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PubMed1985

Binding and activation properties of human factor XII, prekallikrein, and derived peptides with acidic lipid vesicles.

The binding of human factor XII and prekallikrein to vesicles of various compositions and the relationship to activation of factor XII were studied. Factor XII, factor XIIa, and the 40-kilodalton binding fragment of factor XII bound tightly to all of the negatively charged lipids investigated, including sulfatide, phosphatidylserine, and phosphatidylethanolamine, but not to the neutral lipid phosphatidylcholine. Binding could be reversed by high salt, and the dissociation constant for binding to sulfatide vesicles was in the nanomolar range at an ionic strength of 0.15 M. Prekallikrein did not bind significantly to either sulfatide or phosphatidylethanolamine vesicles under the conditions used. Stopped-flow studies showed that the association rate for the factor XII-sulfatide interaction was biphasic and very rapid; the faster rate corresponded to about 30% collisional efficiency. The kinetics of activation of factor XII was investigated and was in agreement with previous studies; sulfatide promoted activation but phosphatidylserine, phosphatidylethanolamine, and phosphatidylcholine did not. Autoactivation rates correlated closely with the packing density of factor XII and factor XIIa on the vesicle surface. In contrast, kallikrein activation of factor XII correlated with the amount of sulfatide-bound factor XII and was relatively insensitive to the density of factor XII on the vesicle surface. When the concentration of factor XII was reduced to only several molecules per vesicle, the autoactivation rate dropped very low whereas kallikrein activation held relatively constant. These results indicated that the autoactivation and the kallikrein activation of factor XII were dependent on different properties of the surface component.

Enzyme Activation↗
PubMed1995

Factor XII deficiency and cardiopulmonary bypass.

Factor XII initiates the intrinsic coagulation cascade and may affect the fibrinolytic system. Routine coagulation tests used during cardiopulmonary bypass (CPB) are abnormal in factor-XII-deficient patients and are useless for monitoring anticoagulation in these patients. A factor-XII-deficient patient requiring CPB is described. The baseline celite activated clotting time (ACT) was greater than 1400 seconds and the thrombin time was 12.4 seconds (control, 11.9 seconds). Two units of plasma were given resulting in an ACT of 173 seconds. Following 300 units/kg of heparin and during CPB, the ACT ranged from 670-596 seconds with the thrombin time greater than 200 seconds. Plasma provides exogenous factor XII allowing an endpoint on the ACT test and may protect against possible postoperative hypofibrinolytic complications. A commercially available modified thrombin time may also be useful and provide an endpoint during high-dose heparinization.

Aged↗
PubMed2001

Aortic valve replacement in a patient with factor XII deficiency: case report.

Congenital factor XII deficiency is a rare condition. We report a case of aortic valve replacement (AVR) in a 63-year-old man with factor XII deficiency. On admission, the patient's activated partial thromboplastin time (aPTT) was prolonged (271 s), and activated clotting time was 500 s. His factor XII level was <3%. The Sonoclot signature showed an abnormal pattern. AVR with a prosthetic valve (St. Jude Medical) was performed safely after the normalization of aPTT and the Sonoclot signature by frozen plasma transfusion. The perioperative management in patients with factor XII deficiency is discussed.

Aortic Valve↗
PubMed1986

Purification of human factor XII from plasma using zinc chelate affinity chromatography.

Human factor XII (Hageman Factor) was isolated from human plasma to apparent homogeneity using a four step procedure with yields up to 30%. The method, which is more rapid than the current conventional procedures, consists of a 25-50% ammonium sulfate fractionation, two affinity chromatography steps using Zinc Chelate Sepharose, followed by gel filtration. The isolated zymogen factor XII was a single protein component when examined by SDS PAGE with a Mr of 80,000. Activation of zymogen factor XII to its active enzymatic forms by kallikrein resulted in factor XIIa and factor XIIf as observed with factor XII purified by other procedures.

Ammonium Sulfate↗
PubMed1989

Clinical implications of factor XII deficiency.

