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PubMedDate not supplied

An HMG-I protein from human endothelial cells apparently is secreted and impairs activation of Hageman factor (factor XII).

A highly purified protein from lysates of human umbilical vein endothelial cells (HUVECs) inhibited the activation of factor XII [Hageman factor (HF)] and removed factor XIIa from an activating surface, thus impairing HF-dependent coagulation and kinin-releasing activities. Two tryptic peptides from this protein had 100% identity with amino acids 31-44 and 89-101 of a nonhistone DNA-binding protein known as high-mobility group protein (HMG-I). In specific antibody experiments, the clot-inhibiting property in purified lysate protein from HUVECs was associated with HMG-I. The molecular weight of the protein that inhibited clotting was consistent with that predicted for HMG-I. Protein that inhibited contact activation and had antigenic properties of HMG-I and HUVEC lysate protein also was found in conditioned media from unchallenged cultured HUVECs. After HUVECs were incubated with 14C lysine, conditioned media contained immunoprecipitable radiolabeled protein with the same molecular weight as that recovered from cell lysates, suggesting that this high-mobility group protein (HMG-I) may be secreted. Purified factor XII antigens were displaced from a glass surface by HMG-I from lysates in proportion to the amount of HMG-I protein that was added. This HMG-I probably inhibits factor XII functions because its high positive charge favors competitive binding to an activating substance.

Amino Acid Sequence↗
PubMed1985

Kinetic studies on surface-mediated activation of bovine factor XII and prekallikrein. Effects of kaolin and high-Mr kininogen on the activation reactions.

The kaolin-mediated reciprocal activation of bovine factor XII and prekallikrein was divided into the following two reactions: the activation of factor XII by plasma kallikrein (reaction 1) and the activation of prekallikrein by factor XIIa (reaction 2). The effects of high-Mr kininogen and kaolin surface on the kinetics of these activation reactions were studied. High-Mr kininogen markedly enhanced the rate of reactions 1 and 2 in the presence of kaolin, and the enhancements were highly dependent on the concentrations of the protein cofactor and amount of kaolin surface. For the activation of factor XII by plasma kallikrein (reaction 1), high-Mr kininogen was required when a low concentration of factor XII and kaolin was used. The molar ratio of the protein cofactor to factor XII for optimal activation was found to be approximately 1:1. The apparent Km value and the kcat/Km value for plasma kallikrein on factor XII were calculated to be 4 nM and 5.2 X 10(7) s-1 X M-1, respectively. The activation of prekallikrein by factor XIIa, (reaction 2) proceeded even in the absence of high-Mr kininogen and kaolin. The addition of the protein cofactor and surface to the reaction mixture remarkably accelerated the reaction, and the apparent Km value for factor XIIa on prekallikrein was reduced from 1 microM to 40 nM. Moreover, the kcat/Km value was altered from 7.3 X 10(4) to 1.1 X 10(6) s-1 X M-1). These results suggest that high-Mr kininogen accelerates the surface-mediated activation of factor XII and prekallikrein by enhancing the susceptibility of factor XII to plasma kallikrein, on the one hand, and the affinity of factor XIIa for prekallikrein, on the other hand. Kaolin may play an important role in the concentration and organization of these components on the negatively charged surface.

Amidohydrolases↗
PubMed1984

Hypotensive effect of human factor XII active fragment in conscious normotensive rats: role of bradykinin.

The active fragment derived from factor XII (factor XIIf) was purified from human plasma and administered intravenously to normotensive conscious rats. Factor XIIf-mediated hypotension was dose-dependent and augmented by pretreatment with captopril, an inhibitor of the bradykinin-processing enzyme kininase II. These results therefore suggest that factor XIIf-mediated hypotension is due to the formation of bradykinin.

Animals↗
PubMed2003

Reduction of factor XII in antiphospholipid antibody-positive patients with thrombotic events in the rheumatology clinic.

Although rheumatological diagnosis often includes an assessment of antiphospholipid (aPL) antibodies, the significance of other prothrombotic factors has not been established in thrombotic patients who are not afflicted with either arteriosclerosis or vasculitis syndrome. We have observed both the presence of antiphospholipid antibodies and a reduction of factor XII in such patients. Our results identified both lupus anticoagulant-positive (50%) and anticardiolipin antibody-positive (58%) patients. In addition, 83% of patients showed factor XII antigen level reduction. Furthermore, 70% of aPL-positive thrombotic patients showed factor XII antigen level reduction. Only two cases had antiphospholipid antibody alone, and 4/12 showed just factor XII antigen reduction. Recently, it has been reported that the presence of antiphospholipid antibodies induces factor XII reduction, and that anti-factor XII autoantibody can be detected in thrombotic patients. However, our results indicate that there are smaller factor XII reductions in non-thrombotic controls who are positive for antiphospholipid antibodies. Furthermore, anti-factor XII autoantibody was not detected in patients with decreased factor XII levels. Kindred research suggested that in two patients there was a genetic component to factor XII reduction. We concluded that the presence of both antiphospholipid antibodies and reduced serum factor XII was observed in most thrombotic patients from our rheumatology clinic. It is therefore possible to consider that the coexistence of these prothrombotic factors can contribute to the onset of thrombosis.

