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PubMed2006

The effects of three factor VII polymorphisms on factor VII coagulant levels in healthy Singaporean Chinese, Malay and Indian newborns.

Factor VII (FVII) is an independent risk factor for coronary artery disease. Three polymorphisms of the factor VII gene (F7) were studied in a group of healthy newborns comprising 561 Chinese, 398 Malays and 226 Asian Indians from Singapore. The allele frequencies of 3 polymorphisms (R353Q, Promoter 0/10bp Del/Ins and Intron 7) in the FVII gene were ascertained through genotyping by polymerase chain reaction and restriction digestion of amplified fragments. In Chinese the minor allele frequencies are Q: 0.04, Ins: 0.03, R7: 0.44; Malays, Q: 0.06, Ins: 0.10, R7: 0.41; and Indians, Q: 0.25, Ins: 0.23, R7: 0.43. Strong linkage disequilibrium (Delta > 0.7) is observed between the 0/10 bp and the R353Q sites in all ethnic groups. We conclude that: (i) the prevalence of the minor Q and Ins alleles of the R353Q and 0/10 bp polymorphisms are significantly higher in the Indian newborns than the Chinese and Malays; (ii) the Q allele is significantly associated (p = 0.01) with a lower plasma FVII coagulant level in the Indian and Malay neonates; and this polymorphism explains up to 3.8% of the variance in FVII coagulant levels; (iii) there is no significant difference in allele frequencies of the three polymorphisms between neonates with and without family histories of CAD.

Antigens↗
PubMed1993

Two independent binding sites on monolayers of human endothelial cells are responsible for interaction with coagulation factor VII and factor VIIa.

The interaction of radiolabeled factor VII (FVII) and factor VIIa (FVIIa) with endotoxin-stimulated endothelial cells (EC), known to express tissue factor (TF), and unstimulated EC was studied. FVII/FVIIa binding to EC-monolayers was saturable within 4.5-6 h, reversible, temperature and calcium dependent on both, endotoxin-stimulated and on unstimulated EC. Upon 2 h of incubation on EC, FVII was partially converted to FVIIa in the absence of protease inhibitors. The affinity of this binding was Kd = 45.4 +/- 18.7 nM with a calculated number of binding sites Bmax = 3.75 +/- 0.31 x 10(6) molecules/cell. In addition to unlabeled FVII and FVIIa, other vitamin K-dependent proteins reduced binding of [125I]-FVII/FVIIa to about 60-70%, and this type of common binding site for vitamin K-dependent proteins revealed a Kd = 32.2 +/- 5.6 nM and a Bmax = 3.03 +/- 0.14 x 10(6) molecules/cell. Moreover, in the presence of 1 microM prothrombin to suppress common binding sites, only on endotoxin-stimulated EC additional inhibition of FVII/FVIIa binding was achieved by anti-TF antibodies. The characteristics of the FVII/FVIIa-TF interaction with a Kd = 17.2 +/- 5.2 nM and a Bmax = 342,000 +/- 1,100 binding sites/cell revealed a similar saturation kinetics in radioligand binding and in functional factor X activation within 90-120 min. These data indicate the presence of at least two independent binding sites for FVII/FVIIa on stimulated EC of which about 10% are TF specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1976

The influence of the thyroid function on the metabolic rate of prothrombin, factor VII, and factor X in the rat.

