PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “FACTOR XI”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 163 records · Page 9Linked to original sources
PubMed1978

Factor XI deficiency: detection and management during urological surgery.

Hereditary factor XI deficiency may remain undiagnosed until severe bleeding is observed after an operation or trauma. Two such cases were encountered and, therefore, a regular screening test for coagulation disorders among urological patients was initiated. During 2 years (1975 and 1976) 10 additional cases of factor XI deficiency were detected: 5 severe and 5 partial. All patients were Ashkenazic Jews of Eastern European origin. The 5 patients with severe factor XI deficiency underwent an operation without any complications. They were transfused with 5 to 20 ml./kg./day of fresh frozen plasma from the day before the operation until 10 to 14 days postoperatively. Of the 5 patients with partial XI deficiency 4 underwent an operation. In 1 of 3 patients who did not receive transfusions postoperative bleeding was observed. A minimal level of 0.3 U./ml. (30 per cent) factor XI was found necessary to ensure good hemostasis during and after an operation. In view of a recent finding of relatively high gene frequency of factor XI deficiency in Ashkenazic Jews it seems warranted to do a partial thromboplastin time in such patients who need an operation.

Adult↗
PubMed2004

Beta 2-Glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: loss of inhibition by clipped beta 2-glycoprotein I.

Activation of factor XI (FXI) by thrombin in vivo plays a role in coagulation by providing an important positive feedback mechanism for additional thrombin generation. FXI is activated in vitro by thrombin, or FXIIa in the presence of dextran sulfate. In this report, we investigated the effect of beta(2)-glycoprotein I (beta(2)GPI) on the activation of FXI. beta(2)GPI bound FXI in vitro and inhibited its activation to FXIa by thrombin and FXIIa. The affinity of the interaction between beta(2)GPI and FXI was equivalent to the interaction between FXI and high molecular weight kininogen. Inhibition of FXI activation occurred with lower concentrations of beta(2)GPI than found in human plasma. Proteolytic clipping of beta(2)GPI by plasmin abolished its inhibition of FXI activation. The results suggest a mechanism of regulation whereby physiological concentrations of beta(2)GPI may attenuate thrombin generation in vivo by inhibition of FXI activation. Plasmin cleavage of beta(2)GPI provides a negative feedback that counteracts its inhibition of FXI activation.

Antiphospholipid Syndrome↗
PubMed1993

Identification and characterization of a binding site for factor XIIa in the Apple 4 domain of coagulation factor XI.

Previously we have characterized a binding site for high M(r) kininogen in the first of four tandem-repeat (Apple) domains within the heavy chain region of factor XI (Baglia, F. A., Jameson, B. A., and Walsh, P. N. (1990) J. Biol. Chem. 265, 4149-4154; Baglia, F. A., Jameson, B. A., and Walsh, P. N. (1991) J. Biol. Chem. 267, 4247-4252), whereas a substrate binding site for factor IX was localized to the second Apple (A2) domain (Baglia, F. A., Jameson, B. A., and Walsh, P. N. (1991) J. Biol. Chem. 266, 24190-24197). To define the factor XI domain that binds factor XIIa, we have screened a panel of synthetic peptides for their capacity to inhibit factor XI activation by factor XIIa. Peptide Gly326-Lys357 (located in the A4 domain) is a noncompetitive inhibitor of factor XI activation by factor XIIa (Ki = 3.75 microM), whereas structurally similar peptides from the A1, A2, and A3 domains were required at > 1000-fold higher concentrations for similar effects. The same peptide (Gly326-Lys357) is a competitive inhibitor of factor XIIa amidolytic activity (Ki = 3.8 microM) suggesting that it binds near the active site of factor XIIa. Computer modeling was used to predict the secondary and tertiary structure of the A4 domain of factor XI that interacts with factor XIIa. Rationally designed, conformationally constrained peptides were synthesized comprising residues Ala317-Gly326, Lys331-Lys340, and Gly344-Gly350, which act in concert to inhibit factor XI-activation by factor XIIa. Finally, a conformationally constrained peptide spanning residues Ala317-Gly350 inhibits factor XIIa-catalyzed factor XI activation 50% at a concentration of 5 x 10(-7) M. These results, interpreted in the context of the model, suggest that the sequence of amino acids from Ala317 through Gly350 of the heavy chain of the A4 domain of factor XI contains three peptide structures, possibly consisting of three antiparallel beta-strands that together comprise a contact surface for interacting with factor XIIa.