Adult↗
PubMed1989

Mapping of a putative surface-binding site of human coagulation factor XII.

We have localized the binding epitope(s) of two murine monoclonal antibodies (B7C9 and P5-2-1) that were shown previously to inhibit the activation of human coagulation factor XII by negatively charged surfaces. A factor XII cDNA expression library in lambda gt11 was screened with antibody B7C9, and 16 immunoreactive bacteriophage were isolated. Fusion proteins from each of the recombinant phage were reactive with both monoclonal antibodies. Two of the phage cDNA inserts were found to code for amino acid residues -6-+31 and +1-+47 of factor XII, respectively, thereby defining the limits of the antigenic peptide to amino acids +1-+31. Each of the remaining 14 recombinant phage contained longer factor XII cDNA inserts that included sequences coding for the amino-terminal 31 amino acid residues. These results were confirmed by direct binding of antibody B7C9 to synthetic peptides containing amino acids 1-14 and 1-28 of factor XII. Further experiments with a set of nested peptides also indicated that amino acid residues 1-4 were essential but not sufficient for binding of B7C9 to the peptides. Hydrophobicity analysis of the amino-terminal region of plasma factor XII revealed a highly hydrophilic region between amino acid residues 5 and 15 that contained positively charged lysine residues at positions 8, 11, and 13. We conclude that a major epitope(s) recognized by monoclonal antibodies B7C9 and P5-2-1 is present in the amino-terminal 28 amino acids of factor XII. It is proposed that binding of these antibodies to factor XII blocks interaction of the positively charged region between residues 5 and 15 with negatively charged surfaces, thereby inhibiting activation.

Antibodies, Monoclonal↗
PubMed1979

Factor XII deficiency with systemic lupus erythematosus. Biological implications.

A patient with Factor XII (Hageman) deficiency and fulminant systemic lupus erythematosus is presented. The Factor XII deficiency was noted prior to the onset of clinical systemic lupus erythematosus and persisted throughout the patient's course without associated hemorrhagic manifestations. There was no evidence for a circulating anticoagulant. The patient had a rapidly progressive fatal course unresponsive to corticosteroid therapy. Factor XII levels did not increase during therapy with steroids. Despite absence of Hageman factor, evidence for activation of complement by the classic pathway and thromboembolic phenomenon was observed. The role of Factor XII in coagulation and inflammatory pathways and the influence of the factor deficiency on the course of the patient's illness are discussed.

Adolescent↗
PubMed2001

[Anesthetic management of a patient with blood coagulation factor XII deficiency].

A 36-yr-old pregnant woman with blood coagulation factor XII deficiency was scheduled to undergo cesarean section. Preoperative blood coagulation scan revealed prolonged activated partial thrombin time of 105.6 s (control, 30.3 s), and a decrease in factor XII level of 3% (normal; 70-120%). Other examinations such as prothrombin time, platelet count and bleeding time were within normal limits. But she reported no history of bleeding. Before the operation, we discussed with obstetricians whether fresh frozen plasma (FFP) should be administered, or not. According to a report, a patient with factor XII deficiency can undergo major surgery without plasma replacement therapy. But another study showed that 15-30% of the factor XII activity was needed for hemostasis. We, therefore, administered 4 units of fresh frozen plasma before the operation. The operation was performed with general anesthesia uneventfully. Generally, a patient with factor XII deficiency has no clinical bleeding problems and unnecessary FFP administration may cause infection. Therefore it is not necessary to administer FFP to this patient.

Adult↗
PubMed1994

Contact factors in plasma from women on oral contraception--significance of factor XI for the measured activity of factor XII.

