Coagulation cascade

The cascade is a multi-component enzyme system of circulating inactive proenzymes, cofactors and inhibitors, forming a sequential self-amplification process. This involves serial activation of zymogens by serine proteases, with cleavage of a vulnerable arginine site. This releases a small peptide, alters the three-dimensional configuration of the protein and exposes an active serine for the subsequent reactions. This leads to: A sequence of reactions resulting in generation of a prothrombin activator, via activated factor X (the formation of which represents the convergence of the intrinsic and extrinsic pathways). Cleavage of prothrombin by the prothrombin activator to form thrombin. This is associated with a positive feedback loop, whereby thrombin activates substrate pro-coagulant proteins. The reaction of thrombin with fibrinogen and factor XIII leads to deposition of cross-linked polymers of fibrin.

The extrinsic pathway is initiated by tissue factor (factor III) and the intrinsic pathway by collagen exposure. Tissue factor is a transmembrane glycoprotein with a large extracellular domain (responsible for haemostatic activity), a transmembrane segment, and a cytoplasmic tail. The distinction between extrinsic and intrinsic pathways is somewhat artificial, but is useful for a conceptual understanding of the coagulation process. It is more than likely that a network model of coagulation can be invoked, which involves a linkage between the two pathways, regulated by a series of positive and negative feedback loops.

FLOW CHART

Tissue trauma

Tissue factor

Vll-VIIa X-Xa

\ Ca2+ prothrombin activator

platelet phospholipids t prothrombin-thrombin Figure 8.3 Extrinsic pathway (contact-activation pathway).

FLOW CHART

Blood trauma or contact with collagen

XII - Xlla

XI -XIa

IX- IXa

Prothrombin activator

Prothrombin-thrombin Figure 8.4 Intrinsic pathway.

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