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PubMed1997

Partial identification of the Zn2+-binding sites in factor XII and its activation derivatives.

With the purpose of identifying the Zn2+-binding sites in factor XII, the effect of chemical modification of His, Glu and Asp residues, amino acids known to participate in the catalytic coordination binding of Zn2+ in a number of Zn2+-binding proteins, was analysed. The number of modifiable His residues in factor XII and alpha-factor XIIa was 16.0+/-0.7 and 17.3+/-0.7, respectively. When factor XII/alpha-factor XIIa was incubated with saturating concentrations of Zn2+ before the diethylpyrocarbonate modification of the His residues, these numbers were reduced to 6.3+/-0.1 and 8.21+/-0.5, indicating that ten and nine His residues, respectively, are involved in the binding. Analysis of the Zn2+-binding capacity of factor XII, alpha-factor XIIa and beta-factor XIIa showed that while factor XII contains four Zn2+-binding sites, alpha-factor XIIa had only three and beta-factor XIIa had none. Modification of the His residues resulted in a complete loss of Zn2+-binding while Asp/Glu modification resulted in loss of two and one Zn2+-binding sites in factor XII and alpha-factor XIIa, respectively. This suggests that two of the four sites in factor XII contain His residues, exclusively, while the two others are comprised of two His residues and one Asp/Glu residue. One of the latter is lost when factor XII is activated to alpha-factor XIIa. Two of the sites are suggested to be located at positions His40-His44 and His78-His82. The location of the remaining two sites are reduced to four possible positions.

Amino Acid Sequence↗
PubMed1986

The function of the heavy and light chain of human plasma kallikrein in the activation of factor XII.

In this paper we report the effect of sulfatides on rate constants of Factor XII activation by kallikrein and its isolated light chain. In free solution kallikrein and the light chain were equally effective in activating Factor XII and both enzymes had their pH optimum at pH 7.0 (k1 = 1.6 X 10(3) M-1 s-1). Sulfatides greatly stimulate Factor XII activation. When sulfatides were present kallikrein was, however, much more effective than its light chain. At 330 microM sulfatides and pH 7.0 the rate constants of Factor XII activation were 5.3 X 10(6) M-1 s-1 and 4.2 X 10(4) M-1 s-1 for kallikrein and its light chain, respectively. In the presence of sulfatides, Factor XII activation by kallikrein had its pH optimum at 6.3 and the rate constant increased considerably at lower ionic strength. Light chain-dependent Factor XII activation in the presence of sulfatides, was optimal at pH 7.0 and was not affected by variation of the ionic strength. Binding studies revealed that kallikrein, Factor XII and the heavy chain of kallikrein bind to the sulfatide surface, whereas no binding of the light chain of kallikrein was detectable. Since the effects of pH and ionic strength on sulfatide-dependent Factor XII activation by kallikrein can be explained by effects on kallikrein binding to sulfatides we conclude that surface-bound Factor XII is activated by surface-bound kallikrein. Our data suggest that sulfatides stimulate Factor XII activation via two distinct mechanisms: a) by making Factor XII more susceptible to proteolytic cleavage and b) by promoting the formation of the enzyme-substrate complex through surface binding of both kallikrein and factor XII.

Enzyme Activation↗
PubMed2000

Human factor XII binding to the glycoprotein Ib-IX-V complex inhibits thrombin-induced platelet aggregation.

