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Peter N. Walsh - One of the best experts on this subject based on the ideXlab platform.
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Factor XI contributes to thrombin generation in the absence of Factor XIi
Blood, 2008Co-Authors: Dmitri V Kravtsov, Peter N. Walsh, Maofu Sun, Andras Gruber, Erik I. Tucker, Anton Matafonov, David GailaniAbstract:During surface-initiated blood coagulation in vitro, activated Factor XII (fXIIa) converts Factor XI (fXI) to fXIa. Whereas fXI deficiency is associated with a hemorrhagic disorder, Factor XII deficiency is not, suggesting that fXI can be activated by other mechanisms in vivo. Thrombin activates fXI, and several studies suggest that fXI promotes coagulation independent of fXII. However, a recent study failed to find evidence for fXII-independent activation of fXI in plasma. Using plasma in which fXII is either inhibited or absent, we show that fXI contributes to plasma thrombin generation when coagulation is initiated with low concentrations of tissue Factor, Factor Xa, or α-thrombin. The results could not be accounted for by fXIa contamination of the plasma systems. Replacing fXI with recombinant fXI that activates Factor IX poorly, or fXI that is activated poorly by thrombin, reduced thrombin generation. An antibody that blocks fXIa activation of Factor IX reduced thrombin generation; however, an antibody that specifically interferes with fXI activation by fXIIa did not. The results support a model in which fXI is activated by thrombin or another protease generated early in coagulation, with the resulting fXIa contributing to sustained thrombin generation through activation of Factor IX.
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crystal structure of the Factor XI zymogen reveals a pathway for transactivation
Nature Structural & Molecular Biology, 2006Co-Authors: Evangelos Papagrigoriou, Peter N. Walsh, Paul A Mcewan, Jonas EmsleyAbstract:Factor XI (FXI), a coagulation protein essential to normal hemostasis, circulates as a disulfide-linked dimer. Here we report the full-length FXI zymogen crystal structure, revealing that the protease and four apple domains assemble into a unique 'cup and saucer' architecture. The structure shows that the thrombin and platelet glycoprotein Ib binding sites are remote within the monomer but lie in close proXImity across the dimer, suggesting a transactivation mechanism.
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the glycoprotein ib ix v complex mediates localization of Factor XI to lipid rafts on the platelet membrane
Journal of Biological Chemistry, 2003Co-Authors: Frank A Baglia, Jose A Lopez, Corie N Shrimpton, Peter N. WalshAbstract:Abstract Factor XI binds to activated platelets where it is efficiently activated by thrombin. The Factor XI receptor is the platelet membrane glycoprotein (GP) Ib-IX-V complex (Baglia, F. A., Badellino, K. O., Li, C. Q., Lopez, J. A., and Walsh, P. N. (2002) J. Biol. Chem. 277, 1662–1668), a significant fraction of which eXIsts within lipid rafts on stimulated platelets (Shrimpton, C. N., Borthakur, G., Larrucea, S., Cruz, M. A., Dong, J. F., and Lopez, J. A. (2002) J. Exp. Med. 196, 1057–1066). Lipid rafts are membrane microdomains enriched in cholesterol and sphingolipids implicated in localizing membrane ligands and in cellular signaling. We now show that Factor XI was localized to lipid rafts in activated platelets (∼8% of total bound) but not in resting platelets. Optimal binding of Factor XI to membrane rafts required prothrombin (and Ca2+) or high molecular weight kininogen (and Zn2+), which are required for Factor XI binding to platelets. An antibody to GPIb (SZ-2) that disrupts Factor XI binding to the GPIb-IX-V complex also disrupted Factor XI-raft association. The isolated recombinant Apple 3 domain of Factor XI, which mediates Factor XI binding to platelets, also completely displaces Factor XI from membrane rafts. To investigate the physiological relevance of the Factor XI-raft association, the structural integrity of lipid rafts was disrupted by cholesterol depletion utilizing methyl-β-cyclodextrin. Cholesterol depletion completely prevented FXI binding to lipid rafts, and initial rates of Factor XI activation by thrombin on activated platelets were inhibited >85%. We conclude that Factor XI is localized to GPIb in membrane rafts and that this association is important for promoting the activation of Factor XI by thrombin on the platelet surface.
