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PubMed1997

The Arg353Gln polymorphism reduces the level of coagulation factor VII. In vivo and in vitro studies.

Factor VII levels are regulated by environmental and genetic factors. Two polymorphisms, a G-to-A transversion at nucleotide 10,976 resulting in Arg353Gln and a decanucleotide insert at position -323 in the 5'-flanking region of the factor VII gene, have been associated with a 20% to 25% reduction in plasma factor VII levels. However Arg353Gln almost always segregates on alleles containing the insert in UK and Italian populations, thereby making it impossible to independently evaluate the impact of Arg353Gln on factor VII levels in these ethnic groups. We have evaluated the influence of genotype on factor VII levels in 99 healthy Polish blood donors and observed that Arg353Gln frequently occurs in the absence of the insert. In univariate analysis, the mean levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) were significantly lower in 16 people who were heterozygous for Arg353Gln and the insert compared with 72 normal subjects who had neither Arg353Gln nor the insert (88.8% of normal and 83.1% versus 102% and 100%, P = .019 and P = .0003, respectively). In nine subjects heterozygous for Arg353Gln alone, VII:C and VII:Ag were significantly decreased compared with the normal subjects (81.9% and 83%, respectively, P = .007 and P = .004). In multivariate analysis, Arg353Gln but not the insert significantly reduced VII:C and VII:Ag after adjustment for age and plasma triglycerides (P < .05 and P = .02, respectively). To evaluate the mechanism responsible for reduced factor VII levels in individuals with Arg353Gln, we performed transient transfection assays with factor VII cDNA containing the base substitution resulting in Gln353 and wild-type factor VII cDNA in COS-1 cells. The levels of VII:Ag in the cell lysates were similar, but the amino acid substitution significantly reduced factor VII secretion into the media to 74.9% of wild-type (P = .0001). Based on these in vivo and in vitro studies, we conclude that the Arg353Gln polymorphism alone can decrease plasma factor VII levels.

Animals↗

PubMedDate not supplied

Critical bleeding in vascular surgery: expanding the indication of recombinant activated factor VII.

Recombinant activated factor VII (rFVIIa) is considered a universal hemostatic agent. We present our experience with rFVIIa in vascular surgery patients who developed major hemorrhagic complications with no obvious major vessel bleeding as an expansion of the indications of rFVIIa. Of 973 major complex vascular procedures, 18 patients with intractable bleeding were administered 40 to 80 mug/kg rFVIIa. Blood and by-products transfused, pH, coagulation profile, platelet count, and preoperative antiplatelets and anticoagulants were recorded.Twelve patients (67%) showed clinical improvement. Six remained unstable despite further hemostatic measures and died perioperatively. Thirty-three percent (n = 6) received over 20 U of blood before rFVIIa administration. All but one died within the first 24 hours (p = .0175). Seven patients had acidosis with a pH of 7.3 or less. Five of them died within 24 hours (p = .05). Six patients had a platelet count below 100,000/cm3, five of whom died perioperatively (p = .0175). Patients with an international normalized ratio above 1.2 had a better survival rate because rFVIIa was used early. There were no signs of systemic or local thrombotic events. The amount of blood and plasma transfused was significantly reduced after rFVIIa administration.rFVIIa is a safe adjunct for patients with significant hemorrhagic complications, with a low risk of thrombotic complications. We found it effective if administered early with measures to achieve hemodynamic stability and correction of acidosis.

Acidosis↗

PubMed1996

Circulating levels of factor VII, fibrinogen, and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM.

