clotting factors

血液凝固因子

WordNet

1. be a contributing factor; "make things factor into a companys profitability"
2. any of the numbers (or symbols) that form a product when multiplied together
3. an independent variable in statistics
4. anything that contributes causally to a result; "a number of factors determined the outcome"
5. consider as relevant when making a decision; "You must factor in the recent developments" (同)factor in, factor out
6. resolve into factors; "a quantum computer can factor the number 15" (同)factor in, factor out

PrepTutorEJDIC

1. (…の)『要因』,(…を生み出す)要素《+『in』+『名』(do『ing』)》 / 囲数,約数 / 代理人,《おもに英》仲買人 / =factorize

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/11/18 15:54:02」(JST)

wiki en

[Wiki en表示]

This article is about blood clotting. For other meanings see Coagulation (disambiguation).

Coagulation (also known as clotting) is the process by which blood changes from a liquid to a gel, forming a 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 along with deposition and maturation of fibrin. Disorders of coagulation are disease states which can result in bleeding (hemorrhage or bruising) or obstructive clotting (thrombosis).

Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. The system in humans has been the most extensively researched and is the best understood.

Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium lining the vessel. Exposure of blood to the space under the endothelium initiates two processes: changes in platelets, and the exposure of subendothilial tissue factor to plasma Factor VII, which ultimately leads to fibrin formation. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: Additional coagulation factors or clotting factors beyond Factor VII (listed below) respond in a complex cascade to form fibrin strands, which strengthen the platelet plug.

Blood coagulation pathways in vivo showing the central role played by thrombin

Physiology

Platelet activation

When the endothelium is damaged, the normally isolated, underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific glycoprotein Ia/IIa surface receptors. This adhesion is strengthened further by von Willebrand factor (vWF), which is released from the endothelium and from platelets; vWF forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils. This localization of platelets to the extracellular matrix promotes collagen interaction with platelet glycoprotein VI. Binding of collagen to glycoprotein 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.

Activated platelets will 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 G_q-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 (completing primary hemostasis).

The coagulation cascade

The classical blood coagulation pathway

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 edition;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 to fibrin formation. These are the contact activation pathway (also known as the intrinsic pathway), and the tissue 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 the tissue factor (extrinsic) 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), which act by cleaving downstream proteins. There are some exceptions. For example, FVIII and FV are glycoproteins, and Factor XIII is a transglutaminase. The coagulation factors circulate as inactive zymogens. The coagulation cascade is therefore classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.

Tissue factor pathway (extrinsic)

The main role of the tissue factor 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:

• Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF) 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 prothrombinase complex, which activates prothrombin to thrombin.
• Thrombin then activates other components of the coagulation cascade, including FV and FVIII (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. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)

Contact activation pathway (intrinsic)

The contact activation pathway begins with 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. Instead, contact activation system seems to be more involved in inflammation.

Final common pathway

The division of coagulation in two pathways is mainly artificial, it originates from laboratory tests in which clotting times were measured after the clotting was initiated by glass (intrinsic pathway) or by thromboplastin (a mix of tissue factor and phospholipids). In fact thrombin is present from the very beginning, already when platelets are making the plug. Thrombin has a large array of functions, not only the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, it is the most important platelet activator and on top of that 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.

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, as well as procoagulant microparticles or microvesicles shed from them. 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. 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 drugs warfarin and related coumarins such as acenocoumarol, phenprocoumon, and dicumarol. 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., in malabsorption) or impaired vitamin K metabolism in disease (e.g., in liver 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.

Regulators

Coagulation with arrows for negative and positive feedback.

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

• 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.
• Antithrombin is a serine 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 of heparan sulfate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria) leads to thrombophilia.
• Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FVII and FX.
• Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.
• Prostacyclin (PGI₂) is released by endothelium and activates platelet G_s 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.

Fibrinolysis

Main article: Fibrinolysis

Eventually, blood clots are reorganised and resorbed by a process termed fibrinolysis. The main enzyme responsible for this process (plasmin) is regulated by various activators and inhibitors.

