3S9C , 1CZS , 1CZV , 3P6Z , 3P70
62-625: FVL may refer to: Factor V , a protein Fox Valley Lutheran High School , in Appleton, Wisconsin, United States Future Vertical Lift , a program of the United States Armed Forces Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title FVL . If an internal link led you here, you may wish to change
124-479: A by making three cleavages (Arg , Arg , Arg ). The cleavages at both Arg and Arg diminish the molecule's attraction to Factor X a , and though the first of these sites is slow to be cleaved, it is entirely necessary to the functioning of Factor V. Protein S aids this process by catalysing the proteolysis at Arg , in which the A2 domain of Factor V is dissociated from the rest of the protein. Protein S also binds to Factor X
186-453: A efficiently. Another is necessary for interacting with thrombomodulin. Post-translational modifications . Human Protein C has at least five types of post-translational modifications : (1) gamma- carboxylation on the first nine glutamic acid residues in the protein sequence. This modification event is performed by a vitamin K-dependent microsomal carboxylase. The full complement of Gla
248-431: A propeptide . Protein C is formed when a dipeptide of Lys and Arg is removed; this causes the transformation into a heterodimer with N -linked carbohydrates on each chain. The protein has one light chain (21 kDa ) and one heavy chain (41 kDa) connected by a disulfide bond between Cys and Cys . Inactive protein C comprises 419 amino acids in multiple domains : one Gla domain (residues 43–88);
310-406: A serine protease zymogen : APC proteolyses peptide bonds in activated Factor V and Factor VIII (Factor V a and Factor VIII a ), and one of the amino acids in the bond is serine . These proteins that APC inactivates, Factor V a and Factor VIII a , are highly procoagulant cofactors in the generation of thrombin , which is a crucial element in blood clotting; together they are part of
372-483: A serine protease since it contains a residue of serine in its active site . In humans, protein C is encoded by the PROC gene , which is found on chromosome 2 . The zymogenic form of protein C is a vitamin K -dependent glycoprotein that circulates in blood plasma . Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a disulfide bond . The protein C zymogen
434-432: A , inhibiting the latter from diminishing APC's inactivation of Factor V a . The inactivation of Factor VIII a is not as well understood. The half-life of Factor VIII a is only around two minutes unless Factor IX a is present to stabilise it. Some have questioned the significance of APC's inactivation of Factor VIII a , and it is unknown to what degree Factor V and protein S are cofactors in its proteolysis. It
496-514: A bleeding tendency associated with the genetic up‐regulation of FV‐short, a minor splicing isoform of FV. This abnormal bleeding tendency occurs in east Texas bleeding disorder, Amsterdam bleeding disorder, and a third and more extreme example described in 2021 by Karen L. Zimowski et al. Other mutations of factor V are associated with venous thrombosis . They are the most common hereditary causes for thrombophilia (a tendency to form blood clots ). The most common one of these, factor V Leiden ,
558-506: A degree, APC's anticoagulant properties are independent of its cytoprotective ones, in that expression of one pathway is not affected by the existence of the other. The activity of protein C may be down-regulated by reducing the amount either of available thrombomodulin or of EPCR. This may be done by inflammatory cytokines , such as interleukin-1β (IL-1β ) and tumor necrosis factor-α (TNF-α). Activated leukocytes release these inflammatory mediators during inflammation, inhibiting
620-508: A fetus is homozygous or compound heterozygous for the deficiency, there may be a presentation of purpura fulminans , severe disseminated intravascular coagulation and simultaneous venous thromboembolism in the womb; this is very severe and usually fatal. Deletion of the protein C gene in mice causes fetal death around the time of birth. Fetal mice with no protein C develop normally at first, but experience severe bleeding, coagulopathy , deposition of fibrin and necrosis of
682-458: A helical aromatic segment (89–96); two epidermal growth factor (EGF)-like domains (97–132 and 136–176); an activation peptide (200–211); and a trypsin -like serine protease domain (212–450). The light chain contains the Gla- and EGF-like domains and the aromatic segment. The heavy chain contains the protease domain and the activation petide. It is in this form that 85–90% of protein C circulates in
