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PubMed1996

Studies of the activation of factor VII bound to tissue factor.

Experiments were performed to evaluate activation of factor VII bound to relipidated tissue factor (TF) in suspension and to TF constitutively expressed on the surface of an ovarian carcinoma cell line (OC-2008). Activation was assessed by measuring cleavage of 125I-factor VII and by the ability of unlabeled factor VII to catalyze activation of a variant factor IX molecule that, after activation, cannot back-activate factor VII. Factor Xa was found to effectively activate factor VII bound to TF relipidated in either acidic or neutral phospholipid vesicles. Autoactivation of factor VII bound to TF in suspension was dependent on the preparation of TF apoprotein used and the technique of its relipidation. This highlights the need for caution in extrapolating data from TF in suspension to the activation of factor VII bound to cell surfaces during hemostasis. A relatively slow activation of factor VII bound to OC-2008 monolayers in the absence of added protease was observed consistently. Antithrombin in the presence or absence of heparin prevented this basal activation, whereas TF pathway inhibitor (TFPI/factor Xa complexes had only a limited inhibitory effect. Adding a substrate concentration of factor X markedly enhanced basal activation of factor VII, but both TFPI/factor Xa and antithrombin/heparin abolished this enhancement. Overall, our data are compatible with the hypothesis that not all factor VII/TF complexes formed at a site of tissue injury are readily activated to factor VIIa (VIIa)/TF complexes during hemostasis. The clinical significance of this is discussed.

Cell Membrane↗
PubMed1993

Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation.

Although the majority of factor VII (FVII) circulates in the zymogen form, low levels of activated factor VII (FVIIa) have been postulated to exist in plasma and to serve a priming function for triggering of the clotting cascade. However, direct measurement of plasma FVIIa has not previously been possible. We have quantified plasma FVIIa levels using a novel, highly sensitive assay that is free from interference by FVII. Specificity of this clot-based assay results from the use of a mutant tissue factor that is selectively deficient in promoting FVII activation, but retains FVIIa cofactor function. In normal adults, FVIIa was found to be present in plasma (mean: 3.6 ng/mL) with considerable variation between individuals (range: 0.5 to 8.4 ng/mL). FVIIa levels were only loosely correlated with FVII coagulant activity, but were elevated in pregnancy and reduced with oral anticoagulant therapy. Incubation of plasma on ice in glass containers (cold activation) resulted in substantial FVIIa generation. Measurement of plasma forms of factor VII is of potential clinical importance because elevated FVII coagulant activity has been implicated as a significant risk predictor for ischemic heart disease. Clinically, this new assay will now permit direct assessment of the role of plasma FVIIa in thrombotic disorders.

Adult↗
PubMed2002

Characterization of two novel splice site mutations in human factor VII gene causing severe plasma factor VII deficiency and bleeding diathesis.

The molecular basis of severe type I factor (F)VII deficiency was investigated in two Algerian patients. One patient, a 13-year-old-girl who has suffered from severe bleeding since birth, was homozygous for a 7-bp deletion (nt 7774-7780) and a 251-bp insertion (nt 7773-7781) of mitochondrial origin, in IVS 4 acceptor splice site. The other patient, an infant who died from massive intracranial haemorrhage, was homozygous for a transversion in the IVS 7 donor splice site (T9726+2-->G) and a missense mutation in exon 8 (G10588-->A; Arg224-->Gln). In both cases, the deleterious mutations are probably the splice site junction abnormalities impairing mRNA processing. These three lesions have not yet been reported.

Adolescent↗
PubMed1992

Plasma fibrinogen and factor VII as risk factors for cardiovascular disease.

The importance of the thrombotic component of coronary heart disease is increasingly recognised, and in particular the role of the coagulation system in this process. The Northwick Park Heart study was the first major prospective study to identify both fibrinogen and factor VIIc as risk factors, as powerful as total cholesterol in predicting ischaemic events. Since then, a number of epidemiological studies have confirmed the importance of fibrinogen, not just in CHD but in stroke as well. A variety of environmental factors are known to influence levels of factor VII and fibrinogen and therefore support their role in the development of coronary thrombosis. Both are known to increase with age and body weight and are relatively elevated in diabetes. Fibrinogen is strongly related to smoking habit and a substantial proportion of the IHD risk associated with smoking is mediated through this relationship. There is a dose response effect between number of cigarettes smoked and level of fibrinogen and an inverse relationship with time since cessation of the habit. Factor VII is known to correlate with total cholesterol level, and there is a relationship between dietary variability of fat intake and factor VII, which is likely to play an important role in the risk of CHD. The case for using either anticoagulation or anti platelet agents in secondary prevention of myocardial infarction is now clear, but there are still uncertainties in primary prevention which relate to the ideal dose intensity of either aspirin or anti-coagulation and the type of patient most likely to benefit. The ongoing Thrombosis Prevention Trial identifies middle-aged males at high risk of a myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Factor VII activity and antigen in a patient with abnormal factor VII.