The influence of the thyroid function on the metabolic rate of prothrombin, factor VII, and X was studied in the rat. Disappearance rates of the three coagulation factors were measured after synthesis had been blocked with appropriate doses of warfarin, and reappearance rates were assessed upon induction of synthesis by high doses of vitamin K1 injected into rats displaying coumarin induced hypocoagulability. No statistically significant difference in the disappearance and production rates of any of the factors could be found between normal euthyroid rats and thyroxin-treated hypothyroid rats proven to be euthyroid. The differences between the two euthyroid groups and the hypothyroid group were highly significant, however: hypothyroidism results in an approximately 50% decrease of the metabolic rates of the three coagulation factors under study. The reappearance of the three factors, under euthyroid as well as hypothyroid conditions, showed a biphasic pattern: in the first two hours after vitamin K1 administration to warfarin treated rats, a rapid reappearance was observed, to the same extent for all three factors, in hypo- as well as euthyroid rats. This finding suggests that in vitamin K1 deficiency an intracellular accumulation of precursor proteins (PIVKAs) occurs, which after rapid conversion into biologically active coagulation factors by vitamin K1 are shed into circulation. The subsequent phase of reappearance is much slower and reflects the synthesis rate of coagulation enzymes. It is characteristic for each factor and clearly slower in hypothyroid rats than in euthyroid rats. From this an influence of thyroid function on the synthesis rate of the protein moiety of coagulation factors can be inferred. An apparent difference between disappearance and reappearance rate of the coagulation factors in the plasma, particularly pronounced for factors VII and X in euthyroid rats, could theoretically be explained as the consequence of the model used for derivation of these rates.

Animals↗
PubMed1990

The importance of residues 195-206 of human blood clotting factor VII in the interaction of factor VII with tissue factor.

Previous studies indicated that human and bovine factor VII exhibit 71% amino acid sequence identity. In the present study, competition binding experiments revealed that the interaction of human factor VII with cell-surface human tissue factor was not inhibited by 100-fold molar excess of bovine factor VII. This finding indicated that bovine and human factor VII are not structurally homologous in the region(s) where human factor VII interacts with human tissue factor. On this premise, we synthesized three peptides corresponding to regions of human factor VII that exhibited marked structural dissimilarity to bovine factor VII; these regions of dissimilarity included residues 195-206, 263-274, and 314-326. Peptide 195-206 inhibited the interaction of factor VII with cell-surface tissue factor and the activation of factor X by a complex of factor VIIa and tissue factor half-maximally at concentrations of 1-2 mM. A structurally rearranged form of peptide 195-206 containing an aspartimide residue inhibited these reactions half-maximally at concentrations of 250-300 microM. In contrast, neither peptide 263-274 nor peptide 314-326, at 2 mM concentration, significantly affected either factor VIIa interaction with tissue factor or factor VIIa-mediated activation of factor X. Our data provide presumptive evidence that residues 195-206 of human factor VII are involved in the interaction of human factor VII with the extracellular domain of human tissue factor apoprotein.

Amino Acid Sequence↗
PubMed1977

Platelet adhesiveness and aggregation in combined factor V and factor VIII deficiency and in combined factor VII and factor VIII deficiency.

Platelet aggregation and adhesiveness were studied in 3 patients with combined factor V and factor VIII deficiency and in 3 patients with combined factor VII and factor VIII deficiency. The first three patients belonged to three different kindreds whereas the second group belonged to the same kindred. Serotonin C14 uptake and release was also found to be normal in these patients. These studies indicate that platelet function is normal in combined defects of factor VIII. These findings were in agreement with the presence of a normal bleeding time and a normal factor VIII antigen level in all these patients.

Blood Coagulation Disorders↗
PubMed1996

The propeptides of human protein C, factor VII, and factor IX are exchangeable with regard to directing gamma-carboxylation of these proteins.

The specificity of the propeptide sequence in directing vitamin K-dependent post-translational gamma-carboxylation has been assessed by examination of the extent of processing of chimeric constructs of blood coagulation factor VII (fVII), factor IX (fIX) and protein C (PC). One chimera consisted of a protein in which the gamma-carboxyglutamic acid (Gla)/helical stack domain of PC (amino acid residues 1 to 46) was replaced by that of fIX (residues 1 to 47) in an otherwise intact PC. Another consisted of the same construction of a fVII/PC Gla domain-based mutant protein. The final chimera contained the leader/propeptide sequence of PC (residues -42 to -1) replaced by that of fIX (residues -46 to -1). In each case, all Glu-precursor Gla residues in the Gla domains of the proteins were fully processed to Gla. These results demonstrate that the propeptides of fIX and PC are capable of directing gamma-carboxylation of the Gla regions of either protein, that the propeptide of PC can fully function in gamma-carboxylation of the Gla region of fVII, and further suggest that, with regard to gamma-carboxylation, communications between the propeptides and Gla domains in intact proteins are general in nature.

