Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “FACTOR XI”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources
PubMed2007

A cross-reactive material positive variant of coagulation factor XI (FXIP520L) with a catalytic defect.

Inherited deficiency of the trypsin-like protease factor (F) XI is associated with a mild to moderate bleeding diathesis. In most cases, FXI protein is reduced in plasma, and examples of dysfunctional circulating FXI variants are rare. We characterized the defect in one such variant with a proline to leucine substitution at residue 520. FXI Pro520 corresponds to chymotrypsin Pro161, and is conserved in most members of the chymotrypsin protease family. Recombinant FXI containing this substitution will be referred to as FXI(P161L). k(cat) for cleavage of chromogenic substrates and for activation of the natural FXIa substrate FIX is approximately 3-fold lower for activated FXI(P161L) (FXIa(P161L)) than for wild-type FXIa (FXIa(WT)), consistent with an abnormal protease active site. Inhibition of FXIa(P161L) by diisopropyl fluorophosphate is 2.4-fold slower than for FXIa(WT), suggesting distortion of the protease oxyanion hole. Binding to p-aminobenzamidine, a probe for the integrity of the S1 substrate-binding site, was similar for FXIa(WT) and FXIa(P161L). Rates of carbamylation of Ile16 were also similar for FXIa(WT) and FXIa(P161L), indicating that the critical salt bridge between Ile16 and Asp194 forms normally during protease activation. Cumulatively, the data demonstrate that Pro161 is required for normal active site oxyanion hole conformation in FXIa. Examination of the FXIa crystal structure and modeling studies indicate that Pro161 forms several hydrophobic contacts with adjacent amino acids that stabilize active site conformation. Leucine can be incorporated at position 161 in FXIa, but would not form the extensive stabilizing network of hydrophobic interactions formed by Pro161.

Aspartic Acid↗
PubMed2003

Factor XI apple domains and protein dimerization.

The coagulation protease zymogen factor (F)XI is a disulfide bond-linked homodimer, a configuration that is necessary for protein secretion and function. The non-catalytic portion of the FXI polypeptide contains four repeats called apple domains (A1-A4). It is clear that FXI A4 plays a key role in dimer formation, however, the importance of other apple domains to this process has not been examined. We prepared recombinant FXI molecules in which apple domains were exchanged with those of the structurally homologous monomeric protein prekallikrein (PK). As expected, FXI/PK chimeras containing FXI A4 are dimers, while those with PK A4 are monomers. FXI A4 contains cysteine at position 321 that forms the interchain disulfide bond, while Cys321 in PK is unavailable for interchain bond formation because it is paired with Cys326. FXI/PK chimeras containing PK A4 were modified by changing Cys326 to glycine, leaving Cys321 unpaired (PKA4-Gly326). FXI with a PK A4 domain is a monomer, however, introducing PKA4-Gly326 results in a disulfide bond-linked dimer. This indicates that dimer formation can occur in the absence of FXI A4. In proteins containing PKA4-Gly326, replacing FXI A3 with PK A3 partially interferes with dimer formation, while substitution of A2, or A2 and A3 prevents dimer formation. PKA4-Gly326 cannot induce the native PK molecule to dimerize. The data indicate that FXI A2 and A3 make contributions to dimer formation. As these domains are involved in activities that require dimeric protein, it seems reasonable that they stabilize this conformation.

Binding Sites↗
PubMed1974

Substrates of Hageman factor. I. Isolation and characterization of human factor XI (PTA) and inhibition of the activated enzyme by alpha 1-antitrypsin.

Unactivated partial thromboplastin antecedent (PTA) has been purified by sequential chromatography of plasma on quaternary aminoethyl Sephadex, sulphoprophyl Sephadex, Sephadex G-150, and passage over an anti-IgG immunoadsorbant. The preparation gave a single band after alkaline disc gel electrophoresis, sodium dodecyl sulfate (SDS) gel electrophoresis and isoelectric focusing in acrylamide gels and was found to have a mol wt of 175,000 by gel filtration, 163,000 by SDS gel electrophoresis, and an isoelectric point of 8.8-9.4 (peak 9.0-9.1). Pre-PTA was activated directly by activated Hageman factor or by Hageman factor prealbumin fragments. Its coagulant activity was inhibited by DFP, soybean trypsin inhibitor and trasylol but not by lima bean trypsin inhibitor or ovomucoid trypsin inhibitor indicating that activated PTA possesses the same inhibition profile utilizing these reagents as does plasma kallikrein. A major plasma inhibitor of activated PTA was found to be a 65,000 mol wt alpha-globulin which was isolated free of alpha(1)-chymotrypsin inhibitor, inter alpha-trypsin inhibitor, alpha(2)-macroglobulin, and the other known inhibitors of activated PTA, the activated first component of complement (C1 INH), and antithrombin III. Its physicochemical properties were identical to alpha(1)-antitrypsin, and it was absent in alpha(1)-antitrypsin-deficient plasma thereby identifying this PTA inhibitor as alpha(1)-antitrypsin.

