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PubMed1986

Characterization of a cDNA coding for human factor XII (Hageman factor).

Affinity-purified antibody against human factor XII (Hageman factor) has been radiolabeled with 125I and employed as a probe to screen a human liver cDNA expression library prepared in lambda gt11. Approximately 3.5 X 10(6) recombinant phages were screened for factor XII, and two positive clones were identified and plaque purified. The largest cDNA coding for factor XII was 1571 base pairs in length and coded for amino acid residues 127-596 in the mature protein, a termination codon of TGA, a 3' noncoding sequence of 147 nucleotides, and a poly(A) tail of 11 nucleotides. The second clone contained an insert of 1334 base pairs and coded for amino acid residues 200-596. The amino acid sequence predicted by the cDNAs was in excellent agreement with that previously determined by amino acid sequence analysis. The amino acid and DNA sequences in human factor XII showed considerable homology with the corresponding domains in other serine proteases, including prothrombin, plasminogen, tissue plasminogen activator, and urokinase.

Amino Acid Sequence↗

PubMed1989

Coagulation factor XII (Hageman factor) Washington D.C.: inactive factor XIIa results from Cys-571----Ser substitution.

Structural studies on a congenital abnormal coagulation factor XII (Hageman factor), factor XII Washington D.C., have been performed to identify the defect responsible for its lack of procoagulant activity. Amino acid sequence analysis of a tryptic peptide isolated from the abnormal factor XII indicated that Cys-571 (equivalent to Cys-220 in the chymotrypsin numbering system) had been replaced by serine. No other substitutions in the active-site triad--namely, His-393, Asp-442, and Ser-544--were found. We propose that the Cys-571----Ser replacement found in this factor XII variant destroys the formation of the disulfide linkage between Cys-540 and Cys-571, giving rise to an altered conformation of the active-site serine residue or the secondary substrate-binding site and, thus, leads to the loss of enzyme activity.

Amino Acid Sequence↗

PubMed1994

Prevalence of factor XII (Hageman factor) deficiency among 426 patients with coronary heart disease awaiting cardiac surgery.

BACKGROUND: Several case reports of myocardial infarction in patients with factor XII deficiency have been published. In the present study we investigated the prevalence of this condition. METHODS: Factor XII activity (one-stage clotting assay), fibrinogen (derived method), and lipoprotein (a) (enzyme-linked immunosorbent assay) were measured in the plasma of 426 consecutive patients with coronary heart disease awaiting cardiac surgery. RESULTS: Among the 426 patients, 44 (10.3%) were found to be moderately deficient in factor XII (factor XII activity 17-50%, antigen 15-57%). The prevalence of factor XII deficiency was significantly higher (P < 0.0001) among patients with coronary heart disease than among 300 healthy blood donors (2.3%). Among coronary heart disease patients with this deficiency, elevated levels of fibrinogen, lipoprotein (a), and blood pressure were no more prevalent than in those without the deficiency; nor were cigarette smoking or a positive family history of thromboembolism more prevalent. CONCLUSIONS: Coronary heart disease patients showed a 10% prevalence of factor XII deficiency. However, the pattern of atherosclerotic risk factors did not differ between patients with or without the deficiency.

Blood Coagulation Tests↗

PubMed1992

Human factor XII (Hageman factor) autoactivation by dextran sulfate. Circular dichroism, fluorescence, and ultraviolet difference spectroscopic studies.

The first event leading to the activation of the plasma kallikrein-kinin system is the surface-dependent conversion of factor XII to an active enzyme. Factor XII autoactivation was investigated using dextran sulfate as a soluble activating surface, and the significance of aggregation and the nature of the conformational change were examined by ultraviolet difference spectroscopy, fluorescence and circular dichroism. Results indicate that DS500 (500-kDa dextran sulfate) induces aggregation of factor XII. Analysis of the binding data suggests that 165-192 factor XII molecules can bind to one DS500 chain, while a 1:1 stoichiometry is observed with 5-kDa dextran sulfate. The interaction of factor XII and dextran sulfate is a biphasic process. It is initiated by a fast contraction of the molecule upon binding, as revealed by an apparent increase in organized secondary structures, and then followed by a slow relaxation process during cleavage and subsequent activation. Overall, the results are consistent with a model in which factor XII undergoes conformational changes upon binding to the activating surface. The rapidity of autoactivation in the presence of DS500, as opposed to 5-kDa dextran sulfate, implies that aggregation provides a special mechanism whereby proteolytic cleavage is accomplished efficiently when factor XII molecules are bound side by side on the DS500 molecule.