BACKGROUND: First-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) have an increased risk of coronary artery disease partly attributable to clustering of risk factors in association with insulin resistance. Circulating levels of some hemostatic factors predict coronary events, and there is growing evidence that insulin resistance is also associated with abnormalities of coagulation and fibrinolysis. This study examined the hypotheses that elevated levels of factor VII coagulant activity (FVII:C), fibrinogen, and von Willebrand factor (vWF) occur (1) in first-degree relatives of NIDDM patients and (2) in association with recognized features of insulin resistance. METHODS AND RESULTS: Fasting blood samples were taken from 132 first-degree relatives of NIDDM patients and 151 age matched control subjects for measurement of FVII:C, fibrinogen, vWF, insulin, total and HDL cholesterol, triglyceride, glucose, and HbAIC. Levels of FVII:C (130% versus 122%, P < .02) and fibrinogen (3.0 versus 2.7 g/L, P = .002) were higher in relatives than in control subjects, and there was no significant difference in levels of vWF (0.98 versus 0.95 IU/mL). There was a graded association with features of insulin resistance, which was strongest for FVII:C, weaker for fibrinogen, and weakest for vWF. CONCLUSIONS: FVII:C and fibrinogen levels are increased in relatives of patients with NIDDM. Levels of FVII:C and, to a lesser extent, fibrinogen and vWF cluster with other risk factors associated with insulin resistance. Abnormalities of circulating hemostatic factors, possibly in relation to insulin resistance, may contribute to cardiovascular risk in relatives of patients with NIDDM.

Adult↗

PubMed1992

Tissue factor-dependent autoactivation of human blood coagulation factor VII.

We recently showed that single-chain zymogen factor VII is converted to two-chain factor VIIa in an autocatalytic manner following complex formation with either cell-surface or solution-phase relipidated tissue factor apoprotein (Nakagaki, T., Foster, D. C., Berkner, K. L., and Kisiel, W. (1991) Biochemistry 30, 10819-10824). We have now performed a detailed kinetic analysis of the autoactivation of human plasma factor VII in the presence of relipidated recombinant tissue factor apoprotein and calcium. Incubation of factor VII with equimolar amounts of relipidated tissue factor apoprotein resulted in the formation of factor VIIa amidolytic activity coincident with the conversion of factor VII to factor VIIa. The time course for the generation of factor VIIa amidolytic activity in this system was sigmoidal, characterized by an initial lag phase followed by a rapid linear phase until activation was complete. The duration of the lag phase was decreased by the addition of exogenous recombinant factor VIIa. Relipidated tissue factor apoprotein was essential for factor VII autoactivation. No factor VII activation was observed following complex formation between factor VII and a recombinant soluble tissue factor apoprotein construct consisting of the aminoterminal extracellular domain in the presence or absence of phospholipids. Kinetic analyses revealed that factor VII activation in the presence of relipidated tissue factor apoprotein can be defined by a second-order reaction mechanism in which factor VII is activated by factor VIIa with an apparent second-order rate constant of 7.2 x 10(3) M-1 S-1. Benzamidine inhibited factor VII autoactivation with an apparent Ki of 1.8 mM, which is identical to the apparent Ki for the inhibition of factor VIIa amidolytic activity by this active site competitive inhibitor. Our data are consistent with a factor VII autoactivation mechanism in which trace amounts of factor VIIa rapidly activate tissue factor-bound factor VII by limited proteolysis.

Benzamidines↗

PubMed1985

Tissue factor accelerates the activation of coagulation factor VII: the role of a bifunctional coagulation cofactor.

One way in which coagulation may be initiated is via the tissue factor pathway in which a non-proteolytic enzyme activator, tissue factor, complexes with a plasma protein, factor VII. Factor VII is the zymogen of a serine protease, factor VIIa. While factor VII-tissue factor has coagulant activity, upon conversion to factor VIIa the activity increases about 120-fold. We now show that tissue factor markedly accelerates the conversion of factor VII to factor VIIa. Thus, this essential coagulation cofactor is clearly bifunctional.

Animals↗

PubMed1986

Studies on immunological assay of vitamin K dependent factors. I. Measurement of factor VII antigen by radioimmunoassay.