Factor XII deficiency has been postulated to be a risk factor for thrombosis suggesting that factor XII is an antithrombotic protein. The biochemical mechanism leading to this clinical observation is unknown. We have previously reported high molecular weight kininogen (HK) inhibition of thrombin-induced platelet aggregation by binding to the platelet glycoprotein (GP) Ib-IX-V complex. Although factor XII will bind to the intact platelet through GP Ibalpha (glycocalicin) without activation, we now report that factor XIIa (0. 37 microm), but not factor XII zymogen, is required for the inhibition of thrombin-induced platelet aggregation. Factor XIIa had no significant effect on SFLLRN-induced platelet aggregation. Moreover, an antibody to the thrombin site on protease-activated receptor-1 failed to block factor XII binding to platelets. Inhibition of thrombin-induced platelet aggregation was demonstrated with factor XIIa but not with factor XII zymogen or factor XIIf, indicating that the conformational exposure of the heavy chain following proteolytic activation is required for inhibition. However, inactivation of the catalytic activity of factor XIIa did not affect the inhibition of thrombin-induced platelet aggregation. Factor XII showed displacement of biotin-labeled HK (30 nm) binding to gel-filtered platelets and, at concentrations of 50 nm, was able to block 50% of the HK binding, suggesting involvement of the GP Ib complex. Antibodies to GP Ib and GP IX, which inhibited HK binding to platelets, did not block factor XII binding. However, using a biosensor, which monitors protein-protein interactions, both HK and factor XII bind to GP Ibalpha. Factor XII may serve to regulate thrombin binding to the GP Ib receptor by co-localizing with HK, to control the extent of platelet aggregation in vivo.

Amino Acid Sequence↗
PubMed2001

Factor XII but not protein C, protein S, antithrombin III, or factor XIII is a predictor of recurrent miscarriage.

OBJECTIVE: To investigate whether a decrease in the values of protein C (PC), protein S (PS), antithrombin III (ATIII), factor XII (FXII), or factor XIII (FXIII) has predictive value for subsequent miscarriages. DESIGN: Prospective study. SETTING: Nagoya City University Medical School. PATIENT(S): A total of 536 patients with a history of two or more first-trimester miscarriages. INTERVENTION(S): One hundred and twelve patients treated with low-dose aspirin were excluded from the analysis. MAIN OUTCOME MEASURE(S): The subsequent pregnancy outcome of 424 patients was compared for abnormal and normal levels of each parameter. RESULT(S): There were no differences in the subsequent miscarriage rates between abnormal and normal values of PC, PS, ATIII, and FXIII. However, the rate with abnormal FXII is significantly higher than that with normal FXII. CONCLUSION(S): A decrease in FXII (but not in PC, PS, ATIII, or FXIII) predicts subsequent miscarriage in patients with a history of first-trimester recurrent miscarriages.

Abortion, Habitual↗
PubMed1987

Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme.

A cDNA for coagulation factor XII has been used to investigate the presence of gene lesions and restriction fragment length polymorphisms in two brothers with Hageman trait and their family. A TaqI polymorphic fragment has been found in the two propositi and in 11 members of the paternal lineage. This polymorphism, absent in the normal population, is correlated with the reduction of factor XII activity and enables the identification of heterozygous factor XII deficiency. Factor XII gene deletion as the cause of Hageman trait in this family has been excluded. A restriction map has been constructed, and the TaqI polymorphic site has been localized within the 5' portion of the gene. The mutation in the polymorphic site is probably the cause of the factor XII deficiency. Data suggest the presence of one factor XII gene per haploid genome.

Collodion↗
PubMed1986

Enhanced specificity of immunoblotting using radiolabeled antigen overlay: studies of blood coagulation factor XII and prekallikrein in plasma.

Immunoblotting of blood coagulation Factor XII and plasma prekallikrein in whole plasma was performed using radiolabeled antigen for detection. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma and transfer to nitrocellulose sheets, the blots were first reacted with polyclonal goat anti-Factor XII or anti-prekallikrein antisera and then with 125I-Factor XII or 125I-prekallikrein, respectively. A major advantage of using radiolabeled antigen rather than radiolabeled secondary antibody was enhanced specificity of immunodetection of these antigens in plasma. This procedure was sensitive to approximately 0.3 ng of either Factor XII or prekallikrein antigen and was useful for detection of Factor XII cleavage fragments in contact activated plasma. Radiolabeled antigen overlay may improve the specificity of immunoblotting of trace antigens in any complex mixtures.

Collodion↗
PubMed1987

Structural and functional characterization of factor XII.

