Coagulation and its cascade
Hemostasis is controlled by the formation of thrombin (factor IIa) the enzyme which converts fibrinogen into fibrin. Thrombin itself is formed from prothrombin (factor II) at the end of the coagulation cascade. The biochemical properties of the coagulation factors can be grouped as follows: Factors II, VII, IX, X, XI and XII are all pro-enzymes. The so called vitamin K dependent factors (factors II, VII, IX and X) contain 10-12 γ-carboxyglutamic acid residues (Gla’s) in the aminoterminal end of the protein, which defines their affinity for phospholipid membranes. Factors V and VIII are pro-cofactors which are activated by thrombin during the coagulation process. Factor XIII, which is also activated by thrombin, is a transglutaminase involved in stabilizing the fibrin clot.
The intrinsic route of coagulation begins with the activation of factor XII via its binding to surfaces like silica or collagen (contact activation).
The extrinsic coagulation pathway is initiated by the binding of factor VII to a complex of tissue factor (TF) and negatively charged phospholipids. Each coagulation factor is activated by limited proteolysis. These reactions occur at the surface of negatively charged phospholipids (activated platelets) in the presence of calcium ions. In vivo, coagulation is mostly initiated via the extrinsic pathway, by exposure of TF to the blood at the site of the vascular lesion or by stimulation of vascular cells by inflammatory compounds like endotoxins, cytokines and TNF.
Thrombin has several functions:
- It activates platelets (release reaction, formation of a procoagulant surface on which the coagulation reactions can take place)
- Activation of the pro-cofactors V and VIII
- Conversion of fibrinogen to insoluble fibrin
- Activation of factor XIII, thus cross-linking fibrin
- Activation of factor XI to XIa on the platelet surface