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PubMed2001

The role of factor XI in thrombin generation induced by low concentrations of tissue factor.

Thrombin generation has been studied in the plasma of severely factor XI deficient patients under conditions in which contact activation did not play a role. In platelet-rich as well as platelet-poor plasma, thrombin generation was dependent upon the presence of factor XI at tissue factor concentrations of between 1 and 20 pg/ml i.e. approximately 0.01 to 0.20% of the concentration normally present in the thromboplastin time determination. The requirement for factor XI is low; significant thrombin generation was seen at 1% factor XI; at 10%, thrombin formation was nearly normalised. A suspension of normal platelets in severely factor XI deficient plasma did not increase thrombin generation. This implies that there is no significant factor XI activity carried by normal platelets, although the presence of factor XI and factor XI inhibitors in platelets cannot be ruled out.

Blood Platelets↗

PubMed1979

Interactions among Hageman factor (HG, Factor XII), plasma thromboplastin antecedent (PTA, Factor XI), plasma prekallikrein (PK, Fletcher factor) and high molecular weight kininogen (HMW-K, Fitzgerald factor) in blood coagulation.

Studies of plasmas from individuals with Hageman trait (factor XII deficiency), plasma thromboplastin antecedent (PTA, factor XI) deficiency, Fletcher trait (plasma prekallikrein deficiency) and Fitzgerald trait (high molecular weight-kininogen deficiency) have revealed the importance of these proteins in blood coagulation. The interactions among them, however, are not fully elucidated. We have studied these reactions by two different approaches. (1) In a purified system, high molecular weight kininogen was absolutely required for activation of PTA by HF and ellagic acid (EA). The yield of activated PTA was proportional to the amount of HF, HMW-K, and PTA in the mixtures, suggesting that these three proteins may form a complex in the presence of EA. (2) In experiments with whole plasma, we took advantage of the adsorption of EA to Sephadex gels. When normal plasma or plasma deficient in HF, PK, HMW-K or PTA was exposed to Sephadex-EA and was separated by centrifugation, each supernatant plasma except that deficient in HF shortened the prolonged partial thromboplastin time (PTT) of HF-deficient plasma. Plasma simultaneously depleted of HMW-K, PK and PTA also shortened the PTT of HF-deficient plasma and of plasma depleted of HF and PK, but had virtually no procoagulant effect upon the PTT of plasma depleted of HF and MHW-K. Thus, exposure of HF in plasma to Sephadex-EA appeared to generate a clot-promoting form of HF in the absence of other clotting factors, but its expression required the presence of HMW-K.

Blood Coagulation↗

PubMed2000

Role of blood coagulation factor XI in downregulation of fibrinolysis.

Factor XI is a component of the intrinsic pathway of coagulation. A deficiency of factor XI is associated with a mild to moderate bleeding disorder especially from tissues with a high local fibrinolytic activity. In contrast, high levels of factor XI are a risk factor for venous thrombosis. The recent finding that factor XI can be activated by thrombin led to a revised model of coagulation. In this model the primary thrombin generation that results in fibrin formation takes place via the extrinsic pathway. Additional thrombin generation takes place inside the fibrin clot via the intrinsic pathway after the activation of factor XI by thrombin. High concentrations of thrombin are formed that are necessary for the activation of thrombin activatable fibrinolysis inhibitor (TAFI). Activated TAFI protects the fibrin clot against lysis. The role of factor XI in hemostasis can therefore be seen as a combination of procoagulant and antifibrinolytic actions. The new insights in the role of factor XI in coagulation and fibrinolysis may lead to new strategies for the treatment of thrombotic disorders.

Animals↗

PubMed1988

A simple and accurate microplate assay for the determination of factor XI in plasma.

