Coagulation cascade

• The coagulation cascade:

  • Series of reactions catalysed by protein enzymes - coagulation factors
  • When activated, these factors trigger the conversion of other factors in the coagulation cascade
  • Results in secondary haemostasis
• Secondary haemostasis:

  • Stabilisation of activated platelets
  • Due to actions of strands of fibrin
  • Fibrin generate a stable mesh - main component in a thrombus
• Primary haemostasis = the activation and adherence of platelets to the damaged endothelium
• Fibrin:

  • Converted from its precursor fibrinogen by thrombin
  • End product of the chain of reactions that make up the coagulation cascade
• Coagulation cascade pathways:

  • Intrinsic
  • Extrinsic
  • Common pathway
• The extrinsic pathway:

  • Initiation of the coagulation cascade by tissue factor
  • Damage to the endothelium
  • Tissue factor comes into contact with blood
  • Tissue factor combines with circulating factor VII
  • Forms a complex that leads to the activation of factor X
  • Triggers the common pathway
  • Also triggers the intrinsic pathway
• Intrinsic pathway:

  • Activated by surface contact - mediated by Kallikrein
  • Also activated by the extrinsic pathway
  • Surface contact activates factor XII
  • Factor XIIa activates factor XI
  • Factor XIa activates factor IX
  • Factor IXa combines with factor VIIIa, platelet membrane phospholipid and calcium ions the activate factor X
  • Factor Xa activates the common pathway to generate more thrombin
• The common pathway:

  • Begins with activation of factor X via either the extrinsic or the intrinsic pathway
  • Factor Xa combines with factor V, platelet membrane phospholipids and calcium ions
  • Prothrombin (factor II) is converted to thrombin (factor IIa)
  • Thrombin then converts fibrinogen (factor I) into fibrin (factor Ia)
  • Thrombin activates many parts of the coagulation cascade via a positive feedback loop through the intrinsic pathway - large amounts of additional thrombin
• Actions of thrombin:

  • Converts fibrinogen into fibrin
  • Intrinsic pathway activation
  • Convers factor XIII into factor XIIIa (fibrin stabilising factor) which cross-links fibrin to generate a fibrin mesh
  • Platelet activation and aggregation
  • Regulation of clot formation
• Regulation:

  • Protein C - leads to protein S activation which then breaks down factors Va and VIIIa
  • Antithrombin - natural anticoagulation that is produced by the liver and destroys factors XIa, Xa and thrombin
• Heparin and fondaparinux enhance the natural effects of antithrombin in inhibiting thrombin and factor Xa.
• Vitamin K dependent clotting factors:

  • II (prothrombin)
  • VII
  • IX
  • X
  • Protein C and S