Role in immune system

The coagulation system overlaps with the immune system. Coagulation can physically trap invading microbes in blood clots. Also, some products of the coagulation system can contribute to the innate immune system by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells. In addition, some of the products of the coagulation system are directly antimicrobial. For example, beta-lysine, an amino acid produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic detergent. Many acute-phase proteins of inflammation are involved in the coagulation system. In addition, pathogenic bacteria may secrete agents that alter the coagulation system, e.g. coagulase and streptokinase.

Assessment

Blood plasma after the addition of Tissue Factor forms a gel-like structure (Test for prothrombin time).

Numerous tests are used to assess the function of the coagulation system:

• Common: aPTT, PT (also used to determine INR), fibrinogen testing (often by the Clauss method), platelet count, platelet function testing (often by PFA-100), thrombodynamics test.
• Other: TCT, bleeding time, mixing test (whether an abnormality corrects if the patient's plasma is mixed with normal plasma), coagulation factor assays, antiphospholipid antibodies, D-dimer, genetic tests (e.g. factor V Leiden, 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.

The tissue factor (extrinsic) pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin.

The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting 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 activation 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 activation pathway, results in an abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen, and some variants of FX that can be detected only by either aPTT or 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 affect all screening tests.

Laboratory findings in various platelet and coagulation disorders (V - T)

Condition	Prothrombin time	Partial thromboplastin time	Bleeding time	Platelet count
Vitamin K deficiency or warfarin	Prolonged	Normal or mildly prolonged	Unaffected	Unaffected
Disseminated intravascular coagulation	Prolonged	Prolonged	Prolonged	Decreased
Von Willebrand disease	Unaffected	Prolonged or unaffected	Prolonged	Unaffected
Hemophilia	Unaffected	Prolonged	Unaffected	Unaffected
Aspirin	Unaffected	Unaffected	Prolonged	Unaffected
Thrombocytopenia	Unaffected	Unaffected	Prolonged	Decreased
Liver failure, early	Prolonged	Unaffected	Unaffected	Unaffected
Liver failure, end-stage	Prolonged	Prolonged	Prolonged	Decreased
Uremia	Unaffected	Unaffected	Prolonged	Unaffected
Congenital afibrinogenemia	Prolonged	Prolonged	Prolonged	Unaffected
Factor V deficiency	Prolonged	Prolonged	Unaffected	Unaffected
Factor X deficiency as seen in amyloid purpura	Prolonged	Prolonged	Unaffected	Unaffected
Glanzmann's thrombasthenia	Unaffected	Unaffected	Prolonged	Unaffected
Bernard-Soulier syndrome	Unaffected	Unaffected	Prolonged	Decreased or unaffected
Factor XII deficiency	Unaffected	Prolonged	Unaffected	Unaffected
C1INH deficiency	Unaffected	Shortened	Unaffected	Unaffected

Role in disease

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

Platelet disorders

Platelet conditions may be congenital or acquired. Some inborn platelet pathologies are Glanzmann's thrombasthenia, Bernard-Soulier syndrome (abnormal glycoprotein Ib-IX-V complex), gray platelet syndrome (deficient alpha granules), and delta storage pool deficiency (deficient dense granules). Most are rare conditions. Most inborn platelet pathologies predispose to hemorrhage. Von Willebrand disease is due to deficiency or abnormal function of von Willebrand factor, and leads to a similar bleeding pattern; its milder forms are relatively common.

Decreased platelet numbers may be due to various causes, including insufficient production (e.g., in myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP), and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced thrombocytopenia/HIT). Most consumptive conditions lead to platelet activation, and some are associated with thrombosis.

Disease and clinical significance of thrombosis

The best-known coagulation factor disorders are the hemophilias. The three main forms are hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild bleeding tendency). Hemophilia A and B are X-linked recessive disorders, whereas Hemophilia C is a much more rare autosomal recessive disorder most commonly seen in Ashkenazi Jews.

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.

Bernard-Soulier syndrome is a defect or deficiency in GPIb. GPIb, the receptor for vWF, can be defective and lead to lack of primary clot formation (primary hemostasis) and increased bleeding tendency. This is an autosomal recessive inherited disorder.

Thrombasthenia of Glanzmann and Naegeli (Glanzmann thrombasthenia) is extremely rare. It is characterized by a defect in GPIIb/IIIa fibrinogen receptor complex. When GPIIb/IIIa receptor is dysfunctional, fibrinogen cannot cross-link platelets, which inhibits primary hemostasis. This is an autosomal recessive inherited disorder.