Carboxylic Acids↗
PubMed2002

Structure, function, and activation of coagulation factor VII.

Factor VII is the coagulation protease responsible for starting a cascade of proteolytic events that lead to thrombin generation, fibrin deposition, and platelet activation. As such, FVII has attracted wide interest as a target for clinical anti-coagulant applications. Commensurate with the critical importance of maintaining balance between thrombosis and hemostasis and its place at the beginning of the coagulation process, FVII is subject to a variety of biological and biochemical control mechanisms, among them allosteric influences exerted by cofactors, substrates, and inhibitors. Sites on FVIIa where allosteric influences are exerted and manifested have been identified and characterized in considerable detail. In recent years, a three-dimensional context for the interpretation of these results has become available from structural studies. New X-ray structures have augmented specific aspects of our understanding, in particular the X-ray structure of a fragment of the FVII zymogen. This review summarizes general allosteric behaviors of FVIIa and recapitulates structural findings since 1996, with particular emphasis on the recently determined zymogen structure.

Binding Sites↗
PubMed1980

Congenital combined factor VII and factor VIII deficiency.

This paper describes two family members who have a combined hereditary deficiency of factors VII and VIII. The propositus, a 16-year-old male, presented with recurrent gastrointestinal bleeding. He and his mother had moderate defects of factors VII and VIII. The propositus received factor VIII cover, during and after a laparatomy. The possible hereditary transmission pattern of the combined defect is discussed.

Adolescent↗
PubMed2002

Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor.

BACKGROUND: Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor pathway inhibitor (TFPI) may be deleterious. METHODS: We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen/quarterly progestin (n = 32); (iii). continuous oral estrogen/progestin (n = 21); (iv). continuous oral estrogen/intrauterine progestin (n = 22); (v). no HRT (n = 26). Blood was collected at baseline, 3, 6 and 12 months. Additional sampling was done before progestin intake in the long cycle group. RESULTS: No variations were observed in the reference group. There was a substantial decrease in TFPI concentrations in the HRT groups irrespective of the type of progestin. In women receiving long-cycle treatment, all factor VII measures increased during the unopposed estrogen periods, and the increase was reversed after progestin intake. The integrated response, AUC, for TFPI was significantly lower in the HRT groups compared with the reference group. CONCLUSION: The observed changes may increase the early thrombotic risk associated with HRT use.

Cholesterol, LDL↗
PubMed2000

Comparison of the factor VII:C clot analysis and a modified activated factor VII analysis for monitoring factor VII activity in patients treated with recombinant activated factor VII (NovoSeven).

Bleeding episodes in haemophilia A and B inhibitor patients are now frequently treated with recombinant activated factor VII (NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark). Until now, the FVII:C coagulation assay has been used to monitor NovoSeven-mediated coagulation. However, a new assay (Staclot VIIa-rTF, Diagnostica Stago, France) has been designed to specifically detect activated factor (F)VII. Replacement of the buffer supplied by the manufacturer with a PIPES buffer containing BSA (modified FVIIa assay), resulted in a linear standard curve, greater sample stability and a reduced coefficient of variation. The FVII:C assay and the modified FVIIa assay were compared in a recovery experiment using the International FVIIa standard No 89/688(IS). Recovery of FVIIa was 93-97% for the modified FVIIa assay and 91-115% for the FVII:C assay. However, because samples in the FVII:C assay were not parallel to the standard curve, confidence limits for recovery were as wide as 67-130% compared with 92-106% for the FVIIa assay. In conclusion, a modified version of the Staclot VIIa-rTF assay, suitable for monitoring treatment with NovoSeven, even at low concentrations, has been developed. It provides an alternative to the FVII:C assay, which is not suitable for monitoring FVIIa at low concentrations.

