Coagulation


Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel forming a blood clot. The process involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin. Coagulation results in hemostasis, the cessation of blood loss from a damaged vessel, allowing repair.
Coagulation begins almost instantly after an injury to the endothelium that lines a blood vessel. Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelial platelet tissue factor to coagulation factor VII, which ultimately leads to cross-linked fibrin formation. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: additional coagulation factors beyond factor VII respond in a cascade to form fibrin strands, which strengthen the platelet plug.
Coagulation is highly conserved throughout biology. In all mammals, coagulation involves both cellular components and proteinaceous components. The pathway in humans has been the most extensively researched and is the best understood. Disorders of coagulation can result in problems with hemorrhage, bruising, or thrombosis.

List of coagulation factors

There are 13 traditional clotting factors, as named below, and other substances necessary for coagulation:

Physiology

Physiology of blood coagulation is based on hemostasis, the normal bodily process that stops bleeding. Coagulation is a part of an integrated series of haemostatic reactions, involving plasma, platelet, and vascular components.
Hemostasis consists of four main stages:
  • Vasoconstriction : Here, this refers to contraction of smooth muscles in the tunica media layer of endothelium.
  • Activation of platelets and platelet plug formation:
  • * Platelet activation: Platelet activators, such as platelet activating factor and thromboxane A2, activate platelets in the bloodstream, leading to attachment of platelets' membrane receptors to extracellular matrix proteins on cell membranes of damaged endothelial cells and exposed collagen at the site of injury.
  • * Platelet plug formation: The adhered platelets aggregate and form a temporary plug to stop bleeding. This process is often called "primary hemostasis".
  • Coagulation cascade: It is a series of enzymatic reactions that lead to the formation of a stable blood clot. The endothelial cells release substances like tissue factor, which triggers the extrinsic pathway of the coagulation cascade. This is called as "secondary hemostasis".
  • Fibrin clot formation: Near the end of the extrinsic pathway, after thrombin completes conversion of fibrinogen into fibrin, factor XIIIa promotes fibrin cross-linking, and subsequent stabilization of fibrin, leading to the formation of a fibrin clot, which temporarily seals the wound to allow wound healing until its inner part is dissolved by fibrinolytic enzymes, while the clot's outer part is shed off.
After the fibrin clot is formed, clot retraction occurs and then clot resolution starts, and these two process are together called "tertiary hemostasis". Activated platelets contract their internal actin and myosin fibrils in their cytoskeleton, which leads to shrinkage of the clot volume. Plasminogen activators, such as tissue plasminogen activator, activate plasminogen into plasmin, which promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels.

Vasoconstriction

When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor substances, such as endothelin and thromboxane, to induce the constriction of the smooth muscles in the vessel wall. This helps reduce blood flow to the site of injury and limits bleeding.

Platelet activation and platelet plug formation

When the endothelium is damaged, the normally isolated underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific glycoprotein Ia/IIa surface receptors. This adhesion is strengthened further by von Willebrand factor, which is released from the endothelium and from platelets; vWF forms additional links between the platelets' glycoprotein Ib/IX/V and A1 domain. This localization of platelets to the extracellular matrix promotes collagen interaction with platelet glycoprotein VI. Binding of collagen to glycoprotein VI triggers a signaling cascade that results in activation of platelet integrins. Activated integrins mediate tight binding of platelets to the extracellular matrix. This process adheres platelets to the site of injury.
Activated platelets release the contents of stored granules into the blood plasma. The granules include ADP, serotonin, platelet-activating factor, vWF, platelet factor 4, and thromboxane A2, 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.

Coagulation cascade

The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation. These are the contact activation pathway, and the tissue factor pathway, which both lead to the same fundamental reactions that produce fibrin. It was previously thought that the two pathways of coagulation cascade were of equal importance, but it is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form.
The coagulation factors are generally enzymes called serine proteases, which act by cleaving downstream proteins. The exceptions are tissue factor, FIV, FV, FVIII, FXIII. Tissue factor, FV, and FVIII are glycoproteins; Factor IV is a calcium ion; and Factor XIII is a transglutaminase. The coagulation factors circulate as inactive zymogens.
The coagulation cascade is therefore classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.

Tissue factor pathway (extrinsic)

The main role of the tissue factor pathway is to generate a "thrombin burst", a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps:
  1. Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor expressed on tissue-factor-bearing cells, forming an activated complex.
  2. TF-FVIIa activates FIX and FX.
  3. FVII is itself activated by thrombin, FXIa, FXII, and FXa.
  4. The activation of FX by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor.
  5. FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.
  6. Thrombin then activates other components of the coagulation cascade, including FV and FVIII, and activates and releases FVIII from being bound to vWF.
  7. FVIIIa is the co-factor of FIXa, and together they form the "tenase" complex, which activates FX; and so the cycle continues.

    Contact activation pathway (intrinsic)

The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen, prekallikrein, and FXII. Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating blood clot formation can be illustrated by the fact that individuals with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation, and innate immunity. Interference with the pathway may confer protection against thrombosis without a significant bleeding risk.
Inhibition of factor XII and PK interferes with innate immunity in animal models. More promising is inhibition of factor XI, which in early clinical trials have shown the expected effect.

Final common pathway

The division of coagulation in two pathways is arbitrary, originating from laboratory tests in which clotting times were measured either after the clotting was initiated by glass, the intrinsic pathway; or clotting was initiated by thromboplastin, the extrinsic pathway.
Further, the final common pathway scheme implies that prothrombin is converted to thrombin only when acted upon by the intrinsic or extrinsic pathways, which is an oversimplification. In fact, thrombin is generated by activated platelets at the initiation of the platelet plug, which in turn promotes more platelet activation.
Thrombin functions not only to convert fibrinogen to fibrin, it also activates Factors VIII and V and their inhibitor protein C. By activating Factor XIII, covalent bonds are formed that crosslink the fibrin polymers that form from activated monomers. This stabilizes the fibrin network.
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.