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Encyclopedia > Coagulation

Coagulation is a complex process by which blood forms solid clots. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a platelet- and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding and/or clotting and embolism. Coagulation is the process by which a liquid changes to a thickened, curdlike, insoluble state by some kind of chemical reaction, rather than by evaporation. ... Human blood smear: a - erythrocytes; b - neutrophil; c - eosinophil; d - lymphocyte. ... Coagulation is the thickening or congealing of any liquid into solid clots. ... Hemostasis refers to a process whereby bleeding is halted in most animals with a closed circulatory system. ... f you all The blood vessels are part of the circulatory system and function to transport blood throughout the body. ... A 250 ml bag of newly collected platelets. ... Fibrin is a protein involved in the clotting of blood. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... An embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. ...


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 therefore the best understood. Conservation is a high degree of similarity in the primary or higher structure of homologous proteins amongst various phyla. ... Subclasses & Infraclasses Subclass †Allotheria* Subclass Prototheria Subclass Theria Infraclass †Trituberculata Infraclass Metatheria Infraclass Eutheria Mammals (class Mammalia) are warm-blooded, vertebrate animals characterized by the presence of sweat glands, including those that produce milk, and by the presence of: hair, three middle ear bones used in hearing, and a neocortex...


Coagulation is initiated almost instantly after an injury to the blood vessel damages the endothelium (lining of the vessel). Platelets immediately form a hemostatic plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously—proteins in the blood plasma, called coagulation factors, respond in a complex cascade to form fibrin strands which strengthen the platelet plug.[1] The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ... A 250 ml bag of newly collected platelets. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Blood plasma is the liquid component of blood, in which the blood cells are suspended. ... Fibrin is a protein involved in the clotting of blood. ...

Contents

Physiology

Platelet activation

Damage to blood vessel walls exposes collagen normally present under the endothelium. Circulating platelets bind to the collagen with the surface collagen-specific glycoprotein Ia/IIa receptor. This adhesion is strengthened further by the large multimeric circulating protein von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/V and collagen fibrils. Tropocollagen triple helix. ... The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ... A glycoprotein is a macromolecule composed of a protein and a carbohydrate (an oligosaccharide). ... Von Willebrand factor is a blood glycoprotein of the coagulation system. ...


The platelets are then activated and release the contents of their granules into the plasma, in turn activating other platelets. The platelets undergo a change in their shape which exposes a phospholipid surface for those coagulation factors that require it. Fibrinogen links adjacent platelets by forming links via the glycoprotein IIb/IIIa. In addition, thrombin activates platelets. Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... A 250 ml bag of newly collected platelets. ...


The coagulation cascade

The coagulation cascade.
The coagulation cascade.

The coagulation cascade of secondary hemostasis has two pathways, the Contact Activation pathway (formerly known as the Intrinsic Pathway) and the Tissue Factor pathway (formerly known as the Extrinsic pathway) that lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the Tissue Factor 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. Image File history File links This is a lossless scalable vector image. ... Image File history File links This is a lossless scalable vector image. ... A zymogen or a proenzyme, is an inactive enzyme precursor. ... Crystal structure of Trypsin, a typical serine protease. ... A glycoprotein is a macromolecule composed of a protein and a carbohydrate (an oligosaccharide). ... The system of Roman numerals is a numeral system originating in ancient Rome, and was adapted from Etruscan numerals. ...


The coagulation factors are generally serine proteases (enzymes). There are some exceptions. For example, FVIII and FV are glycoproteins and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific sites. The coagulation factors circulate as inactive zymogens. Crystal structure of Trypsin, a typical serine protease. ... Neuraminidase ribbon diagram An enzyme (in Greek en = in and zyme = blend) is a protein, or protein complex, that catalyzes a chemical reaction and also controls the 3D orientation of the catalyzed substrates. ... Transglutaminases are a family of enzymes (EC 2. ... A zymogen is an inactive enzyme pre-cursor. ...


