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Coagulation

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This article is about blood clotting. For other uses, seeCoagulation (disambiguation).

Coagulation
Blood coagulation pathwaysin vivoshowing the central role played bythrombin
HealthBeneficial

Coagulation,also known asclotting,is the process by whichbloodchanges from aliquidto agel,forming ablood clot.It results inhemostasis,the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involvesactivation,adhesionand aggregation ofplatelets,as well as deposition and maturation offibrin.

Coagulation begins almost instantly after an injury to theendotheliumthat lines ablood vessel.Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelialplatelet tissue factortocoagulation factor VII,which ultimately leads to cross-linkedfibrinformation. Platelets immediately form a plug at the site of injury; this is calledprimary hemostasis. Secondary hemostasisoccurs simultaneously: additional coagulation factors beyond factor VII (listed below) respond in a cascade to form fibrin strands, which strengthen theplatelet plug.[1]

Coagulation is highlyconservedthroughout biology. In allmammals,coagulation involves both cellular components (platelets) andproteinaceouscomponents (coagulation or clotting factors).[2][3]The pathway in humans has been the most extensively researched and is the best understood.[4]Disorders of coagulation can result in problems withhemorrhage,bruising,orthrombosis.[5]

List of coagulation factors

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There are 13 traditional clotting factors, as named below,[6]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) activatesplatelets,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
  • Calcium
  • Calcium ions
  • Ca2+ions
 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
  • Proaccelerin
  • labile factor
  • Ac-globulin
 Co-factor of factor X with which it forms theprothrombinasecomplex Activated protein C resistance Plasma protein Liver, platelets Extrinsic and intrinsic
Factor VI
  • Unassigned–
    old name of factor Va
    (activated form of factor V)
  • accelerin (formerly)
 N/A N/A N/A
Factor VII*
  • Proconvertin
  • Serum Prothrombin Conversion Accelerator (SPCA)
  • Stable factor
 Activates factors IX, X; increases rate of catalytic conversion of prothrombin into thrombin Congenitalfactor VII deficiency Plasma protein Liver Extrinsic
Factor VIII
  • Antihemophilic factor A
  • Antihemophilic factor (AHF)
  • Antihemophilic globulin (AHG)
 Co-factor of factor IX with which it forms thetenasecomplex Hemophilia A Plasma protein factor Platelets and endothelial cells Intrinsic
Factor IX*
  • Antihemophilic factor B
  • Christmas factor
  • plasma thromboplastin component (PTC)
 Activates factor X, formstenasecomplex with factor VIII Hemophilia B Plasma protein Liver Intrinsic
Factor X*
  • Stuart-Prower factor
  • Stuart factor
 Activates factor II, formsprothrombinasecomplex with factor V Congenital Factor X deficiency Protein Liver Extrinsic and intrinsic
Factor XI
  • Plasma thromboplastin antecedent (PTA)
  • Antihemophilic factor C
 Activates factor IX Hemophilia C Plasma protein Liver Intrinsic
Factor XII Hageman factor Activates XI, VII, prekallikrein and plasminogen Hereditary angioedematype 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 hepaticgamma-glutamyl carboxylasethat adds acarboxylgroup toglutamic acidresidues on factors II, VII, IX and X, as well asProtein S,Protein CandProtein Z[8] Vitamin K deficiency Phytyl-substituted naphthoquinone derivative Gut microbiota
(e.g.E. coli[9]),
dietary sources		 Extrinsic[10]
von Willebrand factor Binds to VIII, mediates platelet adhesion von Willebrand disease Blood glycoprotein Blood vessels'endothelia,
bone marrow[11]
Prekallikrein Fletcher factor Activates XII and prekallikrein; cleaves HMWK Prekallikrein/Fletcher factor deficiency
Kallikrein Activates plasminogen
High-molecular-weight kininogen
  • Fitzgerald factor
  • HMWK
 Supports reciprocal activation of factors XII, XI, and prekallikrein Kininogen deficiency
Fibronectin Mediates cell adhesion Glomerulopathywith fibronectin deposits
AntithrombinIII Inhibits factors IIa, Xa, IXa, XIa, and XIIa Antithrombin III deficiency
Heparin cofactor II Inhibits factor IIa, cofactor for heparin anddermatan 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 offactor X;linked to thrombosis in variouscancers[12]
* Vitamin K is required for biosynthesis of these clotting factors[8]

Physiology

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The interaction of vWF and GP1b alpha. The GP1b receptor on the surface of platelets allows the platelet to bind to vWF, which is exposed upon damage to vasculature. The vWF A1 domain (yellow) interacts with the extracellular domain of GP1ba (blue).