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the role of high molecular weight kininogen and prothrombin as coFactors in the binding of Factor XI a3 domain to the platelet surface
Journal of Biological Chemistry, 2000Co-Authors: Karen O Badellino, David Gailani, Frank A Baglia, Maofu Sun, Mingming Zhao, Peter N. WalshAbstract:Abstract We have reported that prothrombin (1 μm) is able to replace high molecular weight kininogen (45 nm) as a coFactor for the specific binding of Factor XI to the platelet (Baglia, F. A., and Walsh, P. N. (1998) Biochemistry 37, 2271–2281). We have also determined that prothrombin fragment 2 binds to the Apple 1 domain of Factor XI at or near the site where high molecular weight kininogen binds. A region of 31 amino acids derived from high molecular weight kininogen (HK31-mer) can also bind to Factor XI (Tait, J. F., and Fujikawa, K. (1987) J. Biol. Chem. 262, 11651–11656). We therefore investigated the role of prothrombin fragment 2 and HK31-mer as coFactors in the binding of Factor XI to activated platelets. Our experiments demonstrated that prothrombin fragment 2 (1 μm) or the HK31-mer (8 μm) are able to replace high molecular weight kininogen (45 nm) or prothrombin (1 μm) as coFactors for the binding of Factor XI to the platelet. To localize the platelet binding site on Factor XI, we used mutant full-length recombinant Factor XI molecules in which the platelet binding site in the Apple 3 domain was altered by alanine scanning mutagenesis. The recombinant Factor XI with alanine substitutions at positions Ser248, Arg250, Lys255, Leu257, Phe260, or Gln263 were defective in their ability to bind to activated platelets. Thus, the interaction of Factor XI with platelets is mediated by the amino acid residues Ser248, Arg250, Lys255, Leu257, Phe260, and Gln263 within the Apple 3 domain.
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thrombin mediated feedback activation of Factor XI on the activated platelet surface is preferred over contact activation by Factor XIia or Factor XIa
Journal of Biological Chemistry, 2000Co-Authors: Frank A Baglia, Peter N. WalshAbstract:To study the pathways for initiation of intrinsic blood coagulation, activated human platelets were compared with dextran sulfate as surfaces for Factor XI activation by Factor XIIa, Factor XIa, or thrombin. Activated gel-filtered platelets promoted the activation of Factor XI (60 nm) by thrombin (0.02-10 nm, EC(50) approXImately 100 pm, threshold concentration approXImately 10 pm) at initial rates 2- to 3-fold greater than those obtained with dextran sulfate in the presence of either high molecular weight kininogen (45 nm) and ZnCl(2) (25 micrometer) or prothrombin (1.2 micrometer) and CaCl(2) (2 mm). The maXImum rates of Factor XI activation achieved in the presence of activated gel-filtered platelets were 30 nm.min(-1) with thrombin, 6 nm.min(-1) with Factor XIIa and 2 nm.min(-1) with Factor XIa. Values of turnover number calculated at various enzyme concentrations (0.05-1 nm) were 24-167 (mean = 86) min(-1) for thrombin, 4.6-50 (mean = 21) min(-1) for Factor XIIa, and 1.3-14 (mean = 8) min(-1) for Factor XIa. A physiological concentration of fibrinogen (9.0 micrometer) inhibited Factor XI activation by thrombin (but not by Factor XIIa) in the presence of dextran sulfate but not in the presence of gel-filtered platelets. Compared with Factors XIIa and XIa, thrombin is the preferred Factor XI activator, and activated platelets are a relevant physiological surface for thrombin-mediated initiation of intrinsic coagulation in vivo.
David Gailani - One of the best experts on this subject based on the ideXlab platform.