In this article we have reviewed the current knowledge regarding the involvement of Factor XII in contact activation. Clearly in the past decade an overwhelming amount of data and hypotheses have been published regarding the central role of this zymogen in the initiation and further propagation of contact activation reactions. Therefore we feel that it will be helpful to conclude this article with a figure that summarizes those interactions and reactions that are generally believed to reflect the major molecular events occurring during surface-dependent contact activation. The contact factors are capable of very efficient interation with each other, provided a suitable negatively charged surface is present. Such surfaces are thought to stimulate the interactions between the contact factors through binding of the proteins and thus bringing the proteins together. Factor XII readily binds to the negatively charged surface, but for the binding of prekallikrein and Factor XI, the cofactor HMW kininogen is likely to be necessary. Bound at the surface, the zymogens Factor XII and prekallikrein are thought to be involved in a so-called reciprocal activation mechanism in which Factor XIIa activates prekallikrein to kallikrein, which in turn converts Factor XII to Factor XIIa. The formation of Factor XIIa is further promoted by the fact that surface-bound Factor XII is likely more susceptible to proteolytic cleavage and by the fact that the activated Factor XIIa is capable of auto-activating its own zymogen Factor XII. However, the latter effect, although undoubtedly contributing to the formation of Factor XIIa at the surface, seems to be of less importance than the reciprocal activation mechanism. This is underscored by the fact that Factor XII activation is rather slow in prekallikrein-deficient plasma. Surface-bound Factor XIIa is then responsible for the activation of Factor XI to Factor XIa, thereby propagating the initial trigger. Presumably, Factor XIa must leave the surface in order to be able to become involved in the activation of blood coagulation Factor IX.

Amino Acid Sequence↗
PubMed2004

Genetic analyses and expression studies identified a novel mutation (W486C) as a molecular basis of congenital coagulation factor XII deficiency.

We analyzed the factor XII (FXII) gene of a patient with congenital FXII deficiency and identified a novel amino acid substitution (W486C) in the catalytic domain. The proband was an asymptomatic 49-year-old Japanese female with abnormal coagulation test, discovered by chance. The FXII activity and antigen level were both under 10%, suggesting a cross-reacting material-negative FXII deficiency. Sequence analysis of the proband's FXII gene revealed a homozygous nucleotide substitution G --> C in exon 12, resulting in the amino acid substitution W486C in the catalytic domain. We constructed the mutant FXII cDNA in an expression plasmid vector and transfected it into Chinese hamster ovary cells. The recombinant wild-type FXII antigen was detected in the culture medium by immunoprecipitation assay, but the mutant FXII (W486C) was not observed. On the other hand, both the wild-type FXII and W486C cell lysates contained FXII antigen and FXII mRNA, as estimated by western blotting and quantitative reverse transcriptase-polymerase chain reaction. These findings suggest that the W486C substitution of FXII impairs intracellular processing of the protein and/or transport system.

Amino Acid Substitution↗
PubMed2003

Factor XII deficiency is strongly associated with primary recurrent abortions.

OBJECTIVE: To evaluate factor XII deficiency in women with primary and secondary recurrent abortion. DESIGN: Prospective case-control study. SETTING: University hospital. PATIENT(S): Sixty-seven women with primary and 33 women with secondary recurrent abortion of unexplained nature and 49 healthy controls with no history of thrombotic disease or adverse pregnancy outcomes. MAIL OUTCOME MEASURE(S): Plasma factor XII activity, activated protein C resistance, factor V Leiden mutation analysis, protein C, protein S, antithrombin III, karyotyping, and anticardiolipin antibodies. RESULT(S): Ten of 67 women with primary recurrent abortion (14.9%) and 4 of 33 women (12.1%) with secondary recurrent abortion had reduced factor XII activity (<60%). These results are highly significant in the former group and showed a tendency toward significance in the latter group. All controls had normal factor XII activity. CONCLUSION(S): Factor XII deficiency is strongly associated with primary recurrent abortion, and women with secondary recurrent abortion show a tendency toward factor XII deficiency.

Abortion, Habitual↗
PubMed1989

[Polycythemia vera with an inhibitor against factor XII].

