Active and inactive factor VII in Dubin-Johnson syndrome with factor-VII deficiency, hereditary factor-VII deficiency and on coumadin administration.
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Animals↗
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Factor VII polymorphisms associated with plasma factor VII coagulant activity levels in healthy Tunisians.
Factor VII gene polymorphisms may contribute to elevations in factor VII coagulant (FVIIc) levels that have been associated with cardiovascular risk. We therefore studied the association of two polymorphisms--R353Q polymorphism at codon 353 involving the catalytic region and the 10 base pair (bp) insertion polymorphism involving the promoter region--with FVllc levels in 176 healthy Tunisians. The variant Q allele had a frequency of 0.213 (SD 0.021) whereas the frequency of the 10 bp insert allele was 0.250 (SD 0.023). Subjects with R/R genotype had significantly higher FVllc levels than Q353 heterozygote and homozygote subjects (96.36 versus 59.52). FVIIc levels with the 10 bp insertion polymorphism were not significantly different. The Q353 allele of the factor VII gene polymorphism is associated with decreased factor VII and could be protective against cardiovascular disease.
Adolescent↗
Two common functional polymorphisms in the promoter region of the coagulation factor VII gene determining plasma factor VII activity and mass concentration.
Recent studies have provided evidence for associations between common polymorphic markers in the coagulation factor VII (FVII) gene and plasma FVII levels. Here we describe two common, nonrelated, functional polymorphisms in the promoter region of the FVII gene, a G to T substitution at position -401 and a novel G to A substitution at position -402. Both polymorphisms strongly influence the binding properties of nuclear protein(s). The rare -401T allele is associated with a reduced basal rate of transcription of the FVII gene in human hepatoblastoma cells and with reduced plasma concentrations of total FVII (VIIag) and fully activated FVII molecules (VIIa). In contrast, the rare -402A allele confers increased transcriptional activity and is associated with increased plasma FVII levels. Together, the two polymorphisms explained 18% and 28% of the variation in VIIag and VIIa, respectively, in a group of 183 healthy, middle-aged men. It is concluded that these polymorphisms are important for the regulation of the plasma levels of FVII and that they are likely to be useful genetic markers to resolve the issue of whether a causal relationship exists between FVII levels and risk of coronary heart disease.
Adult↗
Population correlates of coagulation factor VII. Importance of age, sex, and menopausal status as determinants of activated factor VII.
Factor VII coagulant activity (FVIIc) has been found to be related to cardiovascular risk factors and may be an independent predictor of coronary heart disease (CHD). Whether these associations are due to changes in FVII activation rather than FVII concentration remain unclear. Therefore, we investigated the relationships between activated factor VII (FVIIa) and CHD risk factors in healthy subjects (336 men and 348 women) aged 25 to 64 years. In addition to direct quantitation of FVIIa by use of a recombinant, truncated tissue factor, FVIIc and factor VII antigen (FVII:Ag) levels were measured by standard procedures. There were highly significant correlations between the three techniques of FVII assay (r > + .55). Plasma FVIIc and FVIIa levels increased with age in both sexes, but the rate of rise was significantly greater in women than men. At younger ages, mean values of FVIIc and FVIIa were significantly lower in women than men, whereas at older ages the reverse was observed. After adjustment for age, postmenopausal women had significantly higher mean levels of FVIIc and FVIIa than did premenopausal women. Hormone replacement therapy significantly reversed the rise in FVIIc in postmenopausal women, and a similar trend in FVIIa was also observed. Age-, sex-, and menopause-related changes in FVIIc were partly explained by a higher proportion of fully active FVII molecules, as indicated by significant differences in the FVIIa-to-FVII:Ag ratio. Oral contraceptive use was associated with high FVIIc levels, and this effect was mainly due to an increase in FVII:Ag. Levels of FVIIa were positively correlated with serum cholesterol concentrations in both sexes. There were no strong associations between FVIIa levels and other CHD risk factors, including smoking habits, alcohol consumption, blood pressure, obesity, glucose, triglycerides, and serum lipoprotein(a) concentrations. Multiple regression analysis showed independent effects of age and cholesterol levels on FVIIa in men, whereas age and menopausal status were the main predictors of FVIIa in women. Our results show that FVII activation is associated with CHD risk factors. These findings are consistent with a possible role for FVII in the pathogenesis of CHD. Furthermore, our data suggest that the dramatic rise in CHD incidence in postmenopausal women as well as the cardioprotective effect of estrogen may be mediated through FVII and blood coagulation.