Circular Dichroism↗

PubMed1985

Surface-dependent activation of human factor XII (Hageman factor) by kallikrein and its light chain.

In this paper we report the effect of sulfatides on the rate constants of factor XII activation by kallikrein and its isolated light chain (the domain of kallikrein that contains the active site of the enzyme). In the absence of sulfatides, kallikrein and the light chain were equally effective in factor XII activation (k1 = 1.57 X 10(3) M-1 s-1 at pH 7.0). The pH optima were the same (pH 7.0) and the reaction was not affected by variation of the ionic strength. Sulfatides strongly increased the rate constants of factor XIIa formation. In the presence of sulfatides kallikrein was, however, much more active than its light chain. At 330 microM sulfatides, pH 7.0 and 100 mM NaCl the rate constants of factor XII activation were 5.34 X 10(6) M-1 s-1 and 4.17 X 10(4) M-1 s-1 for kallikrein and its light chain, respectively. The pH optimum of factor XII activation by kallikrein in the presence of sulfatides was shifted to pH 6.3, and the reaction became highly ionic-strength-dependent. The rate constant increased considerably at decreasing NaCl concentrations. The optimum pH for light-chain-dependent factor XII activation in the presence of sulfatides remained unaltered and the reaction was not affected by the ionic strength. Binding studies revealed that both kallikrein and factor XII bind to the sulfatide surface, whereas no binding of the light chain of kallikrein was detectable. The isolated heavy chain of kallikrein had the same binding properties as kallikrein, which indicates that the heavy-chain domain contains the functional information for kallikrein binding to sulfatides. Since the effects of pH and ionic strength on the rate constants of kallikrein-dependent factor XII activation in the presence of sulfatides correlated with effects on the binding of kallikrein, it is concluded that under these conditions surface-bound factor XII is activated by surface-bound kallikrein. Our data suggest that sulfatides stimulate kallikrein-dependent factor XII activation by two distinct mechanisms: by making factor XII more susceptible to peptide bond cleavage by kallikrein and by promoting the formation of the enzyme-substrate complex through surface binding of kallikrein and factor XII.

Electrochemistry↗

PubMed1978

Surface activation of factor XII (Hageman factor)--critical role of high molecular weight kininogen and another potentiator).

When factor XII was adsorbed to kaolin it slowly became activated and converted prekallikrein to kallikrein. In the presence of HMW-kininogen the rate of activation of factor XII and consequently that of prekallikrein was markedly enhanced. The enhancing effect of HMW-kininogen was a dose-dependent phenomenon. In order to enhance the activation of factor XII on a surface the HMW-kininogen molecule had to be intact. Cleavage of HMW-kininogen by kallikrein decreased the enhancing effect of HMW-kininogen, there being an inverse relation between the bradykinin-generated and the capacity to enhance factor XII activation. Another 'potentiator' of factor XII activation was isolated from proteins adsorbed to aluminum hydroxide. This potentiator further increased the activation of factor XII, also in a dose-dependent fashion. It was postulated that factor XII is slowly converted into its active form by exposure to negatively charged surfaces; that this process is enhanced by kallikrein and further accelerated by HMW-kininogen and the 'potentiator'; and that these enhancing substances probably act by opening active sites on the factor XII molecule.

Factor XII↗

PubMed1982

Additional factor XII (Hageman factor) deficiency in hemophilia A and in von Willebrand syndrome.

Factor XII plasma levels were investigated with several methods in patients with hemophilia A and B and von Willebrand syndrome. There seem to be some families with hemophilia A or von Willebrand syndrome, who have an additional, congenital, partial lack of factor XII (Hageman factor). The mode of inheritance is independent of the other coagulation disorder. Frequently, the first indication of an additional factor XII deficiency is the disproportionate prolongation of the activated partial thromboplastin time (PTT) as regards the factor VIII level. The average factor XII level in patients with hemophilia A and von Willebrand syndrome is significantly lower than in normal subjects or patients with hemophilia B. It cannot be excluded that the frequently low levels of factor XII in patients with severe hemophilia are acquired and probably due to liver cell damage.