The coagulation cascade is 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

The main role of the tissue factor pathway is to generate a "thrombin burst" in which thrombin being the single most important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously. FVIIa circulates in a higher amount than any other activated coagulation factor. Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ...

  • Following damage to the blood vessel, endothelium Tissue Factor (TF) is released, forming a complex with FVII and in so doing, activating it (TF-FVIIa).
  • TF-FVIIa activates FIX and FX.
  • FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa.
  • The activation of 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 FVII (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.

Tissue Factor Pathway Inhibitor (or TFPI) is a protein that can reversibly inhibit Factor Xa (Xa), and after it has inhibted Xa, the Xa-TFPI complex can then inhibit the FVIIa-TF complex. ... Prothrombinase is the protein complex that converts prothrombin to thrombin. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ...

Contact Activation Pathway

There is 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. Tropocollagen triple helix. ... High-molecular weight kininogen (HMWK), also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor is a protein from the blood coagulation system as well as the kinin-kallikrein system. ... Please wikify (format) this article or section as suggested in the Guide to layout and the Manual of Style. ...


Final common pathway

Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, 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. Fibrin is a protein involved in the clotting of blood. ... Protein C is a major physiological anticoagulant. ... Thrombomodulin is an integral membrane protein expressed on the surface of epithelial cells. ... “Covalent” redirects here. ...


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 shedded 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. Deficiency of vitamin K (e.g. in malabsorption), use of inhibiting anticoagulants (warfarin, acenocoumarol and phenprocoumon) or disease (cirrhosis, hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence) this causes partial or non gamma carboxylation and affects the coagulation factors ability to bind to expressed phospholipid.

For other uses, see Calcium (disambiguation). ... Phospholipid Two schematic representations of a phospholipid. ... A 250 ml bag of newly collected platelets. ... Microvesicles are fragments of plasma membrane ranging from 0,1-1µm shed from almost all cell types during activation. ... Vitamin K1 (phylloquinone). ... Carboxyglutamate is an uncommon amino acid found in clotting factors. ... A carboxyl or carboxylic group is a functional group consisting of a carbon atom and an oxygen atom doubly bonded to each other. ... Glutamic acid (Glu, E), is the protonated form of glutamate (the anion). ... Malabsorption is the state of impaired absorption of nutrients in the small intestine. ... Warfarin (also known under the brand names of Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant medication that is administered orally or, very rarely, by injection. ... Acenocoumarol is a anticoagulant that functions as a vitamin K antagonist (like warfarin). ... Phenprocoumon is an anticoagulant, functioning as a Vitamin K antagonist. ... Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ...

Inhibitors

Three mechanisms keep the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis:

  • Protein C is an important co-factor inhibitor, which degrades the co-factors FVa and FVIIIa. It is activated by thrombin with thrombomodulin and requires its co-enzyme Protein S to function. Quantitative or qualitative deficiency of either 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 and FXa, as well as FXIIa, and FIXa. 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 F Xa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia.
  • Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X after its original initiation.

Protein C is a major physiological anticoagulant. ... Thrombophilia is the propensity to develop thrombosis (blood clots) due to an abnormality in the system of coagulation. ... Factor V Leiden (sometimes Factor VLeiden) is the name given to a variant of human factor V that causes a hypercoagulability disorder. ... Image:Antithrombin. ... Serine protease inhibitors or serpins (short for serine protease inhibitor) are a group of proteins that inhibit peptidases (old name: proteases). ... Serpins (short for serine protease inhibitor) are a group of structurally related proteins, many of which inhibit peptidases (enzymes that degrade protein, old name: proteases). ... Heparan Sulfate (HS) is a linear polysaccharide found in all animal tissues. ... Chondroitin sulfate Hyaluronan Glycosaminoglycans (GAGs) or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. ... Heparin, a highly sulfated glycosaminoglycan is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule. ... Proteinuria (from protein and urine) means the presence of an excess of serum proteins in the urine. ... Tissue Factor Pathway Inhibitor (or TFPI) is a protein that can reversibly inhibit Factor Xa (Xa), and after it has inhibted Xa, the Xa-TFPI complex can then inhibit the FVIIa-TF complex. ...

Fibrinolysis

Main article: Fibrinolysis

Eventually, all 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. Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. ... Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. ... Plasmin is an important degrading enzyme (EC 3. ...


Testing of coagulation

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

The contact factor pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test. The partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT or APTT) is a performance indicator measuring the efficacy of both the intrinsic and the common coagulation pathways. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ... The Thrombin Clotting Time (TCT), also known as the Thrombin Time (TT), is a coagulation assay which is usually performed in order to detect for the therapeutic level of the anticoagulant Heparin. ... Bleeding time is a medical test done on someone to assess their platelet function. ... D-dimer is a blood test performed in the medical laboratory to diagnose thrombosis. ... The mixing test is a medical laboratory study used to clarify the differential diagnosis of clotting abnormalities. ... Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is a disorder of coagulation, and causes thrombosis in both arteries and veins, as well as recurrent miscarriage. ... Factor V Leiden (sometimes Factor VLeiden) is the name given to a variant of human factor V that causes a hypercoagulability disorder. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... Dilute Russells viper venom time (dRVVT) is a laboratory test for lupus anticoagulant (LA). ... Thromboelastography (TEG®) is a method of testing the efficiency of coagulation in the blood. ... The partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT or APTT) is a performance indicator measuring the efficacy of both the intrinsic and the common coagulation pathways. ...


The tissue factor pathway is initiated by release of "tissue factor" (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. This is reported as an INR value when used for the dosing of oral anticoagulants such as warfarin. The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ... Warfarin (also known under the brand names of Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant medication that is administered orally or, very rarely, by injection. ...


The quantitative and qualitative screening of fibrinogen is measured by the thrombin 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. The Throbin Clotting Time (TCT), also known as the Thrombin Time (TT), is a coagulation assay which is usually performed in order to detect for the thereputic level of the anticoagulant Heparin. ...


If a coagulation factor is part of the contact 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 factor pathway, results in an abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen and some variants of FX which can only be detected by either aPTT or PT. Haemophilia A (also spelt Hemophilia A or Hæmophilia A) is a blood clotting disorder caused by a mutation of the Factor VIII gene, leading to a deficiency in Factor VIII. It is the most common hemophilia. ...


Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.


Role in disease

Problems with coagulation may dispose to hemorrhage, thrombosis, and occasionally both, depending on the nature of the pathology.


Platelet disorders

Platelet conditions may be inborn 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. von Willebrand disease is due to deficiency or abnormal function of von Willebrand factor. Most inborn platelet pathologies predispose to hemorrhage. Glanzmanns thrombasthenia is an extremely rare, autosomal recessive disorder of the blood, in which the platelets lack GPIIb/IIIa. ... Bernard-Soulier syndrome (BSS, named after Jean Bernard and Jean Pierre Soulier) is a rare congenital bleeding disorder characterized by thrombocytopenia and large platelets and was first described in 1948. ... Grey platelet syndrome is a rare condition caused by a reduction of absence of the platelet alpha-granules in blood platelet, or of the proteins contained in these granules. ... In platelets, the term alpha granules is used to describe granules containing several growth factors (such as insulin-like growth factor 1 and platelet-derived growth factor ) and other clotting proteins (such as thrombospondin and fibronectin. ... Hermansky-Pudlak Syndrome (HPS) is an inherited disease which results in decreased pigmentation (oculocutaneous albinism), bleeding problems due to a platelet abnormality (platelet storage pool defect), and storage of an abnormal fat-protein compound (lysosomal accumulation of ceroid lipofuscin). ... Dense granules are specialized secretory organelles. ... Von Willebrand disease (vWD) is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. ... Von Willebrand factor is a blood glycoprotein of the coagulation system. ...


