The coagulation cascade

• The coagulation cascade can be divided into three segments or pathways:

  ·       Intrinsic

  ·       Extrinsic

  ·       Common pathways
• 1.      Extrinsic pathway

  Initiation of the coagulation cascade is usually mediated by tissue factor via the extrinsic pathway. Tissue factor is expressed on the surface of many cells found outside blood vessels but not on the surface of circulating blood cells or the endothelium. When the endothelium is damaged, tissue factor comes into contact with blood and combines with circulating factor VII to form a complex that leads to the activation of factor X, triggering the common pathway.
• The common pathway begins with activation of factor X via either the extrinsic pathway or the intrinsic pathway. Leads to the formation of thrombin and fibrin. Factor Xa combines with factor V, platelet membrane phospholipids and Ca2+ ions to convert prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin strands which form an important structural component of a thrombus. Thrombin also activates many parts of the coagulation cascade via a positive feedback loop through the intrinsic pathway leading to the formation of large amounts of additional thrombin (a ‘thrombin burst’).
• The intrinsic pathway can be activated by surface contact, when damage to the vascular endothelium leads to exposure of clotting factors to negatively charged subendothelial surfaces, mediated by the molecule Kallikrein. Within blood vessels, thrombin generated from previous activation of the extrinsic pathway also activates the intrinsic pathway. The series of reactions in the intrinsic pathway leads to initiation of the common pathway and therefore amplification of thrombin production through the creation of a positive feedback loop.
• Thrombin:

  ·       Fibrin generation

  ·       Intrinsic pathway activation: positive feedback loop by initiating the intrinsic pathway

  ·       Factor XIII activation: thrombin converts factor XIII into factor XIIIa (fibrin stabilising factor) which then cross-links fibrin to generate a ‘fibrin mesh’ which encapsulates activated platelets creating a thrombus and stopping bleeding

  ·       Platelet activation: thrombin receptors on platelets cause activation and aggregation, further enhancing the haemostatic effects of the coagulation cascade
• Key points:

  ·       Two pathways (the extrinsic and intrinsic) both result in the activation of factor X, which leads to the conversion of prothrombin into thrombin

  ·       Thrombin converts fibrinogen into fibrin and triggers the activation of factor XIII to cross-link the fibrin strands and stabilise the clot

  ·       A stable clot is formed by activated platelets, fibrin and factor XIIIa
• The coagulation cascade:

  A) Factor X

  B) Factor X

  C) Factor Xa

  D) Prothrombin

  E) Thrombin

  F) Fibrinogen

  G) Fibrin

  H) Stable fibrin clot

  I) Factor XIII

  J) Extrinsic

  K) Intrinsic

  L) Common

  
• APTT measures rate of intrinsic pathway, PTT measures rate of extrinsic pathway.

  A) aPTT

  B) PT