Process of forming a blood clot to prevent blood loss from a ruptured vessel. A damaged blood vessel stimulates activation of clotting factors, eventually leading to the formation of long, sticky threads of fibrin. These make a mesh that traps platelets, blood cells, and plasma. This meshwork soon contracts into a resilient clot that can withstand the friction of blood flow. Under abnormal circumstances, clots can form in an intact vessel and may block it. Seealso anticoagulant.
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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 is 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.
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 changed shape from spherical to stellate and the fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets.
The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as the intrinsic pathway) and the tissue factor pathway (formerly known as the extrinsic pathway) that lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. 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 (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 serine proteases (enzymes). There are some exceptions. For example, FVIII and FV are glycoproteins and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific sites. The coagulation factors circulate as inactive zymogens.
The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.
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.
The contact factor pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test.
The tissue factor pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin.
The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot.
If a coagulation factor is part of the contact or tissue factor pathway, a deficiency of that factor will affect only one of the tests: thus hemophilia A, a deficiency of factor VIII, which is part of the contact factor pathway, results in an abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen and some variants of FX which can only be detected by either aPTT or PT. If an abnormal PT or aPTT is present additional testing will occur to determine which (if any) factor is present as aberrant concentrations.
Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.
Decreased platelet numbers may be due to various causes, including insufficient production (e.g. in myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP), and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced thrombocytopenia/HIT). Most consumptive conditions lead to platelet activation, and some are associated with thrombosis.
von Willebrand disease (which behaves more like a platelet disorder except in severe cases), is the most common hereditary bleeding disorder and is characterized as being inherited autosomal recessive or dominant. In this disease there is a defect in von Willebrand factor (vWF) which mediates the binding of glycoprotein Ib (GPIb) to collagen. This binding helps mediate the activation of platelets and formation of primary hemostasis.
Bernard-Soulier syndrome there is a defect or deficiency in GPIb. GPIb, the receptor for vWF, can be defective and lead to lack of primary clot formation (primary hemostasis) and increased bleeding tendency. This is an autosomal recessive inherited disorder.
Thrombasthenia of Glanzman and Naegeli (Glanzmann thrombasthenia) is extremely rare. It is characterized by a defect in GPIIb/IIIa fibrinogen receptor complex. When GPIIb/IIIa receptor is dysfunctional fibrinogen cannot cross-link platelets which inhibits primary hemostasis. This is an autosomal recessive inherited disorder. In liver failure (acute and chronic forms) there is insufficient production of coagulation factors by the liver; this may increase bleeding risk.
Deficiency of Vitamin K may also contribute to bleeding disorders because clotting factor maturation depends on Vitamin K.
Thrombosis is the pathological development of blood clots. These clots may break free and become mobile forming an embolus or grow to such a size that occludes the vessel in which it developed. An embolism is said to occur when the thrombus (blood clot) becomes a mobile embolus and migrates to another part of the body, interfering with blood circulation and hence impairing organ function downstream of the occlusion. This causes ischemia and often leasds to ischemic necrosis of tissue. Most cases of thrombosis are due to acquired extrinsic problems (surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing conditions known collectively as thrombophilia (e.g. antiphospholipid syndrome, factor V Leiden and various other rarer genetic disorders).
Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency towards thrombophlebitis. Other mutations have been linked with a rare form of hereditary angioedema (type III).
Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma are commonly-used coagulation factor products. Recombinant activated human factor VII is are increasingly popular in the treatment of major bleeding.
Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Before its withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products.
Anticoagulants and anti-platelet agents are amongst the most commonly used medicines. Anti-platelet agents include aspirin, clopidogrel, dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used during angioplasty.
Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. Warfarin affects the vitamin K dependent clotting factors (II, VII, IX,X) , while heparin and related compounds increase the action of antithrombin on thrombin and factor Xa. A newer class of drugs, the direct thrombin inhibitors, is under development; some members are already in clinical use (such as lepirudin). Also under development are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g. rivaroxaban).
|Number and/or name||Function|
|I (fibrinogen)||Forms clot (fibrin)|
|II (prothrombin)||Its active form (IIa) activates I, V, VIII, XI, XIII, protein C, platelets|
|Tissue factor||Co-factor of VIIa (formerly known as factor III)|
|Calcium||Required for coagulation factors to bind to phospholipid (formerly known as factor IV)|
|V (proaccelerin, labile factor)||Co-factor of X with which it forms the prothrombinase complex|
|VI||Unassigned – old name of Factor Va|
|VII (stable factor)||Activates IX, X|
|VIII (antihemophilic factor)||Co-factor of IX with which it forms the tenase complex|
|IX (Christmas factor)||Activates X: forms tenase complex with factor VIII|
|X (Stuart-Prower factor)||Activates II: forms prothrombinase complex with factor V|
|XI (plasma thromboplastin antecedent)||Activates IX|
|XII (Hageman factor)||Activates factor XI and prekallikrein|
|XIII (fibrin-stabilizing factor)||Crosslinks fibrin|
|von Willebrand factor||Binds to VIII, mediates platelet adhesion|
|prekallikrein||Activates XII and prekallikrein; cleaves HMWK|
|high molecular weight kininogen (HMWK)||Supports reciprocal activation of XII, XI, and prekallikrein|
|fibronectin||Mediates cell adhesion|
|antithrombin III||Inhibits IIa, Xa, and other proteases;|
|heparin cofactor II||Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")|
|protein C||Inactivates Va and VIIIa|
|protein S||Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein)|
|protein Z||Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPI|
|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|
|alpha 2-antiplasmin||Inhibits plasmin|
|tissue plasminogen activator (tPA)||Activates plasminogen|
|plasminogen activator inhibitor-1 (PAI1)||Inactivates tPA & urokinase (endothelial PAI)|
|plasminogen activator inhibitor-2 (PAI2)||Inactivates tPA & urokinase (placental PAI)|
|cancer procoagulant||Pathological factor X activator linked to thrombosis in cancer|
The theory that thrombin was generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905. At this stage, it was known that thrombokinase/thromboplastin (factor III) was released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), formed thrombin, which converted fibrinogen into fibrin (I).
A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin (initially and later called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated that its function was the generation of accelerin (Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use.
Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups.
Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A.
Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947-1993). His deficiency was described by Dr. Rosemary Biggs and Professor R.G. MacFarlane in Oxford, UK. The factor is hence called Christmas Factor or Christmas Eve Factor. Christmas lived in Canada, and campaigned for blood transfusion safety until succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin component, given by an independent group in California.
Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms. Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in a Mr. Rufus Stuart. Factors XI and XIII were identified in 1953 and 1961, respectively.
The view that the coagulation process was a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane in the UK and by Davie and Ratnoff in the USA, respectively.
Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further factors, and accelerin was found to be activated Factor V.