In liver failure (acute and chronic forms), there is insufficient production of coagulation factors by the liver; this may increase bleeding risk.

Deficiency of Vitamin K may also contribute to bleeding disorders because clotting factor maturation depends on Vitamin K.

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).

Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency toward thrombophlebitis. Other mutations have been linked with a rare form of hereditary angioedema (type III) essentialism.

Pharmacology

Procoagulants

The use of adsorbent chemicals, such as zeolites, and other hemostatic agents are also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms.

Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A.

Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma are commonly used coagulation factor products. Recombinant activated human factor VII is increasingly popular in the treatment of major bleeding.

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 need for blood products.

Anticoagulants

Main articles: Antiplatelet drug and Anticoagulant

Anticoagulants and anti-platelet agents 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 under development are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g., rivaroxaban, dabigatran, apixaban).

Coagulation factors

Coagulation factors and related substances

Number and/or name	Function	Associated genetic disorders
I (fibrinogen)	Forms clot (fibrin)	Congenital afibrinogenemia, Familial renal amyloidosis
II (prothrombin)	Its active form (IIa) activates I, X, VII, VIII, XI, XIII, protein C, platelets	Prothrombin G20210A, Thrombophilia
III (tissue factor or tissue thromboplastin )	Co-factor of VIIa (formerly known as factor III)
IV Calcium	Required for coagulation factors to bind to phospholipid (formerly known as factor IV)
V (proaccelerin, labile factor)	Co-factor of X with which it forms the prothrombinase complex	Activated protein C resistance
VI	Unassigned – old name of Factor Va
VII (stable factor, proconvertin)	Activates IX, X	congenital proconvertin/factor VII deficiency
VIII (Antihemophilic factor A)	Co-factor of IX with which it forms the tenase complex	Haemophilia A
IX (Antihemophilic factor B or Christmas factor)	Activates X: forms tenase complex with factor VIII	Haemophilia B
X (Stuart-Prower factor)	Activates II: forms prothrombinase complex with factor V	Congenital Factor X deficiency
XI (plasma thromboplastin antecedent)	Activates IX	Haemophilia C
XII (Hageman factor)	Activates factor XI, VII and prekallikrein	Hereditary angioedema type III
XIII (fibrin-stabilizing factor)	Crosslinks fibrin	Congenital Factor XIIIa/b deficiency
von Willebrand factor	Binds to VIII, mediates platelet adhesion	von Willebrand disease
prekallikrein (Fletcher factor)	Activates XII and prekallikrein; cleaves HMWK	Prekallikrein/Fletcher Factor deficiency
high-molecular-weight kininogen (HMWK) (Fitzgerald factor)	Supports reciprocal activation of XII, XI, and prekallikrein	Kininogen deficiency
fibronectin	Mediates cell adhesion	Glomerulopathy with fibronectin deposits
antithrombin III	Inhibits IIa, Xa, and other proteases	Antithrombin III deficiency
heparin cofactor II	Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")	Heparin cofactor II deficiency
protein C	Inactivates 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)
alpha 2-antiplasmin	Inhibits plasmin	Antiplasmin deficiency
tissue plasminogen activator (tPA)	Activates plasminogen	Familial hyperfibrinolysis and thrombophilia
urokinase	Activates plasminogen	Quebec platelet disorder
plasminogen activator inhibitor-1 (PAI1)	Inactivates tPA & urokinase (endothelial PAI)	Plasminogen activator inhibitor-1 deficiency
plasminogen activator inhibitor-2 (PAI2)	Inactivates tPA & urokinase (placental PAI)
cancer procoagulant	Pathological factor X activator linked to thrombosis in cancer

History

Initial discoveries

Theories on the coagulation of blood have existed since antiquity. Physiologist Johannes Müller (1801–1858) described fibrin, the substance of a thrombus. Its soluble precursor, fibrinogen, was thus named by Rudolf Virchow (1821–1902), and isolated chemically by Prosper Sylvain Denis (1799–1863). Alexander Schmidt suggested that the conversion from fibrinogen to fibrin is the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin". Arthus discovered in 1890 that calcium was essential in coagulation. Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.

The theory that thrombin is generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905. 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).

Coagulation factors

The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century.

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.

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 recognised 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.

Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947–1993). His deficiency was described by Dr. Rosemary Biggs and Professor R.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-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin component, given by an independent group in California.

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.

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

Nomenclature

The usage of Roman 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. 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, namely prekallikrein and high-molecular-weight kininogen, respectively.

Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further factors, and 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. In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal. The only non-mammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.

References

Further reading

• Hoffman, M; Monroe DM, 3rd (June 2001). "A cell-based model of hemostasis." (PDF). Thrombosis and haemostasis 85 (6): 958–65. PMID 11434702. 
• Hoffman, Maureane; Monroe, Dougald M. "Coagulation 2006: A Modern View of Hemostasis". Hematology/Oncology Clinics of North America 21 (1): 1–11. doi:10.1016/j.hoc.2006.11.004. PMID 17258114. 

External links

3D structures

• UMich Orientation of Proteins in Membranes families/superfamily-97 – Calculated orientations of complexes with GLA domains in membrane
• UMich Orientation of Proteins in Membranes families/superfamily-48 – Discoidin domains of blood coagulation factors

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 止血の概要 overview of hemostasis
• 2. 凝固検査の臨床使用 clinical use of coagulation tests
• 3. 肝臓の合成能の検査（アルブミン、凝固因子、プロトロンビン時間など） tests of the livers biosynthetic capacity eg albumin coagulation factors prothrombin time
• 4. 血漿分画製剤および組換えDNA産生凝固因子 plasma derivatives and recombinant dna produced coagulation factors
• 5. ビタミンKの概要 overview of vitamin k

English Journal

• Combination peel with incorporated fractional prickle coral calcium for the treatment of keratosis pilaris: a pilot study.

• Park KY1, Son IP, Choi SY, Seo SJ, Hong CK.Author information 1Departments of Dermatology, Chung-Ang University College of Medicine , Seoul , South Korea.AbstractBACKGROUND: Keratosis pilaris (KP) is a common condition of follicular plugging with variable erythema. There is a lack of reliable response to the treatment of KP.
• The Journal of dermatological treatment.J Dermatolog Treat.2014 Aug;25(4):314-8. doi: 10.3109/09546634.2012.671914. Epub 2012 Apr 12.
• BACKGROUND: Keratosis pilaris (KP) is a common condition of follicular plugging with variable erythema. There is a lack of reliable response to the treatment of KP.OBJECTIVE: We evaluated the effect and safety of combination peel with fractional prickle coral calcium (FCR™) in the treatment of KP.
• PMID 22385102

• Anticoagulant medication at time of needle biopsy for breast cancer in relation to risk of lymph node metastasis.

• Ljung R1, Sennerstam R, Mattsson F, Auer G, Lagergren J.Author information 1Upper Gastrointestinal Surgery Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.AbstractAnticoagulant treatment might enhance the natural defense against tumor cell dissemination caused by diagnostic needle biopsy by counteracting thrombocyte coating of such cells. To clarify whether women using anticoagulant treatment at the time of biopsy have a lower occurrence of lymph node metastasis, we conducted a nationwide Swedish cohort study of 26,528 female incident breast cancer patients in 2006-2011. Point risk ratio (RR) of risk of lymph node metastasis among users of anticoagulant treatment adjusted for age, T-stage, socioeconomic factors, and concomitant medication was RR = 0.94, (95% CI: 0.87-1.03), and lower in younger women (RR = 0.80, 95% CI 0.50-1.29). Although nonsignificant, these associations may underestimate a true negative association since women using anticoagulant treatment are likely to have more concomitant diseases, lead an unhealthier lifestyle, and have lower participation in mammography screening. These findings provide some support for the hypothesis that anticoagulant medications might counteract breast cancer spread caused by needle biopsy.
• International journal of cancer. Journal international du cancer.Int J Cancer.2014 Jul 1;135(1):238-41. doi: 10.1002/ijc.28671. Epub 2013 Dec 31.
• Anticoagulant treatment might enhance the natural defense against tumor cell dissemination caused by diagnostic needle biopsy by counteracting thrombocyte coating of such cells. To clarify whether women using anticoagulant treatment at the time of biopsy have a lower occurrence of lymph node metasta
• PMID 24346771

• Genotype and phenotype report on patients with combined deficiency of factor V and factor VIII in Iran.

