Structure and function of factor XI

School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
Blood (Impact Factor: 10.45). 04/2010; 115(13):2569-77. DOI: 10.1182/blood-2009-09-199182
Source: PubMed


Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K-dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 "apple domains" that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders.

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Available from: Jonas Emsley, Sep 03, 2014
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    • "FXI circulates in the blood stream [45]. Interaction of FXI with thrombocytes plays an important role under (patho)physiologic conditions, such as in thrombogenesis [45] [46]. Two FXI-like forms were detected in human platelets, whereas only one species was found in plasma [46] [47]. "
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    • "FXI share the same receptor on the platelet surface and bind leucin - rich repeats of glycoprotein Iba , and that binding competition had been observed between these two factors ( Baglia et al , 2004 ; Emsley et al , 2010 ) . Recently , a study has shown that small abnormalities involving VWF and FXI can have clinical relevance , indicating that marginally low , but within the normal range , levels of VWF and mild platelet dysfunction can increase bleeding risk in teenagers ( Gudm - undsdottir et al , 2007 ) . "
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    ABSTRACT: Bleeding risk is not predictable in patients with factor XI (FXI; F11) deficiency. In this prospective study, our objectives were to determine the biological determinants for bleeding risk in patients with heterozygous FXI deficiency. Patients were classified as either bleeding patients or non-bleeding patients by calculating the bleeding score (BS) described for von Willebrand disease. Primary haemostasis, thrombin generation, thromboelastometry, procoagulant proteins, inhibitors, fibrinolysis, and F11 gene mutations were compared between bleeding and non-bleeding patients. Thirty-nine patients were included. BS significantly correlated with clinical assessment (P=0·001), and a score over 3 discriminated between bleeding (n=15) and non-bleeding (n=24) patients (P=0·034). Despite normal values, von Willebrand factor (VWF) and thrombomodulin (TM) plasma levels were significantly lower in bleeding patients than non-bleeding patients [ristocetin cofactor activity (VWF:RCo)=80·6±29·7 iu/dl and 101·8±29·5iu/dl respectively, P=0·043; and VWF antigen (VWF:Ag)=84·0±28·0 iu/dl and 106·3±36·1 iu/dl respectively, P=0·035; and TM=17·7±11·7ng/ml and 23·6±9·7ng/ml respectively, P=0·043]. When considering BS as a continuous variable, only VWF:RCo remained significant (P=0·042), which accounted for 11% of the variability in BS.
    Preview · Article · Nov 2011 · British Journal of Haematology
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    • "The primary substrates of activated FXIII transglutaminase activity include many components of the clotting/fibrinolytic system (e.g., fibrin, fibrinogen, and α 2 -plasmin inhibitor) as well as adhesive and contractile proteins. Clot stabilization by FXIII is derived through the covalent incorporation of α 2 -plasmin inhibitor (α 2 -PI) into the fibrin clot (McDonagh, 1987). Recombinant FXIII (rFXIII) is produced in Saccharomyces cerevisiae as a nonglycosylated FXIII A 2 homodimer that is virtually identical to human cFXIII. "
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    ABSTRACT: Factor XIII (FXIII) is a thrombin-activated plasma coagulation factor critical for blood clot stabilization and longevity. Administration of exogenous FXIII to replenish depleted stores after major surgery, including cardiopulmonary bypass, may reduce bleeding complications and transfusion requirements. Thus, a model of extracorporeal circulation (ECC) was developed in adult male cynomolgus monkeys (Macaca fascicularis) to evaluate the nonclinical safety of recombinant human FXIII (rFXIII). The hematological and coagulation profile in study animals during and after 2 h of ECC was similar to that reported for humans during and after cardiopulmonary bypass, including observations of anemia, thrombocytopenia, and activation of coagulation and platelets. Intravenous slow bolus injection of 300 U/kg (2.1 mg/kg) or 1000 U/kg (7 mg/kg) rFXIII after 2 h of ECC was well tolerated in study animals, and was associated with a dose-dependent increase in FXIII activity. No clinically significant effects in respiration, ECG, heart rate, blood pressure, body temperature, clinical chemistry, hematology (including platelet counts), or indicators of thrombosis (thrombin:anti-thrombin complex and D-Dimer) or platelet activation (platelet factor 4 and beta-thromboglobulin) were related to rFXIII administration. Specific examination of brain, heart, lung, liver, and kidney from rFXIII-treated animals provided no evidence of histopathological alterations suggestive of subclinical hemorrhage or thrombosis. Taken as a whole, the results demonstrate the ECC model suitably replicated the clinical presentation reported for humans during and after cardiopulmonary bypass surgery, and do not suggest significant concerns regarding use of rFXIII in replacement therapy after extracorporeal circulation.
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