Hematology: Coagulation Cascade

Coagulation Cascade

Initial Injury

  • Induces:
    • Vasoconstriction
    • Platelet Adhesion
    • Thrombin Release
  • Initiates the Intrinsic & Extrinsic Pathways

Intrinsic Pathway

  • Initiated By: Exposed Collagen, Pre-Kallikrein, HMW Kininogen
  • Pathway:
    • Activated Factor XII Activates Factor XI
    • Activated Factor XI Activates Factor IX
    • Activated Factor IX & VIII Activates Factor X
  • Associated Factors: Factor 8, 9, 10, 11 & 12

Extrinsic Pathway

  • Initiated By: Tissue Factor (Injured Cells)
  • Pathway:
    • Activated Factor VII Activates Factor X
  • Associated Factors: Factor 7 & 10

Common Pathway

  • Initiated By: Intrinsic or Extrinsic Pathways
  • Pathway:
    • Prothrombin Complex: Activated Factor X, Factor V, Platelet Factor 3 & Prothrombin
      • Converts Prothrombin (Factor II) to Thrombin
    • Thrombin Converts Fibrinogen (Factor I) to Fibrin
  • Thrombin (Factor IIa)
    • Converts Fibrinogen to Fibrin
    • Also Activates Factors V, VIII & XIII
    • Activates Platelets
  • Fibrin (Factor Ia)
    • Links Platelets to Form a Platelet Plug
    • Binds GpIIb/IIIa
  • Fibrin Stabilizing Factor (Factor XIII)
    • Activated by Thrombin
    • Crosslinks Fibrin to Improve Clot Stability

Mediators of Coagulation

Factor Synthesis

  • Factor VIII:
    • Produced in the Endothelium with vWF
  • All Other Factors:
    • Produced in the Liver
    • Vitamin K Dependent Factors: Factor II, VII, IX, X, Protein C & S Mn
      • Through Gamma Carboxylation of Glutamate Residues
    • Half-Life of Vitamin K-Dependent Factors:
      • Factor II: 60-72 Hours
      • Factor VII: 4-6 Hours (Shortest)
      • Factor IX: 21-30 Hours
      • Factor X: 48-72 Hours
      • Protein C: 6-8 Hours (Second Shortest)
      • Protein S: 30-60 Hours

Mediators of Platelet Aggregation

  • Von Willebrand Factor (vWF)
    • Produced by Endothelium
    • Binds to Exposed Collagen at Sites of Vascular Injury for Platelet Adhesion
    • Promotes Platelet Aggregation Through GPIb (Most Efficient When Under Shear Stress)
  • Thromboxane A2 (TXA2)
    • Produced by Activated Platelets
    • Increased Platelet Aggregation
      • Triggers Calcium Release in Platelets (Exposes GpIIb/IIIa Receptor for Fibrin)
    • Induces Vasoconstriction
  • Prostacyclin (PGI2/Prostaglandin I2)
    • Produced by Endothelium
    • Inhibits Platelet Aggregation
      • Increases cAMP in Platelets
    • Induces Vasodilation

Mediators of Anticoagulation

  • Inhibitory Enzymes:
    • Antithrombin III (AT-III)
      • Inhibits Thrombin (IIa) & Factor Xa
      • Activated by Heparin
    • Activated Protein C (APC)
      • Degrades Factors Va & VIIIa
    • Protein S
      • Cofactor for Protein C
  • Fibrinolysis:
    • Tissue Plasminogen Activator (tPA)
      • Released from Endothelium
      • Converts Plasminogen to Plasmin
      • Inhibited by Plasminogen Activator Inhibitor (PAI-1 & PAI-2)
    • Plasmin
      • Function:
        • The Normal Active Clotting Inhibitor (The Most Important Clotting Inhibitor in Plasma)
        • Degrades Fibrin (Platelet Plug) into Fibrin Degradation Products
        • Also Degrades Factors V, VIII & Fibrinogen
      • Plasminogen is Converted to Active Plasmin by tPA, Streptokinase & Urokinase
      • Inhibited by α-2 Antiplasmin
        • Released from Endothelium
        • Decreased Production in Liver Cirrhosis

Mnemonics

Vitamin K-Dependent Factors

  • “2 plus 7 is 9, Knot 10”