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#1732851647419744-453: A heritable resistance to APC was detected by Dahlbäck et al. and associated with familial thrombophilia . In 1994, the relatively common genetic mutation that produces Factor V Leiden was noted (Bertina et al. ). Two years later, Gla-domainless APC was imaged at a resolution of 2.8 Ångströms . Beginning with the PROWESS clinical trial of 2001, it was recognised that many of
806-473: A low dosage to ensure that the protein C deficiency does not present before the vitamin K coagulation factors II, IX and X are suppressed. Activated protein C cleaves Plasmodium falciparum histones which are released during infection: cleavage of these histones eliminates their pro inflammatory effects. In November 2001, the Food and Drug Administration approved Drotrecogin alfa-activated (DrotAA) for
868-527: A product of four factors: calcium (IV) and thrombokinase (III) together acting on prothrombin (II) to produce fibrinogen (I); this model had been outlined by Paul Morawitz in 1905. The suggestion that an additional factor might exist was made by Paul Owren [ no ] (1905–1990), a Norwegian physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from nosebleeds and menorrhagia (excessive menstrual blood loss) for most her life, and
930-468: A region of brain of oxygen, causing tissue death. Promising studies suggest that APC could be coupled with the only currently approved treatment, tissue plasminogen activator (tPA), to protect the brain from tPA's very harmful side effects , in addition to preventing cell death from lack of oxygen ( hypoxia ). Clinical use of APC has also been proposed for improving the outcome of pancreatic islet transplantation in treating type I diabetes . Ceprotin
992-400: A single-chain molecule with a plasma half-life of 12–36 hours. Factor V is able to bind to activated platelets and is activated by thrombin . On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by calcium . The thereby activated factor V (now called FVa) is a cofactor of
1054-560: A triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma. The C domains belong to the phospholipid -binding discoidin domain family (unrelated to C2 domain ), and the C2 domain mediates membrane binding. The B domain C-terminus acts as a cofactor for the anticoagulant protein C activation by protein S . Activation of factor V to factor Va
1116-407: Is a protein involved in coagulation , encoded, in humans, by F5 gene . In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor . Factor V deficiency leads to predisposition for hemorrhage , while some mutations (most notably factor V Leiden ) predispose for thrombosis . The gene for factor V is located on the first chromosome (1q24). It
1178-414: Is a zymogen , that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation , inflammation , and cell death and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C ( APC ) performs these operations primarily by proteolytically inactivating proteins Factor V a and Factor VIII a . APC is classified as
1240-458: Is activated when it binds to thrombin , another protein heavily involved in coagulation, and protein C's activation is greatly promoted by the presence of thrombomodulin and endothelial protein C receptors (EPCRs). Because of EPCR's role, activated protein C is found primarily near endothelial cells (i.e., those that make up the walls of blood vessels), and it is these cells and leukocytes (white blood cells) that APC affects. Because of
1302-451: Is activated; the anticoagulative effects of APC occur when it does not. In this case, protein C functions as an anticoagulant by irreversibly proteolytically inactivating Factor V a and Factor VIII a , turning them into Factor V i and Factor VIII i respectively. When still bound to EPCR, activated protein C performs its cytoprotective effects, acting on the effector substrate PAR-1, protease-activated receptor-1 . To
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#17328516474191364-432: Is an acquired protein C deficiency due to treatment with warfarin , which is a vitamin K antagonist and an anticoagulant itself. However, warfarin treatment may produce paradoxical skin lesions similar to those seen in purpura fulminans. A variant of this response presents as venous limb gangrene when warfarin is used to treat deep vein thrombosis associated with cancer. In these situations, warfarin may be restarted at
1426-408: Is approximately 11,000 bases long. Human protein C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting, such as prothrombin , Factor VII , Factor IX and Factor X . Protein C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acid N-terminus signal peptide preceding