The plasma levels of contact activation factors were measured in women using a low estrogen dose oral contraceptive (OC). Basic values for factor XII (FXII), factor XI (FXI), prekallikrein (PK), and high molecular weight kininogen (HK) were obtained in immunoassays by comparing with control plasma. The plasma levels of FXII and PK were significantly increased in OC plasma, to 147% and 146% respectively, whereas no significant increase could be registered for FXI (106%) or for HK (107%). Functional assays carried out with different peptide substrates (S-2222 for FXIIa, and S-2222, S-2302 and Bz-Pro-Phe-Arg-pNA for kallikrein) showed increases in OC plasma to about 150% for both proteases, in accordance with results obtained in radial immunodiffusion (RID). However, when FXIIa was measured with the high molecular weight substrate PK, no significant increase could be registered. Further experiments suggested this result to be due to the low level of FXI present in OC plasma, as compared to the levels of FXII and PK. Assays were carried out in mixtures of test plasma (OC or control plasma) and plasma deficient in FXI or FXII. The results obtained suggested that FXIa was present in some kind of association with part of FXIIa and part of kallikrein present. At low concentrations of FXI the functional activity of FXIIa was reduced, and the assay data indicated that an appropriate level of FXI was required to obtain maximum rate of hydrolysis of prekallikrein by FXIIa.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Coagulation factor XII activity, but not an associated common genetic polymorphism (46C/T),is linked to recurrent miscarriage.

OBJECTIVE: To investigate whether a factor XII genetic polymorphism is associated with first-trimester embryonal loss. DESIGN: Prospective case-control study. SETTING; Nagoya City University Hospital. PATIENT(S): Eighty-three patients with a history of two or more unexplained first-trimester recurrent miscarriages and 67 controls with no obstetric complications or history of miscarriage. MAIN OUTCOME MEASURE(S): Plasma factor XII activity, a genetic polymorphism (46 C-->T) of factor XII, lupus anticoagulant, and beta(2)glycoprotein I dependent anticardiolipin antibodies. RESULT(S): Ten of the 83 patients and 1 of the 67 controls had decreased factor XII activity; the difference in frequency was statistically significant. Wild-type (CC), heterozygote (CT), and homozygote (TT) allele patterns were observed in 8, 36, and 39 patients, respectively, compared with 11, 20, and 36 of the patients and controls, respectively. The mean (+/- SD) corresponding factor XII activity was 154.8 +/- 44.8%, 112.7 +/- 30.2%, and 66.2 +/- 29.2% in patients and 164.6 +/- 26.7%, 114.3 +/- 28.1%, and 70.4 +/- 18.1% in controls. The two groups did not differ in the frequency of the T allele or categories of factor XII activity. CONCLUSION(S): Factor XII activity overall, but not the 46C/T common genetic polymorphism, is associated with recurrent miscarriage.

Abortion, Habitual↗
PubMed1981

Activation of factor XII in rat plasma: protection by benzamidine of the cofactor function of high molecular weight kininogen.

Factor XII has been assayed as kaolin-activated prekallikrein activator in rat citrated plasma pretreated with acetone (Briseid et al. 1978 & 1979; Briseid & Berstad 1979). In the present work benzamidine added during blood collection increased the extent of activation by a factor of 6. Rat high molecular weight kininogen (HMWK) added to acetone-treated citrated plasma likewise increased the activation, providing evidence of the protection by benzamidine of the cofactor function of HMWK. All cofactor capacity was retained after the removal of the kinin part of HMWK. Experiments carried out with plasminogen-free plasma showed that plasmin could hardly be the the factor responsible for the destruction of HMWK. The stoichiometric factor XII concentration-effect curve obtained by diluting acetone-treated rat plasma with acetone-treated human factor XII deficient plasma showed that factor XII is present in functional excess, the concentration of HMWK deciding the extent of activation. By diluting acetone-treated rat plasma with buffer, HMWK concentration-effect curves were obtained which were approximately linear over a range of 0.03-0.40 microgram (bradykinin equivalents) per ml kaolin incubate. No further activation of factor XII was obtained at 0.80 microgram/ml.

Amidines↗
PubMed1984

Kinetics of activation and autoactivation of human factor XII.

The kinetics of the enzymic reactions that participate in the contact activation system of human plasma were examined. These reactions are potentiated by dextran sulfate, a negatively charged solute that mimics many of the effects of glass or kaolin on this system. The reactions of reciprocal activation, consisting of activation of factor XII by kallikrein and of prekallikrein by activated factor XII, follow Michaelis-Menten kinetics; values of kcat and Km for each of these reactions were determined in the presence of dextran sulfate and in its absence. In the presence of dextran sulfate, the catalytic efficiency for factor XII activation was increased 11 000-fold, and that for prekallikrein was increased 70-fold. Autoactivation of factor XII in the presence of dextran sulfate also follows Michaelis-Menten kinetics with kcat = 0.033 s-1 and Km = 7.5 microM. This finding supports the concept that autoactivation is an enzymic process, initiated by traces of activated factor XII which are invariably present in factor XII preparations. At prekallikrein and factor XII levels equal to those in plasma, reciprocal activation is approximately 2000-fold more rapid than autoactivation. Thus, reciprocal activation is the predominant mode of factor XII activation in normal plasma.

