Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Factor XIIa”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed2005

Demonstration of a threshold response in a proteolytic feedback system: control of the autoactivation of factor XII.

Mathematical analysis of positive feedback loops in proteolytic systems has previously suggested that when the active enzymes are subject to inhibitory control these systems will exhibit threshold behavior. This is demonstrated in the present study, for the autolytic activation of factor XII in the presence of a contact activator and an irreversible inhibitor of factor XIIa. The threshold between the two system states - complete factor XII activation, or complete stability - is dependent on the kinetic balance between the catalytic rate of autoactivation and rate of enzyme (factor XIIa) inhibition. Activation of the system can be brought about by either increasing the catalytic rate (in this study, by using more potent contact-activation conditions), or by lowering the enzyme inhibition rate. Previous mathematical work predicted complete stability in a positive-feedback system that is below threshold, and this has been experimentally confirmed.

Antithrombin III↗
PubMed1998

Complement and contact activation in term neonates after fetal acidosis.

AIMS: To evaluate complement and contact activation after fetal acidosis. METHODS: Fifteen term neonates with hypoxic-ischaemic encephalopathy after umbilical arterial pH < 7.10 were compared with 15 healthy neonates with umbilical arterial pH > 7.20. Determinations of the complement function and C1-inhibitor activity were performed as kinetic tests 22-28 hours after birth. C1q, C1-inhibitor, and factor B concentrations were determined by radial immunodiffusion and those of C3a, C5a, and factor XIIa by enzyme immunoabsorbent assay. RESULTS: Median complement function (46 vs 73%), C1q (4.3 vs 9.1 mg/dl), and factor B (5.2 vs 7.7 mg/dl) decreased after fetal acidosis. The activated split products C3a (260 vs 185 micrograms/l), C5a (5.0 vs 0.6 micrograms/l), and factor XIIa (3.2 vs 1.3 micrograms/l) increased in the neonates after fetal acidosis. No differences were found in the concentration and activity of C1-inhibitor. CONCLUSIONS: Complement and contact activation occurred in the newborns with hypoxic-ischaemic encephalopathy. Activation of these systems generates mediators which can trigger inflammation and tissue injury.

Acidosis↗
PubMed1978

The "Hageman" connection: interrelationships of blood coagulation, fibrino(geno)lysis, kinin generation, and complement activation.

The activation pathways for the generation of enzymes involved in blood clotting, clot lysis, complement activation, and kinin generation are briefly reviewed. The interrelationship of the four systems is illustrated by the multiple functions of four key enzymes: Factor XIIa, kallikrein, plasmin, and C1 esterase. The pivotal role of Factor XIIa in establishing this connection is elucidated.

Blood Coagulation↗
PubMed1995

Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor.

Thromboembolic complications are common in patients with malignant disease. We studied the activation of coagulation in 106 patients with solid tumours and 72 healthy volunteers by measuring plasma levels of tissue factor, factor VIIa, factor XIIa, thrombin-antithrombin complex, and prothrombin fragments 1 + 2. Tissue factor was 67% higher in cancer patients (median 582 vs 349 pg/mL, p = 0.0006) and factor VIIa was 46% higher (100 vs 69 mU/mL, p = 0.0002), indicating extrinsic pathway activation. Modest activation of the intrinsic pathway (elevated factor XIIa) was seen only in patients with advanced disease or those receiving chemotherapy. Excess thrombin generation was manifested by elevations in thrombin-antithrombin complex and prothrombin fragments 1 + 2. Tissue factor pathway is clearly implicated in the hypercoagulable state of cancer.

Blood Coagulation↗
PubMed1992

Autoactivation of human blood coagulation factor XII on dextran derivatives of different molecular weight.

We prepared a derivative of dextran T40 (average M(r) 43,000) from which fractions of different M(r) but with equal charge density were obtained and tested for their ability to promote autoactivation of human blood coagulation factor XII. The mechanism of autoactivation appeared dependent upon the M(r) of the polymer used. Thus, with polymers of 38,000 M(r) or higher only alpha-factor XIIa was formed and the reaction could be completely described in terms of a simple second-order mechanism of autoactivation. With smaller polymer molecules beta-factor XIIa became a major reaction product and as a result of this the autoactivation kinetics did not adhere to the second-order mechanisms thus far described.

Amino Acid Sequence↗
PubMed1998

Complement and contact activation during cardiovascular operations in infants.

