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60-464: 1CFG , 1D7P , 1IQD , 2R7E , 3CDZ , 3HNB , 3HNY , 3HOB , 4BDV , 1FAC , 3J2Q , 3J2S , 4KI5 , 4PT6 , 4XZU 2157 14069 ENSG00000185010 ENSMUSG00000031196 P00451 Q06194 NM_000132 NM_019863 NM_001161373 NM_001161374 NM_007977 NP_000123 NP_063916 NP_001154845 NP_001154846 NP_032003 Coagulation factor VIII ( Factor VIII , FVIII , also known as anti-hemophilic factor ( AHF ))

120-412: 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

180-403: A bleeding disorder. Instead, contact activation system seems to be more involved in inflammation, and innate immunity. Despite this, interference with the pathway may confer protection against thrombosis without a significant bleeding risk. The division of coagulation in two pathways is arbitrary, originating from laboratory tests in which clotting times were measured either after the clotting

240-431: A complex that converts factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein , isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of

300-552: A damaged vessel, followed by repair. The process of coagulation involves activation , adhesion and aggregation of platelets , as well as deposition and maturation of fibrin . Coagulation begins almost instantly after an injury to the endothelium that lines a blood vessel . Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelial platelet tissue factor to coagulation factor VII , which ultimately leads to cross-linked fibrin formation. Platelets immediately form

360-409: A lower cost–benefit ratio . About 25% of items are in the complementary list. Some medications are listed as both core and complementary. While most medications on the list are available as generic products , being under patent does not preclude inclusion. The first list was published in 1977 and included 208 medications. The WHO updates the list every two years. There are 306 medications in

420-585: A major concern for patients receiving therapy against bleeding; the incidence of these inhibitors is dependent of various factors, including the factor VIII product itself. Factor VIII related antigen is used as a target for immunohistochemistry , where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive. In the 1980s, some pharmaceutical companies such as Baxter International and Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available. Under FDA pressure, unheated product

480-481: 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. In acute or chronic liver failure , there

540-491: A plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: additional coagulation factors beyond factor VII ( listed below ) respond in a cascade to form fibrin strands, which strengthen the platelet plug . Coagulation is highly conserved throughout biology. In all mammals , coagulation involves both cellular components (platelets) and proteinaceous components (coagulation or clotting factors). The pathway in humans has been

600-550: 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

660-627: 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 enzymes called serine proteases , which act by cleaving downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII. Tissue factor, FV and FVIII are glycoproteins, and Factor XIII

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720-522: 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

780-448: Is homologous to factor V . The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin . The C domains belong to the phospholipid -binding discoidin domain family, and the C2 domain mediate membrane binding. Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of

840-512: Is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa ) and quickly cleared from the blood stream. Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances. FVIII concentrated from donated blood plasma, or recombinant FVIII can be given to hemophiliacs to restore hemostasis . Bypassing agents such as recombinant FVIIa can be used in acquired hemophilia. Antibody formation to factor VIII can also be

900-410: 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. The main role of the tissue factor (TF) pathway is to generate a "thrombin burst", a process by which thrombin ,

960-414: Is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot. Factor VIII participates in blood coagulation ; it is a cofactor for factor IXa , which, in the presence of Ca and phospholipids , forms

1020-428: Is also required at other points in the coagulation cascade. Calcium ions play a major role in the regulation of coagulation cascade that is paramount in the maintenance of hemostasis. Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII. Vitamin K is an essential factor to the hepatic gamma-glutamyl carboxylase that adds

1080-514: Is an essential blood clotting protein . In humans, it is encoded by F8 gene . Defects in this gene result in hemophilia A , an X-linked bleeding disorder . Factor VIII is produced in the liver 's sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor , until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII

1140-540: Is called thrombocytosis , which may lead to formation of thromboembolisms ; however, thrombocytosis may be associated with increased risk of either thrombosis or hemorrhage in patients with myeloproliferative neoplasm . 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). Von Willebrand disease (which behaves more like

1200-404: 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 blood clot formation can be illustrated by the fact that individuals with severe deficiencies of FXII, HMWK, and prekallikrein do not have

1260-538: 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 A1 domain. This localization of platelets to

