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PubMed1976

A serial study of coagulation factors XII, XI and X in plasma in normal pregnancy and in pregnancy complicated by pre-eclampsia.

A serial study of coagulation factors XII, XI and X in plasma has been carried out on 60 primigravidae, prospectively comparing those who remained normal with those who developed pre-eclampsia. In the normal group of 48 patients, the levels of all factors rose as pregnancy advanced, a secondary increase in factors XI and X occurring in the puerperium. Cord levels of all three factors were depressed. In the pre-eclampsia group of 12 patients, factor XII was significantly higher than in the normal group throughout the study, while factors XI and X were slightly lower. Observed changes failed to support the idea of a strong primary role for the coagulation mechanism in the pathogenesis of pre-eclampsia.

Factor X↗
PubMed1980

A comparison of the effects of intravenous serotonin and dextran on the levels of factor XII, prekallikrein and plasminogen in rat plasma.

It was previously observed that serotonin injected intravenously into the rat caused significant reductions in the prekallikrein activator (PKA) and the benzoyl arginine ethyl ester (BAEe)-esterase activities induced in rat plasma by acetone/kaolin activation. In the present work it was demonstrated that serotonin was unable to exert these effects in vitro, in plasma or in whole blood. The assay of PKA and Baee-esterase activities after gel filtration on Sephadex G-100 of acetone-activated plasma from rats treated with serotonin 0.10 mg/kg revealed reduced fragmentation of factor XII, and reduced levels of kallikrein and of an additional BAEe-esterase. Serotonin also lowered the plasminogen level. The serotonin-induced reductions of PKA and BAEe-esterase were inhibited by pretreatment of the rats with epsilon-aminocaproic acid. Evidence was provided that serotonin did not lower the plasma level of factor XII of the coagulation system, but the level of a factor of significance for the activation of factor XII. All the above-mentioned serotonin effects were fundamentally similar to the corresponding effects caused by dextran. It is concluded that the effects of dextran on the plasma parameters mentioned are mediated by the release of endogenous serotonin.

Aminocaproic Acid↗
PubMed2004

Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo.

To analyze the biological role of factor XII (FXII, Hageman Factor) in vivo, we generated mice deficient for FXII using a gene targeting approach on two distinct genetic backgrounds, i.e. mixed C57Bl/6J X 129X1/SvJ and inbred 129X1/SvJ. Homozygous FXII knockout (FXII(-)/(-)) mice showed no FXII plasma activity and had a markedly prolonged activated partial thromboplastin time (aPTT). In contrast, coagulation factors XI, VIII, IX, X,VII, V, II and fibrinogen did not differ between FXII(-/-) mice and their wild-type littermates. Heterozygous matings segregated according to the Mendelian inheritance indicating that FXII deficiency does not increase fetal loss. Furthermore, matings of FXII(-/-) males and FXII(-/-) females resulted in normal litter sizes demonstrating that total FXII deficiency in FXII(-/-) females does not affect pregnancy outcome. Also, gross and histological anatomy of FXII(-/-) mice was indistinguishable from that of their wild-type littermates on both genetic backgrounds. Thus it appears that deficiency of murine FXII does not cause thrombophilia or impaired fibrinolysis in vivo. These results indicate that FXII deficiency does not affect hemostasis in vivo and we anticipate that the FXII(-/-) mice will be helpful to elucidate the biological role(s) of FXII in health and disease.

Animals↗
PubMed1981

Isolation and properties of an abnormal Hageman factor (Factor XII) molecule in a cross-reacting material-positive hageman trait plasma.

