What is the clotting cascade?

By William Aird

A series of enzyme activation events in plasma, culminating in the formation of an insoluble fibrin clot.

The clotting cascade consists of a series of enzymatic reactions in which a serine protease cleaves and activates an inactive protease (called a zymogen), and the newly formed protease then activates its downstream substrate. In some cases, the enzymatic reaction is accelerated by the presence of a cofactor. There are three pathways: intrinsic, extrinsic and common. The intrinsic pathway is activated in vitro by a negatively charged surface or substance, and is assayed by the activated partial thromboplastin time (aPTT). The extrinsic pathway is activated by tissue factor, expressed in the blood vessel wall and activated monocytes, and is responsible for triggering the clotting cascade in vivo (indicated by the fire starter). The extrinsic pathway is monitored by the prothrombin time (PT). Both the intrinsic and extrinsic pathway converge on the common pathway, with factor IIa (thrombin) ultimately converting fibrinogen into fibrin monomers, which are then crosslinked by factor XIIIa. The human eye and the automated machines that measure PT and aPTT cannot distinguish between crosslinked and uncrosslinked fibrin. Hence, factor XIII deficiency is not detectable using standard coagulation assays. In addition to activating factor X in the common pathway, factor VIIa also activated factor IX in the intrinsic pathway (crosstalk), explaining why the intrinsic pathway is important for in vivo hemostasis. in addition to cleaving fibrinogen, thrombin activates a number of proteases including factors XI, IX and VIII (feedback), as well as platelets (linking secondary to primary hemostasis).