Mechanism of Haemostasis (Coagulation)
Haemostasis is a complex and dynamic physiological process that aims to stop bleeding within the body. The discontinuation of bleeding depends on the interaction of endothelial cells, platelets and coagulation factors. Anticoagulation factors and the fibrinolytic system oppose coagulation and remove clots.
Platelet plug formation
The initial response of a vessel to injury is vasoconstriction, followed by the rapid formation of a platelet plug:
1 Injury to a blood vessel causes disruption of the endothelium and exposure of subendothelial collagen.
2 Von Willebrand factor (vWF) is released from endothelial cells and platelets and forms a bridge between platelets and the exposed collagen.
3 Platelet binding initiates the discharge of intracellular dense and α-granules.
4 Adenosine diphosphate (ADP) and serotonin secretion causes platelet activation and membrane modification to allow fibrinogen binding, resulting in platelet aggregation.
5 Adhesion of platelets sets converts arachidonic acid to thromboxane A2, causing further platelet aggregation and potent vasoconstriction.
6 Platelets contain actin and myosin, which contract in aggregated platelets, compressing and strengthening the platelet plug.
7 Undamaged adjacent endothelial cells convert arachidonic acid to prostaglandin I2 and release nitric oxide, preventing the spread of a platelet plug from the site of injury.
The coagulation cascade
Blood clotting occurs more slowly and reinforces the platelet plug. It is also initiated by disruption to vessel wall endothelium. There are two coagulation cascades in the body that lead to the creation of a fibrin clot, termed the intrinsic and extrinsic pathways (Figure).
The anti-clotting system
Endothelial cells produce tissue factor pathway inhibitor (TFPI), a plasma protein that acts in the initial stages of clot formation. TFPI binds to the tissue factor–factor VIIa complex, preventing factor X activation and limiting thrombin production via the extrinsic pathway.
Thrombin has a role in regulating the coagulation system by binding to thrombomodulin, an endothelial cell receptor. This complex prevents the conversion of fibrinogen to fibrin and activates protein C, a plasma protein. Together with protein S, protein C inactivates factors Va and VIIIa, controlling the extent of the coagulation cascade. Certain plasma proteins act as natural anticoagulants and regulate the activation of thrombin
from prothrombin. The most important is anti-thrombin III, which also limits the activity of factors IXa, Xa, XIa and XIIa. Anti-thrombin III is activated by heparin or heparin-like molecules on the surface of endothelial cells to prevent clots spreading.
The fibrinolytic system
A fibrin clot is a temporary solution until permanent repair of the blood vessel occurs. Fibrin clots are dissolved by plasmin, the active form of the plasma pro-enzyme plasminogen. There are multiple plasminogen activators; the most important is tissue plasminogen factor (tPA). As a clot forms, plasminogen and tPA adhere to fibrinogen and fibrin and are incorporated into the clot. The presence of fibrin increases the enzymatic ability of tPA, triggering the conversion of plasminogen to plasmin (Figure).