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
|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.