Biological Assay↗
PubMed1994

Association of factor VII genotype with plasma factor VII activity and antigen levels in healthy Indian adults and interaction with triglycerides.

Plasma factor VII activity (factor VIIc) is one of the independent risk factors for coronary artery disease and is controlled by both genetic and environmental factors. Several studies in healthy Caucasian subjects have revealed an association of a common genetic polymorphism at residue 353 (Arg-->Gln) of the factor VII gene with plasma factor VIIc. We have investigated the influence of this polymorphism (factor VII Arg/Gln353) on fasting plasma factor VIIc and antigen (factor VIIag) levels and its interaction with triglyceride levels in 185 healthy Dravidian Indians of both sexes (128 men, 57 women). The frequency of Gln353 has been found to be significantly higher in Dravidian Indians (0.29; confidence interval, 0.27 to 0.30) than in Caucasians (0.10). The distribution of factor VII Arg/Gln353 genotypes was at Hardy-Weinberg equilibrium. The carriers of the Gln353 allele had significantly lower plasma factor VIIc and factor VIIag in men (P < .05). The factor VII Arg/Gln353 polymorphism explained 13% and 11% of the total variance of plasma factor VIIc and factor VIIag, respectively, in men (P < .001) and 6% and 9% in women (P > .1). The genotype-specific correlation of factor VIIc and factor VIIag with triglyceride levels was stronger in carriers of the Gln353 allele (r = .38 and .41; P < .001) than in Arg353 homozygotes (r = .09 and .27; P = .19 and .005, respectively).

Adult↗
PubMed1994

Fluorogenic assay of activated factor VII. Plasma factor VIIa levels in relation to arterial cardiovascular diseases in Japanese.

Factor VII (FVII) plays an important role in initiation of the tissue factor-induced coagulation pathway. An increase in FVII coagulant activity (FVIIc) has been proposed as an independent risk factor for coronary artery disease. However, it remains uncertain whether high FVIIc levels are due to an increase in the activation of FVII or an increase in the concentration of FVII mass. We developed a new fluorogenic assay for plasma activated FVII (FVIIa) that used soluble tissue factor. The sensitivity of this assay ranged from 0.2 to 1000 ng FVIIa per milliliter of plasma. Plasma FVIIa levels were measured in 110 healthy subjects and 93 patients with hypertension, diabetes mellitus, and/or cardiovascular disease. The mean plasma FVIIa level in healthy Japanese individuals was 2.5 ng/mL, which was lower than that in Western subjects. Gel filtration analysis showed that most of the circulating FVIIa was in a free form, and binding of FVIIa to tissue factor in plasma was not detected. Aging increased both the FVIIa level and FVII mass, whereas menopause increased mainly the FVII mass. Elderly patients with arterial cardiovascular diseases showed increases in plasma FVIIa levels and FVIIa to FVII antigen (FVII:Ag) ratios. Among the elderly, arterial cardiovascular disease was more common in a high-FVIIa than a low-FVIIa group. Plasma FVIIa levels were not correlated with serum levels of total cholesterol or triglycerides. The FVIIa level and the FVIIa-to-FVII:Ag ratio were positively correlated with fibrinogen level and negatively correlated with body mass index and serum albumin level in the elderly. In conclusion, aging, cardiovascular disease, and malnutrition increased plasma FVIIa levels. FVIIa levels were not correlated with lipid levels or hepatic synthesis, suggesting that FVIIa may be an independent risk factor for cardiovascular disease.

Adolescent↗
PubMed1996

The influence of Helicobacter pylori status on circulating levels of the coagulation factors fibrinogen, von Willebrand factor, factor VII, and factor VIII.