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1320-609: 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 (thrombocytopenia) is due to insufficient production (e.g., myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system ( immune thrombocytopenic purpura ), or consumption (e.g., thrombotic thrombocytopenic purpura , hemolytic-uremic syndrome , paroxysmal nocturnal hemoglobinuria , disseminated intravascular coagulation , heparin-induced thrombocytopenia ). An increase in platelet count

1380-426: Is insufficient production of coagulation factors, possibly increasing risk of bleeding during surgery. 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

1440-527: 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 fibrinogen assay . 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

1500-408: Is regulated by plasmin activators and plasmin inhibitors . 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

1560-406: 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. Numerous medical tests are used to assess

1620-491: Is the integration of immune activation into adaptive clot formation. Immunothrombosis is the pathological result of crosstalk between immunity, inflammation, and coagulation. Mediators of this process include damage-associated molecular patterns and pathogen-associated molecular patterns , which are recognized by toll-like receptors , triggering procoagulant and proinflammatory responses such as formation of neutrophil extracellular traps . Various substances are required for

1680-499: Is used to improve platelet function by activating arginine vasopressin receptor 1A . WHO Model List of Essential Medicines The list is divided into core items and complementary items. The core items are deemed to be the most cost-effective options for key health problems and are usable with little additional health care resources. The complementary items either require additional infrastructure such as specially trained health care providers or diagnostic equipment or have

1740-660: The WHO Model List of Essential Medicines for Children (EMLc), was created in 2007 and is in its 9th edition. It was created to make sure that the needs of children were systematically considered such as availability of proper formulations . Everything in the children's list is also included in the main list. The list and notes are based on the 19th to 23rd edition of the main list. Therapeutic alternatives with similar clinical performance are listed for some medicines and they may be considered for national essential medicines lists. The 9th Essential Medicines List for Children

1800-455: The coagulation cascade . It is a cofactor to factor IXa in the activation of factor X , which, in turn, with its cofactor factor Va , activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII ) into a blood clot. The factor VIII protein has a half-life of 12 hours in the blood stream when stabilized by the von Willebrand factor . No longer protected by vWF, activated FVIII

1860-456: 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

Factor VIII - Misplaced Pages Continue

1920-507: 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, forming a platelet plug and thereby completing primary hemostasis). The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation. These are

1980-400: The sinusoidal cells of the liver . Hemophilia A has been corrected by liver transplantation . Transplanting hepatocytes was ineffective, but liver endothelial cells were effective. In the blood, it mainly circulates in a stable noncovalent complex with von Willebrand factor . Upon activation by thrombin (factor IIa), it dissociates from the complex to interact with factor IXa in

2040-647: 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

2100-500: The 14th list in 2005, 410 in the 19th list in 2015, 433 in the 20th list in 2017, 460 in the 21st list in 2019, and 479 in the 22nd list in 2021. Various national lists contain between 334 and 580 medications. The Essential Medicines List (EML) was updated in July 2023 to its 23rd edition. This list contains 1200 recommendations for 591 drugs and 103 therapeutic equivalents. A separate list for children up to 12 years of age, known as

2160-503: The A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa. FVIII is a glycoprotein pro cofactor . Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium , and

2220-469: 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 (PGI 2 )

2280-480: The blood plasma. The granules include ADP , serotonin , platelet-activating factor (PAF), vWF , platelet factor 4 , and thromboxane A 2 (TXA 2 ), 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 A 2 (PLA 2 ). PLA 2 then modifies

2340-621: 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). Unprovoked venous thrombosis may be related to inherited thrombophilias (e.g., factor V Leiden , antithrombin deficiency, and various other genetic deficiencies or variants), particularly in younger patients with family history of thrombosis; however, thrombotic events are more likely when acquired risk factors are superimposed on

2400-410: The classic extrinsic pathway and contributes to about 5% of thrombin production. The amplified production of thrombin occurs via the classic intrinsic pathway in the propagation phase; about 95% of thrombin generated will be during this second phase. Eventually, blood clots are reorganized and resorbed by a process termed fibrinolysis . The main enzyme responsible for this process is plasmin , which

2460-459: The coagulation factors' ability to bind to phospholipid. Several 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

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2520-458: 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 release the contents of stored granules into

