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PubMed1985

Studies on the procoagulant activity of human amniotic fluid. II. The role of factor VII.

Partially purified Amniotic Fluid Factor (AFF) is found to directly activate human factor X, with a Km for factor X of 0.37 +/- 0.06 M. Added phospholipid has only a slight effect on the activation at low concentrations, and inhibits the reaction at higher concentrations. Both DIPF and PMSF inhibit AFF factor X activation. Although added phospholipid is not required for AFF-activity, phospholipase C rapidly destroys it, indicating the presence of intrinsic phospholipid. Phospholipase C treated AFF releases factor VII activity, which leads to the conclusion that AFF is in fact a thromboplastin: factor VII complex. Both AFF and a human brain thromboplastin factor VII complex prepared in vitro were inhibited by Zn++ ion, while human brain thromboplastin alone is not. AFF is markedly larger than the human brain thromboplastin-factor VII complex as judged by gel filtration.

Amniotic Fluid↗

PubMed2006

Steps towards an effective treatment strategy in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is a consequence of a genetic polymorphism that can produce a wide spectrum of disease severity. Mildly affected patients may experience increased bleeding after surgery, trauma or mucosal bleeding, while spontaneous and life-threatening bleeding occurs in patients who are severely affected. Replacement therapy is the mainstay of treatment for patients with FVII deficiency. This has traditionally been achieved using fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), or plasma-derived FVII concentrates. However, recombinant activated FVII is now widely used for therapy in these patients. As cases of FVII deficiency tend to be encountered infrequently in most centers, no consolidated evidence-based therapeutic regimens have evolved and the side effects of the available treatments have not been comprehensively evaluated. Consequently, an online registry, the Seven Treatment Evaluation Registry (STER) has been set up. This is a prospective study that aims to evaluate the efficacy and safety of the different therapeutic options with which FVII-deficient patients may be treated. Recruitment of patients into the study is currently underway.

Blood Coagulation Factors↗

PubMed1998

Association of factor VII protein concentration with lifestyle factors.

Several studies have demonstrated that changes in fasting levels of factor VII coagulant activity (FVII:C), a thrombotic risk marker, are due to changes in FVII protein concentrations (FVII:Ag). Consequently, studies on FVII now often include measurements of FVII:Ag. The present cross-sectional study examined the association between several behavioural variables (body mass index, physical activity, tobacco or alcohol consumption) or physiological variables (total cholesterol, HDL-cholesterol, triglycerides, glucose, insulin, fibrinogen, resting pulse, systolic blood pressure, bleeding time) and FVII:Ag in 439 51-y-old Danish men. In the multivariate analyses, body mass index (BMI), low physical activity, total cholesterol, short bleeding time, and insulin showed an independent positive association with FVII:Ag. The strongest independent association with FVII:Ag was found for total cholesterol. These results suggest that blood lipids are major determinants of FVII:Ag, but that other lifestyle factors such as insulin, BMI and physical activity can also influence FVII:Ag. Furthermore, the association between FVII:Ag and bleeding time suggests an effect of FVII or the FVII pathway on primary haemostasis.

Adult↗

PubMed1994

Analysis of the partial nucleotide sequences and deduced primary structures of the protease domains of mammalian blood coagulation factors VII and X.

In order to obtain sequence data for the blood coagulation factor VII and factor X in several mammalian species, we amplified and sequenced the DNA segments of exon VIII from each gene by means of the polymerase chain reaction (PCR) method. The DNA segments from the following species were successfully amplified: factor VII from the rhesus monkey and dog, and factor X from the rhesus monkey, Syrian hamster and rat. In each factor, the nucleotide sequences and predicted primary structures of the protease domain showed a high degree of homology among species; amino acid identities of approximately 68%-92% and 80%-98% were demonstrated among species in factor VII and factor X, respectively. The locations of the active site residues and five Cys residues were evolutionarily conserved in both factors. Interestingly, the amino acids involved in the human genetic variants, both factor VII 304-Arg and factor X 326-Arg, were always conserved across species. The data presented here will be helpful for investigating human genetic variants of factor VII or X, and will provide considerable information for constructing in vitro site-specific mutants of these factors.

Amino Acid Sequence↗

PubMed2005

Effect of abdominal obesity on prothrombotic tendency in type 2 diabetes. Behavior of clotting factors VII and VIII, fibrinogen and von Willebrand Factor.