Adolescent↗

PubMed1994

The low pH stability of human coagulation factor XII (Hageman factor) is due to reversible conformational transitions.

Factor XII undergoes autoactivation when bound to negatively charged surfaces. To gain insight into the mechanism of factor XII autoactivation and stability at low pH, structural studies in the presence and absence of a soluble surface, dextran sulfate, at pH 5.3 and pH 8.3 were carried out. The circular dichroism data indicate that the secondary structure at pH 5.3 is only modestly different from that at pH 8.3. However, large changes in the secondary structure are found to occur when factor XII is exposed to pH 5.3 in the presence of surface. Changes in tertiary structure at low pH are also evident from the difference in tryptophan fluorescence and chemical reactivity of the histidine residues. Factor XII binds to the surface even at pH 5.3 though it is inactive at this pH. It is concluded that factor XII adopts a different conformation at pH 5.3 and causes it to interact differently with dextran sulfate. This results in an obstructed cleavage site that accounts for its stability at low pH.

Binding Sites↗

PubMed1994

A model demonstrating different interactions of human coagulation factor XII (Hageman factor) with the surface at physiological and lower pH.

The surface binding activity of human coagulation factor XII is independent of pH while its proteolytic breakdown decreases considerably on lowering the pH (Samuel, M. and Villanueva, G.B. (1992) Biophysical J. 61, 1895). In the present study we showed that the amidolytic activity of factor XII in the presence of a soluble surface, dextran sulfate (DS500; Mr 500,000) decreases on lowering the pH. Electrophoretic and ultraviolet difference spectral studies indicate that factor XII binding stoichiometry to DS500 is reduced to half at pH 5.3 when compared to that at pH 7.4. A model is presented to show the different interactions of factor XII with DS500 which explains its well known stability at low pH.

Chromogenic Compounds↗

PubMed1993

Contact activation in human plasma is triggered by zinc ion modulation of factor XII (Hageman factor).

Conditions for triggering factor XII to function in the autoactivation reaction in blood coagulation in the presence of different surfaces have been studied using prekallikrein-deficient plasma. Autoactivation was recorded in a chromogenic assay by measuring the amidolytic activity of factor XIIa. The results showed that autoactivation of factor XII was achieved only after modulation of factor XII. This modulation was mediated by Zn2+ and did not require an activating surface. Following modulation, the autoactivation proceeded in the presence of a negatively charged phospholipid or sulphatide, but the sulphatide-mediated autoactivation was inhibited by Zn2+. In the presence of Zn2+ (6.6 mumol/ml plasma), the rate constant for the autoactivation following modulation was calculated to be 3.1 x 10(4) M-1 s-1 and 1.2 x 10(4) M-1 s-1 for the phospholipid and the sulphatide-mediated reactions, respectively. In the absence of Zn2+ no activation was observed in the presence of a negatively charged phospholipid. After removal of Zn2+ by EDTA, the rate constant for the sulphatide-mediated autoactivation increased to 5.7 x 10(4) M-1 s-1 in the presence and 1.0 x 10(5) M-1 s-1 in the absence of a negatively charged phospholipid (phosphatidylinositol phosphate). Dextran sulphate was not able to mediate autoactivation, in either the presence or absence of Zn2+. Aprotinin completely blocked the modulation and/or autoactivation. Soy bean trypsin inhibitor prolonged the period required for autoactivation to start, but had no effect on the autoactivation rate. The main conclusions are that Zn2+ is required to initiate contact activation, modulating factor XII for autoactivation. This modulation does not require the presence of an activating surface.

Amino Acid Sequence↗

PubMed1977

Isolation and characterization of bovine factor XII (Hageman factor).