A case of polycythemia vera with an inhibitor against factor XII was reported. A 60-year-old female was admitted to Hokkaido University School Hospital because of erythrocytosis and hepatosplenomegaly. The hemoglobin was 22.5 g/dl and white cell count was 9,500/microliters without immature cells. The platelet count was 484,000/microliters. Bone marrow specimens showed marked hypercellularity. Philadelphia chromosome was not found on chromosome analysis. She was diagnosed as polycythemia vera according to the criteria of polycythemia Vera Study Group. Activity of factor XII was found to be decreased on the initial examination, but she had no personal and familial history of bleeding. In order to clarify the cause of decreased activity of factor XII, her plasma was mixed with normal plasma, and then examined PTT using factor XII deficient plasma. Her plasma mixed with equivalent normal plasma did not show the correction of prolonged PTT. It was suggested that an inhibitor of her plasma was included in the IgG fraction using gel chromatography. The patient was treated with phlebotomy and administration of N4-palmitoyl (1- -D-arabinofurasyl) cytosine (derivative of cytosine arabinoside; PLAC) 200 mg/day and Busulfan (1 mg/day). Factor XII was not corrected by phlebotomy, but corrected gradually by administration of PLAC and Busulfan.

Factor XII↗
PubMed1981

Reduced titers of Hageman factor (factor XII) in Orientals.

Hageman factor (factor XII) is a procoagulant upon which the surface-mediated generation of fibrinolytic activity and kinin formation depends. We found that the clotpromoting activity and antigenic properties of Hageman factor were present in lower levels in the plasma of a small group of Oriental subjects than in that of American whites, whereas the levels of plasma prekallikrein (Fletcher factor), high-molecular-weight kininogen (Fitzgerald factor), and plasma thromboplastin antecedent (factor XI) in plasma samples from Oriental subjects did not significantly differ from those from normal white subjects. In one family, there was an excess of plasma Hageman factor antigens with respect to functional activity. These findings stress the importance of defining the racial characteristics of subjects used to establish standards for clotting assays.

Adult↗
PubMed1983

Role of HMW kininogen in surface-mediated activation of Factor XII.

We have shown that bovine HMW kininogen remarkably accelerates the activation of Factor XII and prekallikrein in the presence of kaolin, adsorbing on kaolin through the fragment 1.2 region and forming a complex with prekallikrein through the light chain region (Sugo et al., 1980; Ikari et al., 1981). The present study was undertaken to examine the role of HMW kininogen in the activation of Factor XII and prekallikrein with other negatively-charged surfaces. The activation system used here was as follows; (1) Activation of prekallikrein by Factor XII, (2) Activation of Factor XII by plasma kallikrein and (3) Activation of prekallikrein by Factor XIIa. Among a variety of foreign surfaces, amylose sulfate and sulfatide were the most efficient in the activation reaction of Factor XII and prekallikrein. Bovene HMW kininogen accelerated all the three reactions triggered by these surfaces. However, the accelerating effect of HMW kininogen on the activation of Factor XII by plasma kallikrein was very weak, when amylose sulfate or sulfatide was used as surface. The three reactions were highly dependent on the amounts of HMW kininogen and surfaces contained in the reaction mixtures. Excess amount of them inhibited these reactions. Among the various fragments, which were prepared from HMW kininogen digests with plasma and urinary kallikreins (Sugo et al., 1980), a large fragment consisting of fragment 1.2 and light chain accelerated the reactions. Thus both fragment 1.2 and the light chain region in HMW kininogen were essential for these activation reactions.

Amylose↗
PubMed1995

Monoclonal antibody F1 binds to the kringle domain of factor XII and induces enhanced susceptibility for cleavage by kallikrein.