Traditionally, factor XI has been determined in the clinical laboratory by a modified activated partial thromboplastin time assay (aPTT) with factor XI-deficient plasma as the substrate. Coagulant assays, however, have high coefficients of variation. We previously developed a chromogenic assay for factor XI that required equipment not normally found in a clinical laboratory. We now present a modification of that assay, which is performed in 96-well microplates and can be done in any clinical laboratory or physician's office. Plasma is subjected to a brief acidification to inactivate most of the plasma protease inhibitors. Soybean trypsin inhibitor is included to stabilize the factor XIa that is generated. Kaolin is used as the contact activating surface, and the chromogenic substrate, S-2366, is used to measure the factor XIa that is formed. Results of the assay, performed in three groups of subjects, correlate well with results of the coagulant assay as performed in our laboratory and clearly differentiate between total factor XI deficiency and the deficiency of any of the other contact proteins. Unlike coagulation assays, the chromogenic assay is not influenced by the presence of heparin. Furthermore, it is not affected by lupus anticoagulants, which are antibodies directed against acidic phospholipids. Two plasma samples from patients with acquired factor XI inhibitors showed dissociation between coagulant and amidolytic activity, suggesting that the antibodies were not primarily directed toward the active site of factor XIa, which is responsible for its amidolytic activity. In contrast, patients with severe congenital deficiency of factor XI showed no activity by either assay.

Amidohydrolases↗

PubMed1992

Production and therapeutic use of a factor XI concentrate from plasma.

Factor XI deficiency is an uncommon bleeding disorder usually manifested by excessive bleeding after surgery or trauma. Until recently the only effective therapy has been fresh-frozen plasma (FFP) infusion. We describe the efficacy and safety of a new factor XI concentrate produced from human donor plasma by a modification of the method used for antithrombin III concentrate. The mean recovery of factor XI in the circulation measured on 62 occasions was approximately 91% of the injected dose, and the mean half-disappearance-time was 52 h. The concentrate was used for 31 invasive procedures in 30 patients, including 16 patients who had a definite bleeding tendency on previous occasions, with normal haemostasis being achieved in all but 1. Only 1 patient (previously experiencing allergy to FFP) experienced adverse effects during infusion. Monitoring of liver function tests and viral antibody status in suitable patients has shown no evidence of transmission of hepatitis viruses, HIV-1 or parvovirus B19. We conclude that this concentrate provides effective treatment for patients with factor XI deficiency. Preliminary results suggest safety from virus transmission, but this needs to be established in further studies of previously untreated patients.

Adolescent↗

PubMed1997

Bleeding predictors in factor-XI-deficient patients.

Bleeding in factor-XI-deficient patients is mainly injury-related. Parameters influencing bleeding particularly in patients with minor factor XI deficiency have not been defined. We utilized a logistic regression model to analyze parameters influencing bleeding tendency in subjects from 45 families with factor XI deficiency. Bleeding manifestations were documented in 58% of 26 homozygous or doubly heterozygous factor-XI-deficient patients, in 20% of 46 heterozygous factor-XI-deficient patients and in 9% of 47 family members with a normal factor XI genotype. Odds ratios for bleeding in homozygotes or double heterozygotes were 13 and in heterozygotes 2.6 with 95% confidence intervals of 3.8-45 and 0.8-9.0, respectively. Bleeding correlated negatively with factor XI level (r = -0.36, P = 0.0001) with major factor XI deficiency being a strong predictor of bleeding (P = 0.011). Minor factor XI deficiency and blood group O slightly contributed to bleeding. Although factor VIII and factor XI levels were correlated (r = 0.48, P = 0.0001), levels of factor VIII and von Willebrand factor were not predictors of bleeding. Bleeding was more common following operative procedure involving mucosal membranes (P < 0.01). The designed model enabled prediction of bleeding manifestations with an overall accuracy of 78% and 82% in heterozygotes.

Case-Control Studies↗

PubMed2003

The function of factor XI in tissue factor-initiated thrombin generation.

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 x 108 mL-1 platelets or the equivalent (2 microm) 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.

