How it all starts: Initiation of the clotting cascade

Abstract

The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and procofactors) in the next step of the cascade via limited proteolysis. The ultimate outcome is the polymerization of fibrin and the activation of platelets, leading to a blood clot. This process is protective, as it prevents excessive blood loss following injury (normal hemostasis). Unfortunately, the blood clotting system can also lead to unwanted blood clots inside blood vessels (pathologic thrombosis), which is a leading cause of disability and death in the developed world. There are two main mechanisms for triggering the blood clotting, termed the tissue factor pathway and the contact pathway. Only one of these pathways (the tissue factor pathway) functions in normal hemostasis. Both pathways, however, are thought to contribute to thrombosis. An emerging concept is that the contact pathway functions in host pathogen defenses. This review focuses on how the initiation phase of the blood clotting cascade is regulated in both pathways, with a discussion of the contributions of these pathways to hemostasis versus thrombosis.

Keywords: Blood coagulation; contact pathway; factor VII; factor XII; polyphosphate; tissue factor.

Figure 1

Overview of the blood clotting cascade. The plasma clotting system is initiated in two distinct mechanisms: the Tissue Factor (TF) Pathway and the Contact Pathway. The TF pathway is triggered when the cell-surface complex of TF and fVIIa (TF:VIIa) activates fIX and/or fX by limited proteolysis. The contact pathway is triggered when fXII, PK and HK assemble on a suitable surface or polymer. This results in the reciprocal activation of fXII to fXIIa by kallikrein, and PK to kallikrein by fXIIa. The resulting generation of fXIIa activates fXI to fXIa, which then converts fIX to fIXa. Both pathways converge at the production of fXa. This final common pathway results in the generation of a burst of thrombin, which converts fibrinogen to fibrin and activates platelets (among many other actions of thrombin that, for simplicity, are not shown here).