In a previous study we have shown that monoclonal antibody F1 (MoAb F1), directed against an epitope on the heavy chain of factor XII distinct from the binding site for anionic surfaces, is able to activate factor XII in plasma (Nuijens JH, et al: J Biol Chem 264; 12941, 1989). Here, we studied in detail the mechanism underlying the activation of factor XII by MoAb F1 using purified proteins. Formation of factor XIIa was assessed by measuring its amidolytic activity towards the chromogenic substrate H-D-Pro-Phe-Arg-pNA (S-2302) in the presence of soybean trypsin inhibitor and by assessing cleavage on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Upon incubation with MoAb F1 alone, factor XII was auto-activated in a time-dependent fashion, activation being maximal after 30 hours. Factor XII incubated in the absence of MoAb F1 was hardly activated by kallikrein, whereas in the presence of MoAb F1, but not in that of a control MoAb, the rate of factor XII activation by kallikrein was promoted at least 60-fold. Maximal activation of factor XII with kallikrein in the presence of MoAb F1 was reached within 1 hour. This effect of kallikrein on the cleavage of factor XII bound to MoAb F1 was specific because the fibrinolytic enzymes plasmin, urokinase, and tissue-type plasminogen activator could not substitute for kallikrein. Also, trypsin could easily activate factor XII, but in contrast to kallikrein, this activation was independent of MoAb F1. SDS-PAGE analysis showed that the appearance of amidolytic activity correlated well with cleavage of factor XII. MoAb F1-induced activation of factor XII in this purified system was not dependent on the presence of high-molecular-weight kininogen (HK), in contrast to the activation of the contact system in plasma by MoAb F1. Experiments with deletion mutants revealed that the epitopic region for MoAb F1 on factor XII is located on the kringle domain. Thus, this study shows that binding of ligands to the kringle domain, which does not contribute to the proposed binding site for negatively charged surfaces, may induce activation of factor XII. Therefore, these findings point to the existence of multiple mechanisms of activation of factor XII.

Amino Acid Sequence↗
PubMed1993

Surface-independent acceleration of factor XII activation by zinc ions. I. Kinetic characterization of the metal ion rate enhancement.

The effect of zinc ions (Zn(II)) on the activation of factor XII in the absence of a procoagulant surface was investigated by initial velocity kinetic studies at I = 0.15, pH 7.4, and 25 degrees C. Zinc ions at concentrations greater than 160 microM potentiated 99-fold the kcat/KM for the activation of factor XII by kallikrein and, at an optimum concentration of 110 microM, accelerated 140-fold the apparent kcat/KM for factor XII autoactivation. High molecular weight kininogen had no effect on either metal-potentiated reaction. Analysis of the factor XII concentration dependence of initial activation rates revealed that Zn(II), at levels that saturate the effect, accelerates kallikrein activation of factor XII by lowering KM (from 52 to 7.3 microM) and raising kcat (from 2.6 to 31 min-1). For the autocatalytic activation reaction of factor XII in the presence of optimal Zn(II), apparent KM and kcat values of 2.4 microM and 0.041 min-1, respectively, were determined, but these parameters were not resolvable in the absence of the metal ion. Zinc ions minimally affected kallikrein enzymatic activity and inhibited factor XIIa enzymatic activity with KI values of 20-40 microM, suggesting that the rate-enhancing effects of the metal ion are due to interactions with the substrate (factor XII) rather than with the enzyme. The Zn(II) inhibition of factor XIIa enzymatic activity accounted for a decreased Zn(II) enhancement of factor XII autoactivation at high metal ion concentrations (> 110 microM). The Zn(II) concentration dependence of the acceleration of factor XII activation reactions were sigmoid and characterized by Hill coefficients of 3.3-4.3, suggesting that cooperative binding of at least four zinc ions to factor XII was responsible for the Zn(II) potentiating effect. The Zn(II) enhancement of the rates of factor XII activation decreased both above and below pH 7.4 with midpoint pH values of 6.5-7.0 and 8.0, consistent with histidine and possibly water ligands mediating Zn(II) binding to the protein. Despite an apparent weaker binding of Zn(II) to factor XII at pH 6.5, indistinguishable maximum accelerating effects of the metal ion were observed at saturation at this pH, indicating that the increased positive charge of factor XII resulting from protonation at the lower pH did not mimic the effect of Zn(II) binding. These results imply that zinc ions induce a conformational change in factor XII that makes it a better substrate for its enzyme activators.

Factor XII↗
PubMed2003

Expression, refolding, and activation of the catalytic domain of human blood coagulation factor XII.