Blood Coagulation↗

PubMed1984

Blood coagulation factor XIa binds specifically to a site on activated human platelets distinct from that for factor XI.

Binding of 125I-Factor XIa to platelets required the presence of high molecular weight kininogen, was enhanced when platelets were stimulated with thrombin, and reached a plateau after 4-6 min of incubation at 37 degrees C. Factor XIa binding was specific: 50- to 100-fold molar excesses of unlabeled Factor XIa prevented binding, whereas Factor XI, prekallikrein, Factor XIIa, and prothrombin did not. When washed erythrocytes, added at concentrations calculated to provide an equivalent surface area to platelets, were incubated with Factor XIa, only a low level of nonspecific, nonsaturable binding was detected. Factor XIa binding to platelets was partially reversible and was saturable at concentrations of added Factor XIa of 0.2-0.4 microgram/ml (1.25-2.5 microM). The number of Factor XIa binding sites on activated platelets was estimated to be 225 per platelet (range, 110-450). We conclude that specific, high affinity, saturable binding sites for Factor XIa are present on activated platelets, are distinct from those previously demonstrated for Factor XI, and require the presence of high molecular weight kininogen.

Binding, Competitive↗

PubMed2004

The endogenous thrombin potential and high levels of coagulation factor VIII, factor IX and factor XI.

High plasma concentrations of factor VIII, factor IX and factor XI have been reported as thrombosis risk factors. Using the thrombin generation test in platelet-poor plasma, it was aimed to describe the mechanism for this increased thrombosis risk. Endogenous thrombin potential was measured in platelet-poor plasma in 180 patients with a history of thromboembolism, and results were compared with those of 180 age-matched and sex-matched controls. Subjects with major hereditary and acquired thrombophilia were excluded. Plasma concentrations of the clotting factor VIII, factor IX and factor XI were significantly elevated in patients compared with controls. The mean endogenous thrombin potential was significantly higher in patients than in controls: 191.3 +/- 3.1 (95% confidence interval, 185.3-197.4) arbitrary units versus 180.8 +/- 2.6 (95% confidence interval, 175.7-185.9) arbitrary units (P = 0.009). The endogenous thrombin potential was significantly higher in patients with elevated factor IX and factor XI, but elevated factor VIII was not associated with a significant increase in endogenous thrombin potential. In conclusion, the increased thrombosis risk associated with high plasma concentrations of factor IX and factor XI may be explained by the increase in endogenous thrombin potential. However, this did not help explain the association between elevated factor VIII and thrombosis risk.

Adult↗

PubMed1990

The effect of combined factor XI deficiency with von Willebrand factor abnormalities on haemorrhagic diathesis.

To account for the lack of correlation between the level of factor XI (FXI) in deficient patients and haemorrhagic manifestations, we correlated the prevalence of combined FXI and von Willebrand's factor (vWF) deficiency in 212 FXI-deficient patients. Fifty-four patients had a combined FXI and vWF deficiency: 16 patients had severe and 38 patients had mild FXI deficiency. In a group of 28 patients with comparably mild FXI deficiency, 14 bleeders had significantly lower mean vWF, Ag, ristocetin cofactor and ristocetin induced platelet aggregation than 14 non-bleeders selected on the basis of comparable FXI levels. These findings suggest that the combination of FXI and vWF deficiency is common and may affect the bleeding tendency in mild FXI deficiency.

Adolescent↗

PubMed1983

Immunologic studies of human coagulation factor XI and its complex with high molecular weight kininogen.

