Coagulation

Activation of the coagulation cascade results in the production of insoluble fibrin. This process involves many steps in which precursor coagulation factors are activated by activated factors. As such, the coagulation cascade is an amplification cascade, with each step resulting in a substantial activation of the next components. This means that a relatively small event can lead to large biological response. Many of the reactions involve serine protease activity cleaving the precursor factor, and the final product is stabilised fibrin, which enmeshes platelet aggregates.

The initiation phase (previously termed extrinsic pathway) involves the release of thromboplastin (tissue factor) from damaged tissues. Thromboplastin then complexes with activated factor VIIa in the plasma and this leads to the activation of factor X. Factor Xa then leads to the activation of prothrombin to thrombin, which hydrolyses fibrinogen to release fibrinopeptides A and B, which are polymerised to form fibrin. Thrombin also activates factor XIII to form XIIIa, which cross-links the fibrin.

Platelet adhesion and aggregation

In parallel with the coagulation cascade is the platelet reaction, in which platelets adhere to subendothelial surface on vessel damage and this is facilitated by binding to von Willebrand’s factor (vWF). Platelet adhesion then leads to the release reaction, in which platelets release adenosine diphosphate (ADP) and thromboxane (TXA₂) to promote platelet aggregation. ADP binds to receptors on platelets and this leads to the expression of glycoprotein IIb/IIIa in the platelet membranes and promotes cross-linking by binding vWF and fibrinogen. TXA₂ promotes aggregation by reducing intracellular levels of cAMP.

Thrombosis

Thrombosis is the unwanted formation of blood clots. On the venous side of the circulation thrombosis is largely associated with stasis of blood. For example, immobility may lead to the formation of deep vein thrombosis (DVTs) in the deep veins of the calf muscles in the legs. The thrombus may break off and enter the circulation where it can become lodged in the lungs. This is a life-threatening pulmonary embolism due to blockade of the pulmonary circulation.

Arterial thrombosis usually forms at atherosclerotic sites, in which the plaque may rupture, leading to platelet adhesion and aggregation. The resulting clot formation can lead to an arterial blockage. In the coronary circulation this leads to a myocardial infarction and in cerebral vessels formation of the blockage or an embolus results in a thromboembolic stroke.

Atrial fibrillation leads to impaired pumping of the blood from the left atrium and the stasis of blood predisposes towards thrombosis. Blood clots form and may then break off and enter the systemic circulation and become lodged in the cerebral circulation leading to a transient ischaemic attack (TIA).