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Coagulation and hemostasis
- 1. Coagulation and hemostasis: An overview and module University of Vermont College of Medicine Attacks and Defenses course January 2011 Tim Plante, MS-IV
- 2. About • This is a learning module I made my senior year of medical school at UVM College of Medicine • It’s broken up into three parts: – Beginni (starting slide 3) - A brief overview of coagulation and hemostasis – Review (starting slide 11) - The individual components of coagulation and hemostasis – (starting slide 19) – The review section except the names are all blanked out. This is the biggest and most helpful part of this presentation!! This is where you should be spending your time! • Students found this very helpful. I challenge you to go through the quiz as many times as you can! You’ll get the material pretty quickly. Review Beginning Quiz
- 3. First things first… • Hemostasis – (good) – normal response to stop blood using platelets and the coagulation cascade • Thrombosis – (bad) – pathologic formation of clots (e.g. deep vein thrombosis) • Hemorrhage – bleeding – Coagulopathy – (bad) – a defect in coagulation, pathologic bleeding (e.g. hemophilia A) • Primary hemostasis – formation of a platelet plug through the platelet’s GpIb-V-IX receptor (connects with the subendothelial von Willebrand Factor) and GpVI receptor (connects with the subendothelial collagen). • Secondary hemostasis – progression of the coagulation cascade resulting in the formation of an insoluble fibrin mesh to strengthen the platelet plug. Beginning
- 4. The main components of the coagulation cascade • Extrinsic X-ase – The main component of the extrinsic pathway, it is made of VIIa, Tissue Factor (TF), membrane, and Ca2+. It converts X Xa for use in the common pathway. It also converts IX IXa for use in the intrinsic pathway. • Intrinsic X-ase – The main component of the intrinsic pathway, it is made of IXa, VIIIa, membrane, and Ca2+. It converts X Xa for use in the common pathway. – Note: there are factors further up on the intrinsic pathway of which deficiencies do not cause bleeding disorders, the exception is XIa. • Prothrombinase - The main component of the common pathway, it is made of Va, Xa, membrane, and Ca2+. It converts II IIa (prothrombin thrombin). Beginning
- 5. Pharmacologic considerations • PT (prothombin time) – measures the function of the extrinsic pathway and the common pathway. Extended by warfarin. • aPTT (partial thomboplastin time) – measures the function of the intrinsic pathway and the common pathway. In vitro extension by heparin. • Vitamin-K dependent coagulation components – Factors X, IX, VII, II, proteins C, S (mnemonic: 1972 [10, 9, 7, 2]). • Warfarin (Coumadin) – inhibits vitamin-K reductase and effective levels of of vitamin-K dependent coagulation components. Will extend the PT. • Heparin (drug) – purified from animals. Increases the activity of ATIII. Will increase the aPTT in vitro. • Thromboxane A2 (TXA2) – synthesis of TXA2 is initiated by activated platelets. TXA2 increases platelet activation and aggregation. Its synthesis is inhibited by aspirin. Beginning
- 6. Endothelium vs. subendothelium • Endothelial cells – line the vessels. Are thromboresistant in nature. They express thrombomodulin and heparin sulfate to keep inappropriate thrombi from forming. They also release tissue plasminogen activator and urokinase in the presence of thrombin shut off the coagulation cascade in the presence of IIa (thombin). • Subendothelium – beneath the endothelium. Are thrombogenic in nature. Express von Willebrand Factor (vWF), collagen, and tissue factor to kick off the coagulation cascade. Endothelium Subendothelium Source: http://facstaff.gpc.edu/~jaliff/vein1.gif Beginning
- 7. Hemostasis: Big picture Coagulation Anticoagulation Fibrinolysis Antifibrinolysis Clot formation Clot breakdown Coagulation stimulation Beginning
- 8. Hemostasis: Clot formation Coagulation Anticoagulation Fibrinolysis Antifibrinolysis Clot formation Soon after injury. Anticoagulation and fibrinolysis has very small effect at the site of injury. In neighboring tissue it remains active and prevents inappropriate clot buildup. Clot breakdown Coagulation stimulation Beginning