Coagulation factor XI was purified from human plasma using ion-exchange chromatography and affinity chromatography on high molecular weight kininogen-Sepharose. A monospecific precipitating antiserum was prepared and used to study factor XI antigen. Factor XI did not migrate during electrophoresis at pH 8.3. High molecular weight kininogen (HMWK), an alpha globulin, reversibly associates with factor XI. Complex formation between HMWK and factor XI was observed under conditions of crossed-immunoelectrophoresis. Using Laurell rocket immunoelectrophoresis, it was shown that the isolated alkylated light chain of kinin-free HMWK formed a complex with factor XI. In contrast to previous studies of prekallikrein, titrations of factor XI with increasing amounts of HMWK did not give a simple titration curve, suggesting that factor XI dissociates from the complex during electrophoresis. Prekallikrein and factor XI were shown to compete for the same HMWK molecules under the conditions of immunoelectrophoresis, and prekallikrein appeared to have a higher affinity for binding to HMWK than factor XI. Quantitative determinations of factor XI antigen in plasma by rocket immunoelectrophoresis were made. The average amount of factor XI measured in plasma samples from 20 normal individuals was 4.5 micrograms/ml (range 3-6). No factor XI antigen was detected in plasma from a patient deficient in factor XI. Normal factor XI antigen levels were detected in 3 different HMWK-deficient plasmas only if the plasmas were reconstituted with purified HMWK (2 U/ml). Addition of HMWK to normal plasma resulted in an increase of the factor XI antigen rocket. At HMWK levels of 2 U/ml, no further increase of the factor XI antigen rocket was observed. Therefore, accurate measurement of factor XI antigen by rocket immunoelectrophoresis is possible only if an excess of HMWK is present.

Binding, Competitive↗

PubMed2000

Thrombin-mediated feedback activation of factor XI on the activated platelet surface is preferred over contact activation by factor XIIa or factor XIa.

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.

Blood Platelets↗

PubMed1999

Phosphorylation of coagulation factor XI by a casein kinase released by activated human platelets increases its susceptibility to activation by factor XIIa and thrombin.

Previous studies suggest that activated platelets facilitate the cleavage of factor XI by both factor XIIa and thrombin. Extracellular phosphorylation is a mechanism by which the function of plasma proteins can be regulated. Phosphorylation is mediated by a casein kinase which is released by activated platelets concomitant with large amounts of ATP and Ca2+. The purpose of this study was to investigate if factor XI is phosphorylated by a platelet casein kinase and whether phosphorylation may affect its activation properties. It was shown that supernatants from platelets which contain platelet casein kinase phosphorylated factor XI. By Western blot analysis it was shown that phosphorylation of factor XI substantially increased its susceptibility to cleavage by factor XIIa, and, to a lesser extent, by thrombin. The generated factor XIa was functionally active in that it cleaved the chromogenic substrate S2366, and in that factor XIa-antithrombin and thrombin-antithrombin complexes were generated when phosphorylated factor XI was added to blood plasma. The present study indicates that platelet-mediated phosphorylation of factor XI enhances the cleavage of factor XI into XIa and that the generated XIa possesses functional activity. Phosphorylation of factor XI might be an essential regulatory mechanism by which platelets mediate amplification of the coagulation cascade.

Blood Platelets↗

PubMed1977

Isolation and characterization of bovine factor XI (plasma thromboplastin antecedent).

Factor XI (plasma thromboplastic antecedent) has been purified approximately 28 000-fold from bovine plasma with an overall yield of about 30%. The isolation procedure involves barium sulfate adsorption of contaminants, ammonium sulfate precipitation, and chromatography on heparin-agarose, CM-Sephadex, and DEAE-Sephadex. The final product was homogeneous when examined by polyacrylamide gel electrophoresis and immunoelectrophoresis. A minimal mol wt of 124 000 was determined by sedimentation equilibrium. Factor XI is composed of two similar or identical polypeptide chain (mol wt of approximately 55 000), and these two chains are held together by a disulfide bond(s). Factor XI is a glycoprotein which contains approximately 11% carbohydrate including 5.4% heose, 4.7% N-acetylhexosamine, and 1.0% N-acetylneuraminic acid. Other properties of this coagulation factor including its amino acid composition and inhibition by antibodies prepared in rabbits are also reported.