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the evolution of Factor XI and the kallikrein kinin system
Blood Advances, 2020Co-Authors: Michal B Ponczek, Maofu Sun, Andras Gruber, Kent S Dickeson, Jonas Emsley, Aleksandr Shamanaev, Alec Laplace, Priyanka Srivastava, Christian J Kastrup, David GailaniAbstract:Factor XI (FXI) is the zymogen of a plasma protease (FXIa) that contributes to hemostasis by activating Factor IX (FIX). In the original cascade model of coagulation, FXI is converted to FXIa by Factor XIIa (FXIIa), a component, along with prekallikrein and high-molecular-weight kininogen (HK), of the plasma kallikrein-kinin system (KKS). More recent coagulation models emphasize thrombin as a FXI activator, bypassing the need for FXIIa and the KKS. We took an evolutionary approach to better understand the relationship of FXI to the KKS and thrombin generation. BLAST searches were conducted for FXI, FXII, prekallikrein, and HK using genomes for multiple vertebrate species. The analysis shows the KKS appeared in lobe-finned fish, the ancestors of all land vertebrates. FXI arose later from a duplication of the prekallikrein gene early in mammalian evolution. Features of FXI that facilitate efficient FIX activation are present in all living mammals, including primitive egg-laying monotremes, and may represent enhancement of FIX-activating activity inherent in prekallikrein. FXI activation by thrombin is a more recent acquisition, appearing in placental mammals. These findings suggest FXI activation by FXIIa may be more important to hemostasis in primitive mammals than in placental mammals. FXI activation by thrombin places FXI partially under control of the vitamin K-dependent coagulation mechanism, reducing the importance of the KKS in blood coagulation. This would explain why humans with FXI deficiency have a bleeding abnormality, whereas those lacking components of the KKS do not.
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an update on Factor XI structure and function
Thrombosis Research, 2018Co-Authors: Bassem M Mohammed, Maofu Sun, Qiufang Cheng, Ivan Ivanov, Anton Matafonov, Kent S Dickeson, David A Sun, Ingrid M Verhamme, Jonas Emsley, David GailaniAbstract:Factor XI (FXI) is the zymogen of a plasma protease, Factor XIa (FXIa), that contributes to thrombin generation during blood coagulation by proteolytic activation of several coagulation Factors, most notably Factor IX (FIX). FXI is a homolog of prekallikrein (PK), a component of the plasma kallikrein-kinin system. While sharing structural and functional features with PK, FXI has undergone adaptive changes that allow it to contribute to blood coagulation. Here we review current understanding of the biology and enzymology of FXI, with an emphasis on structural features of the protein as they relate to protease function.
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Factor XI as a therapeutic target
Arteriosclerosis Thrombosis and Vascular Biology, 2016Co-Authors: David Gailani, Andras GruberAbstract:Factor XIa is a plasma serine protease that contributes to thrombin generation primarily through proteolytic activation of Factor IX. Traditionally considered part of the intrinsic pathway of coagulation, several lines of evidence now suggest that Factor XIa serves as an interface between the vitamin-K-dependent thrombin generation mechanism and the proinflammatory kallikrein-kinin system, allowing the 2 systems to influence each other. Work with animal models and results from epidemiological surveys of human populations support a role for Factor XIa in thromboembolic disease. These data and the clinical observation that deficiency of Factor XI, the zymogen of Factor XIa, produces a relatively mild bleeding disorder suggest that drugs targeting Factor XI or XIa could produce an antithrombotic effect while leaving hemostasis largely intact. Results of a recent trial comparing antisense-induced Factor XI reduction to standard-dose low molecular-weight heparin as prophylaXIs for venous thrombosis during knee replacement are encouraging in this regard. Here, we discuss recent findings on the biochemistry, physiology, and pathology of Factor XI as they relate to thromboembolic disease.
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Factor XI antisense oligonucleotide for prevention of venous thrombosis
The New England Journal of Medicine, 2014Co-Authors: Harry R Buller, David Gailani, Sanjay Bhanot, Brett P. Monia, Claudette Bethune, Gary E Raskob, Annelise Segers, Peter Verhamme, Jeffrey I. WeitzAbstract:Background Experimental data indicate that reducing Factor XI levels attenuates thrombosis without causing bleeding, but the role of Factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a secondgeneration antisense oligonucleotide that specifically reduces Factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty. Methods In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding. Results Around the time of surgery, the mean (±SE) Factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively. Conclusions This study showed that Factor XI contributes to postoperative venous thromboembolism; reducing Factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.)
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Factor XIi promotes blood coagulation independent of Factor XI in the presence of long chain polyphosphates
Journal of Thrombosis and Haemostasis, 2013Co-Authors: Cristina Puy, David Gailani, Andras Gruber, Erik I. Tucker, Sharon H Choi, Stephanie A Smith, James H Morrissey, Zoe C Wong, Owen J. T. MccartyAbstract:Background Inorganic polyphosphates (polyP), which are secreted by activated platelets (short chain polyP) and accumulate in some bacteria (long chain polyP), support the contact activation of Factor XII (FXII), and accelerate the activation of Factor XI (FXI).