Amino Acid Sequence↗
PubMed2004

Response to desmopressin of factors XI, X and V in patients with factor VIII deficiency and von Willebrand disease.

Desmopressin [1-deamino-8-d-arginine vasopressin (DDAVP)] has been successfully used in the treatment of type 1 von Willebrand disease (VWD) and mild haemophilia A (MHA). Data suggest that DDAVP can increase factor XI (FXI) plasma levels and may represent an effective treatment for mild FXI deficiency. We assessed the DDAVP response of FXI coagulant activity (FXI:C), FXI antigen (FXI:Ag), factor V coagulant activity (FV:C), and factor X coagulant activity (FX:C) in 33 individuals with VWD or MHA. DDAVP did not produce a clinically significant increase in FXI:C, FXI:Ag, FX:C or FV:C in any patient. The mean +/- SD FXI:C pre-DDAVP (time 0) and at 1 h post-DDAVP was 90.7 (+/-22.9) U/dl and 92.1 (+/-20.9) U/dl, respectively. The mean (+/-SD) FXI:Ag at time 0 and 1 h was 92.2 (+/-20.1) U/dl and 89.9 (+/-21.3) U/dl, respectively. There was a small reduction at 1 h post-DDAVP in both FV:C, from 101.8 (+/-20.9) U/dl to 97.2 (+/-21.4) U/dl (P < 0.001), and FX:C from 103 (+/-19.5) U/dl to 98.8 (+/-18.7) U/dl (P < 0.001). No significant increase in FXI:C, FXI:Ag, FV:C or FX:C levels was seen at 4 h post-DDAVP. This study failed to demonstrate a clinically significant increase in the levels of FXI, FX or FV following administration of DDAVP.

Adolescent↗
PubMed1994

Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients.

Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.

Adult↗
PubMed1977

Role of high-molecular-weight kininogen in surface-binding and activation of coagulation Factor XI and prekallikrein.

In the contact phase of activation of the kinin-forming, intrinsic clotting, and fibrinolytic systems, high-molecular-weight kininogen acts as a cofactor for the activation of Factor XI, prekallikrein, and Hageman factor. One mechanism by which high-molecular-weight kininogen acts as a cofactor has been studied by using 125I-labeled Factor XI and prekallikrein in kaolin-activated normal human plasma and plasmas deficient in high-molecular-weight kininogen and Hageman factor. High-molecular-weight kininogen was found to be essential for normal binding and cleavage of both Factor XI and prekallikrein on the kaolin surface. Hageman factor was essential for cleavage but not for binding of Factor XI and prekallikrein to kaolin. In normal plasma 80% of the activated Factor XI remained surface-bound, whereas 80% of the kallikrein was not surface-bound. These findings are consistent with the hypothesis that, in the initial phase of contact activation, high-molecular-weight kininogen links both Factor XI and prekallikrein to the exposed surface where they are activated by surface-bound activated Hageman factor. Once activated, the Factor XI molecules remain localized at the site of activation, in contrast to the kallikrein molecules which are found largely in the surrounding plasma.

Adult↗
PubMed1999

Factor XI deficiency in women.

Factor XI (FXI) deficiency is an uncommon autosomally transmitted coagulopathy found predominantly in Jewish kindreds. It is associated with variable bleeding tendency that usually manifests after trauma, surgery, or other challenges to hemostasis. Therefore, women with FXI deficiency are at risk of excessive bleeding during their menstrual periods, childbirth, and after surgery. Increased awareness and close collaboration among hematologists, obstetricians, and gynecologists and availability of management guidelines is essential to minimize these risks. This review provides data from current research in FXI deficiency and pregnancy care, menstrual problems, and the role of screening for this disorder in women referred with menorrhagia.