A patient with abnormal factor VII, which showed different activity when thromboplastin from different sources was used, is reported. The propositus, who was first seen at routine health examination 1 month after delivery, was a girl with no complaints of bleeding. The coagulation pattern was characterized by an abnormal clotting time using Normotest reagent which did not respond to the administration of vitamin K. Factor VII activity was decreased when measured using rabbit brain and lung thromboplastin, mildly decreased using human brain or human placenta thromboplastin and within the normal range using ox brain thromboplastin. The level of factor VII antigen was normal and revealed a normal mobility on immunoelectrophoresis. The molecular weight of this factor VII was not different from normal factor VII when analysed using autoradiography after sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). It seems probable that the propositus had an abnormality similar to the factor VII Padua 1 described previously.

Antigens↗
PubMed2005

Total hip arthroplasty in severe congenital factor VII deficiency: successful use of recombinant activated factor VII for hemostasis.

Congenital factor VII (FVII) deficiency is a rare hemorrhagic disorder, and, in affected patients, surgery is likely to cause excessive bleeding. In this article, we report the first case of total hip arthroplasty in a patient with severe congenital FVII deficiency in which recombinant activated factor VII (rFVIIa, NovoSeven) was successfully used to manage bleeds. The patient was a 68-year-old woman with severe congenital FVII deficiency, who suffered from a hemorrhagic arthrosis of her left hip joint. We administered rFVIIa as intermittent bolus infusions both perioperatively and postoperatively; dosing was based on the results of a preoperative rFVIIa challenge test. During surgery and the 3-day postoperative treatment period, we observed normal hemostasis with no excessive bleeding or complications.

Aged↗
PubMed1999

Use of recombinant, activated factor VII in the treatment of congenital factor VII deficiencies.

BACKGROUND AND OBJECTIVES: Factor VII (FVII) deficiency is a rare coagulation disorder, historically treated with prothrombin complex concentrates or plasma-derived FVII concentrates. We treated such patients (n = 17) with a recombinant, activated FVII preparation. MATERIALS AND METHODS: Twenty-seven spontaneous bleeding episodes were treated and 7 major and 13 minor surgical interventions were carried out. The dosages employed ranged from 8.08 to 70.5 Ig/kg body weight. RESULTS: A mean dose between 22 and 26 Ig/kg was sufficient to normalise the prothrombin time. Fifteen haemarthroses were treated with single doses and results were excellent in 13 cases. In 5/6 bleeding episodes of other types, the treatment gave either excellent or at least effective results. Haemostasis was secured in the 7 major and 13 minor surgical interventions. One patient developed antibodies 4-5 weeks after an extremely high dose. Otherwise, there were no side effects and no evidence of a thrombotic tendency. CONCLUSION: This recombinant concentrate is efficacious in FVII-deficient patients. It is safe since any risk of transmission of blood-borne viruses is eliminated.

Adult↗
PubMed1991

Characterization of factor VII association with tissue factor in solution. High and low affinity calcium binding sites in factor VII contribute to functionally distinct interactions.

Protein-phospholipid as well as protein-protein interactions may be critical for tight binding of the serine protease factor VIIa (VIIa) to its receptor cofactor tissue factor (TF). To elucidate the role of protein-protein interactions, we analyzed the interaction of VII/VIIa with TF in the absence of phospholipid. Binding of VII occurred with similar affinity to solubilized and phospholipid-reconstituted TF. Lack of the gamma-carboxyglutamic acid (Gla)-domain (des-(1-38)-VIIa) resulted in a 10- to 30-fold increase of the Kd for the interaction, as did blocking the Gla-domain by Fab fragments of a specific monoclonal antibody. These results suggest that the VII Gla-domain can participate in protein-protein interaction with the TF molecule per se rather than only in interactions with the charged phospholipid surface. Gla-domain-independent, low affinity binding of VII to TF required micromolar Ca2+, indicating involvement of high affinity calcium ion binding sites suggested to be localized in VII rather than TF. Interference with Gla-domain-dependent interactions with TF did not alter the TF. VIIa-dependent cleavage of a small peptidyl substrate, whereas the proteolytic activation of the protein substrate factor X was markedly decreased, suggesting that the VIIa Gla-domain not only participates in the formation of a more stable TF. VIIa complex but contributes to extended substrate recognition.