Patients with type 2 diabetes and abdominal fat patterning displayed higher plasma activities of clotting factors VII and VIII as well as increased plasma levels of fibrinogen and von Willebrand factor antigen, when compared with not only healthy normal weight controls, but also with diabetic patients at normal body weight. Mechanisms associating abdominal obesity with the above mentioned prothrombotic changes are only partially elucidated and may differ according to the individual haemostatic variable. Actually, according to data in the literature and authors' observations increased plasma factor VII activity is mainly associated with increased plasma triglyceride level, while the hepatic synthesis of fibrinogen as well as the synthesis and release of endothelia-derived von Willebrand factor are stimulated by cytokines originating in the visceral adipose tissue. The relationship between the presently investigated hemostatic variables and features of the metabolic syndrome are less obvious than in the previously recorded association of metabolic risk factors with plasma levels of plasminogen activator inhibitor.

Abdominal Fat↗

PubMed1979

Purification and some characteristics of the human coagulation factor VII.

1. A purification procedure for factor VII (proconvertin) from human plasma is described. The procedure involves barium sulphate adsorption and elution. DEAE-Sephadex column chromatography, barium sulphate adsorption and elution, heparin-Sepharose column chromatography, preparative disc gel electrophoresis and finally adsorption with antiserum to prothrombin coupled to Sepharose and antiserum to albumin coupled to Sepharose. This procedure gave an approximately 8 . 10(5)-fold purification. 2. The factor VII obtained from the electrophoresis step was mainly a single-chain protein with an apparent molecular weight of 53000 +/- 2000. 3. After the final purification step, additional forms of factor VII, resulting from a fragmentation of the factor VII molecule were detected. 4. Amino acid composition data of the purified factor VII are given. 5. Antisera were raised in two different rabbits by injection of the purified factor VII. The antisera obtained gave a good titre against the factor VII activity and were not directed against any of the three other vitamin-K-dependent coagulation factors.

Amino Acids↗

PubMed1986

Electroimmunoassay of factor VII antigen.

A clear precipitating arc of factor VII antigen appeared by immunoelectrophoresis using 125I-labelled anti-factor VII antibody incorporated in the Laurell plate to enhance the sensitivity. A plasma sample could be electrophoresed directly on 1% agarose containing 1% rabbit anti-human factor VII antiserum, 0.1% 125I-labelled anti-human factor VII specific IgG and 0.5% polyethyleneglycol 6000, and after washing, autoradiographed at -70 degrees C for 24 hr. A distinct rocket was seen from 45 ul standard reference plasma to 16-fold after auto-radiography. Of 4 patients with congenital factor VII deficiency, 3 patients had no detectable factor VII antigen, one patient had reduced factor VII antigen.

Antigens↗

PubMed1991

Factor VII clotting assay: influence of different thromboplastins and factor VII-deficient plasmas. CISMEL Study Group.

Being a putative predictor of ischemic heart disease, the measurement of factor VII (FVII) coagulant activity will be presumably requested to clinical laboratories with increasing frequency. To assess the influence on FVII assays of different thromboplastins and FVII-deficient plasmas we compared performances of all possible combinations of 5 thromboplastins and 6 deficient plasmas. The reproducibility of the clotting times of the dose-response curves for human and rabbit thromboplastins were acceptable (CV lower than 7%), whereas bovine thromboplastin had a higher CV. Reproducibility was very similar for all deficient plasmas when they were used in combination with a given thromboplastin. Responsiveness of the dose-response curve did not depend on the deficient plasma but rather on the thromboplastin: one rabbit thromboplastin was the least responsive, the bovine thromboplastin the most responsive, the human and the remaining two rabbit thromboplastins had intermediate responsiveness. Assay sensitivity to cold-activated FVII varied according to the thromboplastin: the bovine thromboplastin was the most sensitive, the human thromboplastin the least sensitive, of the three rabbit thromboplastins two were relatively sensitive, one was almost insensitive. In conclusion, our results indicate that thromboplastin rather than deficient plasma is the crucial factor in the standardization of FVII assay.

Adult↗

PubMed1996

High-affinity calcium-binding site in the gama-carboxyglutamic acid domain of bovine factor VII.