Factor XI Deficiency↗
PubMed2006

An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency.

Recombinant activated factor VII (rFVIIa) has been used in a very limited number of patients with severe factor XI (FXI) deficiency. The dose and duration of treatment has varied greatly between these case reports. In a few of these cases there was also evidence of thrombotic complications. We present here a report on one additional patient with congenital FXI deficiency. For two major orthopaedic procedures in this patient we used rFVIIa as a single bolus dose followed by continuous infusion at a low rate. The data from these treatment episodes, together with those from a review of the published cases, lend support to the concept of using much lower doses than in haemophilia with inhibitors. A bolus dose of 20 microg kg(-1) and thereafter maintenance of the FVII activity at approximately 3 IU mL(-1) appears effective and safe.

Factor VII↗
PubMed1991

Factor XI: a review of its biochemistry and deficiency.

The biochemistry and physiology of Factor XI have been reviewed. The clinical history of our 25 patients was reviewed and compared with others' experiences. Factor XI deficiency remains enigmatic in that there is no correlation between Factor XI levels and clinical manifestations. Approximately 40 to 50% of all persons lacking Factor XI are of Ashkenazi Jewish extraction, and the remainder are represented by nearly all populations. Persons may be found to lack Factor XI because of evaluation for hemorrhage, evaluation of a prolonged PTT, or through family or other genetic studies. Hemorrhage is not as severe as in patients with hemophilia A or B. Data are presented suggesting that hemorrhage may, in part, be associated with aspirin use.

Adolescent↗
PubMed2000

Factor XI binding to activated platelets is mediated by residues R(250), K(255), F(260), and Q(263) within the apple 3 domain.

To localize the platelet binding site on factor XI, rationally designed, conformationally constrained synthetic peptides were used to compete with [(125)I]factor XI binding to activated platelets. The major platelet binding energy resided within the sequence of amino acids T(249)-F(260). Homology scanning, using prekallikrein amino acid substitutions within the synthetic peptide T(249)-F(260), identified a major role for R(250) in platelet binding. Inhibition of [(125)I]factor XI binding to activated platelets by the recombinant Apple 3 domain of factor XI and inhibition by unlabeled factor XI were identical, whereas the recombinant Apple 3 domain of prekallikrein had little effect. A "gain-of-function" chimera in which the C-terminal amino acid sequence of the Apple 3 domain of prekallikrein was replaced with that of factor XI was as effective as the recombinant Apple 3 domain of factor XI and unlabeled factor XI in inhibiting [(125)I]factor XI binding to activated platelets. Alanine scanning mutagenic analysis of the recombinant Apple 3 domain of factor XI indicated that amino acids R(250), K(255), F(260), and Q(263) (but not K(252) or K(253)) are important for platelet binding. Thus, the binding energy mediating the interaction of factor XI with platelets is contained within the C-terminal amino acid sequence of the Apple 3 domain (T(249)-V(271)) and is mediated in part by amino acid residues R(250), K(255), F(260), and Q(263).

Amino Acid Sequence↗
PubMed1986

Studies on a circulating anticoagulant inhibiting factor XI in a patient with congenital deficiency and carcinoma of the prostate.

An inhibitor of plasma thromboplastin antecedent (PTA, factor XI), measured in coagulant and radioimmunoassays, was detected in a 60-year-old man with carcinoma of the prostate who had no evidence of a bleeding tendency. Family studies indicated that the patient was either a homozygote or a heterozygote for hereditary factor XI deficiency. In contrast to earlier described patients with factor XI deficiency in whom inhibitors were detected, the patient was unaware of having been transfused with blood or blood products at any time before the discovery of the inhibitor. The inhibitor of factor XI in the patient's plasma appeared to be predominantly in the IgG4 fraction and to be directed at a locus on the factor XI molecule other than the active site; it did not block the amidolytic properties of activated factor XI (XIa). Rather, it appeared to block adsorption of factor XI to negatively charged surfaces. The inhibitor interfered with measurement of other components of the intrinsic pathway of thrombin formation, perhaps explaining the low titres of other coagulation factors of the intrinsic system reported in patients with strong inhibitors directed against factor XI.