Physiology of blood coagulation is based onhemostasis,the normal bodily process that stops bleeding. Coagulation is a part of an integrated series of haemostatic reactions, involving plasma, platelet, and vascular components.[13]

Hemostasis consists of four main stages:

  • Vasoconstriction(vasospasm or vascular spasm): Here, this refers to contraction of smooth muscles in thetunica medialayer ofendothelium(blood vessel wall).
  • Activation of platelets andplatelet plugformation:
  • 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".[20]
  • Fibrin clotformation: Near the end of the extrinsic pathway, afterthrombincompletes conversion of fibrinogen into fibrin,[21]factor XIIIa(plasma transglutaminase;[21]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 allowwound healinguntil its inner part is dissolved byfibrinolytic enzymes,while the clot's outer part is shed off.

After the fibrin clot is formed,clot retractionoccurs and thenclot resolutionstarts, 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 astissue plasminogen activator(t-PA), activateplasminogeninto plasmin, which promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels.[22]

Vasoconstriction

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Main article:Vasoconstriction

When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor substances, such as endothelin[23]and thromboxane,[24]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

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When the endothelium is damaged, the normally isolated underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specificglycoprotein Ia/IIasurface receptors. This adhesion is strengthened further byvon Willebrand factor(vWF), which is released from the endothelium and from platelets; vWF forms additional links between the platelets'glycoprotein Ib/IX/Vand A1 domain. This localization of platelets to the extracellular matrix promotes collagen interaction with plateletglycoprotein VI.Binding of collagen toglycoprotein VItriggers 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.[25]

Activated platelets release the contents of stored granules into the blood plasma. The granules includeADP,serotonin,platelet-activating factor(PAF),vWF,platelet factor 4,andthromboxane A2(TXA2), which, in turn, activate additional platelets. The granules' contents activate aGq-linked protein receptorcascade, resulting in increased calcium concentration in the platelets' cytosol. The calcium activatesprotein kinase C,which, in turn, activatesphospholipase A2(PLA2). PLA2then modifies theintegrinmembraneglycoprotein IIb/IIIa,increasing its affinity to bindfibrinogen.The activated platelets change shape from spherical to stellate, and thefibrinogencross-links withglycoprotein IIb/IIIaaid in aggregation of adjacent platelets, forming a platelet plug and thereby completing primary hemostasis).[26]

Coagulation cascade

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The classical blood coagulation pathway[27]
Modern coagulation pathway. Hand-drawn composite from similar drawings presented by Professor Dzung Le, MD, PhD, at UCSD Clinical Chemistry conferences on 14 and 21 October 2014. Original schema from Introduction to Hematology by Samuel I. Rapaport. 2nd ed.; Lippencott: 1987. Dr Le added the factor XI portion based on a paper from about year 2000. Dr. Le's similar drawings presented the development of this cascade over 6 frames, like a comic.

The coagulation cascade of secondary hemostasis has two initial pathways which lead tofibrinformation. These are thecontact activation pathway(also known as the intrinsic pathway), and thetissue 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 thetissue factor(extrinsic) pathway. The pathways are a series of reactions, in which azymogen(inactive enzyme precursor) of aserine proteaseand itsglycoproteinco-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 byRoman numerals,with a lowercaseaappended to indicate an active form.[27]

The coagulation factors are generallyenzymescalledserine proteases,which act by cleaving downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII.[28]Tissue factor, FV and FVIII are glycoproteins, and Factor XIII is atransglutaminase.[27]The coagulation factors circulate as inactivezymogens. The coagulation cascade is therefore classically divided into three pathways. Thetissue factorandcontact activationpathways both activate the "final common pathway" of factor X, thrombin and fibrin.[29]

Tissue factor pathway (extrinsic)

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The main role of thetissue factor(TF) pathway is to generate a "thrombin burst", a process by whichthrombin,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:[27]

  1. Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor expressed on tissue-factor-bearing cells (stromalfibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
  2. TF-FVIIa activates FIX and FX.
  3. FVII is itself activated by thrombin, FXIa, FXII, and FXa.
  4. The activation of FX (to form FXa) by TF-FVIIa is almost immediately inhibited bytissue factor pathway inhibitor(TFPI).
  5. FXa and its co-factor FVa form theprothrombinasecomplex, which activatesprothrombinto thrombin.
  6. 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.
  7. 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)

