTP Thrombocytopenia David Lee, MD, FRCPC Platelet formation Platelets in the circulation: Influx, efflux, and redistribution (+) thrombopoietin (platelet count) megakaryocyte fragmentation into platelets PRODUCTION proplatelet formation 30% CIRCULATING PLATELETS 70% DESTRUCTION (or REMOVAL) SPLEEN pseudopodia formation proplatelet release 1 Thrombopoietin Normal platelet count plasma platelet TPO Determinants of bleeding risk in thrombocytopenia • • • • platelet count cause of thrombocytopenia co-existing disorders drugs Thrombocytopenia [TPO]total [TPO]free normal normal normal increased Risk of bleeding & platelet count Major bleeding Minor bleeding ecchymosis & petechiae Bleeds/1000 risk days 300 200 100 0 0-5 6-10 11-15 16-20 >20 Platelet count (x 10 /L) 9 2 Clinical manifestations of thrombocytopenia • petechiae – not seen in hemophilia or vWD Thrombocytopenia rule out pseudothrombocytopenia • • • • • ecchymoses purpura mucosal bleeding menorrhagia intracranial hemorrhage – uncommon, but the most feared SEQUESTRATION look for splenomegaly • DDx of splenomegaly PRODUCTION bone marrow asp & bx review meds • Bone marrow failure DESTRUCTION look for underlying disorders review meds • Immune (plt antibodies) • Non-immune Immune thrombocytopenic purpura (ITP) • idiopathic autoimmune platelet destruction • any age or sex • #1 cause of isolated thrombocytopenia in otherwise healthy young persons ITP: Laboratory features • • • • isolated thrombocytopenia normal PT, PTT no sensitive and specific test for ITP bone marrow investigation not essential in straightforward cases • diagnosis of exclusion • can be preceded by viral infection • presents as bleeding or as incidental finding of thrombocytopenia 3 ITP: Treatment (Adults) Patient is not bleeding • plt > 50: no Rx • plt 20-50: monitor closely - usually no Rx • plt < 20: Rx with one or more of: – prednisone, dexamethasone – IVIG – anti-D – splenectomy, if relapsing severe ITP Prophylactic platelet transfusions • Bone marrow failure: – indicated if platelet count < 10 x 109/L • Increased destruction: – not indicated ITP: Treatment Patient is bleeding • • • • Prednisone and IVIG Transfuse platelets consider urgent splenectomy supportive/resuscitative care ITP: Prognosis • Children: usually permanent remission • Adults: – relapses common – chronically low platelets • may or may not require ongoing Rx 4 Disseminated Intravascular Coagulation (DIC) • Systemic activation of coagulation & fibrinolysis – consumption of factors Causes of DIC • • • • • Infection Obstetrical complications Malignancy Tissue injury - trauma Other: – acute hemolytic transfusion reaction – envenomation • Manifestation of a serious underlying disorder • High mortality Fibrin clot formation & proteolysis coagulation pathway physiologic inhibitors thrombin plasmin fibrinolytic pathway physiologic inhibitors fibrinogen fibrin clot FDP’s 5 Pathophysiology of DIC PATHOPHYSIOLOGIC EVENTS underlying disorder LABORATORY MANIFESTATIONS depletion of clotting factors prolonged PT & PTT CLINICAL MANIFESTATIONS tissue factor release thrombocytopenia (consumption) activation of intrinsic pathway of coagulation (systemic thrombin generation) hemorrhage consumption of physiologic anticoagulants (decreased protein C, S, antithrombin) decreased fibrinogen generalized intravascular fibrin deposition microangiopathic hemolytic anemia activation of fibrinolysis (systemic plasmin generation) thrombosis increased FDP & D-dimer (products of fibrin breakdown) Treatment of DIC • Treat the underlying disorder • Replace the missing blood components – – – – frozen plasma cryoprecipitate packed red cells platelet concentrate Thrombotic Thrombocytopenic Purpura (TTP) Diagnostic pentad: 1. 2. 3. 4. 5. microangiopathic hemolytic anemia thrombocytopenia renal failure neurologic deficit fever • Consider additional pharmacologic therapy – activated protein C, antithrombin, heparin, antifibrinolytic agents 6 Pathophysiology of idiopathic TTP autoantibodies against vWF-cleaving protease (ADAMTS 13) blood flow Treatment and prognosis of TTP • Plasmapheresis reduces mortality from ~100% to ~25% ADAMTS13 vWF plt Normal vessel wall No ADAMTS13 vessel wall TTP vessel wall Overview • • • • • • Normal platelet production and survival Thrombocytopenic bleeding Approach to thrombocytopenia ITP DIC TTP 7