Antibodies, Monoclonal↗
PubMed1990

Monoclonal antibody (VII-M31) to bovine factor VII: a specific epitope in the gamma-carboxyglutamic acid domain.

A murine monoclonal antibody (designated VII-M31) directed against bovine factor VII was prepared and characterized. Antibody VII-M31 inhibited the activations of both factors IX and X catalyzed by factor VIIa in the presence of tissue factor, phospholipids, and Ca2+. It possessed a strong affinity for factor VII in the presence of 5 mM Ca2+ (Kd = 1.12 x 10(-10)M). The immunoblotting test of other bovine proteins with the antibody, such as prothrombin, factor X, factor IX, protein C, protein S, and protein Z, in addition to human factor VII, revealed that it recognizes only a Ca2(+)-dependent epitope in bovine factor VII. Furthermore, this antibody VII-M31 covalently coupled with Affi-Gel allowed a simple and rapid purification of bovine factor VII. To localize the antigenic site in factor VII, various segments including a gamma-carboxyglutamic acid (Gla)-domainless protein, a Gla-domain peptide and the fragments isolated from the lysyl endopeptidase digest, were prepared. Among them, the isolated Gla-domain peptide and Gla-domainless factor VII were no longer recognized by antibody VII-M31, indicating that the sequence around the cleavage site by a-chymotrypsin is required for the interaction between the antibody and factor VII. In accordance with this result, the antibody bound specifically to a Gla-containing peptide corresponding to the NH2-terminal 23-50 residues of factor VII, which contains the chymotryptic cleavage site. These results suggest that the specific epitope of this antibody is localized in the carboxy-terminal 28 residues of the Gla-domain constituting the amino-terminal portion of bovine factor VII.

1-Carboxyglutamic Acid↗
PubMed1994

Elevated levels of factor VII activity in the postprandial state: effect of the factor VII Arg-Gln polymorphism.

A genetic polymorphism (Arg/Gln353) of coagulation factor VII was recently identified and shown to be associated with differences in basal factor VII coagulant activity. Postprandial lipaemia seems to exert an acute but evanescent effect on the activity of factor VII, and the influence of the Arg/Gln353 polymorphism on factor VII activation during postprandial lipaemia was therefore studied in male post-infarction patients [age 48.8 +/- 3.3 years (mean +/- SD)] with Arg/Arg (n = 23) and Arg/Gln (n = 8) genotypes. Factor VII antigen (VIIag) and activity along with plasma lipoproteins were determined before and after intake of a mixed meal-type of oral fat load. Patients with the Arg/Gln genotype had basal VIIag and activated factor VII (VIIa) levels 75% and 48%, respectively, of those of patients homozygous for the Arg allele. In absolute terms, VIIa increased more in homozygotes for the Arg allele (delta 0-6 h VIIa 1.76 +/- 1.48 ng/ml) than in heterozygotes (0.60 +/- 0.27 ng/ml) in response to fat intake, but the percentage increase in VIIa molecules did not differ significantly between subjects with Arg/Arg and Arg/Gln genotypes (37 +/- 32% versus 27 +/- 15%). This suggests that the influence of the Arg/Gln polymorphism on factor VII activity is mainly accounted for by differences in the basal factor VII protein level between genotypes. Since most of our lives are spent in the postprandial state, possession of the factor VII-Gln353 allele is likely to confer protection against coronary heart disease by reducing the amount of VIIa produced in response to fat intake.

Arginine↗
PubMed1999

Coagulation protein function VII: diametric effects of acetaldehyde on factor VII and factor IX function.