Factor XI↗
PubMed1986

The factor of factor XI deficiency in thyroid neoplasia.

Forty-three patients with factor XI deficiency detected by prolonged partial thromboplastin times were reviewed over an 11-year period. They were predominantly Ashkenazim--18 men and 25 women--ranging in age from 20 to 92 years. Thirteen patients had a history of bleeding, and eight had a family history of factor XI deficiency. Six patients with thyroid disease with four significant tumors were found for a 9% incidence of associated neoplasia. These consisted of two adenomas and two papillary-mixed cancers in two men distinguished by an aggressive course by virtue of extensive nodal disease, local recurrence, and systemic metastases in whom factor XI was profoundly decreased. It would appear that there is an undue association of factor XI deficiency and thyroid neoplasia suggestive of a shared genetic disturbance. These cases illustrate the benefit of routine preoperative coagulopathy screening by use of prothrombin time, partial thromboplastin time, and platelet counts. Factor XI deficiency is an infrequent cause of excessive bleeding, and the operative morbidity of surgical management of affected individuals can be avoided by the use of fresh-frozen plasma before and after surgery.

Adult↗
PubMed1988

Enzymes of the contact phase of blood coagulation: kinetics with various chromogenic substrates and a two-substrate assay for the joint estimation of plasma prekallikrein and factor XI.

Kinetic constants (Km and kcat) of kallikrein and factor XIa for the chromogenic substrates H-D-L-prolyl-L-phenylanyl-L-arginine-p-nitroanilide (S-2302) and L-pyroglutamyl-L-propyl-L-arginine-p-nitroanilide (S-2366) were determined. The determined constants allow the use of S-2302 and S-2366 in an assay that leads to the joint estimation of factor XI and prekallikrein in activated plasma. The assay reports approximately 3.1 micrograms/ml factor XIa and 34.5 micrograms/ml kallikrein in kaolin-activated plasma (kaolin content 2 mg/ml). The dual-substrate amidolytic assay shows good correlation with the coagulant assay of both factors (0.92 with the prekallikrein assay and 0.98 with the factor XI assay). It is capable, through the joint estimation of factor XI and prekallikrein levels, of differentiating among plasma samples deficient in components of the contact phase of blood coagulation. Kinetic constants of factor beta-XIIa (factor XII fragment) for these substrates and for N-benzol-L-isoleusyl-L-glutamyl-glycyl-L-arginine-P-nitro ani lide (S-2222) were determined, and they allowed the assessment of the contribution of this factor to this assay and its estimation in the activated phase.

Blood Coagulation↗
PubMed1979

Studies of binding of prekallikrein and Factor XI to high molecular weight kininogen and its light chain.

Prekallikrein and Factor XI have been reported to circulate as complexes with the coagulation cofactor high molecular weight (HMW)-kininogen. In this study we have shown that native HMW-kininogen possesses a strong binding site for prekallikrein and Factor XI with association constants of 3.4 x 10(7) M-1 and 4.2 x 10(8) M-1, respectively. The diminished binding of prekallikrein relative to Factor XI may, in part, account for the ability of kallikrein to leave the surface and interact with other molecules of Hageman factor and HMW-kininogen. Prekallikrein and Factor XI appear to compete for binding to HMW-kininogen, suggesting a single (or closely overlapping) binding site(s). The purified light chain derived from kinin-free HMW-kininogen is shown to compete with native MHW-kininogen for binding to Hageman factor substrates and direct binding of the isolated light chain to prekalikrein and Factor XI is demonstrated. This binding of the light chain to prekallikrein and Factor XI appears to be essential to the function of HMW-kininogen as a coagulation cofactor and further digestion of the light chain with excess kallikrein destroys its coagulant activity.