Amino Acids↗

PubMed1996

Activation of factor VII during alimentary lipemia occurs in healthy adults and patients with congenital factor XII or factor XI deficiency, but not in patients with factor IX deficiency.

Factor VII activity (FVIIc), a risk marker for coronary heart disease, is increased during postprandial lipemia. Factor VII activation accompanies lipolysis of triglyceride-rich lipoproteins, but the nature of this association and whether it is causal remain uncertain. To explore this issue, four patients with homozygous factor XII deficiency, four with complete factor XI deficiency, six with factor IX deficiency, and their respective age- and sex-matched controls were given two isocaloric dietary regimens, one providing on average 136 g fat and the other 19 g fat. Blood was taken before breakfast, immediately before lunch at 195 minutes, and at completion of the study at 390 minutes. All samples for each subject and matched control were assayed as one batch for FVIIc, activated factor VII, and factor VII antigen (FVIIag). Activation of factor VII was observed with the high-fat regimen but not with the low-fat regimen in all controls, factor XII-deficient patients, and factor XI-deficient patients. No factor VII activation was observed during either regimen in factor IX-deficient patients, but a normal postprandial responsiveness of factor VII to dietary fat was restored in one patient who replicated the study after factor IX therapy. Plasma FVIIag was not altered postprandially in either regimen in any group of patients or controls. Factor IX apparently plays an obligatory role in the postprandial activation of factor VII, although the mechanism remains to be determined.

Adult↗

PubMed2004

Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation.

During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N-terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI-Glu555 is activated normally by FXIIa and thrombin, and FXIa-Glu555 binds activated factor IX similarly to wild type FXIa (FXIa(WT)). When compared with FXIa(WT), FXIa-Glu555 activates factor IX at a greatly reduced rate ( approximately 400-fold), and is resistant to inhibition by antithrombin. Interestingly, FXIa(WT) and FXIa-Glu555 cleave the small tripeptide substrate S-2366 with comparable k(cat)s. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2' site and the P2' residues on factor IX and antithrombin. FXI-Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.

Antithrombin III↗

PubMed2003

RETRACTED: The glycoprotein Ib-IX-V complex mediates localization of factor XI to lipid rafts on the platelet membrane.

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 ( approximately 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-beta-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.

Blood Platelets↗

PubMedDate not supplied

Molecular genetics aspects of factor XI deficiency and Glanzmann thrombasthenia.

Factor XI deficiency and Glanzmann thrombasthenia are among the hereditary disorders frequently encountered in Israel. Factor XI deficiency is particularly frequent in Ashkenazi (European) Jews with 1:190 individuals affected by the severe deficiency and 8.1% of the population being heterozygotes. So far 4 mutations causing factor XI deficiency have been identified of which the type II (a non-sense mutation) and type III (a missense mutation) are predominant and type I and IV observed only in 5 families. Recently, the type II mutation was observed in Iraqui-Jews as well with 3.7% of 400 unrelated subjects being heterozygotes and with the type III mutation completely absent. Since Iraqui-Jews represent the original gene pool of Jews who lived in Babylon 2500 years ago we hypothesize that the type II mutation is ancient and that the type III mutation occurred more recently, after the divergence of the original Babylonian Jews into Ashkenazi, Sephardic (Spanish) and Middle Eastern Jews. Preliminary data on factor XI intragenic polymorphic markers indeed indicate that type II and type III mutations reside on chromosomes each characterized by a different specific haplotype. Fifty living patients with type I Glanzmann thrombasthenia (28 families) have been observed in Israel. Most of them are Iraqui-Jewish and the rest are Arabs (5 families) and one Iranian Jewish. All Iraqui-Jewish patients have an IIbp deletion within exon 12 of the glycoprotein (GP) IIIa resulting in a shift of the reading frame that leads to premature termination of the GPIIIa synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Factor XI Deficiency↗