Coagulation
Coagulation | |
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Health | Beneficial |
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.
Coagulation begins almost instantly after an injury to the
Disorders of coagulation are disease states which can result in problems with hemorrhage, bruising, or thrombosis.[2]
Coagulation is highly conserved throughout biology. In all mammals, coagulation involves both cellular components (platelets) and proteinaceous components (here, coagulation factors).[3] The pathway in humans has been the most extensively researched and is the best understood.[4]
List of coagulation factors
There are 12 traditional clotting factors, as named below,[5] and other substances necessary for coagulation:
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 | Hereditary angioedema type III | 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 carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z[7] |
Vitamin K deficiency | Phytyl-substituted naphthoquinone derivative | Gut microbiota (e.g. E. coli[8]), dietary sources |
Extrinsic[9] |
von Willebrand factor | Binds to VIII, mediates platelet adhesion | von Willebrand disease | Blood glycoprotein | Blood vessels' endothelia, bone marrow[10] |
||
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[11] | |||||
* Vitamin K is required for biosynthesis of these clotting factors[7] |
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.[12]
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 activating factor and thromboxane A2,[13] activate platelets in the bloodstream, leading to attachment of platelets' membrane receptors (e.g. glycoprotein IIb/IIIa[14]) to extracellular matrix[15] proteins (e.g. von Willebrand factor[16]) on cell membranes of damaged endothelial cells and exposed collagen at the site of injury.[17]
- Platelet plug formation: The adhered platelets aggregate and form a temporary plug to stop bleeding. This process is often called "primary hemostasis".[18]
- Platelet activation:
- 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".[19]
- factor XIIIa (plasma transglutaminase;[20] 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,
Vasoconstriction
When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor substances, such as endothelin[22] and thromboxane,[23] 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
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).[25]
Coagulation cascade
The coagulation cascade of secondary hemostasis has two initial pathways which lead to
The coagulation factors are generally
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:[26]
- Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
- TF-FVIIa activates FIX and FX.
- FVII is itself activated by thrombin, FXIa, FXII, and FXa.
- The activation of FX (to form FXa) by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).
- FXa and its co-factor FVa form the prothrombinto thrombin.
- Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which forms a complex with 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. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)
Contact activation pathway (intrinsic)
The
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 (a mix of tissue factor and phospholipids), the extrinsic pathway.[citation needed]
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.[citation needed]
Thrombin functions not only to convert fibrinogen to fibrin, it also activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin). By activating Factor XIII, covalent bonds are formed that crosslink the fibrin polymers that form from activated monomers.[26] This stabilizes the fibrin network.[citation needed]
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.[26]
Cell-based scheme of coagulation
A newer model of coagulation mechanism explains the intricate combination of cellular and biochemical events that occur during the coagulation process in vivo. Along with the procoagulant and anticoagulant plasma proteins, normal physiologic coagulation requires the presence of two cell types for formation of coagulation complexes: cells that express tissue factor (usually extravascular) and platelets.[citation needed]
The coagulation process occurs in two phases. First is the initiation phase, which occurs in tissue-factor-expressing cells. This is followed by the propagation phase, which occurs on activated platelets. The initiation phase, mediated by the tissue factor exposure, proceeds via the classic extrinsic pathway and contributes to about 5% of thrombin production. The amplified production of thrombin occurs via the classic intrinsic pathway in the propagation phase; about 95% of thrombin generated will be during this second phase.[30]
Fibrin clot formation
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Fibrinolysis
Eventually, blood clots are reorganized and resorbed by a process termed
Role in immune system
The coagulation system overlaps with the
Cofactors
Various substances are required for the proper functioning of the coagulation cascade:
Calcium and phospholipids
Vitamin K
Regulators
Five mechanisms keep platelet activation and the coagulation cascade in check.[citation needed] Abnormalities can lead to an increased tendency toward thrombosis:
Protein C
Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC). Protein C is activated in a sequence that starts with Protein C and thrombin binding to a cell surface protein thrombomodulin. Thrombomodulin binds these proteins in such a way that it activates Protein C. The activated form, along with protein S and a phospholipid as cofactors, degrades FVa and FVIIIa. Quantitative or qualitative deficiency of either (protein C or protein S) 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.[citation needed]
Antithrombin
Tissue factor pathway inhibitor (TFPI)
Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FVII and FX.[citation needed]
Plasmin
Prostacyclin
Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn, activates adenylyl cyclase, which synthesizes cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade.[31]
Medical assessment
Numerous medical tests are used to assess the function of the coagulation system:[36]
- Common: INR), fibrinogen testing (often by the Clauss method), platelet count, platelet function testing (often by PFA-100), thrombodynamics test.
- Other: prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), miscellaneous platelet function tests, thromboelastography (TEG or Sonoclot), euglobulin lysis time(ELT).
The contact activation (intrinsic) pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test.[citation needed]
The tissue factor (extrinsic) pathway is initiated by release of
The quantitative and qualitative screening of fibrinogen is measured by the
If a coagulation factor is part of the contact activation or tissue factor pathway, a deficiency of that factor will affect only one of the tests: Thus
Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.
Role in disease
Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on the nature of the defect.[37]
Platelet disorders
Platelet disorders are either congenital or acquired. Examples of congenital platelet disorders are
Decreased platelet numbers (thrombocytopenia) is due to insufficient production (e.g.,
Coagulation factor disorders
The best-known coagulation factor disorders are the
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.[medical citation needed]
In acute or chronic liver failure, there is insufficient production of coagulation factors, possibly increasing risk of bleeding during surgery.[39]
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 leads to ischemic necrosis of tissue. Most cases of venous thrombosis are due to acquired states (older age, surgery, cancer, immobility) or inherited thrombophilias (e.g., antiphospholipid syndrome, factor V Leiden, and various other genetic deficiencies or variants).[medical citation needed]
Pharmacology
Procoagulants
The use of
Coagulation factor concentrates are used to treat
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 the need for blood products.
Anticoagulants
Anticoagulants and anti-platelet agents (together "antithrombotics") are amongst the most commonly used medications. Anti-platelet agents include aspirin, dipyridamole, ticlopidine, clopidogrel, ticagrelor and prasugrel; 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) and protein C and protein S, whereas 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 in clinical use are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (the directly acting oral anticoagulants: dabigatran, rivaroxaban, apixaban, and edoxaban).[41]
History
Initial discoveries
Theories on the coagulation of blood have existed since antiquity. Physiologist
The theory that thrombin is generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905.[47] At this stage, it was known that thrombokinase/thromboplastin (factor III) is released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), forms thrombin, which converts fibrinogen into fibrin (I).[48]
Coagulation factors
The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century.[citation needed]
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 its function to be 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.[48]
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 recognized 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.[48]
Factor IX was discovered in 1952 in a young patient with
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.[48]
The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane[49] in the UK and by Davie and Ratnoff[50] in the US, respectively.
Nomenclature
The usage of
Factor VI[citation needed] is unassigned, as accelerin was found to be activated Factor V.
Other species
All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease process.[citation needed] In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal.[citation needed] The only non-mammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.[52]
See also
- Agglutination (biology)
- Antihemorrhagic
- Post-vaccination embolic and thrombotic events
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- Hoffman M, Monroe DM (June 2001). "A cell-based model of hemostasis". Thrombosis and Haemostasis. 85 (6): 958–965. S2CID 18681597.
- Hoffman M, Monroe DM (February 2007). "Coagulation 2006: a modern view of hemostasis". Hematology/Oncology Clinics of North America. 21 (1): 1–11. PMID 17258114.
External links
- Media related to Coagulation at Wikimedia Commons