Human blood coagulation factor XII (FXII; 80 kDa) contains a C-terminal serine protease zymogen domain, which becomes activated upon contacting a negative surface. Activated FXII (alphaFXIIa) brings about reciprocal activation of FXII and kallikrein that by further hydrolysis produces the free catalytic domain (betaFXIIa; 28 kDa). Increased levels of alphaFXIIa are associated with coronary heart disease, sepsis, and diabetes. Biophysical investigation of the structural basis of activation, substrate specificity, and regulation of FXII requires an efficient bacterial system for producing the wild-type and mutant recombinant proteins. Here, the cDNA of the zymogen domain of FXII (betaFXII) was cloned into the pET-28a(+) vector and the plasmid was transformed into Escherichia coli strain BL21 (DE3) and overexpressed. The multi-disulfide, recombinant protein, His(6)-betaFXII (rbetaFXII), expressed as an inclusion body, was purified by means of a Ni(2+)-charged resin. The matrix-bound rbetaFXII was subjected to refolding with the glutathione redox system and activated by the in vivo activator, kallikrein. The active form, rbetaFXIIa, obtained in milligram quantities, exhibited similar structural and comparable functional properties relative to human betaFXIIa, as indicated by circular dichroism spectroscopy and kinetics of substrate hydrolysis. Thermodynamics of enzyme:inhibitor complex formation, including the expected 1:1 stoichiometry, was determined for rbetaFXIIa by isothermal calorimetric titration with a specific recombinant protein inhibitor, Cucurbita maxima trypsin inhibitor-V (rCMTI-V; 7kDa).

Blood Coagulation↗
PubMed1993

[The genetics of factor XII deficiency].

There are two main forms of factor XII deficiency: patients with immunological cross-reacting material (CRM+) and patients without (CRM-). For 1 case of CRM+ an amino acid substitution (Cys571-->Ser) has been described. We are currently investigating two families of Hageman CRM- trait with the typical hemostaseological pattern: one member with virtually no factor XII activity and antigen, whose sisters and children have about 50% of activity and antigen. To elucidate the genetic defect, primers were synthesized for both exon-intron borders for each of the 14 exons. Polymerase chain reaction (PCR) was performed for each single exon and for any two exons in a row with the intron in between (double-exon screening). We were able to demonstrate that homozygous patients do not have major rearrangements, deletions or insertions of the factor XII gene. To localize the molecular defect, the complete gene was sequenced by cloning the PCR products into pBS. In 1 patient, a single base deletion in exon 12, leading to a nonsense protein, was detected. The propositus was shown to be heterozygous for this defect by a deletion-specific restriction fragment length polymorphism of the PCR product.

Base Sequence↗
PubMed1983

Prekallikrein, HMW-kininogen and factor XII in various disease states.

The behaviour of prekallikrein (PKK), factor XII, high molecular weight kininogen (HMWK) and kallikrein-inhibitor (KK-I) in 367 patients with various diseases is described. Malignancies lead to elevation of factor XII and KK-I, and reduction of PKK. The effect is more pronounced in patients with metastases. In renal diseases also one or more of the above mentioned parameters are abnormal. Defects requiring dialysis treatment significantly impair the contact factors. In this group low levels of PKK, Factor XII and HMWK and increased KK-I are common. In chronic renal disease patients, only F XII and KK-I are elevated, whereas PKK and HMWK are normal. Kidney transplantation leads to a rise in KK-I and reduction of PKK and HMWK. The values almost normalize few days after the operation. Factor XII, slightly increased immediately after transplantation, remains high in long term transplant recipients, whereas HMWK falls below normal. In liver disease patients, acute and chronic hepatitis, cirrhosis of the liver and coma, PKK is reduced. In cases with acute hepatitis PKK raises with recovery. Cirrhosis and coma lead to low HMWK and factor XII concentrations. KK-I is mostly affected during acute hepatitis, and is then highly increased. Our results clearly demonstrate that the biologic activity of one or more of contact factors is affected in many diseases.

Factor XII↗