Blood coagulation pathwaysin vivo showing the central role played bythrombin
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Coagulation, also known asclotting, is the process by whichblood changes from aliquid to agel, forming ablood clot. It results inhemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involvesactivation,adhesion and aggregation ofplatelets, as well as deposition and maturation offibrin.
Coagulation begins almost instantly after an injury to theendothelium that lines ablood vessel. Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelialplatelet tissue factor tocoagulation factor VII, which ultimately leads to cross-linkedfibrin formation. Platelets immediately form a plug at the site of injury; this is calledprimary hemostasis. Secondary hemostasis occurs simultaneously: additional coagulation factors beyond factor VII (listed below) respond in a cascade to form fibrin strands, which strengthen theplatelet plug.[1]
Coagulation is highlyconserved throughoutbiology. In allmammals, coagulation involves both cellular components (platelets) andproteinaceous components (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]
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 media layer ofendothelium (blood vessel wall).
Platelet plug formation: The adhered platelets aggregate and form a temporary plug to stop bleeding. This process is often called "primary hemostasis".[19]
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 clot formation: Near the end of the extrinsic pathway, afterthrombin completes 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 healing until its inner part is dissolved byfibrinolytic enzymes, while the clot's outer part is shed off.
After the fibrin clot is formed,clot retraction occurs and thenclot resolution starts, 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), activateplasminogen into plasmin, which promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels.[22]
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.
When the endothelium is damaged, the normally isolated underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specificglycoprotein Ia/IIa surface 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/V and A1 domain. This localization of platelets to the extracellular matrix promotes collagen interaction with plateletglycoprotein VI. Binding of collagen toglycoprotein VI triggers 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]
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 tofibrin formation. 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 protease and itsglycoprotein 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 byRoman numerals, with a lowercasea appended to indicate an active form.[27]
The coagulation factors are generallyenzymes calledserine 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 factor andcontact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.[29]
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]
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.
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.)
Thecontact activation pathway begins with formation of the primary complex oncollagen byhigh-molecular-weight kininogen (HMWK),prekallikrein, andFXII (Hageman factor).Prekallikrein is converted tokallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form thetenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating blood clot formation (or more specifically, physiologicalhemostasis) can be illustrated by the fact that individuals with severe deficiencies of FXII, HMWK, andprekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation,[27] and innate immunity.[30] Interference with the pathway may confer protection against thrombosis without a significant bleeding risk.[30]
Inhibition of factor XII and PK interferes with innate immunity in animal models.[30] More promising isinhibition of factor XI, which in early clinical trials have shown the expected effect.[31]
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.[32]
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.[33]
Thrombin functions not only to convertfibrinogen to fibrin, it also activates Factors VIII and V and their inhibitorprotein C (in the presence ofthrombomodulin). By activating Factor XIII,covalent bonds are formed that crosslink the fibrin polymers that form from activated monomers.[27] This stabilizes the fibrin network.[34]
The coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form thetenase complex until it is down-regulated by the anticoagulant pathways.[27]
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.[35]
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.[36]
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 system by their ability to increase vascular permeability and act aschemotactic agents forphagocytic 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 causelysis of manyGram-positive bacteria by acting as a cationic detergent.[38] Manyacute-phase proteins ofinflammation are involved in the coagulation system. In addition, pathogenic bacteria may secrete agents that alter the coagulation system, e.g.coagulase andstreptokinase.[39]
Calcium andphospholipids (constituents ofplatelet membrane) are required for thetenase and prothrombinase complexes to function.[41] 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 ormicrovesicles shed from them.[42] 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.[43]
Vitamin K is an essential factor to the hepaticgamma-glutamyl carboxylase that adds acarboxyl group toglutamic acid residues on factors II, VII, IX and X, as well asProtein S,Protein C andProtein 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 drugswarfarin and relatedcoumarins such 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.[44]
Coagulation with arrows for negative and positive feedback.
Several mechanisms keep platelet activation and the coagulation cascade in check.[45] Abnormalities can lead to an increased tendency toward thrombosis:
Protein C is a major physiological anticoagulant. It is a vitamin K-dependentserine 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 proteinthrombomodulin. Thrombomodulin binds these proteins in such a way that it activates Protein C. The activated form, along withprotein S and 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 V or high levels of FVIII, also may lead to a thrombotic tendency.[45]
Antithrombin is 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.[45]
Plasmin is 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 (PGI2) is released by endothelium and activates platelet Gs protein-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.[37]
The tissue factor (extrinsic) pathway is initiated by release oftissue factor (a specific cellular lipoprotein), and can be measured by theprothrombin time (PT) test.[50] PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such aswarfarin.[51]
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.[48] 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.
Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on the nature of the defect.[52]
The GP1b-IX receptor complex. This protein receptor complex is found on the surface of platelets, and in conjunction withGPV allows 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.
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).[55]
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.[56]
Thrombosis is the pathological development of blood clots. These clots may break free and become mobile, forming anembolus or grow to such a size that occludes the vessel in which it developed. Anembolism is 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 causesischemia and often leads to ischemicnecrosis of tissue. Most cases ofvenous thrombosis are 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.[57]
The use ofadsorbent chemicals, such aszeolites, and otherhemostatic agents are also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds).Thrombin and fibringlue are used surgically to treat bleeding and to thrombose aneurysms.Hemostatic Powder Spray TC-325 is used to treated gastrointestinal bleeding.[citation needed]
Tranexamic acid andaminocaproic acid inhibit fibrinolysis and lead to ade 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.
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 Schmidt suggested that the conversion from fibrinogen to fibrin is the result of anenzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin".[61][62]Arthus discovered in 1890 that calcium was essential in coagulation.[63][64]Platelets were identified in 1865, and their function was elucidated byGiulio Bizzozero in 1882.[65]
The theory that thrombin is generated by the presence oftissue factor was consolidated byPaul Morawitz in 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]
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 accelerator orproconvertin, 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 elusivehemophilia A; it was identified in the 1950s and is alternatively calledantihemophilic globulin due to its capability to correct hemophilia A.[67]
Factor IX was discovered in 1952 in a young patient withhemophilia B namedStephen Christmas (1947–1993). His deficiency was described by Dr. Rosemary Biggs and ProfessorR.G. MacFarlane in Oxford, UK. The factor is, hence, called Christmas Factor. Christmas lived in Canada and campaigned for blood transfusion safety until succumbing to transfusion-relatedAIDS at 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.
The usage ofRoman numerals rather 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, namelyprekallikrein andhigh-molecular-weight kininogen, respectively.[67]
Factor VI[citation needed] is unassigned, as accelerin was found to be activated Factor V.
All mammals have an extremely closely related blood coagulation process[71], 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.[72] Exemplifying the close links between coagulation andinflammation, the horseshoe crab has a primitive response to injury, carried out by cells known as amoebocytes (orhemocytes) which serve both hemostatic and immune functions.[40][73]
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