A patient with known factor XII deficiency underwent extraction of four impacted third molars. Significant preoperative laboratory values included a partial thromboplastin time (PTT) of greater than 100 seconds and a factor XII level of less than 1%. The third molars were removed without any significant intraoperative or postoperative bleeding. Factor XII not only has an important function in the initiation of the intrinsic pathway of the coagulation cascade, but it also plays a significant role in complement activation, kinin generation, and fibrinolysis. It would seem that a deficiency in this factor would have widespread clinical implications. In fact, the only clinical significance seems to be a predisposition to thromboembolism in factor XII deficient patients.

Adolescent↗
PubMed1997

Interleukin-6 downregulates factor XII production by human hepatoma cell line (HepG2).

Involvement of the contact system of coagulation in the pathogenesis of various inflammatory diseases is suggested by reduced plasma levels of factor XII (Hageman factor) and prekallikrein generally considered to result from activation of the contact system. However, in many of these diseases patients develop an acute-phase response and, therefore, an alternative explanation for the decreased levels of factor XII could be the downregulation of factor XII gene expression in the liver as described for negative acute-phase proteins. We report here that interleukin-6 (IL-6), the principal cytokine mediating the synthesis of most acute-phase proteins in the liver, downregulates the production of factor XII by the human hepatoma cell line HepG2 by up to 75%. The decrease in protein secretion correlated with an equivalent decrease of factor XII mRNA likely indicating a pretranslational control of factor XII gene expression by IL-6. Downregulation of factor XII production by IL-6 in vitro parallelled that of transthyretin, a known negative acute-phase protein. Moreover, we show that, in patients developing an acute-phase response after immunotherapy with IL-2, plasma levels of factor XII correlate (r = .76, P < .0001) with those of transthyretin. Taken together, these results suggest that factor XII behaves as a negative acute-phase protein.

Acute-Phase Reaction↗
PubMed1981

Urinary excretion of Hageman factor (factor XII) and the presence of nonfunctional Hageman factor in the nephrotic syndrome.

Acquired deficiencies of functional Hageman factor (factor XII) and prekallikrein, proteins involved in the plasma kinin-generating system, have been previously reported in the nephrotic syndrome. The basis for these changes, however, is not fully understood. We have examined the levels of Hageman factor and prekallikrein by functional and radioimmunoassays in plasmas and urines of 11 patients with the nephrotic syndrome. All 11 patients had decreased titers of plasma Hageman factor activity (mean +/- standard deviation (SD), 0.29 +/- 0.15 U/ml), but essentially normal titers of immunoreactive Hageman factor (0.68 +/- 0.23 U/ml). The ratio of immunoreactive Hageman factor to functional Hageman factor (2.63 +/- 0.86) was significantly higher than that in nine control patients (1.08 +/- 0.17). Since no circulating anticoagulants against Hageman factor were detected, these data suggest the presence of nonfunctional (altered) Hageman factor in plasmas of patients with the nephrotic syndrome. Urinary excretion of Hageman factor was present in six patients but did not appear to account for the reduced plasma Hageman factor activity. Urinary Hageman factor in one patient had the same size as plasma Hageman factor as assessed by gel filtration and sucrose density gradient centrifugation. The titers of plasma prekallikrein were within the normal range. These studies indicate urinary excretion of Hageman factor and alterations in the functional sites of plasma Hageman factor molecules in the nephrotic syndrome. Whether these changes are related to the pathogenesis of the nephrotic syndrome remains to be determined.

Adolescent↗
PubMed1993

Activation of factor XI in plasma is dependent on factor XII.

The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.

Autoradiography↗
PubMed1984

Inactivation of factor XII active fragment in normal plasma. Predominant role of C-1-inhibitor.