Binding Sites↗
PubMed1991

Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains.

Factor XI is a plasma glycoprotein that participates in the blood coagulation cascade. Of the 19 disulfide bonds present in each of the subunits of the human protein, 16 were determined by amino acid sequence analysis of peptide fragments produced by chemical and enzymatic digestion. Four apple domains of 90 or 91 amino acids were identified in the tandem repeats present in the amino-terminal portion of each subunit of factor XI. The disulfide bonds in the carboxyl-terminal portion of the molecule were similar to those in the catalytic region of other serine proteases. The two identical subunits of factor XI were connected by a single disulfide bond at Cys321 linking each of the fourth apple domains while each of the Cys residues at position 11 in the first apple domains forms a disulfide bond with another Cys residue.

Amino Acid Sequence↗
PubMed1984

Amidolytic assay of human factor XI in plasma: comparison with a coagulant assay and a new rapid radioimmunoassay.

The traditional coagulant assay for plasma factor XI suffers from a relatively high coefficient of variation, the need for rare congenitally deficient plasma, and a poor correlation between precision and sensitivity. We have developed a simple functional amidolytic assay for factor XI in plasma using the chromogenic substrate PyrGlu-Pro-Arg-p-nitroanilide (S-2366). After inactivation of alpha 1-antitrypsin, CI inhibitor, and other plasma protease inhibitors with CHCI3, plasma was incubated with kaolin, in the absence of added calcium, which limited the enzymes formed to those dependent on contact activation. Soybean trypsin inhibitor was used to minimize the action of kallikrein on the substrate. Once the reaction was complete, corn trypsin inhibitor was used to inactive factor XIIa, the enzyme generated by exposure of plasma to negatively charged surfaces, which had activated the factor XI. The assay is highly specific for factor XI, since plasma totally deficient in that zymogen yielded only 1%-3% of the enzymatic activity in normal plasma under identical conditions. The requirements for complete conversion of factor XI to XIa in plasma within 60 min were, respectively, factor XII, 0.6 U/ml, and high molecular weight kininogen, 0.2 U/ml. Prekallikrein was not an absolute requirement for complete activation but did accelerate the reaction. The intraassay coefficient of variation was 3.4%, and the mean of 35 normal plasmas was 1.00 U +/- 0.24 SD. In addition, a new rapid radioimmunoassay was devised using staphylococcal protein A as the precipitating agent for a complex of factor XI antigen with monospecific rabbit antibody. The mean was 1.01 U +/- 0.30 SD. The correlation coefficients for amidolytic versus coagulant and amidolytic versus radioimmunoassay were r = 0.95 for the former and 0.96 for the latter. Thus, a simple, accurate amidolytic assay and a radioimmunoassay have been devised for measuring factor XI in plasma that correlate well with the coagulant activity of factor XI, as determined in our laboratory.

Animals↗
PubMed1999

The role of factor XI in coagulation: a matter of revision.

In 1991 it was demonstrated that, besides factor XII, thrombin is capable of activating factor XI in vitro. Thrombin-dependent activation of factor XI is an integral part of the revised theoretical model of coagulation in which coagulation is initiated by the extrinsic pathway and maintained by thrombin-induced activation of clotting factors V, VIII, and XI. In this review, special interest is given to the new role of factor XI in coagulation, with emphasise on data supporting the concept of thrombin-mediated factor XI activation in vivo. Furthermore, activation of factor XI in human disease, especially atherosclerotic disease, measured by newly developed immunologic assays, is discussed. The relation of factor XI to fibrinolysis through activation of the carboxypeptidase, thrombin-activatable fibrinolysis inhibitor (TAFI) by thrombin provides an explanation for the bleeding tendency observed in factor XI-deficient patients. The probable link with factor XI-mediated TAFI activation may have clinical and therapeutic consequences and deserves further study.

Arteriosclerosis↗