A radioimmunoassay (RIA) for factor VII was developed using 125I-factor VII, anti-factor VII rabbit serum and anti-rabbit IgG goat serum. The lower limit of sensitivity in normal reference plasma was 3 X 10(-3) units/ml. Although the level of factor VII antigen (VII:Ag) in normal plasma samples (n = 20) 0.944 +/- 0.176 units/ml, correlated with that of factor VII coagulant activity (r = 0.89), VII:Ag level in paired normal sera showed a higher value (1.469 +/- 0.376 units/ml). The level of antigen according to RIA of factor VIIa activated by factor Xa increased 2.5-fold compared with that of unactivated factor VII. It is suggested that the polyclonal anti-factor VII produced in a rabbit had higher affinity for factor VIIa than for factor VII. In two out of seven patients with congenital factor VII deficiency, VII:Ag was detectable (0.04, 0.31 units/ml, respectively) whereas VII:C was less than 0.01 units/ml. In 12 warfarin-treated individuals, VII:C showed a lower level (0.121 +/- 0.063 units/ml) that that of VII:Ag (0.518 +/- 0.186 units/ml). During 4 weeks observation after stopping warfarin, VII:C and VII:Ag reached normal levels in 1 week. However, VII:C did not reach equivalence with VII:Ag until 4 weeks had elapsed.

Animals↗

PubMed1995

[Activated factor VII as a new cardiovascular risk factor of atherothrombotic disease].

Factor VII (FVII) is a plasma vitamin K-dependent glycoprotein that plays an important role in the initiation of tissue factor-induced coagulation (extrinsic pathway of blood coagulation). An increase in FVII coagulant activity (FVIIc) has been proposed as an independent risk factor for coronary artery disease. Recently, the coagulation assay using soluble tissue factor(sTF) enables us to measure the plasma levels of the activated form of factor VII(FVIIa) without the effect of the FVII zymogen form. We have developed the fluorogenic assay for FVIIa using sTF and measured the plasma FVIIa in atherosclerotic diseases. The FVIIa level in the Japanese was lower than that reported in Caucasians, suggesting that the incidence of ishemic heart disease is lower in the former. The FVIIa level was higher in the patients with cardiovascular diseases (ischemic heart disease and cerebral infarction), non-insulin-dependent diabetic mellitus, hypertension with microalbuminuria, and renal failure than in the healthy controls. The FVIIa levels were also increased in non-insulin-dependent diabetic patients, and this FVIIa increase was positively correlated with urinary albumin excretion. Furthermore, FVIIa levels were not correlated with the levels of lipids and the activity of hepatic synthesis, indicating that FVIIa may be an independent risk factor for cardiovascular disease.

Biomarkers↗

PubMedDate not supplied

Acquired isolated factor VII deficiency during sepsis.

Isolated acquired factor VII deficiency is uncommon. We report 11 cases of acquired factor VII deficiency associated with severe systemic sepsis. All patients initially displayed a heterozygous-like factor VII deficiency confirmed by both clotting and amidolytic assays, associated with low factor VII antigen levels, and increased haemostasis markers (D-dimers, prothrombin fragments 1.2, thrombin-antithrombin complexes). After sepsis recovery, normal factor VII levels were evidenced. Isolated factor VII consumption or proteolytic degradation by leucocyte proteases can be evoked, but the mechanism of acquired factor VII deficiency during sepsis remains to be elucidated. The knowledge of this syndrome should avoid false diagnosis of congenital factor VII deficiency.

Adult↗

PubMed1992

Characterization of a Ca (II)-independent monoclonal antibody that lacks reactivity with Gla-domainless human factor VII.

Eight murine monoclonal antibodies to human factor VII have been produced and characterized. As tested by direct ELISA, all antibodies bound to immobilized factor VII and this interaction did not require Ca(II). On immunoblotting three antibodies reacted only with native factor VII and activated factor VII (rFVIIa), two with native factor VII, activated factor VII and with the light chain of reduced activated factor VII and three with reduced activated factor VIIa (light chain) only. When coupled to Sepharose five antibodies were capable of immunodepleting factor VII from normal plasma and inhibited coagulant activity with varied potencies. Among these antibodies, one (10C12.2) had peculiar characteristics, lacking reactivity with Gladomainless FVII and with the Ca(II)-dependent conformation. This antibody has been used to develop a two-site ELISA which appears to measure native factor VII but not poorly carboxylated, inactive forms of the molecule.

