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Coagulation
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This page is about the clotting of blood. For other meanings, please see coagulation (disambiguation).
The coagulation of blood is a complex process during which blood forms solid clots. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a fibrin clot to stop hemorrhage and aid repair of the damaged vessel. Disorders in coagulation can lead to increased hemorrhage and/or thrombosis and embolism.

Coagulation is similar in mammals, with all mammals using a combined cellular and serine protease mechanism. The system in humans is the most extensively researched and therefore the best known. This article focuses on human blood coagulation.

Contents [hide]
1 In brief
2 Primary haemostasis
3 Secondary haemostasis
3.1 The coagulation cascade
3.2 Cofactors
3.3 Inhibitors
4 Testing of coagulation
5 Disorders of hemostasis
6 Coagulation factors
7 History
8 References
9 External links
9.1 3D structures of protein complexes involved in blood coagulation



[edit] In brief
In a normal individual, coagulation is initiated within 20 seconds after an injury occurs to the blood vessel damaging the endothelial cells. Platelets immediately form a haemostatic plug at the site of injury. This is called primary haemostasis. Secondary haemostasis then follows—plasma components called coagulation factors respond (in a complex cascade) to form fibrin strands which strengthen the platelet plug. Contrary to popular belief, coagulation from a cut on the skin is not initiated by air or drying out, but by platelets adhering to and activated by collagen in the blood vessel endothelium. The activated platelets then release the contents of their granules, these contain a variety of substances that stimulate further platelet activation and enhance the haemostatic process.

The use of adsorbent chemicals, such as zeolites, and other haemostatic agents is also being explored for use in sealing severe injuries quickly.


[edit] Primary haemostasis
Primary haemostasis is initiated when platelets adhere, using a specific platelet collagen receptor glycoprotein Ia/IIa, to collagen fibers in the vascular endothelium. This adhesion is mediated by von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/V and collagen fibrils.

The platelets are then activated and release the contents of their granules into the plasma, in turn activating other platelets and white blood cells. The platelets undergo a change in their shape which exposes a phospholipid surface for those coagulation factors that require it. Fibrinogen links adjacent platelets by forming links via the glycoprotein IIb/IIIa. In addition, thrombin activates platelets.


[edit] Secondary haemostasis

[edit] The coagulation cascade

The coagulation cascade. Legend: HMWK = High molecular weight kininogen, PK = Prekallikrein, TFPI = Tissue factor pathway inhibitor. Black arrow = conversion/activation of factor. Red arrows = action of inhibitors. Blue arrows = reactions catalyzed by activated factor. Grey arrow = various functions of thrombin.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 can be summarised as follows: -

Tissue Factor pathway: the main role of the tissue factor pathway is to generate a "thrombin burst," thrombin being the single most important constituent of the coagulation cascade in terms of its feedback activation roles. FVIIa circulates in a higher amount than any other activated coagulation factor. Following damage to the blood vessel, endothelium Tissue Factor (TF) is released, forming a complex with FVIIa (TF-FVIIa), which activates FIX and FX. FVII itself is activated by thrombin, FXIa, plasmin, FXII and FXa. The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI). FXa and its co-factor FVa form the prothrombinase complex which activates prothrombin to thrombin. Thrombin then activates other components of the coagulation cascade, including FV and FVII (which activates FXI which in turn activates FIX), and activates and releases FVIII from being bound to vWF. 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: There is formation of the primary complex on collagen by high molecular weight kininogen (HMWK), prekallikrein and FXII (Hageman factor). 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 clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK and prekallikrein do not have a bleeding disorder.
Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a haemostatic 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.


[edit] 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. 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. Deficiency of vitamin K (e.g. in malabsorption), use of inhibiting anticoagulants (warfarin, acenocoumarol and phenprocoumon) or disease (cirrhosis, hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKA's (proteins formed in vitamin K absence) this causes partial or non gamma carboxylation and affects the coagulation factors ability to bind to expressed phospholipid.

[edit] Inhibitors
Three mechanisms keep the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis:

Protein C is an important co-factor inhibitor, which degrades the co-factors FVa and FVIIIa. It is activated by thrombin with thrombomodulin and requires its co-enzyme Protein S to function. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant of Factor V or high levels of FVIII also may lead to a thrombotic tendency.
Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases; thrombin and FXa, as well as FXIIa, and FIXa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan sulfate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to F Xa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia.
Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X after its original initiation.

[edit] Testing of coagulation
Numerous tests are used to assess the function of the coagulation system:

Common: aPTT, INR (PT), TCT, bleeding time, D-dimer
Other: mixing test (whether an abnormality corrects if the patient's plasma is mixed with normal plasma), antiphosholipid antibodies, coagulation factor assays, genetic tests (eg. factor V Leiden, prothrombin mutation G20210A), dilute Russell viper venom test (dRVVT), platelet function tests, thromboelastography (TEG) or thromboelastometry (ROTEG).
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. This is reported as an INR value when used for the dosing of oral anticoagulants such as warfarin.

The quantatative and qualitative screening of fibrinogen is measured by the thrombin 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.

Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests

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http://en.wikipedia.org/wiki/Coagulation