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Thecontact activation pathwaybegins with formation of the primary complex oncollagenbyhigh-molecular-weight kininogen(HMWK),prekallikrein,andFXII (Hageman factor).Prekallikreinis converted tokallikreinand FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form thetenasecomplex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating blood clot formation can be illustrated by the fact that individuals with severe deficiencies of FXII, HMWK, andprekallikreindo not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation,[27]and innate immunity.[30]Despite this, interference with the pathway may confer protection against thrombosis without a significant bleeding risk.[30]

Final common pathway

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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.[31]

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.[32]

Thrombin functions not only to convertfibrinogento fibrin, it also activates Factors VIII and V and their inhibitorprotein C(in the presence ofthrombomodulin). By activating Factor XIII,covalent bondsare formed that crosslink the fibrin polymers that form from activated monomers.[27]This stabilizes the fibrin network.[33]

The coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form thetenasecomplex until it is down-regulated by the anticoagulant pathways.[27]

Cell-based scheme of coagulation

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A newer model of coagulation mechanism explains the intricate combination of cellular and biochemical events that occur during the coagulation processin 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.[34]

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 activatedplatelets.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.[35]

Fibrinolysis

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Main article:Fibrinolysis

Eventually, blood clots are reorganized and resorbed by a process termedfibrinolysis.The main enzyme responsible for this process isplasmin,which is regulated byplasmin activatorsandplasmin inhibitors.[36]

Role in immune system

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The coagulation system overlaps with theimmune system.Coagulation can physically trap invading microbes in blood clots. Also, some products of the coagulation system can contribute to theinnate immune systemby their ability to increase vascular permeability and act aschemotactic agentsforphagocytic cells.In addition, some of the products of the coagulation system are directlyantimicrobial.For example,beta-lysine,an amino acid produced by platelets during coagulation, can causelysisof manyGram-positive bacteriaby acting as a cationic detergent.[37]Manyacute-phase proteinsofinflammationare involved in the coagulation system. In addition, pathogenic bacteria may secrete agents that alter the coagulation system, e.g.coagulaseandstreptokinase.[38]

Immunohemostasis is the integration of immune activation into adaptive clot formation. Immunothrombosis is the pathological result of crosstalk between immunity, inflammation, and coagulation. Mediators of this process includedamage-associated molecular patternsandpathogen-associated molecular patterns,which are recognized bytoll-like receptors,triggering procoagulant and proinflammatory responses such as formation ofneutrophil extracellular traps.[39]

Cofactors

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Various substances are required for the proper functioning of the coagulation cascade:

Calcium and phospholipids

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Calciumandphospholipids(constituents ofplateletmembrane) are required for thetenaseand prothrombinase complexes to function.[40]Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on Factor Xa and Factor IXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles ormicrovesiclesshed from them.[41]Calcium is also required at other points in the coagulation cascade. Calcium ions play a major role in the regulation of coagulation cascade that is paramount in the maintenance of hemostasis. Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII.[42]

Vitamin K

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Vitamin Kis an essential factor to the hepaticgamma-glutamyl carboxylasethat adds acarboxylgroup toglutamic acidresidues on factors II, VII, IX and X, as well asProtein S,Protein CandProtein Z.In adding the gamma-carboxyl group to glutamate residues on the immature clotting factors, Vitamin K is itself oxidized. Another enzyme,Vitamin K epoxide reductase(VKORC), reduces vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important as a target of anticoagulant drugswarfarinand relatedcoumarinssuch asacenocoumarol,phenprocoumon,anddicumarol.These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors. Vitamin K deficiency from other causes (e.g., inmalabsorption) or impaired vitamin K metabolism in disease (e.g., inliver failure) lead to the formation of PIVKAs (proteins formed in vitamin K absence), which are partially or totally non-gamma carboxylated, affecting the coagulation factors' ability to bind to phospholipid.[43]

Regulators

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Coagulation with arrows for negative and positive feedback.

Several mechanisms keep platelet activation and the coagulation cascade in check.[44]Abnormalities can lead to an increased tendency toward thrombosis:

Protein C and Protein S

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Protein Cis a major physiological anticoagulant. It is a vitamin K-dependentserine protease enzymethat 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 proteinthrombomodulin.Thrombomodulin binds these proteins in such a way that it activates Protein C. The activated form, along withprotein Sand a phospholipid as cofactors, degrades FVa and FVIIIa. Quantitative or qualitative deficiency of either (protein C or protein S) may lead tothrombophilia(a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example byhaving the "Leiden" variant of Factor Vor high levels of FVIII, also may lead to a thrombotic tendency.[45]