1488-475: Is at the cleavage site in Factor V for APC. There, Arg is replaced with Gln, producing Factor V Leiden . This mutation is also called a R506Q. The mutation leading to the loss of this cleavage site actually stops APC from effectively inactivating both Factor V a and Factor VIII a . Thus, the person's blood clots too readily, and he is perpetually at an increased risk for thrombosis. Individuals heterozygous for
1550-462: Is conjectured to improve activation of protein C by forming an electrostatic bridge from protein C's Gla domain to the glycosaminoglycan (GAG) domain of thrombomodulin, reducing the Michaelis constant (K M ) for their reaction. In addition, Protein C is inhibited by protein C inhibitor . Protein C is a major component in anticoagulation in the human body. It acts as
1612-652: Is done by cleavage and release of the B domain, after which the protein no longer assists in activating protein C. The protein is now divided to a heavy chain, consisting of 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 Va. Factor V is produced by megakaryocytes , which produce platelets and platelet-derived factor V, and hepatocytes, which produce plasma-derived factor V. The molecule circulates in plasma as
1674-409: Is due to the replacement of an arginine residue with glutamine at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance"). It therefore remains active and increases the rate of thrombin generation. Until the discovery of factor V, coagulation was regarded as
1736-498: Is found at levels approximately 2000 times lower than this. Mild protein C deficiency corresponds to plasma levels above 20 IU/dL, but below the normal range. Moderately severe deficiencies describe blood concentrations between 1 and 20 IU/dL; severe deficiencies yield levels of protein C that are below 1 IU/dL or are undetectable. Protein C levels in a healthy term infant average 40 IU/dL. The concentration of protein C increases until six months, when
1798-404: Is genomically related to the family of multicopper oxidases , and is homologous to coagulation factor VIII . The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa. Factor V protein consists of six domains: A1-A2-B-A3-C1-C2. The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin , and form
1860-742: Is known that APC works on Factor VIII a by cleaving at two sites, Arg and Arg , either of which is sufficient to disable Factor VIII a and convert it to Factor VIII i . When APC is bound to EPCR, it performs a number of important cytoprotective (i.e. cell-protecting) functions, most of which are known to require EPCR and PAR-1. These include regulating gene expression, anti-inflammatory effects, antiapoptotic effects and protecting endothelial barrier function. Treatment of cells with APC demonstrates that its gene expression modulation effectively controls major pathways for inflammatory and apoptotic behaviour. There are about 20 genes that are up-regulated by protein C, and 20 genes that are down-regulated:
1922-473: Is required to give full activity to protein C. (2) beta- Hydroxylation of Asp71 in one of the two EGF-like domains to give erythro-L-beta-hydroxy-aspartate (bHA). The modification is required for functional activity as was demonstrated by mutating Asp71 to Glu. (3) N-linked glycosylation at three possible glycosylation sites. Plasma human Protein C has been reported to be 23% carbohydrate by weight. (4) Disulfide formation. (5) Multiple proteolytic cleavages of
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1984-670: Is the most common genetic cause for thrombosis . Factor V has been shown to interact with Protein S . Protein C 1AUT , 1LQV , 3F6U , 3JTC , 4DT7 5624 19123 ENSG00000115718 ENSMUSG00000024386 P04070 P33587 NM_000312 NM_001042767 NM_001042768 NM_008934 NM_001313938 NP_001362535 NP_001362536 NP_001362537 NP_001362538 NP_001362539 NP_001362540 NP_001362542 NP_001036232 NP_001036233 NP_001300867 NP_032960 Protein C , also known as autoprothrombin IIA and blood coagulation factor XIV ,
2046-738: The Second World War , and while Owren published his results in Norway in 1944, he could not publish them internationally until the war was over. They appeared finally in The Lancet in 1947. The possibility of an extra coagulation factor was initially resisted on methodological grounds by Drs Armand Quick and Walter Seegers, both world authorities in coagulation. Confirmatory studies from other groups led to their final approval several years later. Owren initially felt that factor V (labile factor or proaccelerin) activated another factor, which he named VI. VI
2108-400: The prothrombinase complex: The activated factor X (FXa) enzyme requires calcium and activated factor V (FVa) to convert prothrombin to thrombin on the cell surface membrane. Factor Va is degraded by activated protein C , one of the principal physiological inhibitors of coagulation. In the presence of thrombomodulin , thrombin acts to decrease clotting by activating protein C; therefore,
2170-410: The prothrombinase complex . Cofactors in the inactivation of Factor V a and Factor VIII a include protein S , Factor V, high-density lipoprotein , anionic phospholipids and glycosphingolipids . Factor V a binds to prothrombin and Factor X a , increasing the rate at which thrombin is produced by four orders of magnitude (10,000x). Inactivation of Factor V a thus practically halts
2232-533: The 2004 Surviving Sepsis Campaign Guidelines. However, a 2012 Cochrane review found that its use cannot be recommended since it does not improve survival and increases bleeding risk. In October 2011, Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Protein C's anticoagulant role in the human body was first noted by Seegers et al. in 1960, who gave protein C its original name, autoprothrombin II-a . Protein C
2294-418: The Factor V Leiden mutation carry a risk of venous thrombosis 5–7 times higher than in the general population. Homozygous subjects have a risk 80 times higher. This mutation is also the most common hereditary risk for venous thrombosis among Caucasians . Around 5% of APC resistance are not associated with the above mutation and Factor V Leiden . Other genetic mutations cause APC resistance, but none to
2356-513: The accelerating effect of thrombomodulin on the activation of protein C, the protein may be said to be activated not by thrombin but the thrombin–thrombomodulin (or even thrombin–thrombomodulin–EPCR) complex. Once in active form, APC may or may not remain bound to EPCR, to which it has approximately the same affinity as the protein zymogen. Protein C in zymogen form is present in normal adult human blood plasma at concentrations between 65 and 135 IU / dL . Activated protein C
2418-453: The clinical treatment of adults suffering from severe sepsis and with a high risk of death. Drotrecogin alfa-activated is a recombinant form of human activated protein C (rhAPC). It is marketed as Xigris by Eli Lilly and Company , Drotrecogin alfa-activated was the subject of significant controversy while it was approved for clinical use as it was found to increase bleeding and not to reduce mortality. In October 2011 rhAPC (Xigris)
2480-426: The concentration and action of protein C are important determinants in the negative feedback loop through which thrombin limits its own activation. Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of hemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an autosomal recessive fashion. There exists
2542-486: The consequent serious health effects were described in 1984 by several scientists. cDNA cloning of protein C was first performed in 1984 by Beckmann et al. which produced a map of the gene responsible for producing protein C in the liver. In 1987 a seminal experiment was performed (Taylor et al. ) whereby it was demonstrated that activated protein C prevented coagulopathy and death in baboons infused with lethal concentrations of E. coli . In 1993,
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2604-478: The creation of both thrombomodulin and EPCR, and inducing their shedding from the endothelial surface. Both of these actions down-regulate protein C activation. Thrombin itself may also have an effect on the levels of EPCR. In addition, proteins released from cells can impede protein C activation, for example eosinophil , which may explain thrombosis in hypereosinophilic heart disease. Protein C may be up-regulated by platelet factor 4 . This cytokine
2666-573: The crucial role that protein C plays as an anticoagulant , those with deficiencies in protein C, or some kind of resistance to APC , suffer from a significantly increased risk of forming dangerous blood clots ( thrombosis ). Research into the clinical use of a recombinant form of human Activated Protein C (rhAPC) known as Drotrecogin alfa-activated , branded Xigris by Eli Lilly and Company , has been surrounded by controversy. Eli Lilly ran an aggressive marketing campaign to promote its use for people with severe sepsis and septic shock and sponsored