BACKGROUND: Helicobacter pylori (H. pylori) infection has been associated with an increased risk of developing ischemic heart disease (IHD). It has been suggested that a persisting low-grade acute phase response results from the chronic inflammation caused by H. pylori infection, which may give rise to increased circulating levels of certain coagulation factors. MATERIALS AND METHODS: One hundred three (53 male) nonconsecutive, randomly selected white subjects with symptoms of dyspepsia were recruited for study from an outpatient endoscopy clinic at Leeds General Infirmary. The presence of H. pylori was determined by histological and microbiological investigation, a rapid urease test, and a 13carbon urea breath test (13C-UBT). Fibrinogen was measured by the Clauss method, factor VIII:C (FVIII:C) and factor VII:C (FVII:C) were measured by clotting rate assays, and the von Willebrand factor (vWF) was determined by an enzyme-linked immunosorbent assay. RESULTS: No difference was found in levels of coagulation factors according to H. pylori status. Multiple regression models were used to account for the effect of covariates and H. pylori status on levels of FVII:C, FVIII:C, vWF, and fibrinogen, and again H. pylori status was not a significant determinant of levels of any of these coagulation factors. No difference occurred in full blood count, platelet count, white cell count, or plasma viscosity in individuals who were H. pylori-positive compared with those who were negative. CONCLUSIONS: H. pylori infection is not associated with increased circulating levels of fibrinogen, FVII:C, vWF.Ag, or FVIII:C or hemorrheology in this patient group.

Adult↗
PubMed2000

Unopposed estrogen increases total plasma factor VII, but not active factor VII--a short-term placebo-controlled study in healthy postmenopausal women.

Estrogen therapy may increase the risk of arterial thromboembolism, at least in the short term. In a randomized, double-blind and placebo-controlled study in 25 healthy postmenopausal women (52.5 +/- 2.8 years), we therefore examined the short-term effect of unopposed estrogen on the fasting and fat-load-stimulated plasma levels of total factor VII versus active factor VII. Plasma total factor VII was measured by use of a chromogenic assay; plasma active FVII by a recently developed method using truncated tissue factor. As compared to placebo, 8 weeks of oral 17beta-estradiol (2 mg daily) increased the mean fasting and postprandial plasma levels of total factor VII by 17 and 21% points, respectively (both P < 0.01 ), but did not affect the fasting and/or postprandial plasma levels of active factor VII (mean change both 0.05 ng/mL; P > 0.35). Furthermore, the change in the fasting level of total factor VII after therapy was not associated with the change in the fasting level of active factor VII (r = 0.27; P = 0.21). These findings argue against the idea that elevated levels of total factor VII underlie an increased risk of arterial thromboembolism in postmenopausal women using unopposed estrogen replacement.

Double-Blind Method↗
PubMed1979

Factor VII Padua 2: another factor VII abnormality with defective ox brain thromboplastin activation and a complex hereditary pattern.

A new factor VII abnormality is presented. The propositus was a 9-yr-old child who presented a mild bleeding tendency characterized by epistaxis and easy bruising. The parents were not consanguineous, but they came from the same area. The laboratory features were mild prolongation of prothrombin time and P.P. test and normal partial thromboplastin and Stypven cephalin clotting times. The Thrombotest was moderately prolonged. Factor VII was 40%-50% of normal using rabbit or human brain thromboplastin, but only 13%-24% using ox brain thromboplastin. Factor VII cross-reacting material (CRM) was about 50% of normal. The father, a paternal aunt, and a paternal cousin showed similar clinical and laboratory findings. The brother of the propositus, the mother, and other members of her family showed about 50% factor VII activity and CRM and were considered to be heterozygotes for true factor VII deficiency. Similar findings were also present in the father and in the brother of the affected cousin. The defect in the propositus seems to consist of a double heterozygosity between abnormal factor VII and heterozygous factor VII true deficiency. The factor VII abnormality appears to consist of abnormal reactivity toward ox brain tissue thromboplastins and appears to be different from previously described factor VII abnormalities. The name factor VII Paudua2 is proposed for this condition.

Adolescent↗