Haemostasis

The normal physiological response that prevents significant blood loss following vascular injury is called haemostasis.⁶ Familiarity with haemostasis lays the groundwork for a thorough understanding of the major disease states associated with thrombosis, such as venous thromboembolism (VTE), atherothrombosis (thrombosis triggered by plaque rupture), and cardioembolic stroke.

Excessive coagulation leads to the formation of a thrombus, potentially obstructing blood flow. This is a common problem, especially in hospitalised or immobilised patients. Venous thromboembolic disease, for example, is a major problem in the European Union, where it causes more than one million events or deaths every year.¹²

Excessive bleeding results when certain coagulation factors are lacking, as in patients with haemophilia.¹³

Coagulation involves a complex set of protease reactions involving roughly 30 different proteins.¹⁴ The final result of these reactions is to convert fibrinogen, a soluble protein, to insoluble strands of fibrin. Together with platelets, the fibrin strands form a stable blood clot.

For decades, the coagulation cascade was conceptualised as having two distinct points of initiation, labelled the extrinsic and intrinsic pathways.¹⁵ Over time, however, it has become clear that these pathways do not function in the body as parallel, independent systems.

The finding that the tissue factor-factor VIIa complex from the extrinsic pathway activates factors in both systems suggests that they are linked. This discovery, combined with an evolving understanding of the role of different cells, in particular blood platelets, has led to a cell-based model of coagulation. Unlike the older, intrinsic/extrinsic cascade model, the cell-based model includes the important interactions between cells directly involved in haemostasis (ie, tissue factor-bearing cells and platelets) and coagulation factors. This model more accurately represents the interaction between cellular activity and coagulation proteins that leads to blood clot formation.¹⁵

This model divides the initiation of coagulation into distinct parts: the extrinsic pathway and the intrinsic pathway.⁶ The extrinsic pathway is the primary initiator of coagulation, while the intrinsic pathway leads to the successive activation of Factors IX and X. Activated Factor X (Factor Xa) plays a central role in the coagulation cascade, as it occupies a point where the intrinsic and extrinsic pathways converge.

The cell-based model identifies the membranes of tissue factor–bearing cells and platelets as the sites where activation of specific coagulation factors occurs.¹⁵ This model posits a three-phase process — initiation, amplification, and thrombin action. Initiation occurs after vascular injury, when tissue factor–bearing cells bind to and activate Factor VII. This leads to production of a small amount of thrombin. Thrombin then activates platelets and cofactors during the amplification phase. The prothrombinase complex (comprising Factor Xa and cofactors bound to activated platelets) is responsible for the burst of thrombin production leading to the third phase of clot formation.

Factor Xa plays a central role in the coagulation process in both the older, extrinsic/intrinsic model as well as the more recently proposed cell-based model.

The coagulation cascade is triggered when injury to a blood vessel allows blood to come in contact with tissue factor (TF)–bearing cells. Factor Xa, with activated Factor V (Va) as a cofactor, propagates coagulation by converting prothrombin (Factor II) to thrombin (Factor IIa).¹⁵ Factor Xa is the primary site of amplification in the process: one molecule of Factor Xa catalyses the formation of approximately 1000 thrombin molecules.¹⁶ For this reason, development of medications that inhibit Factor Xa is an active and promising area of pharmaceutical research.¹⁷

In the final step of the series of protease reactions leading to clot formation, thrombin triggers conversion of the soluble protein fibrinogen to insoluble fibrin strands. Thrombin also activates Factor XIII, which stabilises the clot by cross-linking the fibrin. The resulting fibrin mesh traps and holds cellular components of the clot (platelets and/or red blood cells).⁶

Fibrinolysis, as the term implies, is the process that dissolves fibrin. It leads to clot dissolution. Plasminogen is the precursor of plasmin, which breaks up fibrin clots. During initial clot formation, plasminogen activators are inhibited. Over time, endothelial cells begin to secrete tissue plasminogen activators to start dissolving the clot as the structural integrity of the blood vessel wall is restored. Medications that convert plasminogen to plasmin are used to treat acute, life-threatening thrombotic disorders, such as myocardial infarction.⁶