The first metabolite of ethanol, acetaldehyde, has the ability to form adducts with proteins and alter their function. It has been shown that acetaldehyde reacts with various proteins of the blood coagulation pathway and, subsequently, produces a prolongation of the clotting time. This study evaluated the function of clotting proteins from the extrinsic coagulation pathway (factor VII) and the intrinsic coagulation pathway (factor IX) when preincubated with acetaldehyde as compared to a control and compared to preincubation with ethanol. Prior to use in a clotting assay, incubation times with acetaldehyde, ethanol, and the control were the same for both factors VII and IX. An automatic fibrometer measured the clotting times. Factor VII preincubated with acetaldehyde prolonged the clotting time. However, factor IX preincubated with acetaldehyde actually decreased the clotting time. Of interest, both factors VII and IX preincubated with acetaldehyde produced statistically significant results when compared to the control and ethanol. This experiment indicates that acetaldehyde, in forming an adduct with proteins of the blood coagulation pathway, may induce a conformational change of factors VII and IX so as to either increase or decrease the clotting time. Therefore, it is possible that some of the deranged coagulation in alcohol abusers may be a final net result of the interaction of acetaldehyde and proteins of the coagulation pathway.

Acetaldehyde↗
PubMed1995

Prophylaxis and therapy with factor VII concentrate (human) immuno, vapor heated in patients with congenital factor VII deficiency: a summary of case reports.

Hereditary factor VII deficiency is a rare autosomal recessive condition, usually associated with normal or reduced levels of a functionally defective molecule. The available means of treating this condition in North America presents serious health risks to the patient. Transfusion with fresh frozen plasma carries a risk of volume overload and a significant risk for viral transmission. Sustained prothrombin complex therapy is associated with a high risk for thrombogenic complications. This communication describes the use of Factor VII Concentrate (Human) Immuno, Vapor Heated--an intermediate purity factor VII concentrate from Immuno A.G.--for the treatment of 13 patients with factor VII deficiency. Treatment regimens described include those for long-term prophylaxis (three children), acute hemorrhages (two children, one adult), peripartum prophylaxis (one patient), and surgical coverage (two children, four adults). Prophylaxis and therapy were successful in all cases, the medication was well-tolerated, and there were no complications. In the three cases of long-term prophylaxis in children, doses of 10-50 IU/kg were given one to three times a week; one patient has undergone long-term prophylaxis for approximately 8 years, one patient for 1 year, and one patient for 1 1/2 years. Three cases in which Factor VII Concentrate was principally used for treatment of acute episodes of bleeding are described. One infant received Factor VII Concentrate on about 50 occasions for treatment of mucosal bleeding; a correction to 40-100% resulted in cessation of bleeding within 15 min in all cases. For treatment of an episode of intracranial bleeding, an 8-year-old boy received a dose of 37 IU/kg Factor VII Concentrate every 6 hr for peak factor VII levels of approximately 100% and troughs as low as 4% over the 11-day treatment period. A 37-year-old adult male with intracranial bleeding received alternating doses of 16 IU/kg and 8 IU/kg every 6 hr for 10 days with peak factor VII levels in the upper thirties (%). The peak favor VII level during surgical coverage with Factor VII Concentrate (neurosurgery, open reduction of ankle bones, dental surgery, pituitary adenoma surgery, closed liver biopsy) was approximately 100% in all cases, with trough levels ranging from 8 to 65% over treatment periods of 24 hr to 16 days using treatment intervals of 6-12 hr.

Adult↗
PubMed1996

Synthetic peptide analogs of tissue factor and factor VII which inhibit factor Xa formation by the tissue factor/factor VIIa complex.

Factor VII (FVII) and tissue factor (TF) form a binary complex which initiates the extrinsic pathway of the blood coagulation cascade. The infrequent tripeptide motif Trp-Lys-Ser (WKS) is found three times in TF. It has been suggested that the motif is involved in binding of TF to FVII(a). Also. Lys165 and Lys166 of TF have been reported to be important for factor X activation. To elucidate the molecular interactions between TF and FVIIa, and the interactions between the binary complex and FX, we examined the inhibitory effect of synthetic TF and FVII peptide analogs. One- and two-stage chromogenic assays were employed, as well as one-stage coagulation assay. The peptide analogs of TF possessed the WKS motif, the double lysine residues or other regions of TF. Synthetic peptides of FVII encompassing sequences of the FVII285-305 region were included for comparative purposes. TF154-167 and FVII300-305 significantly inhibited both FX activation and plasma coagulation. FVII285-294 acted synergistically, increasing that effect observed by FVII300-305 on FX activation. However, TF163-175 possessing the double lysine residues did not inhibit FX activation, indicating that inhibition of FXa formation and coagulation by TF154-167 is due to the region 154-162 of TF. None of the peptides, including the WKS tripeptide, interfered with the FVIIa activity of the TF/FVIIa complex. Thus, the results do not suggest that the WKS motifs are necessary for binding of TF to FVIIa but that the third WKS motif may be of importance for the activation of FX.

