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 (listed below) 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 (platelets) and proteinaceous components (coagulation or clotting factors). 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:
+ Coagulation factors and related substances Number/Name Synonym(s) Function Associated genetic disorders Type of molecule Source Pathway(s) Factor I Fibrinogen Forms fibrin threads in blood clots Plasma protein Liver Common pathway; converted into fibrin Factor II* Prothrombin Its active form (IIa) activates platelets, factors I, V, VII, VIII, XI, XIII, protein C Plasma protein Liver Common pathway; converted into thrombin Factor III Co-factor of factor VIIa, which was formerly known as factor III Lipoprotein mixture Damaged cells and platelets Extrinsic Factor IV Required for coagulation factors to bind to phospholipids, which were formerly known as factor IV Inorganic ions in plasma Diet, platelets, bone matrix Entire process of coagulation Factor V Co-factor of factor X with which it forms the prothrombinase complex Activated protein C resistance Plasma protein Liver, platelets Extrinsic and intrinsic Factor VI N/A N/A N/A Factor VII* Activates factors IX, X; increases rate of catalytic conversion of prothrombin into thrombin Congenital factor VII deficiency Plasma protein Liver Extrinsic Factor VIII Co-factor of factor IX with which it forms the tenase complex Hemophilia A Plasma protein factor Platelets and endothelial cells Intrinsic Factor IX* Activates factor X, forms tenase complex with factor VIII Hemophilia B Plasma protein Liver Intrinsic Factor X* Activates factor II, forms prothrombinase complex with factor V Congenital factor X deficiency Protein Liver Extrinsic and intrinsic Factor XI Activates factor IX Hemophilia C Plasma protein Liver Intrinsic Factor XII Hageman factor Activates XI, VII, prekallikrein and plasminogen Plasma protein Liver Intrinsic; initiates clotting in vitro; also activates plasmin Factor XIII Fibrin-stabilizing factor Crosslinks fibrin threads Congenital factor XIIIa/b deficiency Plasma protein Liver, platelets Common pathway; stabilizes fibrin; slows down fibrinolysis Vitamin K Clotting vitamin Essential factor to the 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 Vitamin K deficiency Phytyl-substituted naphthoquinone derivative Gut microbiota(e.g. E. coli),dietary sources Extrinsic von Willebrand factor Binds to VIII, mediates platelet adhesion von Willebrand disease Blood glycoprotein Blood vessels' endothelia, bone marrow Prekallikrein Fletcher factor Activates XII and prekallikrein; cleaves HMWK Prekallikrein/Fletcher factor deficiency Kallikrein Activates plasminogen High-molecular-weight kininogen Supports reciprocal activation of factors XII, XI, and prekallikrein Kininogen deficiency Fibronectin Mediates cell adhesion Glomerulopathy with fibronectin deposits Antithrombin III Inhibits factors IIa, Xa, IXa, XIa, and XIIa Antithrombin III deficiency Heparin cofactor II Inhibits factor IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin") Heparin cofactor II deficiency Protein C Inactivates factors Va and VIIIa Protein C deficiency Protein S Cofactor for activated protein C (APC), inactive when bound to C4b-binding protein Protein S deficiency Protein Z Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPI Protein Z deficiency Protein Z-related protease inhibitor ZPI Degrades factors X (in presence of protein Z) and XI (independently Plasminogen Converts to plasmin, lyses fibrin and other proteins Plasminogen deficiency type I (ligneous conjunctivitis) α2-Antiplasmin Inhibits plasmin Antiplasmin deficiency α2-Macroglobulin Inhibits plasmin, kallikrein, and thrombin Tissue plasminogen activator t-PA or TPA Activates plasminogen Urokinase Activates plasminogen Quebec platelet disorder Plasminogen activator inhibitor-1 PAI-1 Inactivates tPA and urokinase (endothelial PAI Plasminogen activator inhibitor-1 deficiency Plasminogen activator inhibitor-2 PAI-2 Inactivates tPA and urokinase Plasminogen activator inhibitor-1 deficiency Cancer procoagulant Pathological activator of factor X; linked to thrombosis in various cancers * Vitamin K is required for biosynthesis of these clotting factors
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 (vasospasm or vascular spasm): Here, this refers to contraction of smooth muscles in the tunica media layer of endothelium (blood vessel wall). 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 (e.g. glycoprotein IIb/IIIa) to extracellular matrix proteins (e.g. von Willebrand factor) 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 (plasma transglutaminase; activated form of fibrin-stabilizing factor) promotes fibrin cross-linking, and subsequent stabilization of fibrin, leading to the formation of a fibrin clot (final blood 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 (t-PA), 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 (vWF), 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 (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, forming a platelet plug and thereby completing primary hemostasis).
Coagulation cascade
The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation. These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic 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 (extrinsic) pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) 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 (TF) 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: