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Factor XI (factor + xi)
Terms modified by Factor XI Selected AbstractsSuccessful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiencyHAEMOPHILIA, Issue 2 2002P. LAWLER Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high-responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62-year-old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL,1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL,1 with an inhibitor titre of 48 BU. She received 90 ,g kg,1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 ,g kg,1 h,1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117,Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy. [source] Factor XI deficiency and its managementHAEMOPHILIA, Issue 2000Bolton-Maggs Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype. Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups. Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study. [source] Structural and functional features of factor XIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009D. GAILANI Summary., Factor XI (FXI) has structural and mechanistic features that distinguish it from other coagulation proteases. A relatively recent addition to vertebrate plasma coagulation, FXI is a homodimer, with each subunit containing four apple domains and a protease domain. The apple domains form a disk structure with binding sites for platelets, high molecular weight kininogen, and the substrate factor IX (FIX). FXI is converted to the active protease FXIa by cleavage of the Arg369,Ile370 bond on each subunit. This converts the catalytic domains to the active forms, and unmasks exosites on the apple domains required for FIX binding. FXI activation by factor XIIa or thrombin proceeds through an intermediate with only one activated submit (1/2-FXIa). 1/2-FXIa activates FIX in a similar manner to FXIa. While the importance of the homodimeric structure of FXI is not certain, it may represent a strategy for binding to FIX and a platelet surface simultaneously. [source] A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiencyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2004P. H. B. Bolton-Maggs Summary., Factor XI (FXI) deficiency is a mild bleeding disorder that is particularly common in Ashkenazi Jews, but has been reported in all populations. In Jews, two FXI gene (F11) mutations (a stop codon in exon 5, E117X, type II, and a point mutation in exon 9, F283L, type III) are particularly common, but in other populations a variety of different mutations have been described. In the Basque region of France one mutation, C38R in exon 3, was found in eight of 12 families studied, haplotype analysis suggesting a founder effect. In the course of screening 78 unrelated individuals (including 15 Jewish and 12 Asian) we have found 10 Caucasian non-Jewish patients with the mutation C128X in exon 5. Individuals were investigated because of a personal or family history of bleeding, or finding a prolonged activated partial thromboplastin time. Individuals negative for the type II and type III mutations were screened by a combination of SSCP and heteroduplex analysis. The C128X mutation was found in 10 families (one previously described). Among three individuals with severe FXI deficiency, one was homozygous for the C128X mutation, and two were compound heterozygotes for the C128X and another mutation; other individuals were carriers of the C128X mutation. This is a nonsense mutation producing a truncated protein; individuals have FXI antigen levels concordant with FXI coagulant activity. Haplotype analysis of 11 families, including a further kindred previously reported from the USA, but which originally came from the UK (in which the index patient was homozygous for C128X), suggests a founder effect. [source] United States' factor XI-deficiency patients need a safer treatmentAMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2005Louis M. Aledort A replacement factor for Factor XI with is virally inactivated is not available in the U.S. Elsewhere an inactivated concentrate has been used. A review of the experience over 15 years suggests that this product is safe and effective and suggests its potential use in the U.S. The most serious complication of the factor was a slight increase in DIC and thrombotic events. Am. J. Hematol. 80:301,302, 2005. © 2005 Wiley-Liss, Inc. [source] Procoagulant factors and the risk of myocardial infarction in young womenEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2006Bea Tanis Abstract:,Objectives:,We investigated whether elevated levels of factor VIII, IX and XI is associated with myocardial infarction (MI) in young women. In addition, we studied ABO blood group, von Willebrand factor (VWF) and C-reactive protein (CRP). Methods and results:,We compared 200 women with MI before age 49 years with 626 controls from a population-based case,control study. Mean levels of factor VIII activity (VIII), von Willebrand factor antigen (VWF), factor IX activity (IX) were higher in patients (133, 134 and 132 IU/dL) than in controls (111, 107 and 120 IU/dL, respectively). Mean levels of factor XI (XI) were equal in patients (114 IU/dL) and controls (113 IU/dL). The odds ratio (OR) for MI for blood group non-O vs. O was 1.6 [95% confidence interval (CI) 1.1,2.3]. The OR adjusted for age, index year and area of residence for the highest quartile >150 IU/dL of factor VIII was 2.7 (95% CI 1.6,4.6), of VWF 4.7 (95% CI 2.3,9.7), of factor IX 2.6 (95% CI 1.3,5.4) and of factor XI 0.9 (95% CI 0.5,1.4), all compared with the lowest quartile <100 