We have previously described two unrelated individuals with homozygous Hageman trait (Factor XII deficiency) whose plasmas contained nonfunctional material immunologically indistinguishable from normal Hageman factor (HF). Abnormal HF from the plasma of one these subjects has now been purified to homogeneity, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, alkaline disc gel electrophoresis, and immunoelectrophoresis. Purified abnormal HF had no clot-promoting activity, but showed the same specific antigenicity as purified normal HF by an immunoassay. The abnormal HF was of a single chain polypeptide with the same molecular weight (80,000) as normal HF and was positively stained by periodic acid-Schiff reagent. Both normal and abnormal HF had similar amino acid compositions and isoelectric points (pI 6.5 approximately 7.1). When 125I-labeled abnormal HF and 131I-labeled normal HF were mixed with normal plasma and exposed to glass, both HF underwent an identical pattern of cleavage, yielding 52,000- and 30,000-mol wt fragments. Similarly, abnormal HF was fragmented by trypsin in the same way as normal HF, but no prekallikrein-activating activity was generated after cleavage. [3H]Diisopropyl phosphorofluoridate was incorporated into a 29,000-mol wt fragment of the trypsin-cleaved normal HF, but not into that of the trypsin-cleaved abnormal HF. These data suggest that the molecular defect in this abnormal HF resides at or near the active site serine residue in the 30,000-mol wt part of the molecule.

Binding Sites↗
PubMed2003

High molecular weight kininogen and factor XII binding to endothelial cells and astrocytes.

We have quantitated the binding of high molecular weight kininogen (HK) to human microvascular endothelial cells of lung and dermal origin as well as to astrocytes and compared the results with those reported for human umbilical vein endothelial cells (HUVEC). We also reassessed parameters of binding to HUVEC employing cells in suspension as well as cells attached to the culture plate and report similar numbers of sites varying from 6.96x10(5) to 7.71x10(5) per cell. The present study shows that HK binds with high specificity and affinity to microvascular endothelial cells (Kd = 1.86 to 4.5 nM) compared to HUVEC (Kd = 10.35 nM) but with lower affinity to astrocytes (Kd = 23.73 nM). Human cytokeratin 1, urokinase plasminogen activator receptor and gC1qR were found to be HK binding proteins present at the surface of microvascular endothelial cells and astrocytes analogous to that seen in HUVEC, as assessed by inhibition of binding with antibody to each protein. Lung microvascular endothelial cells had approximately half the number of HK binding sites as HUVEC while dermal micro vascular endothelial cells and astrocytes had only 8-10% of the sites/cell. The affinity of binding to the microvascular endothelial cells was greater than HUVEC, the affinity of binding to astrocytes was considerably less, nevertheless binding to each cell type involves gC1qR, cytokeratin 1 and u-PAR to varying degrees. We also demonstrate, for the first time, that factor XII binds to all of these cell types in a saturable and Zn(+2) dependent manner. Given that factor XII accelerates the interactions among cell surfaces and proteins of the contact activation cascade to generate bradykinin, binding of factor XII (and the prekallikrein-HK complex) may serve as a mechanism by which these proteins are concentrated locally to facilitate their interactions.

Astrocytes↗
PubMed1987

Loss of the activity of human coagulation factor XII by a chymotrypsin-like protease activated in rat mast cells during degranulation with compound 48/80.

Mediator release from mast cells is an initial step in the immediate-type hypersensitivity. Thus, the interaction of neutral proteases released from mast cells with plasma kallikrein-kinin system was investigated. Two proteases, chymotrypsin-like (CHY) and trypsin-like (TRY) proteases, were activated in purified rat mast cells after degranulation with compound 48/80. Three fourths of the CHY activity remained in the cell residue, and the activity was inhibited by chymostatin, whereas most of the TRY activity was released in the medium and was inhibited by leupeptin. The incubation of rat or human plasma with degranulated mast cell (DMC) suspension did not cause the activation of plasma prekallikrein, but did cause a loss in the activity of coagulation factor XII, as ascertained by the lack of activation of prekallikrein in either the DMC-treated plasma by glass powder or in the incubation of DMC-treated human plasma with factor XII deficient plasma activated by kaolin. The prekallikrein and high-molecular-weight kininogen levels were sufficient for activation of factor XII.