Enzyme Activation↗
PubMed1979

Determination of Hageman factor (HG, factor XII) and plasma prekallikrein (Fletcher factor) by radioimmunoassays.

The titers of components of the plasma kallikrein-kinin system have been measured conventionally by their biological functions. The functional assays are, however, antagonized by the presence of inhibitors and/or the absence of potentiators in test samples. Immunologic assays obviate these difficulties. We have developed specific, sensitive and reproducible radioimmunoassays (RIA) for HF and prekallikrein, and have applied these assays to some clinical conditions. Normal pooled human plasma contained approximately 40 microgram of HF and 50 microgram of prekallikrein per ml. RIA were able to measure concentrations of HF and prekallikrein as low as 0.1% and 0.3% that of normal pooled plasma respectively. A good correlation existed between titers measured by clotting and radioimmunoassays among 40 normal subjects (correlation co-efficient = 0.82 for HF and 0.71 for prekallifrein). There was no significantly reduced in plasmas of patients with advanced liver cirrhosis or disseminated intravascular coagulation (DIC) and in cord serums, but they were normal in plasmas obtained after strenuous physical exercise and in plasmas of patients under treatment with warfarin.

Animals↗
PubMed1987

Acceleration of surface-dependent autocatalytic activation of blood coagulation factor XII by divalent metal ions.

The effect of divalent metal ions on the rate of dextran sulfate dependent autocatalytic activation of human blood coagulation factor XII was studied at pH 7.4 and 25 degrees C. Zn2+ and Cu2+, but not Co2+, increased the rate of factor XII activation induced by dextran sulfate with optimum effects at approximately 5 and 1 microM, respectively, while Ca2+ acceleration required much higher concentrations (millimolar). Further investigation of the effect of Zn2+ on factor XII activation demonstrated a complete dependence on the presence of dextran sulfate, lack of inhibition by soybean trypsin inhibitor, the appearance of alpha-XIIa as the primary reaction product, and reaction kinetics characteristic of an autocatalytic process. These results were consistent with Zn2+ affecting only the rate of surface-mediated factor XII autoactivation. The initial turnover velocity of dextran sulfate induced factor XII autoactivation increased linearly with factor XII concentration in the absence of Zn2+ up to 0.9 microM factor XII but showed saturation behavior over this same concentration range in the presence of 5 microM Zn2+, indicating that Zn2+ increased the reaction rate primarily by lowering the apparent Km. Comparison of the kinetics of autoactivation at mu = 0.15 and 0.24 revealed that the enhancement in the apparent kcat/Km brought about by Zn2+ increased from 19-fold to 520-fold, respectively, due to a differential dependence of the Zn2+-stimulated and unstimulated reactions on ionic strength.(ABSTRACT TRUNCATED AT 250 WORDS)

Cations, Divalent↗
PubMed1985

Interaction of factor XII, high-molecular-weight (HMW) kininogen and prekallikrein with sulfatide: analysis by fluorescence polarization.

The interaction of high-molecular-weight (HMW) kininogen, Factor XII and prekallikrein with sulfatide was studied by fluorescence polarization. Fluorescein-conjugated derivatives of HMW kininogen, Factor XII and prekallikrein were prepared by reacting the purified bovine factors with fluorescein isothiocyanate (FITC). The apparent dissociation constant (Kd) for the binding of FITC-labeled HMW kininogen (F-HMW kininogen) with sulfatide was calculated to be 3.2 (+/- 0.3) X 10(-8) M. This binding was partially inhibited by three kininogen derivatives, fragment 1 X 2, kinin-free protein and fragment 1 X 2-light chain, but not by kinin and fragment 1 X 2-free protein. In the presence of Factor XII, the binding of F-HMW kininogen with sulfatide was strongly inhibited, suggesting that the zymogen and the protein cofactor compete for the same or a closely related binding site on the sulfatide surface. In contrast, the binding of FITC-labeled Factor XII (F-Factor XII) with sulfatide was weakly inhibited by HMW kininogen but not by prekallikrein. The Kd value for binding of F-Factor XII with sulfatide was calculated to be 2.0 (+/- 0.3) X 10(-8) M. F-Prekallikrein did not interact with sulfatide. Moreover, the fluorescence polarization value of F-HMW kininogen decreased in the presence of prekallikrein, leveling off at a one-to-one molar ratio of prekallikrein to F-HMW kininogen. The Kd value for binding of F-HMW kininogen-light chain (F-light chain) with prekallikrein was calculated to be 3.8 (+/- 0.6) X 10(-8) M and the stoichiometry was estimated as 1 to 1.2 on a molar basis from the Scatchard plot.

