07/18 - RGD releases three new interactive diagram pages for the coagulation cascade and related protein C anticoagulant and vitamin K cycle pathways

The coagulation cascade is triggered in response to vascular injury in order to prevent bleeding. It is tightly regulated by several anticoagulant systems and is in an intimate relationship with the complement cascade of innate immunity. Of the various anticoagulant systems, the protein C anticoagulant pathway is a major one. Both the coagulation cascade and protein C pathway are dependent upon the proper metabolism of the vitamin K cycle. Many of the coagulation enzymes and principal components of the protein C system are posttranslationally modified in a vitamin K-dependent manner, a modification important for their function. Vitamin K cofactor, oxidized in the modification reaction, needs to be converted back to its reduced form.
Coagulation cascade pathway

Protein C anticoagulant pathway

Vitamin K cycle pathway

The coagulation cascade initiated via tissue factor – the extrinsic pathway, or via contact – the intrinsic pathway, converges into a common pathway leading to formation of insoluble fibrin clots. Sequential activation of zymogens (inert enzyme precursors) and cofactors through limited proteolysis yields the active serine proteases and their factors. Thrombin or factor 2 (F2), the last enzyme of the cascade, cleaves fibrinogen into fibrin peptides that can polymerize. F2 also activates the protein C anticoagulant pathway and, independent of coagulation, members of protease-activated receptors (PARs). Click here to explore this complex system.

The protein C anticoagulant pathway is an important regulatory system of the coagulation cascade. The pathway is dependent upon activation by thrombin, or factor 2 (F2), the last enzyme of the coagulation cascade. Binding of F2 to thrombomodulin receptor confers its anticoagulant properties. Activated protein C, in addition to targeting essential components of the coagulation cascade, also prompts cytoprotective effects, outside of coagulation, by activating protease-activated receptors (PARs). Click here to investigate this vital system.

The vitamin K cycle is part of vitamin K metabolism and essential for the supply of a reduced form that acts as a cofactor in the carboxylation reaction that modifies glutamate (Glu) residues to gamma-carboxyglutamate (Gla). The modification allows for the calcium-dependent binding of proteins known as ‘vitamin K-dependent proteins’ (VKD) to negatively charged phospholipids of membranes. This is important for coagulation factors and anticoagulants; their localization at/near sites of vascular injury is crucial for proper hemostatic function. Click here to find out more about this important metabolic pathway.