Animals↗
PubMed2002

Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII.

Bradykinin is a major mediator of swelling in C1 inhibitor deficiency as well as the angioedema seen with ACE inhibitors and may contribute to bronchial hyperreactivity in asthma. Formation of bradykinin occurs in the fluid phase and along cell surfaces requiring interaction of factor XII, prekallikrein, and high M(r) kininogen (HK). Recent data suggest that activation of the kinin-forming cascade can occur on the surface of endothelial cells, even in the absence of factor XII. We sought to further define this factor XII-independent mechanism of kinin formation. Both cytosolic and membrane fractions from endothelial cells possessed the ability to catalyze prekallikrein conversion to kallikrein, and activation depended on the presence of HK and zinc ion. We fractionated the cytosol by ion exchange chromatography and affinity chromatography by using corn trypsin inhibitor as ligand. The fractions with peak activity were subjected to SDS gel electrophoresis and ligand blot with biotinylated corn trypsin inhibitor, and positive bands were sequenced. Heat shock protein 90 (Hsp90) was identified as the protein responsible for zinc-dependent prekallikrein activation in the presence of HK. Zinc-dependent activation of the prekallikrein-HK complex also depended on addition of either alpha and beta isoforms of Hsp90 and the activation on endothelial cells was inhibited on addition of polyclonal Ab to Hsp90 in a dose-dependent manner. Although the mechanism by which Hsp90 activates the kinin-forming cascade is not understood, this protein represents the cellular contribution to the reaction and may become the dominant mechanism in pathologic circumstances in which Hsp90 is highly expressed or secreted.

Amino Acid Sequence↗
PubMed1999

Antibodies to factor XII associated with lupus anticoagulant.

Falsely low levels of factor XII (FXII) have been documented in patients who are lupus anticoagulant positive (LA+). In addition, we have previously noted a surprisingly high incidence (20.9%) of apparently true FXII deficiency in patients who were LA+. We have hypothesised that this may be partly due to the presence of antibodies to FXII. The aim of the present study was to investigate whether LA+ patient plasmas contain antibodies directed either against FXII or FXII in association with phospholipids. Plasma samples from 60 blood donors, all LA negative, and 51 LA+ patients were tested using ELISA assays employing purified FXII, phosphatidylserine (PS) and phosphatidylethanolamine (PE). We have identified seven patients whose plasma contained either IgG or IgM that reacted with purified FXII in the absence of PS or PE. When PS was included in the assay system four additional patient plasmas were shown to contain either IgG or IgM that reacted with FXII. The plasma of one patient contained IgG that reacted with FXII both in the presence and absence of PS. There was no reactivity to FXII with either IgG or IgM when PE was included in the assay system. Affinity purified IgG from three patients whose plasma reacted with FXII in the ELISA assay in the absence of PS, gave a positive reaction in an immunoblot assay. These results suggest that FXII antibodies are present in a significant proportion of LA+ patients and may lead to an erroneous diagnosis of FXII deficiency.

Antibody Specificity↗
PubMed2005

Defective thrombus formation in mice lacking coagulation factor XII.

Blood coagulation is thought to be initiated by plasma protease factor VIIa in complex with the membrane protein tissue factor. In contrast, coagulation factor XII (FXII)-mediated fibrin formation is not believed to play an important role for coagulation in vivo. We used FXII-deficient mice to study the contributions of FXII to thrombus formation in vivo. Intravital fluorescence microscopy and blood flow measurements in three distinct arterial beds revealed a severe defect in the formation and stabilization of platelet-rich occlusive thrombi. Although FXII-deficient mice do not experience spontaneous or excessive injury-related bleeding, they are protected against collagen- and epinephrine-induced thromboembolism. Infusion of human FXII into FXII-null mice restored injury-induced thrombus formation. These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo. The results establish FXII as essential for thrombus formation, and identify FXII as a novel target for antithrombotic therapy.