Uri Seligsohn - One of the best experts on this subject based on the ideXlab platform.
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abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe Factor XI deficiency
Journal of Thrombosis and Haemostasis, 2014Co-Authors: Michal Zucker, Uri Seligsohn, Ophira Salomon, Alisa S. WolbergAbstract:Background Factor XI (FXI) deficiency is a rare autosomal recessive disorder. Many patients with even very low FXI levels (<20 IU/dL) are asymptomatic or exhibit only mild bleeding, whereas others experience severe bleeding usually following trauma. Neither FXI antigen nor activity predicts bleeding risk in FXI-deficient patients.
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patients with severe Factor XI deficiency have a reduced incidence of deep vein thrombosis
Thrombosis and Haemostasis, 2010Co-Authors: Ophira Salomon, Ariella Zivelin, David M Steinberg, Michal Zucker, David Varon, Uri SeligsohnAbstract:Factor XI (FXI) plays a dual role in haemostasis and thrombosis. It contributes to thrombin generation and promotes inhibition of fibrinolysis. Severe FXI deficiency was shown to confer protection against arterial and venous thrombosis in animal models without compromising haemostasis. We have previously shown that patients with severe FXI deficiency have a low incidence of ischaemic stroke, but display the usual incidence of myocardial infarction. In the present study, we compared the incidence of deep-vein thrombosis (DVT) in 219 unrelated patients with severe FXI deficiency aged 20–94 to the incidence in a large population-based study. No cases of DVT were observed in the FXI-deficient cohort, a result that is significantly lower than the expected number (4.68) computed from the population-based study. The low incidence remains statistically significant when compared to three other population-based studies. These data suggest that severe FXI deficiency provides protection against DVT.
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Factor XI deficiency in humans
Journal of Thrombosis and Haemostasis, 2009Co-Authors: Uri SeligsohnAbstract:Factor XI (FXI) deficiency is an autosomal recessive injury-related bleeding tendency, which is common in Jews particularly of Ashkenazi origin. To date, 152 mutations in the FXI gene have been reported with four exhibiting founder effects in specific populations, Glu117stop in Ashkenazi and Iraqi Jews and Arabs, Phe283Leu in Ashkenazi Jews, Cys38Arg in Basques, and Cys128stop in the United Kingdom. Severe FXI deficiency does not confer protection against acute myocardial infarction, but is associated with a reduced incidence of ischemic stroke. Inhibitors to FXI develop in one-third of patients with very severe FXI deficiency following exposure to blood products. Therapy for prevention of bleeding during surgery in patients with severe FXI deficiency consists of plasma, Factor XI concentrates, fibrin glue and antifibrinolytic agents. In patients with an inhibitor to FXI, recombinant Factor VIIa is useful.
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simultaneous genotyping of coagulation Factor XI type ii and type iii mutations by multiplex real time polymerase chain reaction to determine their prevalence in healthy and Factor XI deficient italians
Haematologica, 2008Co-Authors: Giorgia Zadra, Uri Seligsohn, Rosanna Asselta, Maria Luisa Tenchini, Giancarlo Castaman, Pier Mannuccio Mannucci, Stefano DugaAbstract:Background Factor XI deficiency is a rare autosomal recessive coagulopathy, which is, however, common among Ashkenazi Jews, in whom the so-called type II (E117X) and type III (F283L) mutations account for 98% of alleles. In non-Jewish populations, a higher level of allelic heterogeneity has been reported. However, the type II mutation was found in individuals from England, Portugal, and Italy, and haplotype analysis confirmed its Jewish origin. The aims of this study were to develop a rapid and accurate assay for the simultaneous detection of type II/type III mutations and to determine the frequency of these mutations in a large Italian population of healthy individuals and in a cohort of Factor XI-deficient Italian patients. Design and Methods Type II and III mutations were detected using a newly developed multiplex four-color real-time polymerase chain reaction assay. Haplotype analysis was performed by either DNA sequencing or fragment-length analysis. Results Both type II and type III mutations were found among 3879 healthy Italians with an allele frequency of 0.00064 and 0.00051, respectively. Among the 31 analyzed Factor XI-deficient patients, the type II mutation was found in three individuals in the homozygous state and in eight individuals in the heterozygous state (one compound heterozygote type II/III). Haplotype analysis revealed the Jewish origin of both mutations. Conclusions The newly developed assay is highly specific and reliable (0.02% false positives); and offers a useful means for the molecular diagnosis of Factor XI deficiency. Type II and III mutations are present in the Italian population and should be searched for first in Factor XI-deficient patients.