BACKGROUND: By comparing the results of cardiac operations with or without cardiopulmonary bypass (CPB) in infants in a prospective study, we sought to determine which part of the postoperative systemic inflammatory response was caused by CPB. METHODS: Thirty-five patients were divided into two groups: 11 infants operated on without CPB and 24 infants operated on with CPB. Blood samples were drawn before, during, and after the operation. We assessed complement function and the concentrations or activities of C1q, C3, C4, C1 inhibitor, factor B, the activated split product C3a, and prekallikrein and factor XIIa of the contact system. RESULTS: All of the patients exhibited a decrease of complement proteins. This was greater in infants who underwent CPB. A increase in C3a and factor XIIa and changes in prekallikrein activity occurred only in infants during CPB. CONCLUSIONS: Complement activation occurs in all infants, but is significantly higher in the group with CPB. Contact activation only occurs in patients who undergo CPB. Thus, the inflammatory response is caused by the use of a CPB circuit and to a lesser degree by surgical procedures and anesthesia.

Cardiac Surgical Procedures↗
PubMed1993

Recombinant C1 inhibitor P5/P3 variants display resistance to catalytic inactivation by stimulated neutrophils.

Proteolytic inactivation of serine protease inhibitors (serpins) by neutrophil elastase (HNE) is presumed to contribute to the deregulation of plasma cascade systems in septic shock. Here, we report a supplementary approach to construct serpins, in our case C1 inhibitor, that are resistant to catalytic inactivation by HNE. Instead of shifting the specificity of alpha 1-antitrypsin towards the proteases of the contact activation and complement systems, we attempted to obtain a C1 inhibitor species which resists proteolytic inactivation by HNE. 12 recombinant C1 inhibitor variants were produced with mainly conservative substitutions at the cleavage sites for HNE, 440-Ile and/or 442-Val. Three variants significantly resisted proteolytic inactivation, both by purified HNE, as well as by activated neutrophils. The increase in functional half-life in the presence of FMLP-stimulated cells was found to be 18-fold for the 440-Leu/442-Ala variant. Inhibitory function of these variants was relatively unimpaired, as examined by the formation of stable complexes with C1s, beta-Factor XIIa, kallikrein, and plasmin, and as determined by kinetic analysis. The calculated association rate constants (k(on)) were reduced twofold at most for C1s, and appeared unaffected for beta-Factor XIIa. The effect on the k(on) with kallikrein was more pronounced, ranging from a significant ninefold reduction to an unmodified rate. The results show that the reactive centre loop of C1 inhibitor can be modified towards decreased sensitivity for nontarget proteases without loss of specificity for target proteases. We conclude that this approach extends the possibilities of applying recombinant serpin variants for therapeutic use in inflammatory diseases.

Amino Acid Sequence↗
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↗
PubMed1984

The possible role of platelets in bypassing the contact phase of blood coagulation.

Data presented herein and previously support an active role for platelets in promoting the interaction and activation of the coagulation proteins of the contact phase of intrinsic coagulation. The platelet membrane, activated by ADP collagen or thrombin, can promote the proteolytic activation of factor XII to factor XIIa in the presence of kallikrein and high molecular weight kininogen. The zymogen factor XI associates with high molecular weight kininogen in plasma and becomes bound to a site on the membrane of thrombin or collagen activated platelets. Thereafter, platelet bound factor XI can be proteolytically activated to factor XIa either in the presence of factor XIIa or in the presence of kallikrein. These observations could explain the absence of bleeding complications in patients with factor XII deficiency. In addition, platelets contain a molecule which has a higher molecular weight than plasma factor XI and possibly consists of a tetramer of four identical subunits of 52000 daltons each of which is functionally and immunologically similar to plasma factor XI. Since this molecule is present in the platelets of patients with severe plasma factor XI deficiency and no evidence of bleeding, we postulate that platelet factor XI can substitute for plasma factor XI in hemostasis and possibly account for the considerable variability in clinical severity observed in patients with factor XI deficiency.

Blood Coagulation↗
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↗
PubMed1979

Dextran-induced lowering of parameters of the kallikrein-kinin system in rat plasma.