Animals↗
PubMed1975

Failure of ellagic acid to affect platelet aggregation in normal and in factor XII deficient plasma.

Ellagic acid solutions, regardless of the concentration, failed to alter platelet aggregation induced by ADP, Adrenalin, Collagen, Thrombofax and Ristocetin in normal and in factor XII deficient plasma. A moderate inhibition was noted after addition of ADP both in normal and in factor XII deficient plasma but this was present also in the control systems and was therefore due to the buffer-dextrose solution and not to ellagic acid. These data indicate that Hageman factor plays on role in platelet aggregation.

Adenosine Diphosphate↗
PubMed1991

Functional characterization of an abnormal factor XII molecule (F XII Bern).

An 18-year-old healthy woman was found to have cross-reacting material (CRM)-positive factor XII (F XII) deficiency, F XII clotting activity was less than 0.01 U/mL, whereas F XII antigen was 0.11 U/mL. An F XII inhibitor was excluded. To partially characterize the molecular defect of the abnormal F XII, immunologic and functional studies were performed on the proposita's plasma. The abnormal F XII was a single chain molecule with the same molecular weight (80 Kd) and the same isoelectric points (pl, 5.9 to 6.8) as normal F XII. Dextran sulfate activation of the proposita's plasma showed no proteolytic cleavage of F XII even after 120 minutes, whereas F XII in pooled normal plasma, diluted 1:10 with CRM-negative F XII-deficient plasma, was completely cleaved after 40 minutes. Adsorption to kaolin was identical for both abnormal and normal F XII. In the presence of dextran sulfate and exogenous plasma kallikrein, the abnormal F XII was cleaved with the same rate as normal F XII. However, kallikrein-cleaved abnormal F XII was not able to cleave factor XI and plasma prekallikrein, in contrast to activated normal F XII. Thus, these studies show that the functional defect of this abnormal F XII, denoted as F XII Bern, is due to the lack of protease activity of the kallikrein-cleaved molecule. Therefore, the structural defect is likely to be located in the light chain region of F XII, containing the enzymatic active site.

Adsorption↗
PubMed2004

Thrombosis-free surgical procedures in severe (Homozygote) factor XII deficiency: report of four additional cases and literature review.

The outcome of various surgical procedures carried out in patients with severe (homozygote) factor XII deficiency were investigated for the appearance of blood coagulation-related complications with particular emphasis on thrombotic complications. The surgical procedures were total mastectomy, tonsillectomy and adenoidectomy, placement of a hip prosthesis, and double hernia repair. None of the patients slowed any complication. Several other reported cases of surgical procedures carried out in several patients ware found in the literature. Bleeding or thrombotic complications were noted in none of these cases. The surgical procedures in some cases were minor such as adenoidectomy, tonsillectomy, or nasal polyp removal. However several major surgical procedures were carried out in some patients (cholecystectomy, gastrectomy, repair of atrial septal defect, coronary bypass). All patients remained asymptomatic. In some cases whole blood and/or plasma were used as requested by the caring surgeons. In a few patients, the plasma was given prophylactically because of the long partial thromboplastin time. Finally, three patients (two for cardiac surgery and one after hip replacement) received heparin prophylaxis as foreseen by accepted procedures without the undue sequels. These data supply further evidence that factor XII deficiency does not only show any bleeding tendency but also can withstand even major surgical procedures without thrombotic complications.

Adolescent↗
PubMed1992

Behçet's syndrome and factor XII deficiency.

Several mechanisms have been proposed to explain thrombotic tendency in Behçet's syndrome. We report the case of a 43-year old woman presenting retinal-vein thrombosis, factor XII deficiency and Behçet's syndrome. This kind of association has thus far never been reported. Factor XII deficiency is known to possibly induce various types of thrombosis and might explain the prevalence of ocular symptoms in our patient.

Adult↗
PubMed1996

Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase.