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reduced incidence of ischemic stroke in patients with severe Factor XI deficiency
Blood, 2008Co-Authors: Ophira Salomon, David M Steinberg, Nira Korenmorag, David Tanne, Uri SeligsohnAbstract:Inherited disorders of hemostasis are natural models for investigating mechanisms of thrombosis and development of antithrombotic therapy. Because mice with total Factor XI deficiency are protected against ischemic stroke and do not manifest excessive bleeding, we investigated the incidence of ischemic stroke in patients with severe inherited Factor XI deficiency. Incidence of ischemic stroke in 115 patients aged 45 years or more with severe Factor XI deficiency (activity less than 15 U/dL) was compared with incidence in the Israeli population as estimated from a stroke survey of 1528 patients. Adjustment for major risk Factors of stroke (hypertension, diabetes mellitus, hypercholesterolemia, current smoking) was based on comparison of their prevalence in the stroke survey to an Israeli health survey of 9509 subjects. Incidence of myocardial infarction in the Factor XI cohort was also recorded. After adjustment for the 4 major risk Factors of ischemic stroke, the expected incidence of ischemic stroke was 8.56 compared with one observed (P = .003). The reduced 1:115 incidence of ischemic stroke contrasted with a 19:115 incidence of myocardial infarction, similar to the expected incidence. Thus, severe Factor XI deficiency probably is protective against ischemic stroke but not against acute myocardial infarction.
Joost C M Meijers - One of the best experts on this subject based on the ideXlab platform.
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in vitro evaluation of Factor ix as novel treatment for Factor XI deficiency
bioRxiv, 2019Co-Authors: Kamran Bakhtiari, Joost C M MeijersAbstract:Factor XI deficiency is associated with mild to moderate bleeding upon injury. Treatment of bleeding in patients can be a challenge due to the limited availability of Factor XI concentrates that may also have thrombotic side effects, and the volume overload as a result of plasma transfusion. In our in vitro study, we established that recombinant Factor IX concentrate Benefix (Pfizer) was able to potently enhance thrombin generation in Factor XI depleted plasma when coagulation was initiated via the extrinsic pathway. This was due to the contamination of Benefix with very low amounts of Factor IXa that compensated for the lack of Factor XI in plasma. Our data suggest that bleeding due to Factor XI deficiency or antithrombotic therapy targeting Factor XI may be treated with certain Factor IX concentrates, which should be investigated in future clinical studies.
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Factor XI Regulates Pathological Thrombus Formation on Acutely Ruptured Atherosclerotic Plaques
Arteriosclerosis thrombosis and vascular biology, 2014Co-Authors: Maurits L. Van Montfoort, Joris J T H Roelofs, Marijke J.e. Kuijpers, Véronique L. Knaup, Sanjay Bhanot, Brett P. Monia, Johan W. M. Heemskerk, Joost C M MeijersAbstract:Objective—Coagulation Factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of Factor XI inhibitors influence atheroscl...
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dominant Factor XI deficiency caused by mutations in the Factor XI catalytic domain
Blood, 2004Co-Authors: Dmitri V Kravtsov, Joost C M Meijers, Maofu Sun, Morey A Blinder, Thao P Dang, Hongli Wang, David GailaniAbstract:The bleeding diathesis associated with hereditary Factor XI (fXI) deficiency is prevalent in Ashkenazi Jews, in whom the disorder appears to be an autosomal recessive condition. The homodimeric structure of fXI implies that the product of a single mutant allele could confer disease in a dominant manner through formation of heterodimers with wild-type polypeptide. We studied 2 unrelated patients with fXI levels less than 20% of normal and family histories indicating dominant disease transmission. Both are heterozygous for single amino acid substitutions in the fXI catalytic domain (Gly400Val and Trp569Ser). Neither mutant is secreted by transfected fibroblasts. In cotransfection experiments with a wild-type fXI construct, constructs with mutations common in Ashkenazi Jews (Glu117Stop and Phe283Leu) and a variant with a severe defect in dimer formation (fXI-Gly350Glu) have little effect on wild-type fXI secretion. In contrast, cotransfection with fXI-Gly400Val or fXI-Trp569Ser reduces wild-type secretion about 50%, consistent with a dominant negative effect. Immunoprecipitation of cell lysates confirmed that fXI-Gly400Val forms intracellular dimers. The data support a model in which nonsecretable mutant fXI polypeptides trap wild-type polypeptides within cells through heterodimer formation, resulting in lower plasma fXI levels than in heterozygotes for mutations that cause autosomal recessive fXI deficiency.
