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.

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“…The extrinsic pathway is so named due to the requirement of an exogenous agent, the TF, which is exposed upon breakage of the endothelial barrier. 12 In an alternate mechanism, coagulation may also be carried out via the intrinsic pathway. This pathway is named so since all the components required for this pathway are present in the blood.…”

“…and X to IXa and Xa in the presence of Ca 2C ions. 11,12 Subsequently, the prothrombinase complex is formed that is responsible for activating prothrombin to thrombin. This complex, assembled on the negatively charged phospholipid membrane in the presence of Ca 2C ions, is composed of factor Xa and its co-factor Va.…”

“…In this pathway, factor XII (Hageman factor) gets activated and forms factor XIIa by contact activation via negatively charged surfaces like glass, collagen, kaolin or even membranes of some microorganisms. 12,13 Factor XIIa can further activate plasma prekallikrein to plasma kallikrein which in turn catalyzes the activation of factor XII in a positive feedback loop. 12 Active factor XIIa, along with high molecular weight kininogen as a co-factor, subsequently activates factor XI to factor XIa.…”

“…12,13 Factor XIIa can further activate plasma prekallikrein to plasma kallikrein which in turn catalyzes the activation of factor XII in a positive feedback loop. 12 Active factor XIIa, along with high molecular weight kininogen as a co-factor, subsequently activates factor XI to factor XIa. In the presence of Ca 2C ions, factor XIa converts factor IX to factor IXa.…”

“…11 This causes the release of tissue factor (TF, thromboplastin), a membrane protein that is constitutively expressed by cells surrounding the vascular bed. 12 It is a receptor for both zymogen and activated forms of factor VII i.e., factor VIIa. A fraction of factor VII circulates in the blood in the active form.…”