The calcium-mediated interaction of factor VIIa with tissue factor is considered to be the primary trigger of blood coagulation. To determine the role of calcium ions in the action of factor VII, we prepared monoclonal antibodies whose binding to factor VII was calcium-dependent. A monoclonal antibody designated C6 strongly inhibited factor VII-induced clotting at a molar ratio of factor VII to antibody of 1:1. The half-maximal binding of factor VII to the C6 antibody was observed at a concentration of calcium ions of 80 microM. Proteolytic fragments of factor VII were assayed for their ability to inhibit competitively the binding of 125I-factor VII to immobilized C6 antibody. The binding was inhibited by increasing amounts of factor VII, by a fragment that contained the gamma-carboxyglutamic acid (Gla) domain linked to first epidermal growth factor-like domain, and by a Gla domain peptide (residues 1-41), over a range of concentration of 10(-9) to 10(-7) M. The antigenic site recognized by the monoclonal antibody C6, which was generated upon the high-affinity binding of calcium ions, was located in the Gla domain. The C6 antibody inhibited the activation of factor X and the amidolytic activity of factor VIIa in the presence of tissue factor. These results demonstrate that a high-affinity calcium-binding site(s) is located in the Gla domain of factor VII, which is concerned with the initiation of tissue factor-mediated blood coagulation by factor VIIa.

1-Carboxyglutamic Acid↗

PubMed1996

Kinetics of human factor VII activation.

In this study the activation of human factor VII by a variety of potential activators in the presence and absence of mixed phospholipid vesicles [25% phosphatidylserine (PS), 75% phosphatidylcholine (PC)] is evaluated. At the plasma concentration of factor VII, 10 nM, the activation rate of the zymogen by 0.05 nM factor Xa is anionic phospholipid (PCPS) dependent and achieves a maximum value of 18 pM/s at 5-20 microM PCPS; further increases in the levels of PCPS decrease the activation rate of factor VII. The maximum activation rate of factor VII (10 nM) by the factor VIIa-tissue factor complex (0.1 nM), 0.76 pM/s, is achieved at 200 microM PCPS. No detectable activation of 10 nM factor VII is observed under similar conditions when either thrombin (0.1 nM) or factor IXa (0.1 nM) is used as an activator. Factor VIIa (10 nM) and factor XIa (1 nM) are not observed to activate factor VII at detectable rates. The observed Michaelis-Menten constants (KM) for factor VII activation in the presence of PCPS at optimal concentrations vary from 1.2 microM for factor Xa to 3.2 microM for the factor VIIa-tissue factor complex. The highest catalytic constant (kcat) value (15.2 s-1) is observed for factor Xa-PCPS. The factor VIIa-tissue factor complex, factor IXa, and thrombin kcat values are 1.4, 0.32, and 0.061 s-1, respectively. Tissue factor does not increase the factor VII activation rate by factor Xa, factor IXa, or thrombin. Factor VIIIa in the presence of PCPS has no effect on factor VII activation by factor IXa. In contrast, factor Va decreases the factor VII activation rate by factor Xa, reaching saturation at concentrations consistent with complete prothrombinase complex formation. The formed prothrombinase complex activates factor VII at approximately 30% the rate of factor Xa bound to phospholipids. These data allow us to conclude that the predominant physiological factor VII activator is, most likely, membrane-bound factor Xa.

Amino Acid Sequence↗

PubMed1990

The role of factor VII in haemostasis: infusion studies of factor VIIa in a canine model of factor VIII deficiency.

The role of factor VIIa in haemostasis has been studied using a canine model of factor VIII deficiency. Highly purified human factor VIIa was administered to dogs at a dosage of 0.5 microgram/kg. At selected times pre- and post-infusion, haemostasis was evaluated by the cuticle bleeding time. Plasma was collected for the assay of various parameters, including fibrinopeptide A (FPA) as a marker for thrombin generation in vivo. Factor VIIa infusion resulted in a 6-fold increase of factor VII clotting activity with a t1/2 of 2 h. FPA levels, which were 1.4 ng/ml before infusion, did not increase significantly in haemophilic dogs. In normal dogs, however, FPA levels rose to a mean value of 190 ng/ml 30 min post-infusion. It appeared that thrombin generation by factor VIIa infusion had occurred mainly via the intrinsic, factor VIII-dependent pathway. In factor VIII-deficient dogs, factor VIIa infusion did not correct cuticle bleeding, but an inconsistent haemostatic effect was observed 15-30 min post-infusion. Similar results were obtained in haemophilic dogs with circulating antibodies against factor VIII. The haemostatic effectivity could not be improved by increasing the factor VIIa dosage up to 40-fold. Although these data suggest that the extrinsic, factor VII-dependent factor X activation provides only a minor pathway of thrombin generation in vivo, it is possible that the suboptimal haemostatic effect noted may be promoted in bleeding situations where tissue factor availability is less limited. As such, factor VIIa may prove useful in the treatment of haemophilia A patients with acquired inhibitors to factor VIII.