To define the factors responsible for the inactivation of the active fragment derived from Factor XII (Factor XIIf ) in plasma, we studied the inactivation kinetics of Factor XIIf in various purified and plasma mixtures. We also analyzed the formation of 125I-Factor XIIf -inhibitor complexes by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). In purified systems, the bimolecular rate constants for the reactions of Factor XIIf with C-1-inhibitor, alpha 2-antiplasmin, and antithrombin III were 18.5, 0.91, and 0.32 X 10(4) M-1 min-1, respectively. Furthermore, SDS-PAGE analysis revealed that 1:1 stoichiometric complexes were formed between 125I-Factor XIIf and each of these three inhibitors. In contrast, kinetic and SDS-PAGE studies indicated that Factor XIIf did not react with alpha 1-antitrypsin or alpha 2-macroglobulin. The inactivation rate constant of Factor XIIf by prekallikrein-deficient plasma was 14.4 X 10(-2) min-1, a value that was essentially identical to the value predicted from the studies in purified systems (15.5 X 10(-2) min-1). This constant was reduced to 1.8 X 10(-2) min-1 when Factor XIIf was inactivated by prekallikrein-deficient plasma that had been immunodepleted (less than 5%) of C-1-inhibitor. In addition, after inactivation in normal plasma, 74% of the active 125I-Factor XIIf was found to form a complex with C-1-inhibitor, whereas 26% of the enzyme formed complexes with alpha 2-antiplasmin and antithrombin III. Furthermore, 42% of the labeled enzyme was still complexed with C-1-inhibitor when 125I-Factor XII was inactivated in hereditary angioedema plasma that contained 32% of functional C-1-inhibitor. This study quantitatively demonstrates the dominant role of C-1-inhibitor in the inactivation of Factor XIIf in the plasma milieu.

Antithrombin III↗
PubMed1987

A monoclonal antibody recognizing an icosapeptide sequence in the heavy chain of human factor XII inhibits surface-catalyzed activation.

A monoclonal antibody (mAb B7C9) to human factor XII was raised in murine somatic cell using purified factor XII antigen. The purified antibody was subtyped IgG1 kappa and had a KD of 9.8 nM for antigen factor XII. Functional studies indicated that mAb B7C9 blocks surface-mediated coagulant activity of factor XII but not the amidolytic activity of factor XIIa against the small substrate H-D-Pro-Phe-Arg-p-nitroanilide (S-2302), suggesting that the mAb B7C9 epitope is located at or near the surface binding domain of the heavy chain region of factor XII. Western blot analysis indicated that the antibody reacts with factor XII and the heavy chain of factor XIIa. Affinity isolation of factor XII peptides, produced after cleavage by kallikrein, resulted in three factor XII heavy chain domain segments that were identified in the known factor XII sequence by limited N-terminal analysis. The epitope was located to a 20-amino acid sequence of 2.5 kDa in the heavy chain of factor XII which is the putative surface binding region of factor XII. The 2.5-kDa peptide was synthesized and demonstrated to react with mAb B7C9. mAb B7C9 was immobilized on an affinity resin and was successfully utilized to purify functionally active factor XII from plasma.

Animals↗
PubMed1983

Mechanism of surface-mediated activation of bovine Factor XII and prekallikrein.

The mechanism of kaolin-mediated activation of bovine Factor XII was studied in the presence of prekallikrein and HMW kininogen. The activated enzymes were assayed using fluorogenic peptides, Boc-Glu (OBzl)-Gly-Arg-4-methylcoumaryl-7-amide (MCA) for Factor XIIa and Z-Phe-Arg-MCA for plasma kallikrein. The rates of activation of the zymogens were separately measured by blocking either of the active enzymes with specific inhibitors, corn inhibitor for Factor XIIa (Ki = 6.7 nM) and Trasylol for plasma kallikrein (Ki = 3.9 nM). The result was as follows: (1) At the early stage of the activation reaction, kallikrein activity was first generated after short lag time, and then Factor XIIa activity was generated with a sigmoidal curve. In the presence of corn inhibitor, the activation of prekallikrein was observed, but in the presence of Trasylol, the activation of Factor XII was not observed. In the presence of high concentration of Ala-Phe-Arg-Ch2Cl, which inactivates immediately both of the active enzymes, the cleavage of a single chain prekallikrein into the two chain form by Factor XII was shown by SDS-PAGE, using nonlabelled and tritiated prekallikrein. (2) The incubation of Factor XII alone in a quartz cuvette or in the presence of kaolin and HMW kininogen did not result in the activation of Factor XII. The concave upward curve due to an autocatalytic activation was not observed even after the addition of Factor XIIa to Factor XII preparation. Moreover, no structural change of Factor XII during the incubation with kaolin and HMW kininogen was shown by SDS-PAGE, using 3H-Factor XII. (3) The rates of activation of prekallikrein by Factor XII and by Factor XIIa were approximately the same at higher concentration of prekallikrein. However, at lower concentration of prekallikrein the rate of activation of prekallikrein by Factor XII was shown to be a sigmoidal curve and slower than that by Factor XIIa. These results indicate that the activation of bovine Factor XII is initiated by the attack of Factor XII on prekallikrein, followed by the reciprocal activation of Factor XII by plasma kallikrein generated. The autocatalytic activation of bovine Factor XII by Factor XIIa was not demonstrated.