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. Idiopathic thrombocytopenic purpura is the condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic). ... Thrombotic thrombocytopenic purpura (TTP or Moschcowitz disease) is a rare disorder of the blood coagulation system. ... In medicine, Hemolytic-uremic syndrome (or haemolytic-uraemic syndrome, abbreviated HUS) is a disease characterised by microangiopathic hemolytic anemia, acute renal failure and a low platelet count (thrombocytopenia). ... Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired life-threatening disease of the blood characterised by hemolytic anemia, thrombosis and red urine due to breakdown of red blood cells. ... Disseminated intravascular coagulation (DIC) is a pathological process in the body where the blood starts to coagulate throughout the whole body. ... Heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT) is thrombocytopenia (low platelet counts) due to the administration of heparin. ...


Factor disorders and 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). Together with von Willebrand disease (which behaves more like a platelet disorder except in severe cases), these conditions predispose to bleeding. Most hemophilias are inherited. In liver failure (acute and chronic forms) there is insufficient production of coagulation factors by the liver; this may increase bleeding risk. Haemophilia or hemophilia is the name of any of several hereditary genetic illnesses that impair the bodys ability to control bleeding. ... Haemophilia A (also spelt Hemophilia A or Hæmophilia A) is a blood clotting disorder caused by a mutation of the Factor VIII gene, leading to a deficiency in Factor VIII. It is the most common hemophilia. ... Haemophilia B (also spelled Hemophilia B or Hæmophilia B) is a blood clotting disorder caused by a mutation of the Factor IX gene. ... A mild form of hemophilia that mainly occurs in Jews of Ashkenazi descent. ... Liver failure is the final stage of liver disease. ... For the bird, see Liver bird. ...


Thrombosis is the pathological development of blood clots, and embolism is said to occur when a blood clot (thrombus) migrates to another part of the body, interfering with organ function there. Most cases of thrombosis are due to acquired extrinsic problems (surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing conditions (e.g. antiphospholipid syndrome, factor V Leiden and various other rarer causes of thrombophilia). Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ... An embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. ... Blood clot diagram. ... “Surgeon” redirects here. ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... Economy class syndrome was coined in the late 1990s when it turned out that people who has traveled long distances by aeroplane were at an increased risk for thrombosis, especially deep venous thrombosis and its main complication, pulmonary embolism. ... This article, image, template or category should belong in one or more categories. ... Factor V Leiden (sometimes Factor VLeiden) is the name given to a variant of human factor V that causes a hypercoagulability disorder. ... Thrombophilia is the propensity to develop thrombosis (blood clots) due to an abnormality in the system of coagulation. ...


Pharmacology

Procoagulants

The use of adsorbent chemicals, such as zeolites, and other hemostatic agents is also being explored for use in sealing severe injuries quickly. Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms. Zeolite The micro-porous molecular structure of a zeolite, ZSM-5 Zeolites (Greek, zein, to boil; lithos, a stone) are minerals that have a micro-porous structure. ...


Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A. Desmopressin (DDAVP®, Stimate®, Minirin®) is a synthetic drug that mimics the action of antidiuretic hormone, also known as arginine vasopressin. ... Arginine vasopressin receptor 1A (AVPR1A) is a protein that acts as receptor for arginine vasopressin. ...


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 are increasingly popular in the treatment of major bleeding. Haemophilia or hemophilia is the name of any of several hereditary genetic illnesses that impair the bodys ability to control bleeding. ... Prothrombin complex concentrate (PCC) is a combination of several blood clotting factors used to treat bleeding in patients using certain anticoagulants or to prepare them for emergency surgery. ... Cryoprecipitate is a blood product manufactured by warming frozen plasma. ... Categories: Possible copyright violations ... Factor VII (formerly known as proconvertin) is one of the central proteins in the coagulation cascade. ...


Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Aprotinin is used in some forms of major surgery to decrease bleeding risk and need for blood products. Tranexamic acid (commonly marketed as Cyclokapron) is often prescribed for excessive bleeding. ... Aminocaproic acid (marketed as Amicar) is a drug used to treat bleeding disorders. ... Aprotinin (Trasylol®, Bayer) is an injection used to reduce bleeding and clotting during heart surgery. ...


Anticoagulants

Main articles: Antiplatelet drug and Anticoagulant

Anticoagulants and anti-platelet agents are amongst the most commonly used medicines. Anti-platelet agents include aspirin, clopidogrel, dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used during angioplasty. An antiplatelet drug is a member of a class of pharmaceuticals that decreases platelet aggregation and inhibits thrombus formation. ... An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. ... An antiplatelet drug is a member of a class of pharmaceuticals that decreases platelet aggregation and inhibits thrombus formation. ... This article is about the drug. ... A box of Plavix Clopidogrel is a potent oral antiplatelet agent often used in the treatment of coronary artery disease, peripheral vascular disease, and cerebrovascular disease. ... Dipyridamole is a drug that inhibits platelet aggregation and causes vasodilation. ... Ticlopidine is a drug used for its antiplatelet action. ... In medicine, a glycoprotein IIb/IIIa inhibitors, also GpIIb/IIIa inhibitors, is class of antiplatelet agents. ... This article does not cite any references or sources. ...


Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. Warfarin interacts with vitamin K, while 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). Warfarin (also known under the brand names of Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant medication that is administered orally or, very rarely, by injection. ... Coumarin is a chemical compound; a toxin found in many plants, notably in high concentration in the tonka bean, woodruff, and bison grass. ... Heparin, a highly sulfated glycosaminoglycan is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule. ... Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. ... Lepirudin is an anticoagulant which functions as a direct thrombin inhibitor. ... Rivaroxaban (also known as BAY 59-7939) is an oral anticoagulant under development by Bayer. ...


Coagulation factors

Coagulation factors and related substances
Number and/or name Function
I (fibrinogen) Forms clot (fibrin)
II (prothrombin) Its active form (IIa) activates I, V, VII, XIII, protein C, platelets
Tissue factor Co-factor of VIIa (formerly known as factor III)
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
VI Unassigned – old name of Factor Va
VII (stable factor) Activates IX, X
VIII (antihemophilic factor) Co-factor of IX with which it forms the tenase complex
IX (Christmas factor) Activates X: forms tenase complex with factor VIII
X (Stuart-Prower factor) Activates II: froms prothrombinase complex with factor V
XI (plasma thromboplastin antecedent) Activates XII, IX and prekallikrein
XII (Hageman factor) Activates prekallikrein and fibrinolysis
XIII (fibrin-stabilizing factor) Crosslinks fibrin
von Willebrand factor Binds to VIII, mediates platelet adhesion
prekallikrein Activates XII and prekallikrein; cleaves HMWK
high molecular weight kininogen (HMWK) Supports reciprocal activation of XII, XI, and prekallikrein
fibronectin Mediates cell adhesion
antithrombin III Inhibits IIa, Xa, and other proteases;
heparin cofactor II Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")
protein C Inactivates Va and VIIIa
protein S Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein)
protein Z Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPI
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
alpha 2-antiplasmin Inhibits plasmin
tissue plasminogen activator (tPA) Activates plasminogen
urokinase Activates plasminogen
plasminogen activator inhibitor-1 (PAI1) Inactivates tPA & urokinase (endothelial PAI)
plasminogen activator inhibitor-2 (PAI2) Inactivates tPA & urokinase (placental PAI)
cancer procoagulant Pathological factor X activator linked to thrombosis in cancer