In previous studies, we have shown that administration of monoclonal antibody (MoAb) C6B7 against human factor XII to baboons challenged with a lethal dose of Escherichia coli abrogates activation of the contact system and modulates secondary hypotension. To evaluate the contribution of activated contact proteases to the appearance of other inflammatory mediators in this experimental model of sepsis, we studied the effect of administration of MoAb C6B7 on activation of complement and fibrinolytic cascades, stimulation of neutrophil degranulation, and release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Activation of the complement system, as reflected by circulating C3b/c and C4b/c levels, was significantly reduced in five animals that had received MoAb C6B7 before a lethal dose of E coli as compared with five control animals that had been given a lethal challenge only. Inhibition of contact activation also modulated the fibrinolytic response, since the release of tissue-type plasminogen activator (t-PA) and the appearance of plasmin-alpha2-antiplasmin (PAP) complexes into the circulation was significantly attenuated upon pretreatment with anti-factor XII MoAb. In contrast, plasma levels of plasminogen activator inhibitor (PAI) were modestly enhanced in the treatment group. Degranulation of neutrophils, as assessed by circulating elastase-alpha1-protease inhibitor complexes, and release of IL-6 but not of TNF-alpha was decreased in anti-factor XII-treated animals. Observed differences in the inflammatory response between treatment and control groups were not likely due to different challenges, since the number of E coli that had been infused, as well as circulating levels of endotoxin after the challenge, were similar for both groups. These data suggest that activation of the contact system modulates directly or indirectly various mediator systems involved in the inflammatory response during severe sepsis in nonhuman primates.

Animals↗
PubMed1983

Assay of Factor XII clotting activity in heparinized plasma.

Clotting tests based upon the activated partial thromboplastin time are disturbed by heparin. This brief communication shows that Factor XII clotting activity in plasma samples heparinized in vitro and in vivo can be measured accurately by means of an aPTT-test using congenitally deficient substrate plasma when the plasma dilution buffer contains hexadimethrine bromide (Polybrene), 15 mg/L. This method of neutralizing heparin obviates more complicated procedures such as heparin adsorption to anion exchange resins.

Blood Coagulation Tests↗
PubMed1980

Hemophilia A in a phenotypic female with normal male karyotype associated with a low factor XII level.

Hemophilia A was detected in a 40-year-old black Gabonese female prior to thoracic surgery for empyema. The diagnosis of mild hemophilia A was supported by the findings of low factor VIII coagulant activity (VIII:C 4%), normal levels of factors VIII related antigen (VIIIR:Ag) and VIII von Willebrand (VIIIR:WF), without detectable circulating anticoagulant. Neither the patient nor her immediate relatives had past histories of abnormal bleeding. The physical features were phenotypically female with developed breasts, pubic hair and normal external genitalia: however, she had primary amenorrhea, a blind vagina with no uterus and her karyotype was 46,XY. These findings are consistent with the diagnosis of testicular feminization thereby explaining the apparent contradiction between the phenotype and the known six-linked inheritance of hemophilia A. In addition to factor VIII deficiency a low level of factor XII (20%) was detected although it cannot be concluded whether the patient is truly factor XII deficient or whether she represents a low variant of the normal distribution.

Adult↗
PubMed1993

The effect of chemical modification of basic amino acid residues on the activation and amidolytic activity of Hageman factor (factor XII).

Modification of arginyl residues of Hageman factor by phenylglyoxal hydrate inhibits activation of this clotting factor in a plasma-free system, that is, in the absence of the other constituents of the contact activation system. Activation is also inhibited by alteration of the other two basic amino acid residues present, lysine and histidine. Chemical modification of histidine and arginine residues does not inhibit the amidolytic activity of activated Hageman factor. In contrast, modification of amino group(s) in N-terminal and lysine residues inhibits activated Hageman factor. Thus, basic amino acid residues essential to the activation or activity of Hageman factor appear to be variably accessible to chemical modification.

Amides↗