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14-September-2008 18:38:45 - Coagulation Redirected from Clotting This article is about the clotting of blood. For other uses, see Coagulation disambiguation. Coagulation is a complex process by which blood forms 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 hemorrhage and/or 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 therefore is the best understood. 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 Contents 1 Physiology 1.1 Platelet activation 1.2 The coagulation cascade 1.2.1 Tissue factor pathway extrinsic 1.2.2 Contact activation pathway intrinsic 1.2.3 Final common pathway 1.3 Cofactors 1.4 Regulators 1.5 Fibrinolysis 2 Testing of coagulation 3 Role in disease 3.1 Platelet disorders 3.2 Disease and clinical significance of thrombosis 4 Pharmacology 4.1 Procoagulants 4.2 Anticoagulants 5 Coagulation factors 6 History 6.1 Initial discoveries 6.2 Coagulation factors 6.3 Nomenclature 7 Other species 8 References 9 External links 9.1 3D structures Physiology Platelet activation Damage to blood vessel walls exposes subendothelium proteins, most notably collagen, present under the endothelium. Circulating platelets bind collagen with surface collagen-specific glycoprotein Ia/IIa receptors. The adhesion is strengthened further by the large, multimeric circulating proteins von Willebrand factor vWF, which forms links between the platelets glycoprotein Ib/IX/V and the collagen fibrils. This adhesion activates the platelets. Activated platelets release the contents of stored granules into the blood plasma. The granules include ADP, serotonin, platelet activating factor PAF, vWF, platelet factor 4 and thromboxane A2 TXA2 which in turn activate additional platelets. The granules contents activate a Gq-linked protein receptor cascade resulting in increased calcium concentration in the platelets' cytosol. The calcium activates protein kinase C which in turn activates phospholipase A2 PLA2. PLA2 then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen. The activated platelets changed shape from spherical to stellate and the fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent 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. 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. 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 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 instantaneously. FVIIa circulates in a higher amount than any other activated coagulation factor. 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 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. 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. 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. 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 for 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. Other deficiencies of vitamin K e.g. in malabsorption, or disease 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. Regulators 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 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 FIX 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 which inhibits excessive fibrin formation. Prostacyclin PGI2 is released by endothelium and activates platelet Gs protein linked receptors. This in turn activates adenylyl cyclase which synthesizes cAMP. cAMP inhibits platelet activation by counteracting the actions that result from increased 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, 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. Testing of coagulation 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. Other: TCT, bleeding time, mixing test whether an abnormality corrects if the patient's plasma is mixed with normal plasma, coagulation factor assays, antiphosholipid antibodies, D-dimer, genetic tests eg. factor V Leiden, prothrombin mutation G20210A, dilute Russell's viper venom time dRVVT, miscellaneous platelet function tests, thromboelastography TEG or ROTEM, euglobulin lysis time ELT, . 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 tissue factor 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 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. 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. 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. 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 much more rare autosomal dominant 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 herary 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 there 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 Glanzman 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 leasds to ischemic necrosis of tissue. 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 known collectively as thrombophilia e.g. antiphospholipid syndrome, factor V Leiden and various other rarer genetic disorders. Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency towards thrombophlebitis. Other mutations have been linked with a rare form of herary angioedema type III. 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. 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 are 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 medicines. Anti-platelet agents include aspirin, clopidogrel, dipyridamole and ticlopidine; 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 , 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. 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, VIII, XI, 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: forms prothrombinase complex with factor V XI plasma thromboplastin antecedent Activates IX XII Hageman factor Activates factor XI and prekallikrein 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 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 was the result of an enzymatic process, and labeled the hypothetical enzyme thrombin and its precursor prothrombin.23 Arthus discovered in 1890 that calcium was essential in coagulation.45 Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.6 The theory that thrombin was generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905.7 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.8 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 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.8 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.8 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.8 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.8 The view that the coagulation process was a cascade or waterfall was enunciated almost simultaneously by MacFarlane9 in the UK and by Davie and Ratnoff10 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.11 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.8 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 known to use serine proteases for blood coagulation is the horseshoe crab. References ^ Furie B, Furie BC 2005. Thrombus formation in vivo. J. Clin. Invest. 115 12: 3355-62. doi:10.1172/JCI26987. PMID 16322780. Full text at PMC: 1297262 ^ Schmidt A 1872. Neue Untersuchungen ueber die Fasserstoffesgerinnung. Pflüger's Archiv für die gesamte Physiologie 6: 413-538. doi:10.1007/BF01612263. ^ Schmidt A. Zur Blutlehre. Leipzig: Vogel, 1892. ^ Arthus M, Pagès C 1890. Nouvelle theorie chimique de la coagulation du sang. Arch Physiol Norm Pathol 5: 739-46. ^ Shapiro SS 2003. Treating thrombosis in the 21st century. N. Engl. J. Med. 349 18: 1762-4. doi:10.1056/NEJMe038152. PMID 14585945. ^ Brewer DB 2006. Max Schultze 1865, G. Bizzozero 1882 and the discovery of the platelet. Br. J. Haematol. 133 3: 251-8. doi:10.1111/j.1365-2141.2006.06036.x. PMID 16643426. ^ Morawitz P 1905. Die Chemie der Blutgerinnung. Ergebn Physiol 4: 307-422. ^ a b c d e f Giangrande PL 2003. Six characters in search of an author: the history of the nomenclature of coagulation factors. Br. J. Haematol. 121 5: 703-12. doi:10.1046/j.1365-2141.2003.04333.x. PMID 12780784. ^ MacFarlane RG 1964. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 202: 498-9. doi:10.1038/202498a0. PMID 14167839. ^ Davie EW, Ratnoff OD 1964. Waterfall sequence for intrinsic blood clotting. Science 145: 1310-2. doi:10.1126/science.145.3638.1310. PMID 14173416. ^ Wright IS 1962. The nomenclature of blood clotting factors. Can Med Assoc J 86: 373-4. PMID 14008442. Full text at PMC: 1848865 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 v d e Proteins: coagulation Coagulation factors primary hemostasis: vWF intrinsic pathway: HMWK/Bradykinin - Kallikrein - Hageman / FXII - FXI - FIX - FVIII extrinsic pathway: Tissue factor / FIII - FVII common pathway: FX - FV - Prothrombin / FII, Fibrin / FI - FXIII Coagulation inhibitors Antithrombin inhibits II, IX, X, XI, XII - Protein C inhibits V, VIII/Protein S cofactor for protein C - Protein Z inhibits X - ZPI inhibits X, XI - TFPI inhibits III Fibrinolysis Plasmin - tPA/urokinase - PAI-1/2 - α2-AP - α2-macroglobulin - TAFI Retrieved from http://en..org/wiki/Coagulation Categories: Hematology | Coagulation system Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Anglo-Saxon AzÉ™rbaycan ÄŒesky Dansk Deutsch Español Ù?ارسی Français Italiano עברית Lietuvių Nederlands 日本語 Oromoo Polski Português РуÑ?Ñ?кий Simple English SlovenÅ¡Ä?ina СрпÑ?ки / Srpski Suomi Svenska தமிழà¯? Tiếng Việt ייִדיש ä¸æ–‡ This page was last modified on 11 September 2008, at 10:01
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