IU/dL. Conclusions:,Non-O blood group, high VWF, factor VIII and factor IX levels are associated with an increased risk of MI in young women, while high factor XI levels are not. [source] Pregnancy and rare bleeding disordersHAEMOPHILIA, Issue 5 2009R. KADIR Summary., Rare bleeding disorders include deficiency of fibrinogen, prothrombin, factor V, factor VII, factor X, factor XI and factor XIII together with combined deficiency disorders, factor V+VIII deficiency, and deficiency of the vitamin K-dependent factors (factor II, VII, IX and X). They account for 3,5% of all inherited coagulation disorders. Due to their rarity, information about pregnancy complications and management is limited and mostly derived from case reports. Deficiency of fibrinogen and FXIII are both found to be strongly associated with increased risk of recurrent miscarriage and placental abruption. Factor replacement is used to reduce these risks. However, the risk of miscarriage and ante-partum complications is less clear in women with other bleeding disorders. Haemostatic abnormalities in women with rare bleeding disorders seem to persist throughout pregnancy especially if the defect is severe. Therefore women affected with these disorders are at risk of post-partum haemorrhage. The fetus can also be affected and potentially at risk of bleeding complications. Specialised multidisciplinary management is essential to minimise the potential maternal and neonatal complications and ensure an optimal outcome. This paper presents literature review for pregnancy complications in each of the rare bleeding disorders. In addition general principles for management of pregnancy, labour and delivery are discussed. [source] Screening for factor XI deficiency amongst pregnant women of Ashkenazi Jewish originHAEMOPHILIA, Issue 6 2006R. A. KADIR Summary., A pilot study was conducted over a 6-month period to evaluate antenatal screening for factor XI (FXI) deficiency amongst Ashkenazi Jewish women booking for their pregnancy in a single obstetric unit. Fifty-four women of Ashkenazi Jewish origin were recruited during their visit for the routine first trimester ultrasound scan. They completed a questionnaire about their personal bleeding symptoms and had blood taken for FXI levels (FXI:C). Seven (13%) women had partial FXI deficiency. Five (9%) were newly diagnosed, and in the remaining two, the diagnosis was known previously. One infant with severe FXI deficiency was identified as a result of maternal testing. This study has shown that FXI deficiency is common amongst women of Ashkenazi Jewish origin and supports its antenatal screening in this population. However, further studies are required to evaluate its cost-effectiveness and the effect on pregnancy outcome. [source] Factor XI deficiency and its managementHAEMOPHILIA, Issue 2000Bolton-Maggs Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype. Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups. Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study. [source] Involvement of the contact phase and intrinsic pathway in herpes simplex virus-initiated plasma coagulationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2010E. S. GERSHOM Summary.,Background:,A hemostatic response to vascular injury is initiated by the extrinsic pathway of coagulation and amplified by the intrinsic pathway. We previously reported that purified herpes simplex virus type-1 (HSV1) has constitutive extrinsic pathway tissue factor (TF) and anionic phospholipid on its surface derived from the host cell, and can consequently bypass strict cellular control of coagulation. Objective:,The current work addresses the hypothesis that HSV1-induced plasma coagulation also involves intrinsic pathway, factor VIII (FVIII), and upstream contact activation pathway, factor XII (FXII). Results:,HSV1-initiated clotting was accelerated when purified FVIII was added to FVIII-deficient plasma and in normal plasma attenuated by an inhibitory anti-FVIII antibody (Ab). High HSV1 concentrations predictably reduced the effect of FVIII due to the availability of excess viral TF. To further define TF-independent clotting mechanisms initiated by HSV1, the extrinsic pathway was disabled using factor VII-deficient plasma. The intrinsic pathway is triggered by activation of FXII associated with surface-bound kallikrein, which subsequently activates factor XI. Here we found that an inhibitor of activated FXII, corn trypsin inhibitor, and anti-FXII, anti-kallikrein and anti-FXI Abs inhibited HSV1-initiated clotting. HSV1-enhanced activation of purified FXII was confirmed by Western blot, but required prekallikrein. Conclusion:,The current work shows that HSV1 can trigger and amplify coagulation through the contact phase and intrinsic pathway, and suggests an additional mechanism that may contribute to vascular pathology. [source] Structural and functional features of factor XIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009D. GAILANI Summary., Factor XI (FXI) has structural and mechanistic features that distinguish it from other coagulation proteases. A relatively recent addition to vertebrate plasma coagulation, FXI is a homodimer, with each subunit containing four apple domains and a protease domain. The apple domains form a disk structure with binding sites for platelets, high molecular weight kininogen, and the substrate factor IX (FIX). FXI is converted to the active protease FXIa by cleavage of the Arg369,Ile370 bond on each subunit. This converts the catalytic domains to the active forms, and unmasks exosites on the apple domains required for FIX binding. FXI activation by factor XIIa or thrombin proceeds through an intermediate with only one activated submit (1/2-FXIa). 