Antithrombin

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Antithrombinis aserine protease inhibitor(serpin) that degrades the serine proteases: thrombin, FIXa, FXa, FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is increased by the presence ofheparan sulfate(aglycosaminoglycan) or the administration ofheparins(different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., inproteinuria) leads to thrombophilia.[46]

Tissue factor pathway inhibitor (TFPI)

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Tissue factor pathway inhibitor(TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FVII and FX.[47]

Plasmin

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Plasminis generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This cleavage is catalyzed bytissue plasminogen activator(t-PA), which is synthesized and secreted by endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.[citation needed]

Prostacyclin

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Prostacyclin(PGI2) is released by endothelium and activates platelet Gsprotein-linked receptors. This, in turn, activatesadenylyl 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.[36]

Medical assessment

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Numerous medical tests are used to assess the function of the coagulation system:[3][48]

The contact activation (intrinsic) pathway is initiated by activation of thecontact activation system,and can be measured by theactivated partial thromboplastintime (aPTT) test.[50]

The tissue factor (extrinsic) pathway is initiated by release oftissue factor(a specific cellular lipoprotein), and can be measured by theprothrombin time(PT) test.[51]PT results are often reported as ratio (INRvalue) to monitor dosing of oral anticoagulants such aswarfarin.[52]

The quantitative and qualitative screening of fibrinogen is measured by thethrombin clotting time(TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using theClauss fibrinogen assay.[49]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 activation or tissue factor pathway, a deficiency of that factor will affect only one of the tests: Thushemophilia A,a deficiency of factor VIII, which is part of the contact activation pathway, results in an abnormally prolonged aPTT test but a normal PT test. Deficiencies of common pathway factors prothrombin, fibrinogen, FX, and FV will prolong both aPTT and 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 prolong PT, aPTT, thrombin time, andreptilase time.

Role in disease

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Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on the nature of the defect.[53]

The GP1b-IX receptor complex. This protein receptor complex is found on the surface of platelets, and in conjunction withGPVallows for platelets to adhere to the site of injury. Mutations in the genes associated with the glycoprotein Ib-IX-V complex are characteristic ofBernard–Soulier syndrome.

Platelet disorders

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Platelet disorders are either congenital or acquired. Examples of congenital platelet disorders areGlanzmann's thrombasthenia,Bernard–Soulier syndrome(abnormalglycoprotein Ib-IX-V complex),gray platelet syndrome(deficientalpha granules), anddelta storage pool deficiency(deficientdense granules). Most are rare. They predispose to hemorrhage.Von Willebrand diseaseis due to deficiency or abnormal function ofvon Willebrand factor,and leads to a similar bleeding pattern; its milder forms are relatively common.[citation needed]

Decreased platelet numbers (thrombocytopenia) is due to insufficient production (e.g.,myelodysplastic syndromeor other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura), or consumption (e.g.,thrombotic thrombocytopenic purpura,hemolytic-uremic syndrome,paroxysmal nocturnal hemoglobinuria,disseminated intravascular coagulation,heparin-induced thrombocytopenia).[54]An increase in platelet count is calledthrombocytosis,which may lead to formation ofthromboembolisms;however, thrombocytosis may be associated with increased risk of either thrombosis or hemorrhage in patients withmyeloproliferative neoplasm.[55]

Coagulation factor disorders

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The best-known coagulation factor disorders are thehemophilias.The three main forms arehemophilia A(factor VIII deficiency),hemophilia B(factor IX deficiency or "Christmas disease" ) andhemophilia C(factor XI deficiency, mild bleeding tendency).[56]

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 chronicliver failure,there is insufficient production of coagulation factors, possibly increasing risk of bleeding during surgery.[57]

Thrombosisis the pathological development of blood clots. These clots may break free and become mobile, forming anembolusor grow to such a size that occludes the vessel in which it developed. Anembolismis said to occur when thethrombus(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 causesischemiaand often leads to ischemicnecrosisof tissue. Most cases ofvenous thrombosisare due to acquired states (older age, surgery, cancer, immobility). Unprovoked venous thrombosis may be related to inheritedthrombophilias(e.g.,factor V Leiden,antithrombin deficiency, and various other genetic deficiencies or variants), particularly in younger patients with family history of thrombosis; however, thrombotic events are more likely when acquired risk factors are superimposed on the inherited state.[58]

Pharmacology

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Procoagulants

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"Coagulant (drug)" redirects here. For other uses, seeCoagulant (drug) (disambiguation).