Adult↗
Factor VII and activated-factor-VII content of prothrombin complex concentrates. The PCC Study Group.
BACKGROUND AND OBJECTIVES: The aim of this study was to determine the potencies of factor VII (FVII) and of activated FVII (FVIIa) in prothrombin complex concentrates (PCC). MATERIALS AND METHODS: We examined 56 lots of PCC from 5 manufacturers. Three brands were licensed preparations, and 1 product series had been involved in thromboembolic complications. FVII and FVIIa were measured using a two-stage amidolytic assay and a specific clotting assay, respectively. We also quantified FVII clotting activity by a one-stage assay reflecting a mixture of FVII zymogen and FVIIa. RESULTS: All PCC contained substantial amounts of FVII, and FVIIa could be detected in all lots. There were marked differences between manufacturers and some significant variabilities between batches. The two lots involved in thromboembolic events contained considerably more FVIIa than the PCC still licensed. The lowest FVIIa potencies were observed in an experimental product series, indicating that PCC can be produced without activation of FVII during the manufacturing process. CONCLUSION: FVIIa is present in all PCC containing FVII. High FVIIa potencies may contribute to the thrombogenic potential of these preparations, and determination of FVIIa potencies should be included in the in vitro characterization of PCC.
Blood Coagulation Tests↗
A rare inherited coagulation disorder: combined homozygous factor VII and factor X deficiency.
The combined presence in the homozygous state of more than one recessively transmitted coagulation defect may rarely occur in countries with a high rate of consanguinity. In an Iranian family consisting of two parents (second cousins) and two affected siblings, initial phenotypic analysis led to a diagnosis of mild FX deficiency (10-19% FX activity, 42-54% FX:Ag), and genotyping revealed a new homozygous missense mutation in the corresponding gene (Ser3Cys). As both of the sibs had a severe bleeding history that was not compatible with mild deficiency of FX, further phenotypic analysis revealed the additional presence of severe FVII deficiency (<1% FVII activity; 63-111% FVII:Ag) associated with the homozygous missense gene mutation Cys310Phe. In this kindred, lack of identification of the double coagulation defect might have led not only to incomplete understanding of the clinical phenotype but also to an incorrect prenatal diagnosis.
Adult↗
The activation of human factor X in sodium citrate: the role of factor VII.
Human factor X was purified by several different procedures yielding products which had varying amounts of factor VII and factor IX. Treatment with CHCl3 during the fractionation of the factor X removed 95% of the factor VII and factor IX activity and the resulting factor X activated more slowly when incubated in 25% sodium citrate. Removal of residual factor VII by DEAE cellulose chromatography yielded a factor X which activated still more slowly and less completely. When the factor VII, removed by chromatography, was added to the chromatographed factor X, the ability to be activated in 25% sodium citrate was restored. Confirmatory evidence for the role of factor VII in this reaction was the inhibition of the conversion of the factor X by both DFP and SBTI.
Citrates↗
Activation of human factor VII by activated factors IX and X.
Factor VII clotting activity increases about five-fold when blood is clotted in glass. Prior studies suggested that this results from activation induced by activated factor IX (IXa). However, in purified systems containing phospholipid and calcium, activated factor X (Xa) is known to activate factor VII rapidly. Therefore, we studied activation of factor VII by IXa and X, in systems using purified human factors. Concentrations of IXa and Xa were calculated from total activated protein concentrations rather than from active site concentrations. In the presence of phospolipid and calcium, both IXa and Xa activated factor VII 25-fold; however, Xa was roughly 800 times more efficient than IXa. Without added phospholipid, activation of factor VII by both Xa and IXa was markedly slowed, and Xa was roughly 20 times more efficient than IXa. When both phospholipid and calcium were omitted, activation of factor VII by either enzyme was negligible. Adding normal prothrombin, but not decarboxylated prothrombin, substantially slowed activation of factor VII by both Xa and IXa. Adding thrombin-activated factor VIII and antithrombin-III did not change rates of factor VII activation by either enzyme. These results from purified systems do not provide an explanation for the prior data from plasma systems.
Blood Coagulation Tests↗
Affinity purification of human brain tissue factor utilizing factor VII bound to immobilized anti-factor VII.