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characterization of the h kininogen binding site on Factor XI a comparison of Factor XI and plasma prekallikrein
Journal of Biological Chemistry, 2002Co-Authors: Thomas Renne, Joost C M Meijers, David Gailani, Werner MulleresterlAbstract:Abstract Factor XI (FXI), the zymogen of the blood coagulation protease FXIa, and the structurally homologous protein plasma prekallikrein circulate in plasma in noncovalent complexes with H-kininogen (HK). HK binds to the heavy chains of FXI and of prekallikrein. Each chain contains four apple domains (F1–F4 for FXI and P1–P4 for prekallikrein). Previous studies indicated that the HK-binding site on FXI is located in F1, whereas the major HK-binding site on prekallikrein is in P2. To determine the contribution of each FXI apple domain to HK-FXI complex formation, we examined binding of recombinant single apple domain-tissue plasminogen activator fusion proteins to HK. The order of affinity from highest to lowest is F2 ≫ F4 > F1 ≫ F3. Monoclonal antibodies against F2 are superior to F4 or F1 antibodies as inhibitors of HK binding to FXI. Antibody αP2, raised against prekallikrein, cross-reacts with FXI F2 and inhibits FXI-HK binding with an IC50 of 8 nm. HK binding to a platelet-specific FXI variant lacking the N-terminal half of F2 is reduced > 5-fold compared with full-length FXI. A chimeric FXI molecule in which F2 is replaced by P2 is cleaved within P2 during activation by Factor XIIa, resulting in greatly reduced HK binding capacity. In contrast, wild-type FXI is not cleaved within F2, and its binding capacity for HK is unaffected by Factor XIIa. Our data show that HK binding to FXI involves multiple apple domains, with F2 being most important. The findings demonstrate a similarity in mechanism for FXI and prekallikrein binding to HK.
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High levels of coagulation Factor XI as a risk Factor for venous thrombosis.
The New England journal of medicine, 2000Co-Authors: Joost C M Meijers, Bonno N. Bouma, Winnie L.h. Tekelenburg, Rogier M. Bertina, Frits R. RosendaalAbstract:Background Factor XI, a component of the intrinsic pathway of coagulation, contributes to the generation of thrombin, which is involved in both the formation of fibrin and protection against fibrinolysis. A deficiency of Factor XI is associated with bleeding, but a role of high Factor XI levels in thrombosis has not been investigated. Methods We determined Factor XI antigen levels in the patients enrolled in the Leiden Thrombophilia Study, a large population-based, case–control study (with a total of 474 patients and 474 controls) designed to estimate the contributions of genetic and acquired Factors to the risk of deep venous thrombosis. Odds ratios were calculated as a measure of relative risk. Results The age- and sex-adjusted odds ratio for deep venous thrombosis in subjects who had Factor XI levels above the 90th percentile, as compared with those who had Factor XI levels at or below that value, was 2.2 (95 percent confidence interval, 1.5 to 3.2). There was a dose–response relation between the facto...
Ophira Salomon - One of the best experts on this subject based on the ideXlab platform.
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the association between Factor XI deficiency and the risk of bleeding cardiovascular and venous thromboembolic events
Thrombosis and Haemostasis, 2021Co-Authors: Sarah Sharman Moser, Ophira Salomon, Gabriel Chodick, Dan Chalothorn, Mingdauh Wang, Alan R Shuldiner, Lori C Morton, Jessica J JalbertAbstract:The objective of this study was to assess the relationship between Factor XI (FXI) deficiency and the risks of bleeding and cardiovascular (CV) events. We conducted a retrospective cohort study using data from Maccabi Healthcare Services (MHS). We identified adults with FXI deficiency (severe:
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Exploring the global landscape of genetic variation in coagulation Factor XI deficiency.
