Coagulation
is a complex process by which blood forms clots. It is an important part of hemostasis (the cessation of blood loss from a damaged
vessel), wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of
the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis).
Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein
(coagulation factor) component. The system in humans has been the most extensively researched and, therefore, the best-understood.
Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium (lining of the vessel). Platelets
immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: Proteins
in the blood plasma, called coagulation factors or clotting factors, respond in a complex cascade to form fibrin strands, which
strengthen the platelet plug.
Platelet activation
Damage to blood vessel walls exposes subendothelium proteins, most notably collagen, present under the endothelium. Circulating
platelets bind collagen with surface collagen-specific glycoprotein Ia/IIa receptors. The adhesion is strengthened further by the large,
multimeric circulating proteins von Willebrand factor (vWF), which forms links between the platelets glycoprotein Ib/IX/V and the
collagen fibrils. This adhesion activates the platelets.
Activated platelets release the contents of stored granules into the blood plasma. The granules include ADP, serotonin, platelet-
activating factor (PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2), which, in turn, activate additional platelets. The granules'
contents activate a Gq-linked protein receptor cascade, resulting in increased calcium concentration in the platelets' cytosol. The
calcium activates protein kinase C, which, in turn, activates phospholipase A2 (PLA2). PLA2 then modifies the integrin membrane
glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen. The activated platelets change shape from spherical to stellate, and the
fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets.
Final common pathway
Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic
plug. In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates
Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers.
Following activation by the contact factor or tissue factor pathways, the coagulation cascade is maintained in a prothrombotic state by
the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways.
Cofactors
Various substances are required for the proper functioning of the coagulation cascade:
Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to
function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the
phospholipid surfaces expressed by platelets, as well as procoagulant microparticles or microvesicles shed from them.
Calcium is also required at other points in the coagulation cascade.
Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid
residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z. In adding the gamma-carboxyl group to
glutamate residues on the immature clotting factors Vitamin K is itself oxidized. Another enzyme, Vitamin K epoxide
reductase, (VKORC) reduces vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important
as a target for anticoagulant drugs warfarin and related coumarins such as acenocoumarol, phenprocoumon, and dicumarol.
These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors.
Other deficiencies of vitamin K (e.g., in malabsorption), or disease (hepatocellular carcinoma) impairs the function of the
enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence); this causes partial or non-gamma
carboxylation, and affects the coagulation factors' ability to bind to expressed phospholipid.