Pretreatment of rats with tranexamic acid inhibited the rapid lowering of the plasma levels of acetone/kaolin-activated prekallikrein proactivator and prekallikrein caused by intravenous injection of dextran, but did not inhibit the reduction in the level of plasminogen, and potentiated the lowering of high molecular weight kininogen. By acetone/kaolin activation of normal rat plasma a mixture of surface-bound factor XIIa and unbound XIIf was obtained, and a BAEe-esterase (MW about 47,000) possessing weak kininogenase activity was present in addition to kallikrein. In activated plasma from dextran-treated rats the cleavage of XIIa was strongly reduced, and the second esterase was almost absent. It is suggested that dextran induces the loss of a plasma factor which is important for the cleavage of factor XIIa in the adopted procedure. This factor was not high molecular weight kininogen, and the lowering of plasminogen was too small to account for the reduction in PKA-activity.

Animals↗
PubMed1998

Levels of activated FXII in survivors of myocardial infarction--association with circulating risk factors and extent of coronary artery disease.

Little data is available regarding the activated form of factor XIIa (FXIIa) in survivors of myocardial infarction. 292 Caucasian patients characterised for extent of coronary atheroma by angiography and for a past history of myocardial infarction and 77 healthy controls were included in the study. To investigate the relationship between coronary artery disease, activated factor XII and other circulating factors, we studied levels of FXIIa, cholesterol, triglycerides, fasting insulin, fibrinogen, FVII:C, t-PA antigen and PAI-1 antigen. Factor XIIa levels were higher in all patients [2.5 (2.3-2.6) ng/ml] and in patients with a history of MI [2.6 (2.4-2.9) ng/ml] than in controls [1.9 (1.7-2.1) ng/ml], p < 0.0001. In patients, FXIIa levels positively correlated with FVII:C, BMI, cholesterol, insulin, PAI-1 antigen, t-PA antigen and triglycerides. In controls FXIIa levels only correlated with PAI-1 antigen and triglycerides. FXIIa levels were strongly associated with extent of coronary stenosis: 2.8 (2.6-3.1) ng/ml and 2.6 (2.3-2.9 ng/ml) in those with 2 and 3 vessels stenosed compared to 2.1 (1.9-2.3) ng/ml in those with 0 vessel stenosed (p = 0.0004). Activated FXII relates to both extent of coronary atheroma and to a past history of myocardial infarction and clusters with features of insulin resistance.

Case-Control Studies↗
PubMed1992

Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency.

A high factor VII coagulant activity (VIIc), a marker of increased risk of coronary heart disease, is frequently found in types IIb and IV hyperlipidaemia, but its cause is not fully understood. Factor VII can be activated by factor XIIa, generated from factor XII upon activation of the contact system of coagulation. Ten patients with familial lipoprotein-lipase (LPL) deficiency and 10 healthy control subjects were therefore compared to explore the hypothesis that high concentrations of unesterified fatty acids (UFA), released from triglyceride-rich lipoproteins by LPL, are a source of factor XII activation and hence the increased VIIc that is observed post-prandially and in non-LPL-deficient hypertriglyceridaemic states. Mean plasma cholesterol and triglyceride concentrations were, respectively, 1.5- and 19-fold higher in the patients than controls, due to increases in very-low-density lipoproteins and chylomicrons. The concentration and composition of plasma UFA were similar in both groups. In conformity with the hypothesis, VIIc was not increased in the LPL-deficient group, despite their massive hypertriglyceridaemia. Furthermore, when the patients' plasma was treated with LPL, factor XII was activated promptly and substantially, whereas no similar effect was observed in the controls. These results suggest that high concentrations of circulating triglyceride-rich lipoproteins will increase VIIc in the presence of LPL.

Adult↗
PubMed2006

Procoagulant activity of surface-immobilized Hageman factor.

Procoagulant activity of surface-immobilized coagulation factor XIIa (activated Hageman factor) is reported. Activity of FXIIa immobilized onto the surfaces of three silanized-glass procoagulants spanning a wide range of wettability was assayed in normal and FXII-deficient plasmas. Previously published mathematical models were used to characterize the procoagulant activity of protein-immobilized materials and soluble enzymes. Results show that FXIIa activity is unrelated to underlying procoagulant surface chemistry and is similar to soluble FXIIa activity. The uninfluential role of the surface on FXIIa suggests that the solid surface activates FXII in biomaterial-induced blood coagulation but is not otherwise involved in FXIIa activity as described by the classical mechanism.

Adsorption↗
PubMed1988

Enzymes of the contact phase of blood coagulation: kinetics with various chromogenic substrates and a two-substrate assay for the joint estimation of plasma prekallikrein and factor XI.