Antibodies, Monoclonal↗

PubMed1989

Factor VII half-life after transfusion of a steam-treated prothrombin complex concentrate in a patient with homozygous factor VII deficiency.

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Adult↗

PubMed2002

Experience with use of recombinant activated factor VII.

Recombinant activated factor VII (rFVIIa) has recently been introduced for improving haemostasis in haemophiliac patients developing alloantibodies (inhibitors) to factor VIII (FVIII) or factor IX (FIX). We describe the successful management of haemorrhagia with rFVIIa in five different situations: an episode of surgical bleeding in a patient with haemophilia A and non-surgical haemorrhages in four patients with haemophilia A, acquired haemophilia, congenital severe FV defect and pseudo-acquired haemophilia, respectively. In each case, rFVIIa was effective and safe. There is no doubt that rFVIIa is useful in the therapeutic management of patients with antibodies to FVIII or FIX. However, the treatment is expensive and a cost-effectiveness analysis would be useful.

Adult↗

PubMed1989

Autoactivation of human recombinant coagulation factor VII.

Single-chain human recombinant factor VII produced by transfected baby hamster kidney cells was purified to homogeneity in the presence of benzamidine. The amidolytic activity of single-chain recombinant factor VII with a peptidylnitroanilide substrate, methoxycarbonyl-D-cyclohexanylglycyl-L-arginine-p-nitroanilide, was less than 1% of that obtained with factor VIIa. Purified single-chain recombinant factor VII spontaneously activated in the absence of inhibitor. The activation reaction was enhanced by at least 2 orders of magnitude in the presence of a positively charged surface, provided either as an anion-exchange matrix or as poly(D-lysine). The progress curve for factor VIIa generation was sigmoidal. Benzamidine inhibits recombinant factor VIIa activity and factor VII activation with identical inhibition constants (Ki) of 11 mM. In contrast, benzamidine inhibition of bovine factor Xa and bovine factor IIa was observed at Ki values equal to 0.3 and 0.5 mM, respectively. Bovine factors Xa and IIa are known activators of factor VII and the most likely contaminants of our recombinant factor VII preparations. Single-chain recombinant factor VII purified from cells cultured in the absence of bovine serum activated at the same rate as factor VII from cells cultured in the presence of bovine serum. This also excluded the possibility that the activation reaction was caused by contaminating bovine proteases. On the basis of these observations, we propose that factor VII is autoactivated in vitro in the presence of a positively charged surface.

Animals↗

PubMed1996

Activation of factor VII during alimentary lipemia occurs in healthy adults and patients with congenital factor XII or factor XI deficiency, but not in patients with factor IX deficiency.

Factor VII activity (FVIIc), a risk marker for coronary heart disease, is increased during postprandial lipemia. Factor VII activation accompanies lipolysis of triglyceride-rich lipoproteins, but the nature of this association and whether it is causal remain uncertain. To explore this issue, four patients with homozygous factor XII deficiency, four with complete factor XI deficiency, six with factor IX deficiency, and their respective age- and sex-matched controls were given two isocaloric dietary regimens, one providing on average 136 g fat and the other 19 g fat. Blood was taken before breakfast, immediately before lunch at 195 minutes, and at completion of the study at 390 minutes. All samples for each subject and matched control were assayed as one batch for FVIIc, activated factor VII, and factor VII antigen (FVIIag). Activation of factor VII was observed with the high-fat regimen but not with the low-fat regimen in all controls, factor XII-deficient patients, and factor XI-deficient patients. No factor VII activation was observed during either regimen in factor IX-deficient patients, but a normal postprandial responsiveness of factor VII to dietary fat was restored in one patient who replicated the study after factor IX therapy. Plasma FVIIag was not altered postprandially in either regimen in any group of patients or controls. Factor IX apparently plays an obligatory role in the postprandial activation of factor VII, although the mechanism remains to be determined.