2728-720: The exact mechanisms by which apoptosis is inhibited. It is known that APC is neuroprotective . Antiapoptosis is achieved with diminished activation of caspase 3 and caspase 8 , improved Bax/Bcl-2 ratio and down-regulation of p53. Activated protein C also provides much protection of endothelial barrier function. Endothelial barrier breakdown, and the corresponding increase in endothelial permeability, are associated with swelling , hypotension and inflammation, all problems of sepsis. APC protects endothelial barrier function by inducing PAR-1 dependent sphingosine kinase-1 activation and up-regulating sphingosine-1-phosphate with sphingosine kinase . Several studies have indicated that
2790-448: The extent that Factor V Leiden does. These mutations include various other versions of Factor V, spontaneous generation of autoantibodies targeting Factor V, and dysfunction of any of APC's cofactors. Also, some acquired conditions may reduce the efficacy of APC in performing its anticoagulative functions. Studies suggest that between 20% and 60% of thrombophilic patients suffer from some form of APC resistance. Warfarin necrosis
2852-859: The former are generally anti-inflammatory and antiapoptotic pathways, while the latter tend to be proinflammatory and proapoptotic. APC's mechanisms for altering gene expression profiles are not well understood, but it is believed that they at least partly involve an inhibitory effect on transcription factor activity. Important proteins that APC up-regulates include Bcl-2 , eNOS and IAP . APC effects significant down-regulation of p53 and Bax . APC has anti-inflammatory effects on endothelial cells and leukocytes . APC affects endothelial cells by inhibiting inflammatory mediator release and down-regulating vascular adhesion molecules . This reduces leukocyte adhesion and infiltration into tissues, while also limiting damage to underlying tissue. APC supports endothelial barrier function and reduces chemotaxis . APC inhibits
2914-450: The inside of blood vessels). The presence of thrombomodulin accelerates activation by several orders of magnitude, and EPCR speeds up activation by a factor of 20. If either of these two proteins is absent in murine specimens, the mouse dies from excessive blood-clotting while still in an embryonic state. On the endothelium, APC performs a major role in regulating blood clotting, inflammation, and cell death ( apoptosis ). Because of
2976-601: The link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=FVL&oldid=745077867 " Category : Disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Factor V 2153 14067 ENSG00000198734 ENSMUSG00000026579 P12259 O88783 NM_000130 NM_007976 NP_000121 NP_032002 Coagulation factor V ( Factor V ), also less commonly known as proaccelerin or labile factor ,
3038-587: The liver. The frequency of protein C deficiency among asymptomatic individuals is between 1 in 200 and 1 in 500. In contrast, significant symptoms of the deficiency are detectable in 1 in 20,000 individuals. No racial nor ethnic biases have been detected. At least 177 disease-causing mutations in this gene have been discovered. Activated protein C resistance occurs when APC is unable to perform its functions. This disease has similar symptoms to protein C deficiency. The most common mutation leading to activated protein C resistance among Caucasians
3100-572: The mean level is 60 IU/dL; the level stays low through childhood until it reaches adult levels after adolescence . The half-life of activated protein C is around 15 minutes. The protein C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body. Protein C is pleiotropic , with two main classes of functions: anticoagulation and cytoprotection (its direct effect on cells). Which function protein C performs depends on whether or not APC remains bound to EPCR after it
3162-653: The plasma as a zymogen , waiting to be activated. The remaining protein C zymogen comprises slightly modified forms of the protein. Activation of the enzyme occurs when a thrombin molecule cleaves away the activation peptide from the N-terminus of the heavy chain. The active site contains a catalytic triad typical of serine proteases (His , Asp and Ser ). The Gla domain is particularly useful for binding to negatively charged phospholipids for anticoagulation and to EPCR for cytoprotection . One particular exosite augments protein C's ability to inactivate Factor V
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#17328516474193224-410: The polypeptide backbone to remove an 18 amino acid signal peptide , a 24 amino acid propeptide and then cleavages at amino acids 155-156 and 157-158 to yield the two-chain structure of the circulating zymogen. The activation of protein C is strongly promoted by thrombomodulin and endothelial protein C receptor (EPCR), the latter of which is found primarily on endothelial cells (cells on