Amino Acid Chloromethyl Ketones↗
PubMed1996

Estrogen induction and contact phase activation of human factor XII.

This paper reviews data reported in the literature and results of our experiments on the transcriptional control of Factor XII by estrogens and on the activation of Factor XII in the plasma. Coagulation Factor XII (Hageman factor, FXII) is a serine protease secreted by the liver and activated by negative charged surfaces to play roles in fibrinolysis, coagulation, and inflammation. Multiple effects on hemostasis involving these processes via Hageman factor have been reported in relation to estrogen therapy. The nucleotide sequence of 3,174 base pair (bp) DNA at the 5' end of the Factor XII gene indicates that the Factor XII promoter is typical of TATA-less, liver-specific, and serine protease-type eukaryotic genes involved in clotting. In addition the Factor XII promoter contains at position -44/-31 a palindrome similar, but not identical, to an estrogen-responsive element (ERE) together with four hemisite EREs between positions -1314 and -608. These promoter regions may underlie the mechanism by which estrogens enhance Factor XII concentrations in plasma. In vivo, a 6-fold stimulation of FXII gene transcription by 17 beta-estradiol was observed in ovariectomized rats. In vitro a 230-bp promoter fragment of Factor XII (-181/+49) confers a strong 17 beta-estradiol responsiveness onto a chlorampenicol acetyltransferase reporter when transiently co-transfected with the human estrogen receptor. The domain structure of Factor XII allows identification of those parts of the protein with particular functions. cDNA constructs, in which sequences coding for selected domains were deleted, were used to produce recombinant deleted Factor XII proteins in a vacinia virus expression system. To identify the domain(s) responsible for contact phase activation, these recombinant proteins were tested for their capacity to bind to negatively charged substrates, to become activated by kallikrein, and to sustain blood clotting and amidolytic activity. In addition to the N-terminal domain, the growth factor and kringle domains and, to a lesser extent, the polyproline region also interact with negatively charged surfaces and presumably thus contribute to activation.

Animals↗
PubMed1991

Factor XII deficiency and pregnancy.

A 19-year-old primigravida with known factor XII deficiency (prepregnant factor XII level of 21%) presented with placental abruption and preterm labor at 26 weeks' gestation. A healthy 925-g female infant was born by spontaneous vaginal delivery. The mother had no postpartum hemorrhage or further complications, and the infant demonstrated no intracranial or other forms of hemorrhage up to 70 days of age. The infant's factor XII level was 34% (normal for her age). There are only two previous reports of factor XII deficiency in pregnancy cited in the English literature, and both were uncomplicated. In view of the risk of thromboembolic complications in nonpregnant individuals with factor XII deficiency, pregnant women with a prolonged activated partial thromboplastin time and no lupus anticoagulant or anticardiolipin antibody syndrome should also be investigated for deficiencies of factors VIII, IX, and XII. These patients should be given the appropriate counseling and should be monitored for features of thromboembolism if factor XII deficiency is confirmed.

Abruptio Placentae↗
PubMed1993

Molecular cloning and sequence analysis of the cDNA for a human serine protease reponsible for activation of hepatocyte growth factor. Structural similarity of the protease precursor to blood coagulation factor XII.

Hepatocyte growth factor (HGF) is a potent mitogen for parenchymal liver cells, epithelial cells, and endothelial cells and may play an important role in liver regeneration following hepatic injury. HGF is homologous to plasminogen and is first synthesized and secreted as an inactive single-chain precursor and then activated to a heterodimeric form by endoproteolytic processing. Recently, a novel serine protease responsible for this processing (HGF activator) has been purified from fetal bovine serum (Shimomura, T., Ochiai, M., Kondo, J., and Morimoto, Y. (1992) Cytotechnology 8, 219-229). In this study, we purified HGF activator from human serum and determined its partial amino acid sequence. Based on the amino acid sequence, we have molecularly cloned the cDNA for human HGF activator. The nucleotide sequence of the cDNA revealed that HGF activator is derived from the COOH-terminal half region of a precursor protein of 655 amino acids and that the precursor consists of multiple putative domains homologous to those observed in blood coagulation factor XII. These domains may be involved in the conversion of the precursor to the active form of HGF activator.