• Karimi M1, Cairo A, Safarpour MM, Haghpanah S, Ekramzadeh M, Afrasiabi A, Shahriari M, Menegatti M.Author information 1aHematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran bA. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan and Luigi Villa Foundation, Milan, Italy cShiraz University of Medical Sciences, Shiraz, Iran.AbstractCombined factor V (FV) and factor VIII (FVIII) deficiency is a rare autosomal recessive bleeding disorder characterized by mild-to-moderate bleeding. Epistaxis, postsurgical bleeding and menorrhagia are the most common symptoms. The aim of this study is to report the phenotype-genotype characterization carried out in patients affected with combined FV and FVIII deficiency from Iran. A cross-sectional study was conducted in Shiraz Hemophilia Center, southern Iran. Twelve cases, seven men and five women coming from eight families were included in our study after taking consent form. Coagulation activity for all patients was measured. All exons and intron-exon junctions of lectin mannose binding protein 1 (LMAN1) gene and multiple coagulation factor deficiency 2 genes were amplified by PCR, and subsequently sequenced by the Sanger method. Patients[Combining Acute Accent] age ranged from 6 to 59 years mean ± SD: 23.8 ± 15.4 years and median: 22 years. No patient presented with severe bleeding symptom. Only one patient had severe FV and FVIII deficiency (both factor levels <1%). Four different type of mutations (duplication, insertion, splice site and nonsense), occurring in different locuses, were identified on LMAN1 gene in 12 Iranian patients. There was a significant correlation between FV and FVIII levels, which is indicative of association with loss of function of LMAN1 gene, and reduced plasma levels of both factors. Our study showed that all of our characterized patients with combined FV and FVIII deficiency present different homozygous mutations on LMAN1 gene introducing a premature stop codon. Larger studies are needed to calculate the correlation between factor levels, genetic and bleeding symptoms.
• Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.Blood Coagul Fibrinolysis.2014 Jun;25(4):360-3. doi: 10.1097/MBC.0000000000000046.
• Combined factor V (FV) and factor VIII (FVIII) deficiency is a rare autosomal recessive bleeding disorder characterized by mild-to-moderate bleeding. Epistaxis, postsurgical bleeding and menorrhagia are the most common symptoms. The aim of this study is to report the phenotype-genotype characterizat
• PMID 24389588

Japanese Journal

• Silent Cerebral Ischemic Lesions After Catheter Ablation of Atrial Fibrillation in Patients on 5 Types of Periprocedural Oral Anticoagulation　– Predictors of Diffusion-Weighted Imaging-Positive Lesions and Follow-up Magnetic Resonance Imaging –

• Circulation Journal 80(4), 870-877, 2016
• NAID 130005139553

• Silent Cerebral Ischemic Lesions After Catheter Ablation of Atrial Fibrillation in Patients on 5 Types of Periprocedural Oral Anticoagulation　– Predictors of Diffusion-Weighted Imaging-Positive Lesions and Follow-up Magnetic Resonance Imaging –

• Circulation Journal advpub(0), 2016
• NAID 130005126824

• The First Case of Deceased Donor Liver Transplantation for a Patient with End-Stage Liver Cirrhosis Due to Human Immunodeficiency Virus and Hepatitis C Virus Coinfection in Japan

• Japanese Journal of Infectious Diseases 69(1), 80-82, 2016
• NAID 130005120241

Related Links

• Clotting factors | definition of clotting factors by Medical dictionary

Clotting factors Substances in the blood that act in sequence to stop bleeding by forming a clot. Mentioned in: Partial Thromboplastin Time coagulation factors; clotting factors approximately 20 soluble plasma factors, including ...

• What are clotting factor deficiencies? - World Federation of ...

What are rare clotting factor deficiencies? Rare clotting factor deficiencies are a group of inherited bleeding disorders caused by a problem with one or several clotting factors. Clotting factors are proteins in the blood that control ...

Related Pictures

---

★リンクテーブル★

関連記事	「factor」「clotting」

「factor」

　　[★]

• n.

• 因子、要因、要素、ファクター

関

element、elementary、factorial、parameter

　 　 　 　 　 　 　

「clotting」

　　[★]

• n.

• 凝固

関

clot、coagulate、coagulation、solidification、solidify、hemostasis