3286-414: The production of thrombin. Factor VIII, on the other hand, is a cofactor in production of activated Factor X, which in turn converts prothrombin into thrombin. Factor VIII a augments Factor X activation by a factor of around 200,000. Because of its importance in clotting, Factor VIII is also known as anti-haemophilic factor, and deficiencies of Factor VIII cause haemophilia A . APC inactivates Factor V
3348-546: The protein's modulation of the immune system. The biologic instructions for synthesising protein C in humans are encoded in the gene officially named "protein C (inactivator of coagulation factors Va and VIIIa)". The gene's symbol approved by the HUGO Gene Nomenclature Committee is "PROC" from " pro tein C ". It is located on the second chromosome (2q13-q14) and comprises nine exons . The nucleotide sequence that codes for human protein C
3410-453: The proteolytic activity of APC contributes to the observed cytoprotective properties of APC, but variants that are proteolytically inactive also are able to regulate formation of PAR-activators thrombin and factor Xa and express cytoprotective properties in vitro and in vivo. A genetic protein C deficiency , in its mild form associated with simple heterozygosity , causes a significantly increased risk of venous thrombosis in adults. If
3472-423: The release of inflammatory-response mediators in leukocytes as well as endothelial cells, by reducing cytokine response, and maybe diminishing systemic inflammatory response, such as is seen in sepsis . Studies on both rats and humans have demonstrated that APC reduces endotoxin -induced pulmonary injury and inflammation. Scientists recognise activated protein C's antiapoptotic effects, but are unclear as to
3534-477: The symptoms of sepsis may be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased. Near the end of that year, Drotrecogin alfa (activated) , a recombinant human activated protein C, became the first drug approved by the U.S. FDA for treating severe sepsis . In 2002, Science published an article that first showed protein C activates protease-activated receptor-1 (PAR-1) and this process accounts for
3596-480: Was first isolated by Johan Stenflo from bovine plasma in 1976, and Stenflo determined it to be a vitamin K-dependent protein . He named it protein C because it was the third protein ("peak C") that eluted from a DEAE-Sepharose ion-exchange chromotograph . Seegers was, at the time, searching for vitamin K-dependent coagulation factors undetected by clotting assays , which measure global clotting function. Soon after this, Seegers recognised Stenflo's discovery
3658-548: Was found to have a prolonged prothrombin time , suggesting either vitamin K deficiency or chronic liver disease leading to prothrombin deficiency. However, neither were the case, and Owren demonstrated this by correcting the abnormality with plasma from which prothrombin had been removed. Using Mary's serum as index, he found that the "missing" factor, which he labeled V (I–IV having been used in Morawitz' model), had particular characteristics. Most investigations were performed during
3720-483: Was identical with his own. Activated protein C was discovered later that year, and in 1977 it was first recognised that APC inactivates Factor V a . In 1980, Vehar and Davie discovered that APC also inactivates Factor VIII a , and soon after, Protein S was recognised as a cofactor by Walker. In 1982, a family study by Griffin et al . first associated protein C deficiency with symptoms of venous thrombosis . Homozygous protein C deficiency and
3782-412: Was the factor that accelerated the conversion from prothrombin to thrombin. It was later discovered that factor V was "converted" (activated) by thrombin itself, and later still that factor VI was simply the activated form of factor V. The complete amino acid sequence of the protein was published in 1987. In 1994 factor V Leiden , resistant to inactivation by protein C , was described; this abnormality
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#17328516474193844-445: Was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. APC has been studied as way of treating lung injury, after studies showed that in patients with lung injury, reduced APC levels in specific parts of the lungs correlated with worse outcomes. APC also has been considered for use in improving patient outcome in cases of ischemic stroke , a medical emergency in which arterial blockage deprives
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