- 9. Hemostasis: Clot maintenance Coagulation Anticoagulation Fibrinolysis Antifibrinolysis Clot formation Clot development slows. This is a dynamic process with new clot being layed down while fibrinolysis of old clot occurs. The rates between formation and breakdown of clot will vary based upon the distance from the injury (i.e. pro-coagulation and antifibrinolysis near the injury, anticoagulation and fibrinolysis on the periphery). Clot breakdown Coagulation stimulation Variable rates coagulation and fibrinolysis Beginning
- 10. Hemostasis: Clot breakdown Coagulation Anticoagulation Fibrinolysis Antifibrinolysis Clot formation As stimulus for coagulation declines, anticoagulation blocks the vast majority of new clot formation, the fibrinolytic pathway predominates and the existing clot is broken down. Clot breakdown Coagulation stimulation Beginning
- 11. Review time! • The next 6 slides are ridiculously detailed and cover the “what to know” about coagulation and hemostasis • We will come back to go through each of the steps in quiz mode • Note: There’s an overview of “where we are” in the top
- 12. INJURY! Platelet plug! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va GP IIb-IIIa and fibrinogen TF TF TF IIa (thrombin) receptor Adjacent normal endothelium Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Fibrin secondary hemostasis primary hemostasis Constitutive inhibition anticoagulation TXA2 synthesis Clot breakup Antifibrinolysis fibrinolysis Review
- 13. Extrinsic pathway Intrinsic pathway VIIa* Tissue Factor …and Ca2+ on a cell membrane X Xa Va …and Ca2+ on a cell membrane Xa IXa VIIIa …and Ca2+ on a cell membrane XXa IXaIX IIaII Common pathway Extrinsic X-ase components: Intrinsic X-ase components: Prothrombinase components: TF XIa XIISecondary hemostasis Measured by PT Measured by aPTT IIa (thrombin) * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Fibrin secondary hemostasis primary hemostasis Constitutive inhibition anticoagulation Clot breakup Antifibrinolysis fibrinolysis Review
- 14. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! Va, VIIIa (cofactors)V, VIII IIa VII, XI, XIII VIIa, XIa, XIIIa (zymogens) Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Fibrin secondary hemostasis primary hemostasis Constitutive inhibition Protein C & S Activated protein C & S tPA Urokinase anticoagulation Clot breakup Antifibrinolysis fibrinolysis Review
- 15. D and E domain interactions cause polymerization in half-staggered pattern Insoluble fibrin mesh stabilizing the platelet plug Fibrin clot XIIIa IIa (thrombin) Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Fibrin secondary hemostasis primary hemostasis Constitutive inhibition anticoagulation Clot breakup Antifibrinolysis fibrinolysis Review
- 16. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Fibrin secondary hemostasis primary hemostasis Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) Constitutive inhibition IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways VIIa Tissue Factor Extrinsic pathway Xa IXa Recently described inhibitor that shuts off the extrinsic X-ase upon binding with Xa. Explains the severity of intrinsic pathway defects as TFPI makes the intrinsic X-ase the only source of Xa! Intrinsic pathway Va Common pathway VIIIa VIIIa Va Xa IXa IIa Meanwhile in the plasma… Protein C & S Protein C Protein S APC* APS *Activated protein C IIa + thrombomodulin Destruction of VIIIa and Va when not in their intrinsic x-ase and prothrombinase complexes. Thrombomodulin is a constitutively expressed endothelial protein. anticoagulation anticoagulation Clot breakup Antifibrinolysis fibrinolysis Review
- 17. Fibrinolysis Clot breakup Antifibrinolysis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Fibrin secondary hemostasis primary hemostasis Constitutive inhibition Urokinase Plasminogen Plasmin IIa tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (fromplatelets) Plasminogen activator inhibitor (PAI-1 & 2) Streptokinase* (bacteria) *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. (Positive feedback) anticoagulation D & E monomers D-dimers & E-monomers Fibrin monomer Crosslinked fibrin Clot breakup Antifibrinolysis fibrinolysis Alpha-2 anti-plasmin Review
- 18. Quiz time! • The next 81 slides cover the last 6 slides except with the names blanked out! • Go through this as many times as you can – the first few will be pretty rough, but you’ll get it soon enough! • Try spending an hour or so just going through this section a bunch of times to start.