Fibrin is a protein involved in the clotting of blood. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... Thromboplastin is a substance present in tissues, platelets, and leukocytes necessary for the coagulation of blood; in the presence of calcium ions thromboplastin is necessary for the conversion of prothrombin to thrombin, an important step in coagulation of blood. ... For other uses, see Calcium (disambiguation). ... Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. ... Prothrombinase is the protein complex that converts prothrombin to thrombin. ... Factor VII (formerly known as proconvertin) is one of the central proteins in the coagulation cascade. ... Factor VIII (FVIII) is an essential clotting factor. ... The tenase complex is formed by the activated forms of the blood coagulation factors factor VIII and factor IX. It forms on a phospholipid surface in the presence of calcium and is responsible for the activation of factor X. ... Factor IX (or Christmas factor or Christmas-Eve factor) is one of the serine proteases (EC 3. ... The tenase complex is formed by the activated forms of the blood coagulation factors factor VIII and factor IX. It forms on a phospholipid surface in the presence of calcium and is responsible for the activation of factor X. ... Factor X, also known by the eponym Stuart-Prower factor or as thrombokinase, is an enzyme ( EC 3. ... Prothrombinase is the protein complex that converts prothrombin to thrombin. ... Factor XI or plasma thromboplastin antecent is one of the enzymes ( EC 3. ... Hageman factor is a plasma protein now usually known as factor XII. It is part of the coagulation cascade and activates factor XI and prekallikrein. ... Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. ... Factor XIII or fibrin stabilizing factor is an enzyme (EC 2. ... Von Willebrand factor is a blood glycoprotein of the coagulation system. ... Please wikify (format) this article or section as suggested in the Guide to layout and the Manual of Style. ... High-molecular weight kininogen (HMWK), also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor is a protein from the blood coagulation system as well as the kinin-kallikrein system. ... Fibronectin is a high-molecular-weight glycoprotein containing about 5% carbohydrate that binds to receptor proteins that span the cells membrane, called integrins. ... Image:Antithrombin. ... Heparin cofactor II is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate (minor antithrombin). MeSH Heparin+Cofactor+II He L, Vicente C, Westrick R, Eitzman D, Tollefsen D (2002). ... Dermatan sulfate is a glycosaminoglycan, formerly called a mucopolysaccharide, found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs. ... Protein C is a major physiological anticoagulant. ... Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver and it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. ... Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. ... Protein Z-dependent protease inhibitor is a protein circulating in the blood which inhibits factors Xa and XIa of the coagulation cascade. ... Plasmin is an important degrading enzyme (EC 3. ... Alpha 2-antiplasmin (or α2-antiplasmin or plasmin inhibitor) is a serine protease inhibitor (serpin) responsible for inactivating plasmin, an important enzyme that participates in fibrinolysis and degradation of various other proteins. ... In blood coagulation, tissue plasminogen activator (tPA) is an enzyme (EC 3. ... Urokinase, also called urokinase-type Plasminogen Activator (uPA) is an enzyme (EC 3. ... Plasminogen activator inhibitor-1 is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis (the physiological breakdown of blood clots). ... Plasminogen activator inhibitor-2 (placental PAI) is a coagulation factor which inactivates tPA & urokinase. ... The placenta is an ephemeral (temporary) organ present in female placental vertebrates, such as some mammals and sharks during gestation (pregnancy). ... Cancer procoagulant is a hypothesised protein, most likely a cysteine protease enzyme (EC 3. ... Factor X, also known by the eponym Stuart-Prower factor or as thrombokinase, is an enzyme ( EC 3. ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ...

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). Arthus discovered in 1890 that calcium was essential in coagulation.[2] Alexander Schmidt suggested that the conversion from fibrinogen to fibrin was the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin".[3][4] Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.[5] Johannes Peter Müller (July 14, 1801, Koblenz – April 28, 1858, Berlin), was a German physiologist, comparative anatomist, and ichthyologist not only known for his discoveries but also for his ability to synthesize knowledge. ... [[ Rudolf Ludwig Karl Virchow (born October 13, 1821, in Schivelbein (Pomerania); died September 5, 1902, in Berlin) was a German doctor, anthropologist, public health activist, pathologist, prehistorian, biologist and politician. ... Nicolas Maurice Arthus was a French immunologist and physiologist. ... Alexander Schmidt (1831 - April 22, 1894) was a physiologist who was born on the Island of Mohn, which today is called Muhu, Estonia. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... A 250 ml bag of newly collected platelets. ... Giulio Bizzozero (1846-1901) was an Italian doctor and medical researcher. ...