2580-422: The fibrin clot is formed, clot retraction occurs and then clot resolution starts, and these two process are together called "tertiary hemostasis". Activated platelets contract their internal actin and myosin fibrils in their cytoskeleton, which leads to shrinkage of the clot volume. Plasminogen activators , such as tissue plasminogen activator (t-PA), activate plasminogen into plasmin, which promotes lysis of

2640-407: The fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels. When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor substances, such as endothelin and thromboxane, to induce the constriction of the smooth muscles in the vessel wall. This helps reduce blood flow to the site of injury and limits bleeding. When the endothelium

2700-487: The fibrin network. 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. A newer model of coagulation mechanism explains the intricate combination of cellular and biochemical events that occur during the coagulation process in vivo . Along with the procoagulant and anticoagulant plasma proteins, normal physiologic coagulation requires

2760-580: The function of the coagulation system: The contact activation (intrinsic) pathway is initiated by activation of the contact activation system , 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

2820-410: The inherited state. 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. Hemostatic Powder Spray TC-325 is used to treated gastrointestinal bleeding. Desmopressin

2880-401: The initiation of the platelet plug, which in turn promotes more platelet activation. Thrombin functions not only to convert fibrinogen to fibrin, it also activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin ). By activating Factor XIII, covalent bonds are formed that crosslink the fibrin polymers that form from activated monomers. This stabilizes

2940-551: The most extensively researched and is the best understood. Disorders of coagulation can result in problems with hemorrhage , bruising , or thrombosis . There are 13 traditional clotting factors, as named below, and other substances necessary for coagulation: Physiology of blood coagulation is based on hemostasis , the normal bodily process that stops bleeding. Coagulation is a part of an integrated series of haemostatic reactions, involving plasma, platelet, and vascular components. Hemostasis consists of four main stages: After

3000-451: 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: 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

3060-406: The most important medications needed in a basic health system . Factor VIII was first characterized in 1984 by scientists at Genentech. The gene for factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene ( F8A1 ) is embedded in one of its introns . Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and

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3120-469: The nature of the defect. Platelet disorders are either congenital or acquired. Examples of congenital platelet disorders 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. They predispose to hemorrhage. Von Willebrand disease

3180-440: The phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism . Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII. Factor VIII is available as a medication that is on the WHO Model List of Essential Medicines ,

3240-427: The presence of two cell types for formation of coagulation complexes: cells that express tissue factor (usually extravascular) and platelets. The coagulation process occurs in two phases. First is the initiation phase, which occurs in tissue-factor-expressing cells. This is followed by the propagation phase, which occurs on activated platelets . The initiation phase, mediated by the tissue factor exposure, proceeds via

3300-470: 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 . Immunohemostasis

3360-443: The proper functioning of the coagulation cascade: Calcium and phospholipids (constituents of platelet membrane) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on Factor Xa and Factor IXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles or microvesicles shed from them. Calcium

3420-637: 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. Deficiencies of common pathway factors prothrombin, fibrinogen, FX, and FV will prolong both aPTT and PT. If an abnormal PT or aPTT is present, additional testing will occur to determine which (if any) factor is present as aberrant concentrations. Deficiencies of fibrinogen (quantitative or qualitative) will prolong PT, aPTT, thrombin time, and reptilase time . Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on

3480-405: Was first discovered in 1937, but it was not until 1979 that its purification by Edward Tuddenham , Frances Rotblat and coworkers led to the molecular identification of the protein. Blood clotting Coagulation , also known as clotting , is the process by which blood changes from a liquid to a gel , forming a blood clot . It results in hemostasis , the cessation of blood loss from

3540-401: Was initiated by glass, the intrinsic pathway; or clotting was initiated by thromboplastin (a mix of tissue factor and phospholipids), the extrinsic pathway. Further, the final common pathway scheme implies that prothrombin is converted to thrombin only when acted upon by the intrinsic or extrinsic pathways, which is an oversimplification. In fact, thrombin is generated by activated platelets at

3600-482: Was pulled from US markets, but was sold to Asian, Latin American, and some European countries. The product was tainted with HIV, a concern that had been discussed by Bayer and the U.S. Food and Drug Administration (FDA). In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy. Factor VIII

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