The use ofadsorbentchemicals, such aszeolites,and otherhemostatic agentsare also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibringlueare used surgically to treat bleeding and to thrombose aneurysms.Hemostatic Powder Spray TC-325is used to treated gastrointestinal bleeding.[citation needed]

Desmopressinis used to improve platelet function by activatingarginine vasopressin receptor 1A.[59]

Coagulation factor concentrates are used to treathemophilia,to reverse the effects of anticoagulants, and to treat bleeding in people with impaired coagulation factor synthesis or increased consumption.Prothrombin complex concentrate,cryoprecipitateandfresh frozen plasmaare commonly used coagulation factor products.Recombinant activated human factor VIIis sometimes used in the treatment of major bleeding.

Tranexamic acidandaminocaproic acidinhibit fibrinolysis and lead to ade factoreduced bleeding rate. Before its withdrawal,aprotininwas used in some forms of major surgery to decrease bleeding risk and the need for blood products.

Rivaroxabandrug bound to thecoagulation factor Xa.The drug prevents this protein from activating the coagulation pathway by inhibiting itsenzymatic activity.

Anticoagulants

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Main articles:Antiplatelet drugandAnticoagulant

Anticoagulants and anti-platelet agents (together "antithrombotics" ) are amongst the most commonly used medications.Anti-platelet agentsincludeaspirin,dipyridamole,ticlopidine,clopidogrel,ticagrelorandprasugrel;the parenteralglycoprotein IIb/IIIa inhibitorsare used duringangioplasty.Of the anticoagulants,warfarin(and relatedcoumarins) andheparinare 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, thedirect thrombin inhibitors,is under development; some members are already in clinical use (such aslepirudin,argatroban,bivalirudinanddabigatran). Also in clinical use are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (thedirectly acting oral anticoagulants:dabigatran,rivaroxaban,apixaban,andedoxaban).[60]

History

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Initial discoveries

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Theories on the coagulation of blood have existed since antiquity. PhysiologistJohannes Müller(1801–1858) described fibrin, the substance of athrombus.Its soluble precursor,fibrinogen,was thus named byRudolf Virchow(1821–1902), and isolated chemically byProsper Sylvain Denis(1799–1863).Alexander Schmidtsuggested that the conversion from fibrinogen to fibrin is the result of anenzymaticprocess, and labeled the hypothetical enzyme "thrombin"and its precursor"prothrombin".[61][62]Arthusdiscovered in 1890 that calcium was essential in coagulation.[63][64]Plateletswere identified in 1865, and their function was elucidated byGiulio Bizzozeroin 1882.[65]

The theory that thrombin is generated by the presence oftissue factorwas consolidated byPaul Morawitzin 1905.[66]At this stage, it was known thatthrombokinase/thromboplastin(factor III) is released by damaged tissues, reacting withprothrombin(II), which, together withcalcium(IV), formsthrombin,which converts fibrinogen intofibrin(I).[67]

Coagulation factors

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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 ofproaccelerin(initially and later called Factor V) byPaul Owren[no](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.[67]

Factor VII (also known asserum prothrombin conversion acceleratororproconvertin,precipitated by barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups.

Factor VIIIturned out to be deficient in the clinically recognized but etiologically elusivehemophilia A;it was identified in the 1950s and is alternatively calledantihemophilic globulindue to its capability to correct hemophilia A.[67]

Factor IX was discovered in 1952 in a young patient withhemophilia BnamedStephen Christmas(1947–1993). His deficiency was described by Dr. Rosemary Biggs and ProfessorR.G. MacFarlanein Oxford, UK. The factor is, hence, called Christmas Factor. Christmas lived in Canada and campaigned for blood transfusion safety until succumbing to transfusion-relatedAIDSat age 46. An alternative name for the factor isplasma thromboplastin component,given by an independent group in California.[67]

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.[67]

The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane[68]in the UK and by Davie and Ratnoff[69]in the US, respectively.

Nomenclature

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The usage ofRoman numeralsrather than eponyms or systematic names was agreed upon during annual conferences (starting in 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I–XII.[70]This committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to further coagulation-related proteins, namelyprekallikreinandhigh-molecular-weight kininogen,respectively.[67]

Factor VI[citation needed]is unassigned, as accelerin was found to be activated Factor V.

Other species

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All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease process.[citation needed]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 thehorseshoe crab.[71]Exemplifying the close links between coagulation and inflammation, the horseshoe crab has a primitive response to injury, carried out by cells known as amoebocytes (orhemocytes) which serve both hemostatic and immune functions.[72][73]

See also

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References

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Further reading

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