Adult↗

PubMed2004

Prophylactic effect of recombinant factor VIIa in factor VII deficient patients.

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder associated with a bleeding tendency. We describe three patients with congenital FVII deficiency who have been treated with activated recombinant factor VII (rVIIa). Two patients had novel mutations and were treated prophylactically with 1.2 mg rVIIa two to three times a week. Patients 1 and 2 had a severe bleeding tendency. The frequency and severity of bleeding decreased by treatment with rVIIa compared with similar treatment with plasma-derived FVII. The third patient with a moderate bleeding phenotype was treated on demand and showed no change in the frequency of bleeding upon treatment with rVIIa or plasma products. The beneficial effect of rVIIa cannot be explained by the rVIIa half-lives. Pharmacokinetical analysis showed rVIIa activity half-lives of 35, 50 and 54 min for patients 1, 2 and 3, respectively. In conclusion, prophylactic treatment of FVII deficient patients with rVIIa appears to be applicable, safe and successful, although the mechanism of action remains to be elucidated.

Child↗

PubMed1985

Activation of human factor VII during clotting in vitro.

We have studied factor VII activation by measuring the ratio of factor VII clotting to coupled amidolytic activity (VIIc/VIIam) and cleavage of 125I-factor VII. In purified systems, a low concentration of Xa or a higher concentration of IXa rapidly activated 125I-factor VII, yielding a VIIc/VIIam ratio of 25 and similar gel profiles of heavy and light chain peaks of VIIa. On further incubation, VIIa activity diminished and a third 125I-peak appeared. When normal blood containing added 125I-factor VII was clotted in a glass tube, the VIIc/VIIam ratio rose fivefold, and 20% of the 125I-factor VII was cleaved. Clotting normal plasma in an activated partial thromboplastin time (APTT) system yielded a VIIc/VIIam ratio of 25 and over 90% cleavage of 125I-factor VII. Clotting factor XII-deficient plasma preincubated with antibodies to factor X in an APTT system with added XIa yielded a VIIc/VIIam ratio of 19 and about 60% cleavage, which indicates that IXa, at a concentration achievable in plasma, can effectively activate factor VII. Clotting normal plasma with undiluted tissue factor yielded a VIIc/VIIam ratio of 15 to 20 and 60% cleavage of 125I-factor VII, whereas clotting plasma with diluted tissue factor activated factor VII only minimally. We conclude that both Xa and IXa can function as significant activators of factor VII in in vitro clotting mixtures but believe that only small amounts of factor VII may be activated in vivo during hemostasis.

Animals↗

PubMed1995

Suppression of plasma-activated factor VII levels by warfarin therapy.

To investigate the effect of warfarin treatment on the early phase of tissue factor-induced coagulation, we measured plasma-activated factor VII (factor VIIa) levels by a direct fluorogenic assay in 74 cardiovascular disease patients on long-term oral anticoagulation. We divided the patients into three groups based on the international normalized ratio (INR). In the patients with INR ranges of < 1.7 and 1.7 to 2.5, factor VIIa levels were 42% and 61% lower, respectively, than in age- and sex-matched controls. Factor VII coagulant activity (factor VIIc), factor VII antigen (factor VIIag), protein C, and factor X levels were also reduced to a similar extent in both groups. However, in patients with an INR > 2.5, the factor VIIa level was not decreased compared with that at an INR of 1.7 to 2.5, although the factor VIIc, factor VIIag, factor X, and protein C levels were all decreased further. Although the precise relation between the reduction of factor VIIa levels and the increase of INR requires appropriately designed long-term clinical trials, our data suggest that an INR range of 1.7 to 2.5 is sufficient for the suppression of factor VIIa. During the long-term follow-up of three patients with congenital antithrombin III or protein C deficiency, the factor VIIa level was more responsive to changes in the warfarin dose than the INR, and there were generally no corresponding changes of the thrombin-antithrombin III complex (TAT) level. However, one patient showed a transient marked increase of factor VIIa during the discontinuation of warfarin that was accompanied by an increase in TAT. Based on these findings, factor VIIa could be useful for monitoring both hypercoagulable and hypocoagulable states.

