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Fibrinolytic System of Hemostasis

Fibrinolytic System of Hemostasis. Breakdown of the Fibrin Clot. Fibrinolytic System General Characterization. Need mechanism to remove clot for wound healing Must be inactive unless needed Must remain localized at site of clot Work from within the clot

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Fibrinolytic System of Hemostasis

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  1. Fibrinolytic System of Hemostasis Breakdown of the Fibrin Clot

  2. Fibrinolytic SystemGeneral Characterization • Need mechanism to remove clot for wound healing • Must be inactive unless needed • Must remain localized at site of clot • Work from within the clot • Must not work in solution (plasma or blood) • Must be slow to be activated • Must be slow to break down the clot structure

  3. Clot Formation and BreakdownCoagulation and Fibrinolysis Coagulation Fibrin Clot Wound Healing (FDP) (D-dimer) Fibrinogen Fibrinolysis

  4. Fibrinolytic SystemGeneral Mechanisms • Similar to coagulation mechanisms • Most components are proenzymes • Activated by enzymes • Forms Enzyme-Cofactor Complexes • Most important complex is Fibrin clot • Extrinsic and Intrinsic Systems • Has regulatory mechanisms

  5. Fibrinolytic ReactionsConcept of Complexes Fibrin Clot Enzyme Enzyme Proenzyme Fibrin Clot

  6. Fibrinolytic SystemMade Simple Intrinsic Extrinsic Kallikrein Endothelial Cell sc-uPA uPA tPA Plasminogen Plasmin Fibrin Clot FDP

  7. Fibrinolytic SystemMade Complex! FXII FXIIa HMWK Neg Surface Kallikrein Prekallikrein Endothelial Cell sc-uPA uPA tPA PAI-2 PAI-1 Plasminogen Plasmin α2-antiplasmin TAFI Fibrin Clot FDP

  8. Clot Breakdown and D-Dimer Formation X D D D E D E X X D E X D D D E Fibrinolysis E D X D D X D D-dimer D X D X D D

  9. Fibrinolytic SystemClinical Implications • Increased fibrinolysis causes bleeding • Defects in the components can cause thrombosis • Defects in regulators cause bleeding

  10. Regulatory Systems of Hemostasis Control of the Fibrin Clot Formation

  11. Regulatory SystemsGeneral Characterization • Need mechanisms to stop excessive clot formation (thrombosis) • Systems to activate as needed and remain local • Need mechanisms to stop clot formation in other areas of the vessels • System to work when unwanted components escape

  12. Regulatory SystemsGeneral Characterization • Must be inactive unless needed • Systems must be redundant • Must be slow to be activated • Multiple types of mechanisms

  13. Regulatory SystemsGeneral Mechanisms • Three major systems • Inhibition of Enzymes • Inhibition of Cofactors • Inhibition of Initiating Mechanism • Molecular Mechanism are: • Enzyme Complex formation • Protein Inhibitor

  14. Regulatory SystemsMechanisms • Antithrombin • Inhibits coagulation enzymes • Mainly thrombin and factor Xa • Inhibits active site • Potentiated by heparin-like molecules on EC surface • Protein C System • Inactivates cofactors factor V and VIII • Requires complex formation • Tissue factor Pathway Inhibitor • Inhibits factors VIIa and Xa • Inhibits active site

  15. Regulatory SystemsAnticoagulant Mechanisms Tissue Factor Pathway Inhibitor XII XI VII TF IX Antithrombin VIII X Antithrombin Protein C-Protein S V Thrombin Fibrinogen

  16. Coagulation Regulatory Mechanisms“Physiologic” Regulators TF FIXa FXI FVIII FVIIa FXa Cofactor Regulator FV Initiation Phase Regulator FXa Thrombin Enzyme Regulator Fibrin clot

  17. Antithrombin Mechanism Thrombin AT Heparin

  18. Protein C Pathway Mechanism Inh Ext Int APC-Inh PL VIIIa VIIIi APC PS Va Vi Thr PL PC Fibrin Clot APC Thr TM

  19. Tissue Factor Pathway InhibitorMechanism TFPI FXa FXa TFPI FVIIa FXa FVIIa TF TF

  20. Coagulation Regulatory SystemsClinical Implications • Decreases in levels of components increase risk for thrombosis

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