Animals↗

PubMed2002

Genotypic heterogeneity may explain phenotypic variations in inherited factor VII deficiency.

Inherited factor VIl (FVII) deficiency is a rare autosomal recessive coagulation disorder characterized by a wide genet-ic heterogeneity and a poor relationship between FVII activity (FVII:C) levels and severity of the hemorrhagic diathesis. Given both the rarity and the heterogeneity of this disorder,genotype-phenotype relationships are difficult to clarify. The analysis of three FVII-deficient patients enabled us to offer some explanations.

Factor VII↗

PubMed1998

[New possibilities in the management of hemorrhagic diathesis caused by factor deficiency and thrombocytopenia: recombinant active factor VII concentrate].

Recombinant Factor VIIa, a new therapeutic tool to treat severe bleeding caused by inhibitory haemophilia cases, some cases of thrombocytopenia and thrombocytopathy (e.g. severe type III von Willebrand disease) receives growing attention in clinical practice. Exogeneous FVIIa-in a supraphysiological concentration (clearly over 6 U/ml) seems to be able to generate quickly and safely (without thrombotic side effects) thrombin--the final enzyme of clotting--in physiological, or pathological conditions. A concise review about the possible mechanisms of action, indications, monitoring and clinical experience gained sofar with FVIIa is given in this report.

Factor VII↗

PubMed1999

Factor VII deficiency detected in pregnancy: a case report.

Factor VII deficiency is a rare hereditary coagulation disorder with an incidence estimated at 1 in 500,000 individuals. In this report, we describe the 13th case in pregnancy. The diagnosis of severe factor VII deficiency (factor VII level <5%) was established at 10 weeks' gestation after initial laboratory testing showed a markedly prolonged prothrombin time and a normal activated partial thromboplastin time. There was a history of two preterm deliveries, but there was no evidence of previous bleeding manifestations. Antenatal progress of the index pregnancy was unremarkable. Prophylactic treatment with fresh frozen plasma was started at the onset of labor and the patient had a vaginal delivery of a live girl at 36 weeks' gestation. There was no postpartum hemorrhage and mother and newborn were discharged in good condition. The patient's postpartum level of factor VII remained undetectable. Two aspects are outlined: the absence of any significant increase in factor VII clotting activity during this pregnancy and the need to give replacement therapy at labor in patients with severe factor VII deficiency to decrease the risk of postpartum hemorrhage.

Adult↗

PubMed1991

Initiation of the extrinsic pathway of blood coagulation: evidence for the tissue factor dependent autoactivation of human coagulation factor VII.

Previous studies demonstrated proteolytic activation of human blood coagulation factor VII by an unidentified protease following complex formation with tissue factor expressed on the surface of a human bladder carcinoma cell line (J82). In the present study, an active-site mutant human factor VII cDNA (Ser344----Ala) has been constructed, subcloned, and expressed in baby hamster kidney cells. Mutant factor VII was purified to homogeneity in a single step from serum-free culture supernatants by immunoaffinity column chromatography. Mutant factor VII was fully carboxylated, possessed no apparent clotting activity, and was indistinguishable from plasma factor VII by SDS-PAGE. Cell binding studies indicated that mutant factor VII bound to J82 tissue factor with essentially the same affinity as plasma factor VII and was cleaved by factor Xa at the same rate as plasma factor VII. In contrast to radiolabeled single-chain plasma factor VII that was progressively converted to two-chain factor VIIa on J82 monolayers, mutant factor VII was not cleaved following complex formation with J82 tissue factor. Incubation of radiolabeled mutant factor VII with J82 cells in the presence of recombinant factor VIIa resulted in the time-dependent and tissue factor dependent conversion of single-chain mutant factor VII to two-chain mutant factor VIIa. Plasma levels of antithrombin III had no discernible effect on the factor VIIa catalyzed activation of factor VII on J82 cell-surface tissue factor but completely blocked this reaction catalyzed by factor Xa. These results are consistent with an autocatalytic mechanism of factor VII activation following complex formation with cell-surface tissue factor, which may play an important role in the initiation of extrinsic coagulation in normal hemostasis.

