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- Coagulation is the thickening or congealing of any liquid into solid clots. This article is about a specific medical usage of the term with reference to human blood's mechanisms for forming scabs over wounds.
The coagulation of human blood is a fairly complex process by which liquid blood becomes solid clots. It is an important part of hemostasis where a damaged blood vessel is ultimately covered by a fibrin clot to stop hemorrhage. Disorders in coagulation can lead to increased hemorrhage on the one side and thrombosis and embolism on the other.
In brief
Ordinarily coagulation is initiated within seconds after an injury occurs when platelets form a plug at the site of injury. This is called primary hemostasis. Following this, various plasma components, called clotting factors respond (in a complex cascade) to form fibrin strands which strengthen the platelet plug.
The use of adsorbent chemicals, such as zeolite, and other hemostatic agents is also being explored for use in sealing severe injuries quickly.
Primary hemostasis
Primary hemostasis is initiated when platelets adhere, using a specific platelet collagen receptor glycoprotein Ia/IIa, to collagen fibers in vascular endothelium. This adhesion is stabilized by von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/X and collagen fibrils.
The platelets are then activated to secrete the contents of their granules in to the plasma, which causes a change in their shape. Fibrinogen, which links adjacent platelets by forming links via the glycoprotein IIb/IIIa.
Secondary hemostasis
The coagulation cascade
The coagulation cascade. Legend: HWMK = 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 catalysed by activated factor. Grey arrow = various functions of thrombin.
The coagulation cascade of secondary hemostasis has two pathways, the intrinsic and the extrinsic one, which join in a common pathway that leads to fibrin formation. The pathways are a series of reactions, in which a stable form of a protein is activated to become an enzyme which then catalyzes the next reaction in the cascade. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form, ultimately resulting in cross-linked fibrin.
The coagulation reaction can be summarised into four reactions:
- Intrinsic pathway: Formation of the primary complex on collagen by high molecular weight kininogen (HMWK), prekallikrein and F XII (Hageman factor), the latter of which is activated. F XIIa converts F XI into F XIa. There may be other mechanisms by which F XI is activated. Factor IX is in turn activated by F XIa.
- Extrinsic pathway: Activation of F VII by Tissue Factor, which is released from cellular membranes during injury. Factor VIIa activates F IX and F X.
- Common pathway: Factor X is activated by F IXa and/or F VIIa. The process requires Factor VIIIa, which, like its activator thrombin, is always present in small amounts.
- Thrombin generation: Factor Xa activates thrombin, a process that requires Factor Va. Factor V, like VIII, is activated in a positive feedback loop by thrombin itself. Thrombin has a large array of functions. Its main action is the conversion of fibrinogen to fibrin, the building block of a thrombus. In addition, it activates Factors VIII and V and their inhibitor Protein C, and it activates Factor XIII, which crosslinks fibrin polymers which form from activated monomers. In addition, thrombin activates platelets.
Most coagulation factors are serine proteases, which act by cleaving other proteins. Factor XIII is a transglutaminase. Protein C and S, too, are serine proteases.
Cofactors and inhibitors
Various substances are required for the proper functioning of the coagulation cascade:
- Calcium and phospholipid (a cell membrane constituent) are cofactors to the activation of factors VII, IX, X and II.
- Vitamin K is an essential factor to a hepatic decarboxylase that adds a second carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S and Protein C. Deficiency of vitamin K (e.g. in malabsorption) or use of inhibiting anticoagulants (warfarin, acenocoumarol and phenprocoumon) impairs the function of these factors by inhibiting their contact with calcium and phospholipid.
Three mechanisms keep the coagulation cascade in check. Malfunctioning can lead to an increased propensity to thrombosis:
- Protein C is an important inhibitor, which degrades F Va and F VIIIa. Its activation by thrombin requires Protein S. Deficiency of either leads to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by Factor V, "Leiden" variant, leads to a milder thrombosis tendency.
- Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases thrombin and F Xa, as well as F XIIa, F XIa and F Xa. It is constantly active, but its adhesion to these factors is increased manifold by the presence of heparan sulfate (a glycosaminoglycan) or the medication class of heparins (different heparinoids increase affinity to F Xa, F IIa, or both). Deficiency (inborn or acquired, e.g. in proteinuria) of antithrombin leads to a severe thrombophilia.
- Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X after its original initiation.
Testing of coagulation
The intrinsic pathway is initiated by activation of contact factors of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test.
The extrinsic pathway is initiated by exposure of blood to "tissue factor" (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test, sometimes reported as an INR value.
The common pathway is reached by completion of either or both of the above pathways, and results in the elaboration of thrombin.
If a coagulation factor is part of the intrinsic or extrinsic 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 intrinsic pathway, results in an abnormally prolonged PT test but a normal PTT test.
Disorders of hemostasis
- disorders of the platelet and vessel wall
- disorders of coagulation and thrombosis
- disorders predisposing to thrombosis
Coagulation factors
| Coagulation factors and related substances
|
| Number and/or name | Function
|
| I/fibrinogen | gels to form clot (fibrin)
|
| II/prothrombin | activates I, V, VII, XIII, protein C, platelets
|
| III | -
|
| IV | -
|
| V/proaccelerin | supports X, activates II
|
| VI | -
|
| VII/stable factor) | activates IX, X
|
| VIII/antihemophilic factor) | supports IX, activates X
|
| IX/Christmas factor | activates X
|
| X/Stuart-Prower factor | activates II
|
| XI/plasma thromboplastin antecedent) | activates XII and prekallikrein
|
| XII/Hageman factor | activates XI, prekallikrein and fibrinolysis
|
| XIII/fibrin-stabilizing factor | crosslinks fibrin
|
| von Willebrand factor | binds 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; cofactor for heparin
|
| heparin cofactor II | inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")
|
| protein C | inactivates V and VIII
|
| protein S | cofactor for activated protein C (APC, binds C4b-binding protein)
|
| plasminogen | converts to plasmin, lyses fibrin and other proteins
|
| alpha 2-antiplasmin | inhibits plasmin
|
| prourokinase | activates plasminogen
|
| tissue plasminogen activator (tPA) | activates plasminogen
|
| plasminogen activator inhibitor I (PAI1) | inactivates tPA
|
| plasminogen activator inhibitor II (PAI2) | inactivates urokinase
|
Laboratory tests of coagulation
Common: APTT, INR (PT), TCT
Other: factor assays, mixing test, antiphosholipid antibodies, genetic tests,
dilute Russell viper venom test (dRVVT), bleeding time
de:Gerinnungsfaktor
nl:Stollingsfactor
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