Amino Acid Sequence↗
PubMed1982

Factor XII and other hemostatic protein abnormalities in nephrotic syndrome patients.

Factor XII clotting activities and antigen levels were assayed in 14 plasma samples from 10 patients with nephrotic syndrome; the group was heterogeneous clinically and histologically. Factor XII was low at initial sampling in 7 of the 10 patients; in 7 of the 14 samples, factor XII antigen was in excess over clotting activity. Inhibition of factor XII could not be demonstrated; excess plasma antigen and urinary antigen (when present) had normal patterns on crossed-immunoelectrophoresis, indicating no major changes in charge or size. In 3 patients tested more than once, plasma levels of factor XII were increased up to 6fold in steroid-induced remission. Of other hemostatic factors assessed for comparison, factor VIII was elevated in 11 of the 14 samples; eight of these had elevated factor VII levels as well. Eight samples from six patients showed low antithrombin III levels; one of these patients had recurrent thromboses. Antithrombin III levels correlated with the serum albumin concentration. Only two of the eight urines tested had detectable factor XII antigen; a third had factor IX and prothrombin and no factor XII. Plasminogen and antithrombin III were readily demonstrated in all urine samples with higher concentrations in those patients with less selective proteinuria. Urinary and plasma levels were not correlated, suggesting that increased consumption or turnover was not simply related to increased filtration.

Adolescent↗
PubMed1980

The inheritance pattern of factor XII (Hageman) deficiency in domestic cats.

Measurements of coagulation factor XII levels in F1 progeny of a cat having factor XII deficiency revealed an autosomal recessive pattern similar to that reported in humans (Hageman trait). A study of the pedigree of the colony revealed that F1 kittens had approximately 50% factor XII activity while kittens produced by backcrossing with an F1 progeny possessed an average of 50% and a less than 2% factor XII activity in an approximate 1:1 ratio. Kittens having an average of 50% factor XII activity were postulated heterozygous for the trait while progeny with less than 2% activity were considered genetically homozygous.

Animals↗
PubMed1993

Surface-independent acceleration of factor XII activation by zinc ions. II. Direct binding and fluorescence studies.

To determine the role of Zn(II)-factor XII interactions in the rate-enhancing effect of Zn(II) on factor XII activation demonstrated in the preceding paper, equilibrium binding of zinc ions to factor XII, and the spectroscopic changes accompanying this binding were investigated. Equilibrium dialysis provided direct evidence for the binding of Zn(II) to factor XII. The binding data were consistent with 7.8 +/- 0.3 zinc ions binding with an indistinguishable Kd of 91 +/- 6 microM. Binding of Zn(II) was accompanied by a 10% quenching of the intrinsic protein fluorescence and a 2-nm red shift of the wavelength of maximum emission. These spectroscopic changes were specific for factor XII and were not observed with factor XIIa. The Zn(II) concentration dependence of factor XII fluorescence quenching was sigmoid and paralleled the Zn(II)-accelerating effect of factor XII activation by kallikrein and factor XIIa, indicating that the spectral change was reporting Zn(II)-factor XII interactions responsible for the enhanced activation rate. The apparent cooperativity of Zn(II) effects on factor XII fluorescence quenching and activation kinetics, and the apparent noncooperativity in Zn(II) binding to factor XII measured by equilibrium dialysis could be explained by a two-state model in which Zn(II) binding is linked to a conformational change in the protein. The Zn(II)-induced quenching of factor XII fluorescence exhibited a pH dependence consistent with the involvement of histidine residues in the binding of Zn(II). Dynamic quenching of factor XII protein fluorescence by iodide or acrylamide, in the absence and presence of Zn(II), revealed heterogeneity in the environment of the 13 tryptophan residues of factor XII that was markedly reduced by metal ion binding. Together, these results indicate that cooperative interactions of Zn(II) with factor XII induce structural changes in the zymogen that facilitate its proteolytic cleavage and activation.

Acrylamide↗