Factor XII was purified approximately 14 000-fold from bovine plasma by ammonium sulfate fractionation followed by heparin-agarose, DEAE-Sephadex, CM-cellulose, arginine-agarose, and benzamidine-agarose column chromatography. By this method, about 15 mg of protein was purified from 15 L of plasma with an overall yield of 18%. The purified protein was homogeneous as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and amino-terminal analysis. Bovine factor XII is a glycoprotein with a mol wt of 74 000 as determined by sedimentation equilibrium centrifugation. It contains 13.5% carbohydrate including 3.4% hexose, 4.7% N-acetylhexosamine, and 5.4% N-acetylneuraminic acid. Factor XII is a single polypeptide chain with an NH2-terminal sequence of Thr-Pro-Pro-Trp-Lys-Gly-Pro-?-Lys-His. This sequence is homologous to the reactive-site regions of a number of protease inhibitors. The amino acid sequence of a carboxyl-terminal fragments prepared by cyanogen bromide digestion was found to be Leu-Cys-Ala-Gly-Phe-Leu-Glu-Gly-Gly-Thr-Asp-Ala-Cys-Gln-Gly-Asp-SER-Gly-Gly-Pro-Leu-Val-Cys-Glu-Asp-Glu. This sequence is homologous with the active site of a number of plasma serine proteases including thrombin, factor IXa, factor Xa, and plasmin. These data indicate that bovine factor XII is a precursor to a serine enzyme with an inhibitor sequence and a catalytic site located in the same single polypeptide chain.

Amino Acid Sequence↗

PubMed1996

An enzyme-linked immunosorbent assay (ELISA) for the measurement of activated factor XII (Hageman factor) in human plasma.

A direct enzyme-linked immunosorbent assay (ELISA) employing 2/215 mouse monoclonal hybridoma antibody is described. The assay is capable of detecting activated factor XII in human plasma and can be used to assess early detection of the intrinsic blood coagulation pathway. No cross reactivity with human factor XII zymogen has been found. The assay was used to assess activation of factor XII in patients with renal failure, pregnancy and diabetes compared to a control group.

Antibodies, Monoclonal↗

PubMed1997

Influence of Zn2+ on the kinetic events that contribute to the 500-kDa dextran-sulfate-dependent activation of factor XII (Hageman factor).

The effect of zinc ions on kinetic and equilibrium steps that may contribute to the activation and subsequent autoactivation of human blood coagulation factor XII in the presence of 500-kDa dextran sulfate was studied. To analyze the results, the expression of the overall autoactivation constant that had been established from the model presented in a previous study was used. Comparison of the kinetics obtained at different levels of zinc, which included amounts lower than the residual concentration introduced by NaCl in the incubation mixture, suggested that the addition of Zn2+ up to 5 microM lowered the mean number of sites available for the binding of factor XII to the surface from 220 to 172 and increased the rate of the first-order activation of factor XII by one order of magnitude, from (1.6 +/- 0.4) x 10(-4) s(-1) to (8.0 +/- 0.4) x 10(-4) s(-1) in the presence of 550 nM dextran sulfate. Neither the factor XII/surface dissociation constant (1 microM), the apparent catalytic constant, nor the apparent Michaelis-Menten constant associated with the postulated multi-stage kinetic sequence were affected by the presence of zinc. Most experimental trends induced by the presence of zinc could be successfully interpreted by using the model, thus reinforcing its reliability under different conditions.

Binding Sites↗

PubMed1971

The first component of the kinin-forming system in human and rabbit plasma. Its relationship to clotting factor XII (Hageman Factor).

The isolation and characterization of the first component of the kinin-forming system in human and rabbit plasma are presented. Functionally, the molecule is the precursor of the activator of prekallikrein (Pre-PKA) and evidence is presented that it is identical with Hageman factor (clotting factor XII). The component from each plasma possessed similar characteristics. This molecule was found to have a mol wt of 110,000 and sedimentation rate of 4.6S. It migrated in electrophoresis as a beta-globulin, having an isoelectric point of 6.1. Upon activation with glass, kaolin, diatomaceous earth, ellagic acid, or trypsin, the activated molecule converted purified prekallikrein (prokininogenase) to the active enzyme. Clot-promoting activity was associated with the capacity to activate prekallikrein through each procedure of isolation. The clot-promoting factor was in precursor form, requiring treatment with kaolin or trypsin to gain activity. Evidence indicated that the protein was Hageman factor (factor XII): it promoted clotting of factor XII-deficient, but not Factor XI- or IX-deficient plasma, and did not convert fibrinogen to fibrin it bound to and was activated by kaolin or other negatively charged particles in the presence of chelating agents; the activation by kaolin could be prevented by pretreating the kaolin with hexadimethrine bromide (H Br); prekallikrein-activating and clot-promoting activities were identical in their physical properties; and the prekallikrein activator could not be detected in Hageman factor-deficient plasma. Activation of Hageman factor was accompanied by cleavage of the molecule into several fragments, one of which possessed prekallikrein-activating (PKA) and clot-promoting properties. The PKA fragment sedimented at 2.6S and by gel filtration was found to have a molecular weight of 32,000. The PKA possessed only 1/50 the clot-promoting capacity of the freshly activated native molecule.