1/2-FXIa activates FIX in a similar manner to FXIa. While the importance of the homodimeric structure of FXI is not certain, it may represent a strategy for binding to FIX and a platelet surface simultaneously. [source] Factor XI deficiency in animal modelsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009T. RENNÉ Summary., The blood coagulation system forms fibrin to limit blood loss from sites of injury, but also contributes to occlusive diseases such as deep vein thrombosis, myocardial infarction, and stroke. In the current model of a coagulation balance, normal hemostasis and thrombosis represent two sides of the same coin; however, data from coagulation factor XI-deficient animal models have challenged this dogma. Gene targeting of factor XI, a serine protease of the intrinsic pathway of coagulation, severely impairs arterial thrombus formation but is not associated with excessive bleeding. Mechanistically, factor XI may be activated by factor XII following contact activation or by thrombin in a feedback activation loop. This review focuses on the role of factor XI, and its deficiency states as novel target for prevention of thrombosis with low bleeding risk in animal models. [source] Real-Time quantitative PCR analysis of factor XI mRNA variants in human plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2004A. Podmore Summary., Coagulation factor XI (FXI) plays an essential role in blood coagulation. A deficiency of FXI is an unusual hemorrhagic diathesis in that the bleeding tendency can be highly variable, ranging from severe deficiencies with no symptoms to mild and moderate deficiencies requiring multiple blood transfusions for hemorrhages. This variability in bleeding has been attributed to a number of factors including the presence of a novel form of FXI associated with platelets, which ameliorates the bleeding in some cases of FXI deficiency. However, the nature of this platelet FXI molecule is controversial. Hsu et al. (J Biol Chem 1998; 273: 13787,93) suggest that it is a product of normal FXI , but lacking exon V whilst Martincic et al. (Blood 1999; 94: 3397,404) were unable to detect this alternatively spliced variant using RT-PCR. In order to resolve this controversy, we have employed the highly sensitive technique of real-time quantitative RT-PCR using RNA isolated from FXI-deficient patients. Our results indicate that the platelets of both normal and FXI deficient individuals contain FXI mRNA that is identical to the mRNA found in liver. An exon V deleted splice variant was not detected. Thus the FXI message is not alternatively spliced in platelets and therefore would not be able to produce an unusual FXI protein. [source] The function of factor XI in tissue factor-initiated thrombin generationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003S. Butenas Summary., The influence of plasma and platelet factor (F)XI on thrombin generation initiated with 10 pm tissue factor (TF) in a synthetic coagulation model was evaluated in the presence of either 2 × 108 mL,1 platelets or the equivalent (2 µm) phospholipids. In either system, with all proteins present at physiological concentrations, FXI (30 nm) had no effect on thrombin generation. With phospholipids in the absence of FXI, an increase in vitamin K-dependent proteins (VKDP) (up to 500%) significantly prolonged the initiation phase of thrombin generation and decreased maximum thrombin levels. The inhibition was principally caused by the elevated prothrombin and FIX concentrations. When 30 nm FXI was added with elevated VKDP and phospholipids, the initiation phase was decreased and the maximum thrombin levels generated substantially increased. In experiments with platelets (with and without plasma FXI), an increase in VKDP had little effect on the initiation phase of thrombin generation. These data indicate that (i) FXI has no effect on thrombin generation at 10 pm TF and physiological concentrations of VKDP; (ii) platelets and plasma FXI are able to compensate for the inhibitory effects of elevated VKDP. [source] Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitorsACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2005Pramod Pandey Activated factor XI (FXIa) is a key enzyme in the amplification phase of the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser bleeding liabilities and provide a safe alternative for antithrombosis therapy to available drugs on the market. In a previous report, the crystal structures of the catalytic domain of FXIa (rhFXI370,607) in complex with various ecotin mutants have been described [Jin et al. (2005), J. Biol. Chem.280, 4704,4712]. However, ecotin forms a matrix-like interaction with rhFXI370,607 and is impossible to displace with small-molecule inhibitors; ecotin crystals are therefore not suitable for iterative structure-based ligand design. In addition, rhFXI370,607 did not crystallize in the presence of small-molecule ligands. In order to obtain the crystal structure of rhFXI370,607 with a weak small-molecule ligand, namely benzamidine, several rounds of surface-residue mutation were implemented to promote crystal formation of rhFXI370,607. A quadruple mutant of rhFXI370,607 (rhFXI370,607 -S434A,T475A,C482S,K437A) readily crystallized in the presence of benzamidine. The benzamidine in the preformed crystals was easily exchanged with other FXIa small-molecule inhibitors. These crystals have facilitated the structure-based design of small-molecule FXIa inhibitors. [source] | ||||||||||