Blood, 2017Co-Authors: Rosanna Asselta, Valeria Rimoldi, Flora Peyvandi, Elvezia Maria Paraboschi, Marzia Menegatti, Ophira Salomon, Stefano DugaAbstract:Factor XI (FXI) deficiency is an autosomal bleeding disorder, usually posttrauma or postsurgery, characterized by reduced levels of coagulation FXI in plasma. The disease is highly prevalent in Ashkenazi Jews (heterozygote frequency, ∼9%), whereas it is considered a rare condition in most populations (prevalence of the severe deficiency, 1 in 106 in the white population). So far, >190 causative mutations have been identified throughout the F11 gene. To have a global landscape of genetic variation of F11, we explored publicly available exome-based data obtained from >60 000 individuals belonging to different ethnicities (Exome Aggregation Consortium resource). This analysis revealed profound differences in heterozygote frequencies among populations (allele frequencies: African = 0.0016; East Asian = 0.0045; European = 0.0036; Finnish = 0.00030; Latino = 0.0021; South Asian = 0.0015), and a prevalence significantly higher than that reported so far (eg, the calculated prevalence of the severe deficiency in Europeans would be: 12.9 in 106). In addition, this analysis allowed us to evidence recurrent and ethnic-specific mutations: p.Phe223Leu in Africans (23.5% of all mutated alleles), p.Gln263X and p.Leu424CysfsX in East Asians (28.2% and 20.5%, respectively), and p.Ala412Thr in Latinos (25%).
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abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe Factor XI deficiency
Journal of Thrombosis and Haemostasis, 2014Co-Authors: Michal Zucker, Uri Seligsohn, Ophira Salomon, Alisa S. WolbergAbstract:Background Factor XI (FXI) deficiency is a rare autosomal recessive disorder. Many patients with even very low FXI levels (<20 IU/dL) are asymptomatic or exhibit only mild bleeding, whereas others experience severe bleeding usually following trauma. Neither FXI antigen nor activity predicts bleeding risk in FXI-deficient patients.
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congenital Factor XI deficiency an update
Seminars in Thrombosis and Hemostasis, 2013Co-Authors: Stefano Duga, Ophira SalomonAbstract:Severe Factor XI (FXI) deficiency is an injury-related bleeding disorder, common in Ashkenazi Jews (with two mutations prevailing), but rare worldwide (with heterogeneous mutations). In the past two decades, more than 220 mutations in the FXI gene have been reported in patients with FXI deficiency, of which 7 showed a founder effect. Inhibitors to FXI were described in patients with null-allele mutations, following exposure to plasma, FXI concentrates, or anti-RhD immunoglobulin. Treatment of patients with severe FXI deficiency remains challenging because Factors influencing bleeding risks are still unknown. The use of lower doses of recombinant activated Factor VII in comparison with the doses commonly applied in hemophilia A or B seems promising also when assessed in vitro by thrombin generation test. Recently, FXI has been shown to have a separate role in hemostasis and in thrombosis. In animal models, targeting FXI by knocking out the gene or by using FXI-neutralizing antibodies, antisense oligonucleotides, and peptidomimetic inhibitors, prevents arterial and vein thrombosis. The homology between human and murine FXI and the significant antithrombotic effect of FXI deficiency in animal models resulted in the development of a novel approach of targeting FXI for prevention of thrombosis without impairing hemostasis in high-risk patients. The acceptance of FXI as a risk Factor for thrombosis is a new concept, and patients with severe FXI deficiency might gain profit during life course.
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patients with severe Factor XI deficiency have a reduced incidence of deep vein thrombosis
Thrombosis and Haemostasis, 2010Co-Authors: Ophira Salomon, Ariella Zivelin, David M Steinberg, Michal Zucker, David Varon, Uri SeligsohnAbstract:Factor XI (FXI) plays a dual role in haemostasis and thrombosis. It contributes to thrombin generation and promotes inhibition of fibrinolysis. Severe FXI deficiency was shown to confer protection against arterial and venous thrombosis in animal models without compromising haemostasis. We have previously shown that patients with severe FXI deficiency have a low incidence of ischaemic stroke, but display the usual incidence of myocardial infarction. In the present study, we compared the incidence of deep-vein thrombosis (DVT) in 219 unrelated patients with severe FXI deficiency aged 20–94 to the incidence in a large population-based study. No cases of DVT were observed in the FXI-deficient cohort, a result that is significantly lower than the expected number (4.68) computed from the population-based study. The low incidence remains statistically significant when compared to three other population-based studies. These data suggest that severe FXI deficiency provides protection against DVT.