Adult↗

PubMed1998

Genetic influence of the R/Q353 genotype on factor VII activity is overwhelmed by environmental factors in Chinese patients with Type II (non-insulin-dependent) diabetes mellitus.

We studied the effects of genetic and environmental influences on factor VII coagulant activity (VIIc) in Chinese diabetic patients (263 with Type II [non-insulin-dependent] diabetes mellitus, 78 with Type I [insulin-dependent] diabetes mellitus) and 143 normal control subjects. VIIc was measured by a one-stage biological assay. The R/Q353 or Msp1 polymorphism at codon 353 of the factor VII gene was detected after Msp1 digestion of polymerase chain reaction-amplified genomic DNA. In both diabetic and control subjects the allele frequencies of the R (M1) and Q (M2) alleles were 0.96 and 0.04; the corresponding reported frequencies in Caucasians being 0.90 and 0.10: VIIc were 21% lower in Chinese control subjects and Type I diabetic patients with R/Q, compared with R/R subjects (p < 0.001 and p < 0.05). The corresponding difference was 4% for Type II diabetc patients (p = NS). Type II diabetic patients had higher mean VIIc levels than control subjects and Type I diabetic patients (p < 0.01); they were also older, and had higher serum creatinine and triglyceride (all p < 0.01). They also had higher VIIc levels than an age-matched older control group (p < 0.01; n = 182) in whom the genotype effect was clearly seen. On stepwise linear regression analysis, the significant independent determinants of VIIc were serum triglyceride (contributing 20% and 25% to variance in control subjects and diabetic patients), the R/Q353 genotype (contributing to 12% of the variance in control subjects but only 1% in diabetic patients), age and total cholesterol in all subjects, and in the diabetic patients female sex, urinary albumin excretion rate and serum creatinine. VIIc was higher in diabetic patients with macroangiopathy and retinopathy (both p < 0.0001). We conclude that compared with Caucasians, the Q allele frequency is significantly lower in these Chinese subjects. Plasma VIIc is determined by both genetic and environmental influences such that in Chinese Type II diabetic patients, the effect of environmental factors predominates, almost negating the influence of the R/Q353 genotype. High VIIc may contribute to the increased cardiovascular risk in Type II diabetic patients.

Adult↗

PubMed1993

Positive association between self-reported fatty food consumption and factor VII coagulant activity, a risk factor for coronary heart disease, in 4246 middle-aged men.

Raised levels of factor VII coagulant activity (VIIc) have been reported to increase the incidence of CHD. Preliminary evidence from observational and experimental studies suggests that dietary fat intake is positively associated with VIIc. We explored this further in 4,246 men aged 45-69, who were found to be free of major CHD when screened for a primary prevention trial of antithrombotic medication. All men were asked about their consumption of fatty foods and changes in consumption in the last month. In the 9% of men who reported avoidance of fatty foods in the month before interview, age adjusted VIIc was 7.8% of standard (95% CI 5.1-10.6%) lower than in the remainder. Serum cholesterol and body mass index (BMI) were also significantly lower. The extent to which fat consumed in the past month had deviated from usual intake was significantly and positively related with VIIc, serum cholesterol and BMI. Thus, the VIIc difference between those eating much less fatty food than usual and those eating much more than usual was 11% of standard, with those eating their usual amount having an intermediate level. This study adds to the evidence that dietary fat intake influences VIIc and coagulability. The effect is rapid, so that much of the benefit of dietary fat reduction on thrombogenic risk in CHD is likely to occur within a short time. Thus, the results reinforce the value of a low fat diet, even in individuals with advanced atheroma, in whom dietary intervention has sometimes been considered unlikely to be effective.

Antigens↗