The theory that thrombin was generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905.[6] At this stage, it was known that thrombokinase/thromboplastin (factor III) was released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), formed thrombin, which converted fibrinogen into fibrin (I).[7] Thromboplastin is a substance present in tissues, platelets, and leukocytes necessary for the coagulation of blood; in the presence of calcium ions thromboplastin is necessary for the conversion of prothrombin to thrombin, an important step in coagulation of blood. ... Paul Morawitz in 1920 Paul Oskar Morawitz (1879-04-03 in St. ... Calcium plays a vital role in the anatomy, physiology and biochemistry of organisms and of the cell, particularly in signal transduction pathways. ...


Coagulation factors

The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century. (19th century - 20th century - 21st century - more centuries) Decades: 1900s 1910s 1920s 1930s 1940s 1950s 1960s 1970s 1980s 1990s As a means of recording the passage of time, the 20th century was that century which lasted from 1901–2000 in the sense of the Gregorian calendar (1900–1999...


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 that its function was 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.[7]


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.[7] Haemophilia A (also spelt Hemophilia A or Hæmophilia A) is a blood clotting disorder caused by a mutation of the factor VIII gene, leading to a deficiency in Factor VIII. It is the most common hemophilia. ... the first thing that was invented was the automatic DILDO. Education grew explosively because of a very strong demand for high school and college education. ...


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 or Christmas Eve 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.[7] Haemophilia B (also spelled Hemophilia B or Hæmophilia B) is a blood clotting disorder caused by a mutation of the Factor IX gene. ... Stephen Christmas (1947-1993) was a 5 year old boy when he became the first patient described to have Christmas disease (or Haemophilia B) in 1952 by a group of British doctors. ... For other uses, see AIDS (disambiguation). ...


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.[7]


Nomenclature

The usage of Roman numerals rather than eponyms or systematic names was agreed upon during annual conferences (starting in 1955) of hemostasis experts. 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.[7] The system of Roman numerals is a numeral system originating in ancient Rome, and was adapted from Etruscan numerals. ... Please wikify (format) this article or section as suggested in the Guide to layout and the Manual of Style. ... High-molecular weight kininogen (HMWK), also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor is a protein from the blood coagulation system as well as the kinin-kallikrein system. ...


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 nonmammalian animal that uses serine proteases for blood coagulation is the horseshoe crab. Binomial name Linnaeus, 1758 The horseshoe crab, horsefoot, king crab, or sauce-pan (Limulus polyphemus, formerly known as Limulus cyclops, Xiphosura americana, Polyphemus occidentalis) is a chelicerate arthropod. ...


References

  1. ^ Furie B, Furie BC (2005). "Thrombus formation in vivo". J. Clin. Invest. 115 (12): 3355-62. PMID 16322780. 
  2. ^ Arthus M, Pagès C. Nouvelle theorie chimique de la coagulation du sang. Arch Physiol Norm Pathol 1890;5:739–46.
  3. ^ Schmidt A. Zur Blutlehre. Leipzig: Vogel, 1892.
  4. ^ Shapiro SS. Treating thrombosis in the 21st century. N Engl J Med 2003;349:1762-4. PMID 14585945.
  5. ^ Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006;133:251-8. PMID 16643426.
  6. ^ Morawitz. Die Chemie der Blutgerinnung. Ergebn Physiol 1905;4:307-422.
  7. ^ a b c d e f Giangrande PL. Six characters in search of an author: the history of the nomenclature of coagulation factors. Br J Haematol 2003;121:703-12. PMID 12780784.

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

  Results from FactBites:
 
Blood Coagulation (2316 words)
The platelets stimulate local activation of plasma coagulation factors, leading to generation of a fibrin clot that reinforces the platelet aggregate.
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