Animals↗

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↗

PubMed2000

Activated factor XII levels are dependent on factor XII 46C/T genotypes and factor XII zymogen levels, and are associated with vascular risk factors in patients and healthy subjects.

Coagulation factor XII (FXII) is activated on contact with various biologic surfaces, including subendothelial tissues and lipoprotein particles. Thus, the plasma level of activated FXII (XIIa) might represent vascular lesions or be a marker of abnormal lipid metabolism. A 46C/T polymorphism was recently described in the FXII gene close to the ATG translation initiation codon, which was associated with inter-individual variation of plasma FXII zymogen levels. The present paper reports the association of the 46C/T polymorphism with plasma XIIa levels in apparently healthy subjects, and in patients with ischemic cerebrovascular disease (CVD) and arteriosclerosis obliterans (ASO). XIIa levels were not significantly different between patients and controls, but were strongly dependent on XII 46C/T genotypes (2.07 +/- 0.81, 1.65 +/- 0.63, and 0.93 +/- 0.41 ng/ml for C/C, C/T, and T/T genotypes, respectively; P < 0.0001). This association was evident for each group studied (P < 0.0001 for CVD and controls; P= 0.0007 for ASO). There were positive correlations between plasma FXII clotting activity and XIIa levels. In a univariate analysis, XIIa correlated with total cholesterol, triglycerides, plasminogen activator inhibitor-1, and C-reactive protein (CRP), although the presence of conventional cardiovascular risk factors (male sex, smoking, hypertension, hypercholesterolemia, diabetes) did not significantly increase XIIa. Stepwise regression analyses revealed that the XII clotting activity had the strongest association with XIIa. In conclusion, XIIa levels depended on XII 46C/T genotype and correlated with some cardiovascular risk factors. Thus, the FXII genotype should be taken into consideration for interpretation of plasma XIIa levels.

Aged↗

PubMed1987

The autoactivation of factor XII (Hageman factor) induced by low-Mr heparin and dextran sulphate. The effect of the Mr of the activating polyanion.

Human Factor XII is known to undergo autoactivation in the presence of dextran sulphate of Mr 500,000. We have now studied the dependence of this reaction on the Mr of the dextran sulphate by using fractions resolved by gel filtration. We have found that autoactivation can be induced by dextran sulphate fractions with Mr as low as 3000, and there is a marked dependence of the rate constant of autoactivation on the Mr value. Fractions with Mr below 8000 gave very low rates of autoactivation; there was a sharp increase in the rate obtained when the Mr of the dextran sulphate was greater than 10,000. Various preparations of heparin were also able to support the autoactivation of Factor XII and gave a very similar relationship between molecular size and reaction rate. The data provide support for the hypothesis that the mechanism by which the 'surface' acts in contact activation involves the presence, on the same particle, of multiple binding sites for the proteins.

Binding Sites↗

PubMed1994

Potential-mediated and time-controlled first order activation of factor XII (Hageman factor) adsorbed to carbon surfaces.

Direct potential-mediated and time-controlled activation of purified human factor XII (FXII) immobilized on carbon has been demonstrated. Initial experiments were required to find a procedure for characterizing the immobilization of FXII and its activated form, factor XIIa (FXIIa). After achieving saturation of the carbon surface with FXII, surface catalytic activities could be generated under negative potential conditions. Activities depended on the duration and amplitude of the polarization applied to the immobilized FXII. The activities thus electrochemically induced in the surface-bound FXII molecules were tested biologically in the presence of normal human plasma and FXII-deficient plasma. The shortening of the activated partial thromboplastin time test suggested identity of the catalytic activities with that of activated FXII molecules. The electrochemical activation mechanism was consistently analysed according to first-order kinetics. The apparent rate constants increased in the presence of zinc ions.

Adsorption↗