Animals↗
PubMed2003

Antibodies to factor XII: a possible predictive marker for recurrent foetal loss.

Antibodies to factor XII (FXIIabs) have been demonstrated in some patients with the anti-phospholipid syndrome (APS). The presence of these antibodies were shown to lead to statistically significantly reduced levels of FXII (p = 0.02). In an extension to this study forty female patients with either primary APS (n = 26) or systemic lupus erythematosus (APS positive) (n = 14) were investigated for levels of factor XII, the presence of lupus anticoagulant and antibodies to cardiolipin, beta 2-glycoprotein I and factor XII. Twenty one of the forty patients had a history of foetal loss (> 2, mean = 2.6). Lupus anticoagulant positivity showed a weak association with foetal loss (odds ratio = 1.1). While there was no association between the presence of antibodies to cardiolipin or beta 2-glycoprotein I with foetal loss, antibodies to factor XII showed a strong and statistically significant association (odds ratio = 5.4, p = 0.025).

Abortion, Habitual↗
PubMed1992

Control of human coagulation by recombinant serine proteases. Blood clotting is activated by recombinant factor XII deleted of five regulatory domains.

The availability of engineered serine proteases allows one to study the activation, substrate specificity and regulation of human coagulation and fibrinolytic activities. Human coagulation factor XII is composed of the protease catalytic region at the C-terminus, a hinge proline-rich region and regulatory domains at the N-terminus. From cDNA clones coding for factor XII, two DNA molecules were constructed, one being full length and the other being deleted of exons coding for the regulatory domains. Engineered factor-XII cDNA species were inserted by a homologous recombination technique into vaccinia viruses, which were used to infect the human hepatoma cell line HepG2. Two recombinant proteins were prepared from the culture media and identified by their antigenic properties and electrophoretic mobilities. The recombinant protein of larger size was identified as the full-length factor XII of 80 kDa and its specific activities and activation patterns, determined both by the coagulation and the amidolytic assays, are very similar to these of native human factor XII. The recombinant protein of smaller size was identified as a 319-amino-acid-deleted factor-XII protein of 32 kDa, containing only the entire protease region and part of the proline-rich hinge. This protein was expected to be the 'minimal' portion of factor XII able to sustain protease but unable to recognize substrates and surfaces necessary to activate the contact phase of coagulation. However, this 'minimal' factor-XII protein displays a marked protease activity and, although lacking five regulatory domains of factor XII, is bound and activated by negative charges and promotes coagulation with high efficiency.

Base Sequence↗
PubMed1996

Structure/function analysis of human factor XII using recombinant deletion mutants. Evidence for an additional region involved in the binding to negatively charged surfaces.

The binding site of human factor XII (FXII) for negatively charged surfaces has been proposed to be localized in the N-terminal region of factor XII. We have generated two recombinant factor XII proteins that lack this region: one protein consisting of the second growth-factor-like domain, the kringle domain, the proline-rich region and the catalytic domain of FXII (rFXII-U-like), and another consisting of only 16 amino acids of the proline-rich region of the heavy-chain region and the catalytic domain (rFXII-1pc). Each recombinant truncated protein, as well as recombinant full-length FXII (rFXII), were produced in HepG2 cells and purified by immunoaffinity chromatography. The capability of these recombinant proteins to bind to negatively charged surfaces and to initiate contact activation was studied. Radiolabeled rFXII-U-like and, to a lesser extent, rFXII-lpc bound to glass in a concentration-dependent manner, yet with lower efficiency than rFXII. The binding of the recombinant proteins was inhibited by a 100-fold molar excess of non-labeled native factor XII. On native polyacrylamide gel electrophoresis, both truncated proteins appeared to bind also to dextran sulfate, a soluble negatively charged compound. Glass-bound rFXII-U-like was able to activate prekallikrein in FXII-deficient plasma (assessed by measuring the generation of kallikrein-C1-inhibitor complexes), but less efficiently than rFXII, rFXII-U-like and rFXII-lpc exhibited coagulant activity, but this activity was significantly lower than that of rFXII. These data confirm that the N-terminal part of the heavy-chain region of factor XII contains a binding site for negatively charged activating surfaces, and indicate that other sequences, possibly located on the second epidermal-growth-factor-like domain and/or the kringle domain, contribute to the binding of factor XII to these surfaces.

Base Sequence↗