Kinetic constants (Km and kcat) of kallikrein and factor XIa for the chromogenic substrates H-D-L-prolyl-L-phenylanyl-L-arginine-p-nitroanilide (S-2302) and L-pyroglutamyl-L-propyl-L-arginine-p-nitroanilide (S-2366) were determined. The determined constants allow the use of S-2302 and S-2366 in an assay that leads to the joint estimation of factor XI and prekallikrein in activated plasma. The assay reports approximately 3.1 micrograms/ml factor XIa and 34.5 micrograms/ml kallikrein in kaolin-activated plasma (kaolin content 2 mg/ml). The dual-substrate amidolytic assay shows good correlation with the coagulant assay of both factors (0.92 with the prekallikrein assay and 0.98 with the factor XI assay). It is capable, through the joint estimation of factor XI and prekallikrein levels, of differentiating among plasma samples deficient in components of the contact phase of blood coagulation. Kinetic constants of factor beta-XIIa (factor XII fragment) for these substrates and for N-benzol-L-isoleusyl-L-glutamyl-glycyl-L-arginine-P-nitro ani lide (S-2222) were determined, and they allowed the assessment of the contribution of this factor to this assay and its estimation in the activated phase.

Blood Coagulation↗
PubMed1982

[Use of chromogenic substrates in the clarification of disorders in the early stages of blood coagulation].

The kallikrein specific chromogenic peptide substrates S-2302 (KABI) and Chromozym PK (Boehringer) were used in the first analysis of a familial defect in the early stage of clotting. Slight to extensive prolongation of the activated partial thromboplastin time was seen in the affected persons. Using dextransulfate for activation of plasma marked deficiency in kallikrein activity was found in 3 persons. Using factor XIIa (activated Hageman factor) for activation normal prekallikrein levels were found in 2 of them whereas factor XII levels, however, were below normal. The third had a prekallikrein deficiency presumably caused by oral contraceptives. In a fourth member of the family factor XII deficiency was found with normal kallikrein activity. The application of chromogenic peptide substrates for analysing the early stage of clotting has to take into account the special mechanisms of activation.

Adolescent↗
PubMed1994

Factor XI deficiency in Kerry Blue Terriers.

A 9-year-old female Kerry Blue Terrier with postoperative hemorrhage and prolonged activated partial thromboplastin and activated clotting times was determined to have factor XI deficiency. Transfusions of fresh-frozen plasma given on 4 consecutive days transiently returned the values for activated clotting time and plasma factor XI activity to within reference range limits and controlled the hemorrhage. Analysis of data from 10 other factor XI-deficient Kerry Blue Terriers with a tendency for mild posttraumatic or postoperative bleeding was suggestive of an autosomal mode of inheritance, with a mild tendency for posttraumatic or postoperative bleeding in homozygous and heterozygous dogs. Factor XI deficiency is the only contact phase protein defect that causes a bleeding disorder in animals, which can be explained by the fact that thrombin is more efficient than factor XIIa in activating factor XI. Factor XIa plays a key role in sustaining coagulation.

Animals↗
PubMed1993

Chemical synthesis, molecular cloning, overexpression, and site-directed mutagenesis of the gene coding for pumpkin (Curcubita maxima) trypsin inhibitor CMTI-V.

The gene encoding for a pumpkin (Curcubita maxima) trypsin inhibitor CMTI-V was synthesized chemically. The synthetic gene was prepared from four overlapping oligonucleotides by overlapping extension. The synthetic gene was amplified by polymerase chain reaction, cloned into a T7 expression vector and expressed in Escherichia coli as a fusion protein. The clone, namely 70-1, encoded a fusion protein containing 7 amino acid residues of the N-terminus of the bacterial protein rho 10 and the entire 68 residues of CMTI-V. The wild-type fusion protein constituted approximately 15% of the total bacterial protein mass and was purified to homogeneity in a single step by antibody affinity chromatography. The wild-type fusion protein possesses inhibitory activity toward trypsin and beta-Factor XIIa, but to a lesser extent when compared to the natural CMTI-V. A mutant, T43A, in which threonine at position 43 (P2 position) was replaced by alanine, was constructed. This mutant showed considerably lower specific inhibitory activity toward both trypsin and beta-Factor XIIa.

Amino Acid Sequence↗