1. Week 7: Fibrinolysis and Thrombophilia Secondary fibrinolysis Secondary fibrinolysis Primary fibrinolysis Primary fibrinolysis Plasminogen Plasminogen FDP FDP D-dimer D-dimer DIC DIC 3P test 3P test Hypercoagulable state Thrombophilia Activated protein C resistance (APCR) Factor V Leiden Antithrombin deficiency Anticoagulant therapy

3. Fibrinolysis Plasminogen Activators Plasminogen Activators  Thrombin  Tissue plasminogen activator (t-PA)  Streptokinase  Urokinase  Kallikrein Fibrinolysis Inhibitors Fibrinolysis Inhibitors   2 antiplasmin   2 macroglobulin

5. Fibrin(ogen) Degradation Product X fragment: D-E-D X fragment: D-E-D Y fragment: D-E Y fragment: D-E Smallest fragments: D and E Smallest fragments: D and E D-dimers from fibrin degradation only (ie, 2 o fibrinolysis, not 1 o ) D-dimers from fibrin degradation only (ie, 2 o fibrinolysis, not 1 o )

6. Fibrin Degradation

7. FDP Screen Thrombo-Wellco Thrombo-Wellco  Anti-fibrinogen coated latex D-dimers D-dimers  Positive only with 2 o fibrinolysis Plasma protaminesulfate paracoagulation (3P) Plasma protaminesulfate paracoagulation (3P)  Dissociate FM-FDP to allow FM to re-associate  Also specific to 2 o fibrinolysis

8. Disseminated Intravascular Coagulation Triggering mechanism Triggering mechanism  Trauma, injury, surgery  Hemolysis  AML M3  Snake venom  Amniotic fluid  Dead fetus  Gram negative endotoxin Consumptive  Low PLT  Long PT/APTT  Low fibrinogen  FDP, D-dimer  Schistocyte Treatment  Remove source of Tpl  Heparin to stop cascade

9. Disseminated Intravascular Coagulation

11. DIC Syndrome, not disease Syndrome, not disease 1:1,000 hospitalized patients, but many asymptomatic 1:1,000 hospitalized patients, but many asymptomatic Tx: removal of underlying cause if possible Tx: removal of underlying cause if possible Support with FFP, PLT, RBC, etc. Support with FFP, PLT, RBC, etc. Low molecular weight heparin (LMWH) Low molecular weight heparin (LMWH)

12. Primary Fibrinolysis Plasminogen activation without clotting Plasminogen activation without clotting Unknown mechanism Unknown mechanism Labs similar to DIC but important differences  PLT unaffected  No schistocyte  Long PT/APTT  Low fibrinogen  FDP but no D-dimer

13. Thrombophilia Tendency to form thombi Tendency to form thombi Hereditary and acquired Hereditary and acquired Hypercoagulable state Hypercoagulable state Arterial thrombi: usually in areas of atherosclerotic plaques Arterial thrombi: usually in areas of atherosclerotic plaques Venous thrombi: thrombophlebitis, DVT, pulmonary embolism Venous thrombi: thrombophlebitis, DVT, pulmonary embolism

14. Venous Thromboembolism Venous stasis Venous stasis Activated protein C resistance, factor V Leiden Activated protein C resistance, factor V Leiden Protease inhibitor deficiency (antithrombin, protein C, protein S) Protease inhibitor deficiency (antithrombin, protein C, protein S)

15. Hereditary Thrombophilia Antithrombin deficiency Antithrombin deficiency  Recurrent DVT Protein C deficiency Protein C deficiency  Vitamin K dependent  Inactivated Va and VIIIa Protein S deficiency Protein S deficiency  Vitamin K dependent  Protein C cofactor APCR  Factor V Leiden Prothrombin gene mutation 20210

16. Acquired Thrombophilia Antiphospholipid antibody: e.g., Lupus- anticoagulant Antiphospholipid antibody: e.g., Lupus- anticoagulant Malignancy Malignancy Oral contraceptives Oral contraceptives Post-op and trauma Post-op and trauma Myeloproliferative disorders Myeloproliferative disorders

17. Therapies Heparin Heparin  Monitor with APTT  LMWH no HIT Oral anticoagulants (e.g., Coumadin) Oral anticoagulants (e.g., Coumadin)  Monitor with PT Thrombolytic agents (plasminogen activators) Thrombolytic agents (plasminogen activators)  Streptokinase  Urokinase  t-PA Anti-platelet agents  Aspirin  Plavix  IV inhibitors Direct thrombin inhibitors (e.g., hirudin - from leech saliva)  Not dependent on AT- III  Act on thrombin’s fibrin binding site

18. Problems with Oral Anticoagulants GI hemorrhage GI hemorrhage Skin necrosis Skin necrosis Antidote: vitamin K Antidote: vitamin K

19. Problems with Heparin Unfractionated Heparin may cause heparin induced thrombocytopenia (HIT) due to antibody against heparin-PF4 complex Unfractionated Heparin may cause heparin induced thrombocytopenia (HIT) due to antibody against heparin-PF4 complex LMWH: almost exclusively against Xa, less osteoporosis, less HIT LMWH: almost exclusively against Xa, less osteoporosis, less HIT Antidote: protamine sulfate Antidote: protamine sulfate