Blood Coagulation and Regulation Pathway Suite

In response to vascular injury, the hemostatic system triggers platelet aggregation and initiation of the coagulation cascade, primary and secondary hemostasis, respectively, to prevent bleeding. An intimate relationship exists between blood coagulation and the complement system of innate immunity, cross-talking occurring at various points. The coagulation cascade leads to the formation of insoluble fibrin clots. The fibrinolytic cascade follows coagulation to lyse fibrin and protect against blood clotting. Major components of fibrinolysis are targets of several inhibitory systems. Coagulation is also tightly regulated, with several anticoagulant systems acting upon it. One important system is represented by the protein C anticoagulant pathway. Major coagulation and several anticoagulation components are vitamin K-dependent (VKD) proteins. The posttranslational carboxylation of glutamate residues, a vitamin K-dependent reaction, is important for the function of VKD proteins. The vitamin, oxidized in the reaction, is recycled back to its reduced form in the vitamin K cycle metabolic pathway. Drugs that antagonize the cycle, such as the widely-used warfarin, act as anticoagulants. Newer drugs directly target important coagulation factors. There are both advantages and disadvantages in the use of these drugs. Highlighted in purple are the pathways that currently have interactive diagram pages.
Coagulation cascade pathway

Protein C anticoagulation pathway

 
Fibrinolysis 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 fibrinolytic pathway is activated by fibrin clots. Coagulation, anticoagulant systems and fibrinolysis pathways coordinate to maintain proper hemostasis. The main component of fibrinolysis is plasmin – the active form of plasminogen (PLG). Plasmin processing of fibrin leads to dissolution of clots. Several inhibitory systems are in place to tightly regulate fibrinolysis. Click here to explore this important regulatory system.
Vitamin K cycle pathway

 
Warfarin drug pathway

 
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. Warfarin, which has the trade name Coumadin, is a widely-used drug for the prevention of thrombosis and venous and arterial thromboembolism. Several effects due to dosage, diet or variants as well side effects are reported. Click here to see the overall aspects of the warfarin pathway.