Amino Acid Sequence↗

PubMed1998

Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction.

BACKGROUND: High blood levels of coagulation factor VII are associated with a risk of ischemic vascular disease. Although factor VII levels may be genetically determined, the relation between genetic polymorphisms of factor VII, factor VII blood levels, and the risk of myocardial infarction has not been established. METHODS: We performed a case-control study of 165 patients with familial myocardial infarction (mean [+/-SD] age, 55+/-9 years) and 225 controls without a personal or family history of cardiovascular disease (mean age, 56+/-8 years). The polymorphisms involving R353Q and hypervariable region 4 of the factor VII gene were studied. Factor VII clotting activity and antigen levels were also measured. RESULTS: Patients with the QQ or H7H7 genotype had a decreased risk of myocardial infarction (odds ratios, 0.08 [95 percent confidence interval, 0.01 to 0.9] and 0.22 [95 percent confidence interval, 0.08 to 0.63], respectively). For the R353Q polymorphism, the RR genotype was associated with the highest risk, followed by the RQ genotype and then by the QQ genotype (P<0.001). For the polymorphism involving hypervariable region 4, the combined H7H5 and H6H5 genotypes were associated with the highest risk, followed in descending order by the H6H6, H6H7, and H7H7 genotypes (P<0.001). Patients with the QQ or H7H7 genotype had lower levels of both factor VII antigen and factor VII clotting activity than those with the RR or H6H6 genotype. Patients with the lowest level of factor VII clotting activity had a lower risk of myocardial infarction than those with the highest level (odds ratio, 0.13; 95 percent confidence interval, 0.05 to 0.34). CONCLUSIONS: Our findings suggest that certain polymorphisms of the factor VII gene may influence the risk of myocardial infarction. It is possible that this effect may be mediated by alterations in factor VII levels.

Analysis of Variance↗

PubMed2003

Sensitivity of different prothrombin time assays to factor VII deficiency in canine plasma.

The factor VII sensitivity of prothrombin time (PT) in dogs was tested using five different PT reagents and a commercial PT variant. The five PT reagents were used according to manufacturers' instructions (standard test, PT([ST])) and also using a modified test instruction (modified test, PT([MT])). Plasma samples with defined factor VII levels (10-100%) were prepared by adding increasing quantities of canine factor VII deficient plasma to the pooled plasma of healthy dogs. Statistical comparison based on prothrombin time ratios (PTR = PT sample: PT measured for 100% factor VII activity level) revealed significant differences between different reagents for PT([ST]) and also for PT([MT]). Factor VII activity at which PT was prolonged to the upper limit of the reference values (FVII([X(0.975)])) was 16-39% (PT([ST])) and 23-35% (PT([MT])). Factor VII sensitivity measured by PTR and also by FVII([X(0.975)]) values, was higher in four of five PT reagents using PT([MT]) when compared with PT([ST]). The results of this study indicate the importance of selecting a sensitive reagent and method for PT measurement and for careful interpretation of PT test results using canine plasma.

Animals↗

PubMed1977

A CRM-Positive variant of factor-VII deficiency and the detection of heterozygotes with the assay of factor-like antigen.

Nine patients with severe factor-VII deficiency, belonging to seven pedigrees were studied for the presence of factor-VII-CRM with an inhibitor neutralization assay. The antibody, raised in rabbits, did not precipitate the antigen and could only be used in a fluid phase assay to measure the capacity of plasma to neutralize inhibitory activity directed against factor-VII activity. In one of these nine patients normal amounts of factor-VII-CRM could be demonstrated. The CRM + patient did not show a clinical picture at variance with that of the CRM-patients. The investigation into this CRM+ pedigree revealed heterozygosity in nine out of 12 persons when using the ratio between biological factor-VII activity and factor-VII-CRM as the criterion.

Adolescent↗