Factor VII↗
PubMed2004

Prevalence in a Tunisian Arabic population of factor VII DNA variants and relation to factor VII plasma levels.

BACKGROUND: A raised plasma factor VII (FVII) level is a risk factor for coronary heart disease. DNA variants have been described to be associated with alteration in FVII levels. The prevalence of FVII polymorphisms is unknown in the Tunisian Arab population. METHODS: In a group of 240 healthy Tunisians, we examined the relationship between levels of FVII coagulant activity (FVIIc) and two polymorphisms in the FVII gene. One polymorphism alters arginine at position 353 to glutamine (R/Q) and the other is a 10 base pair insertion (0/10 bp). RESULTS: The FVII distribution was in accordance with the Hardy-Weinberg equilibrium. The allele frequencies of Q and 10 bp were 0.212 and 0.235, respectively. There were significant differences in these allelic frequencies between Tunisian and other populations (p<0.001). We observed lower FVIIc levels among subjects with the Q allele compared to RR subjects (RR: 98.17%, RQ/QQ: 57.41%, p<0.0001). For the 0/10 polymorphism, no statistically difference was observed. CONCLUSION: The prevalence of the Q allele which was found to be associated with lower plasma FVIIc levels is high in Tunisian population. Further analyses should yield information on the protective role of carrying the Q allele for coronary heart disease.

Adult↗
PubMed2002

Model of a ternary complex between activated factor VII, tissue factor and factor IX.

Upon binding to tissue factor, FVIIa triggers coagulation by activating vitamin K-dependent zymogens, factor IX (FIX) and factor X (FX). To understand recognition mechanisms in the initiation step of the coagulation cascade, we present a three-dimensional model of the ternary complex between FVIIa:TF:FIX. This model was built using a full-space search algorithm in combination with computational graphics. With the known crystallographic complex FVIIa:TF kept fixed, the FIX docking was performed first with FIX Gla-EGF1 domains, followed by the FIX protease/EGF2 domains. Because the FIXa crystal structure lacks electron density for the Gla domain, we constructed a chimeric FIX molecule that contains the Gla-EGF1 domains of FVIIa and the EGF2-protease domains of FIXa. The FVIIa:TF:FIX complex has been extensively challenged against experimental data including site-directed mutagenesis, inhibitory peptide data, haemophilia B database mutations, inhibitor antibodies and a novel exosite binding inhibitor peptide. This FVIIa:TF:FIX complex provides a powerful tool to study the regulation of FVIIa production and presents new avenues for developing therapeutic inhibitory compounds of FVIIa:TF:substrate complex.

Algorithms↗
PubMed2005

Influence of factor VII gene polymorphisms and environmental factors on plasma coagulation factor VII concentrations in middle-aged women with and without manifest coronary heart disease.

Plasma concentrations of coagulation factorVII (FVII) are determined by environmental and genetic factors. The influence of functional polymorphisms in the FVII gene (-670A>C, -402G>A, -401G>T and R353Q) and of established cardiovascular risk factors on plasma concentrations of FVII were investigated in a representative sample of middle-aged women with (n=238) and without (n=220) coronary heart disease (CHD). Specific and sensitive assays were used to measure FVII antigen (VIIag) and activated factorVII (VIIa). The effect of genotypes was markedly stronger on VIIa than on VIIag, with the percentage variation in FVII levels accounted for by genotypes being greater in controls than in patients. Of the four polymorphisms examined, only the R353Q contributed to the variation inVIIa (24.1% in patients and 30.3% in controls). The -401G>T and -670A>C promoter polymorphisms together accounted for 12.2% of the variation in VIIag amongst patients whereas the -401G>T polymorphism alone contributed 19.7% of the variation in VIIag in controls. Serum triglycerides exerted a major influence onVIIag in both patients (13.0%) and controls (7.2%). Three main haplotypes emerged from the four polymorphisms which accounted for 98% of all haplotypes. Large-scale prospective studies of CHD including FVII haplotypes and sensitive and specific FVII measurements are needed in women.

Analysis of Variance↗