- 19. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of ##. Activated platelet Primary hemostasis Name me hit the “Page Down” key to continue Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 20. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •## and ## which adhere to platelets and initiate primary hemostasis. Platelet Primary hemostasis ## ## Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 21. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis ## ## ##Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •## which initiates secondary hemostasis ## Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 22. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet ?Will eventually bind to fibrogen Primary hemostasis ## ## Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis TF Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 23. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet ?Binds to TF Primary hemostasis ## ## Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis TF Unactivated GP IIb-IIIa Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 24. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet ?Binds to collagen Primary hemostasis ## ## Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis TF Unactivated GP IIb-IIIa GP Ib-IX Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 25. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis ## ## ?Binds to thrombinExposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis TF Unactivated GP IIb-IIIa GP Ib-IX GP VI Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 26. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis ## ## Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis TF Unactivated GP IIb-IIIa GP Ib-IX GP VI IIa (thrombin) receptor Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 27. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis GP Ib-IX Unactivated GP IIb-IIIa GP VI IIa (thrombin) receptor α- granule Dense granule TF Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 28. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis GP Ib-IX Unactivated GP IIb-IIIa GP VI IIa (thrombin) receptor α- granule Dense granule TF Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 29. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis GP Ib-IX Unactivated GP IIb-IIIa GP VI IIa (thrombin) receptor α- granule Dense granule TF Activated platelet GP Ib-IX & vWF Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 30. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis GP Ib-IX Unactivated GP IIb-IIIa GP VI IIa (thrombin) receptor α- granule Dense granule TF ?will bind to fibrinogen Activated platelet GP Ib-IX & vWF Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 31. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Platelet Primary hemostasis Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis GP Ib-IX Unactivated GP IIb-IIIa GP VI IIa (thrombin) receptor α- granule Dense granule TF Activated platelet Activated GP IIb-IIIa GP Ib-IX & vWF Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 32. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va TFIIa (thrombin) receptor TXA2 synthesis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 33. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va TF TF TF IIa (thrombin) receptor Adjacent normal endothelium TXA2 synthesis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 34. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va TF TF TF IIa (thrombin) receptor Adjacent normal endothelium TXA2 synthesis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 35. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va TF TF TF IIa (thrombin) receptor Adjacent normal endothelium TXA2 synthesis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 36. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va TF TF TF IIa (thrombin) receptor Adjacent normal endothelium TXA2 synthesis What’s missing? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 37. INJURY! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va TF TF TF IIa (thrombin) receptor Adjacent normal endothelium TXA2 synthesis GP IIb-IIIa and fibrinogen Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 38. INJURY! Platelet plug! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va GP IIb-IIIa and fibrinogen TF TF TF IIa (thrombin) receptor Adjacent normal endothelium TXA2 synthesis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 39. INJURY! Platelet plug! Endothelial damage: can be mechanical, chemical, or biological in nature Vascular constriction: as a result reflex neurogenic mechanisms and local endothelial secretion of endothelin. Exposure of the subepithelium: contains thrombogenic extracellular matrix consisting of •von Willebrand’s Factor (vWF) and fibrillar collagen which adhere to platelets and initiate primary hemostasis. •tissue factor which initiates secondary hemostasis Platelet Activated platelet Unactivated GP IIb-IIIa GP Ib-IX & vWF GP Ib-IX GP VI Activated GP IIb-IIIa Primary hemostasis α- granule Dense granule ADP Serotonin PAI Factor Va Fibrinogen vWF Va GP IIb-IIIa and fibrinogen TF TF TF IIa (thrombin) receptor Adjacent normal endothelium TXA2 synthesis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 40. Extrinsic pathway Intrinsic pathway ## Tissue Factor …and ## on a ## ## ## ## …and ## on a ## ## ## ## …and ## on a ## #### #### #### Common pathway Extrinsic X-ase components: TF Secondary hemostasis Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 41. Extrinsic pathway Intrinsic pathway ## ## ## …and ## on a ## ## ## ## …and ## on a ## #### #### #### Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 42. Extrinsic pathway Intrinsic pathway ## ## …and ## on a ## ## ## …and ## on a ## #### #### Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX Intrinsic X-ase components: Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 43. Extrinsic pathway Intrinsic pathway ## ## …and ## on a ## #### Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane #### Where else am I from? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 44. Extrinsic pathway Intrinsic pathway ## ## …and ## on a ## #### #### Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane XIa XIINote: Deficiencies in these factors do not cause disease. Don’t stress too much over them. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 45. Extrinsic pathway Intrinsic pathway ## ## …and ## on a ## #### Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane XXa Prothrombinase components: XIa XII Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 46. Extrinsic pathway Intrinsic pathway #### Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane XXa Xa Va …and Ca2+ on a cell membrane Where am I from? XIa XII Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 47. Extrinsic pathway Intrinsic pathway #### Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane XXa Xa Va …and Ca2+ on a cell membrane IIa and α & dense granules from platelets! IIa XIa XII Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 48. Extrinsic pathway Intrinsic pathway Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane XXa Xa Va …and Ca2+ on a cell membrane IIaII What does PT measure? XIa XII Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 49. Extrinsic pathway Intrinsic pathway Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane XXa Xa Va …and Ca2+ on a cell membrane IIaII What does aPTT measure? Measured by PT XIa XII Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 50. Measured by aPTT Measured by PT Extrinsic pathway Intrinsic pathway Common pathway Secondary hemostasis VIIa* Tissue Factor …and Ca2+ on a cell membrane * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa X Xa IXaIX IXa VIIIa …and Ca2+ on a cell membrane XXa Xa Va …and Ca2+ on a cell membrane IIaII XIa XII Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 51. Extrinsic pathway Intrinsic pathway VIIa* Tissue Factor …and Ca2+ on a cell membrane X Xa Va …and Ca2+ on a cell membrane Xa IXa VIIIa …and Ca2+ on a cell membrane XXa IXaIX IIaII Common pathway Secondary hemostasis Measured by PT Measured by aPTT IIa (thrombin) * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa XIa XII What do I activate above? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 52. Extrinsic pathway Intrinsic pathway VIIa* Tissue Factor …and Ca2+ on a cell membrane X Xa Va …and Ca2+ on a cell membrane Xa IXa VIIIa …and Ca2+ on a cell membrane XXa IXaIX IIaII Common pathway XIa XIISecondary hemostasis Measured by PT Measured by aPTT IIa (thrombin) * VIIa is present in low levels in the plasma but IIa (thrombin) increases levels dramatically through the conversion of VII VIIa Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 53. IIa (thrombin) ## ## Best known effect of thrombin Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 54. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains ## ## ## γ chain γ chain Fibrin’s subdomains Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 55. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain Where do I come from? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 56. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 57. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! ## ## Anticoagulant activated by IIa Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 58. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! Protein C & S Activated protein C & S Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 59. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! ## ## Protein C & S Activated protein C & S Fibinolytic enzymes released from endothelial cells Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 60. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! ##, ####, ## Protein C & S Activated protein C & S tPA Urokinase Cofactors activated Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 61. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! ##, ##, ## ##, ##, ## Protein C & S Activated protein C & S tPA Urokinase Va, VIIIa (cofactors)V, VIII Zymogens activated Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 62. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! Va, VIIIa (cofactors)V, VIII VII, XI, XIII VIIa, XIa, XIIIa (zymogens) Protein C & S Activated protein C & S tPA Urokinase More on me later Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 63. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! Va, VIIIa (cofactors)V, VIII VII, XI, XIII VIIa, XIa, XIIIa (zymogens) Protein C & S Activated protein C & S tPA Urokinase Effect on platelets Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 64. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! Va, VIIIa (cofactors)V, VIII IIa VII, XI, XIII VIIa, XIa, XIIIa (zymogens) Protein C & S Activated protein C & S tPA Urokinase Activation! Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 65. IIa (thrombin) Fibrinogen Fibrin monomer Aα chain Bβ chain Aα chain Bβ chain Cleavage of A and B peptides from Aα and Bβ chains D domain E domain D domain γ chain γ chain From alpha and dense granules! Va, VIIIa (cofactors)V, VIII IIa VII, XI, XIII VIIa, XIa, XIIIa (zymogens) Protein C & S Activated protein C & S tPA Urokinase Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 66. How do the fibrin sheets form? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 67. D and E domain interactions cause polymerization in half-staggered pattern To the platelet plug! Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 68. Fibrin clot Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 69. Fibrin clot Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 70. Fibrin clot XIIIa IIa (thrombin) Remember me?? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 71. Insoluble fibrin mesh stabilizing the platelet plug! Fibrin clot XIIIa IIa (thrombin) Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 72. Meanwhile in the plasma… ATIII (antithrombin III) anticoagulation Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Constitutive inhibition Quiz
- 73. VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways anticoagulation Who do I degrade? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Constitutive inhibition Quiz
- 74. VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway anticoagulation And… Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Constitutive inhibition Quiz
- 75. VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway anticoagulation Destruction of VIIa in the extrinsic X-ase itself! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Constitutive inhibition Quiz