Chromatography, Gel↗
PubMed2001

Factor XI assembly and activation on human umbilical vein endothelial cells in culture.

Biotin-FXI optimally bound to HUVEC in the presence of 40 nM high molecular weight kininogen (HK) and > or =7 microM Zn2+. There was little specific FXI binding in the absence of added HK and at concentrations of Zn2+ <15 microM. FXI and prekallikrein, but not prothrombin, blocked biotin-FXI binding to HUVEC in the presence of HK with an IC50 of 18 nM and 180 nM, respectively. Monoclonal antibody HKL16 and peptide SDD31 also inhibited biotin-XI binding in the presence of HK with an IC50 of 4.7 nM and 50 microM, respectively. Alternatively, peptide T249-F260 of FXI's apple domain 3 and heparin monosulfate were weak inhibitors of FXI binding to HUVEC. FXI bound to HUVEC with an apparent Kd of 6.9 +/- 3.0 nM and Bmax of 13 +/- 2.6 x 10(6) sites/cell. FXI bound to HK on HUVEC, but not prothrombin, became converted to FXIa. FXI activation on HUVEC resulted from tissue culture media bovine factor XIIa. HUVEC grown in human factor XI-deficient serum did not support FXI activation. FXI binding to HUVEC in culture was mostly mediated by HK and FXI activation on HUVEC is dependent on cell-associated factor XIIa.

Binding, Competitive↗
PubMed1985

Inhibitors of plasma thromboplastin antecedent (factor XI): studies on mechanism of inhibition.

Acquired inhibitors of plasma thromboplastin antecedent (PTA) have been described in several recent studies, which collectively emphasize the heterogeneity of PTA functions that are impaired by this class of circulating anticoagulants. To clarify whether acquired inhibitors of PTA exhibit inhibitory properties that vary widely from one patient to the next, IgG inhibitors from four patients were isolated. The effect of these inhibitors on the binding of PTA to glass, the activation of kaolin-bound PTA, the coagulant activity of both kaolin-bound and fluid phase activated PTA (aPTA), and the enzymatic activity of aPTA against a low molecular weight substrate was quantified. The relative inhibition of these individual components of PTA activation and function by the four anticoagulants was quite similar. The results indicate that the principal binding sites for acquired inhibitors of PTA are PTA domains involved with surface binding and conversion of PTA to aPTA, with less effective steric impairment of aPTA enzymatic activity.

Adult↗
PubMed2001

The role of factor XI in a dilute thromboplastin assay of extrinsic coagulation pathway.

Blood coagulation has been thought to be composed of both intrinsic and extrinsic pathways. Recent evidence strongly supports the critical role of the extrinsic pathway in the initiation of blood coagulation. This investigation established an assay that examines the role of FXI in the thromboplastin-initiated (extrinsic) coagulation based on this new concept. Plasma clotting times were measured at different concentrations of thromboplastin with activated FXII inhibited (FXIIa-inhibited Diluted Thromboplastin Time, FXIIaiDTT). Only at low concentrations of thromboplastin was FXIIaiDTT of FXI-deficient plasma significantly prolonged than that of normal plasma. Depletion of FXI from normal plasma prolonged its FXIIaiDTT and replenishment of FXI shortened it. FXIIaiDTTs of both FVIII-deficient and FIX-deficient plasma were remarkably prolonged, and addition of normal plasma dose-dependently shortened it. Furthermore, earlier alpha-thrombin inhibition was directly correlated with decreasing FXa generation. The amount of FXa production was: platelet-rich plasma > platelet-poor plasma > FXI-deficient plasma. Therefore, our findings from the FXIIaiDTT assays not only support the critical role of extrinsic pathway in blood coagulation initiation, but also demonstrate the importance of FXI as an amplifier of thrombin generation in thromboplastin-initiated coagulation.

Blood Coagulation↗