- 76. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways anticoagulation Who do I complex with? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 77. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways anticoagulation Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 78. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways VIIa Tissue Factor Extrinsic pathway Xa IXa anticoagulation Then who do I inhibit? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 79. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways VIIa Tissue Factor Extrinsic pathway Xa IXa Recently described inhibitor that shuts off the extrinsic X-ase upon binding with its own product, Xa. This explains the severity of intrinsic pathway defects as TFPI makes the intrinsic X-ase the only source of Xa! anticoagulation Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 80. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways VIIa Tissue Factor Extrinsic pathway Xa IXa Recently described inhibitor that shuts off the extrinsic X-ase upon binding with Xa. Explains the severity of intrinsic pathway defects as TFPI makes the intrinsic X-ase the only source of Xa! Meanwhile in the plasma… Protein C & S Protein C Protein S APC* APS *Activated protein C anticoagulation ## Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 81. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways VIIa Tissue Factor Extrinsic pathway Xa IXa Recently described inhibitor that shuts off the extrinsic X-ase upon binding with Xa. Explains the severity of intrinsic pathway defects as TFPI makes the intrinsic X-ase the only source of Xa! Meanwhile in the plasma… Protein C & S Protein C Protein S APC* APS *Activated protein C anticoagulation IIa + ## Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 82. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways VIIa Tissue Factor Extrinsic pathway Xa IXa Recently described inhibitor that shuts off the extrinsic X-ase upon binding with Xa. Explains the severity of intrinsic pathway defects as TFPI makes the intrinsic X-ase the only source of Xa! Meanwhile in the plasma… Protein C & S Protein C Protein S APC* APS *Activated protein C anticoagulation IIa + thrombomodulin Who do I inhibit? Thrombomodulin is a constitutively expressed endothelial protein. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 83. Constitutive inhibition VIIa Tissue Factor Extrinsic pathway Xa IXa Intrinsic pathway Xa ATIII Destruction of VIIa in the extrinsic X-ase itself! Destruction of IXa, Xa, and IIa when not bound to their complexes. The intrinsic X-ase and prothrombinase complexes are left alone, just the products are destroyed! Heparin sulfate * glycosaminoglycan on endothelial cells greatly enhances ATIII activity. Meanwhile in the plasma… ATIII (antithrombin III) IIa Common pathway Meanwhile in the plasma… TFPI (tissue factor pathway inhibitor) TFPI+ Xa *heparin is used clinically, in vitro it extends the PTT which measures the intrinsic and common pathways VIIa Tissue Factor Extrinsic pathway Xa IXa Recently described inhibitor that shuts off the extrinsic X-ase upon binding with Xa. Explains the severity of intrinsic pathway defects as TFPI makes the intrinsic X-ase the only source of Xa! Intrinsic pathway Va Common pathway VIIIa VIIIa Va Xa IXa IIa Meanwhile in the plasma… Protein C & S Protein C Protein S APC* APS *Activated protein C IIa + thrombomodulin Destruction of VIIIa and Va when not in their intrinsic x-ase and prothrombinase complexes. Thrombomodulin is a constitutively expressed endothelial protein. anticoagulation Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 84. Fibrinolysis Clot breakup ## Plasminogen Plasmin IIa Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin secondary hemostasis primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 85. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 86. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase Does plasmin have negative or positive feedback? Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 87. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase Positive feedback! Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 88. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase ## Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 89. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 90. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) ## (bacteria) Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 91. Antifibrinolysis ## ## Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Big players in antifibrinolysis: Streptokinase* *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation ## ## Quiz
- 92. Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin Fibrinolysis Clot breakup Plasminogen Plasmin IIa Beginning Review Quiz Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Where am I from? Streptokinase* *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Quiz
- 93. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Streptokinase* *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin What do I inhibit? (fromplatelets) Quiz
- 94. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Streptokinase* *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin (fromplatelets) What do I inhibit? Quiz
- 95. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Streptokinase* *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin (fromplatelets) Plasmin wherever possible! Quiz
- 96. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Streptokinase* *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin (fromplatelets) Fibrin monomer Crosslinked fibrin Quiz
- 97. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Streptokinase* Fibrin monomer ## *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin (fromplatelets) Crosslinked fibrin Quiz
- 98. Fibrinolysis Clot breakup Plasminogen Plasmin IIa Urokinase tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) (bacteria) Streptokinase* Fibrin monomer D & E monomers Crosslinked fibrin ## *streptokinase works allosterically with plasmin to increase its rate of conversion of plasminogen to plasmin. It is not itself an enzyme. Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin (fromplatelets) Quiz
- 99. Fibrinolysis Clot breakup Urokinase Plasminogen Plasmin IIa tPA (tissue plasminogen activator, only highly effective in insoluble fibrin) Streptokinase* D & E monomers D-dimers & E-monomers Fibrin monomer Crosslinked fibrin (bacteria) Extrinsic pathway Intrinsic pathway Common pathway Thrombin Fibrin clotPlatelet Plug INJURY! Clot breakup Antifibrinolysis Fibrin primary hemostasis fibrinolysis Constitutive inhibition anticoagulation Antifibrinolysis Plasminogen activator inhibitor (PAI-1 & 2) Alpha-2 anti-plasmin (fromplatelets) Quiz
- 100. That’s it! • Go back to slide 19 to start the quiz again. • Go through this quiz as many times as you can!