An efficient procedure for affinity purification of human tissue factor apoprotein that requires binding of only microgram quantities of human factor VII to anti-factor VII agarose is described. Factor VII was added to a 2% Triton X-100 extract of acetone brain powder in the presence of calcium. The resultant factor VII/tissue factor/calcium complex was bound to anti-factor VII-agarose, and the bound tissue factor was then eluted with EDTA. The eluate was passed through anti-goat IgG-agarose to remove contaminating goat IgG that leaks from the anti-factor VII column. Yield (units of activity) was 27%; specific activity was 2400 U/mg, which corresponds to that reported by others. The purified apoprotein migrated as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with an apparent molecular weight of 47,000. Immunostaining with a goat anti-tissue factor IgG raised against the purified material yielded a major band of the same apparent molecular weight. Factor VII remains bound to the column and, therefore, for subsequent use preincubation of tissue factor with factor VII and calcium is not required. Thus, the present purification procedure markedly reduces the amount of factor VII needed as affinity ligand to purify tissue factor apoprotein.
Brain Chemistry↗
The tissue factor region that interacts with factor Xa in the activation of factor VII.
Tissue factor is the cell membrane-anchored cofactor for factor VIIa and triggers the coagulation reactions. The initial step is the conversion of factor VII to factor VIIa which, in vitro, is efficiently catalyzed by low concentrations of factor Xa. To identify the tissue factor region that interacts with the activator factor Xa during this process, we evaluated a panel of soluble tissue factor (1-219) mutants for their ability to support factor Xa-mediated activation of factor VII. The tissue factor residues identified as most important for this interaction (Tyr157, Lys159, Ser163, Gly164, Lys165, Lys166, and Tyr185) were identical to those found to be important for the interaction of substrate factor X with the tissue factor.factor VIIa complex. The residues form a continuous surface-exposed patch with an area of about 500 A(2), which appears to be located outside the tissue factor-factor VII contact zone. In agreement, the two monoclonal antibodies 5G6 and D3H44-F(ab')(2), whose epitopes overlap with this identified region, inhibited the rates of factor VII activation by 86% and 95%, respectively. These antibodies also strongly inhibited the conversion of (125)I-labeled factor VII when cell membrane-expressed, full-length tissue factor (1-263) was employed. Together the results suggest the usage of a common surface region of tissue factor in its dual role-as a cofactor for factor Xa-mediated factor VII activation and as a cofactor for factor VIIa-mediated factor X activation. The finding that factor Xa and factor X may engage in similar, if not identical, molecular interactions with tissue factor further indicates that factor Xa and factor X are similarly oriented toward their respective interaction partners in the ternary catalytic complexes.
1-Carboxyglutamic Acid↗
Elevated factor VII as a risk factor for recurrent fetal loss. Relationship to factor VII gene polymorphisms.
Haemostatic abnormalities can be detected in a portion of the women who have recurrent fetal loss. We measured factor VII coagulant activity (FVII:C) in 65 women with 3 or more fetal losses (recurrent cases), 31 women with one 2nd or 3rd trimester loss (late loss cases), and 81 women with only live births (controls). FVII:C was greater than 2 standard deviations above the mean for controls in 9 recurrent cases (13.8%) and 2 controls (2.5%) for an odds ratio of 6.35 (95% CI 1.32-30.52, p=0.012). In recurrent cases, mean levels were significantly higher than controls for FVII:C (p=0.003), FVII antigen (p=0.024), and FVIIa (p=0.001). Late loss cases had an odds ratio of 4.23 (95% CI 0.67-26.67, p=0.098) with FVII:C, FVII antigen, and FVIIa not significantly different from the controls. DNA was examined for the presence of mutations or polymorphisms in the promoter region of the FVII gene, using denaturing HPLC. Abnormal patterns were confirmed with direct sequencing. A previously reported polymorphism, -402 G>A, was found to be present in 11/14 subjects with elevated FVII:C (79%) and 43% of those with normal levels (p=0.029). FVII:C, FVII antigen and FVIIa varied significantly with genotype; however, genotype frequencies did not differ between controls and either case group. No other promoter polymorphisms were identified. This is the first report of a significant elevation of FVII in a population with recurrent fetal loss. These data suggest the need for further investigation of this potential risk factor.
Abortion, Habitual↗
Factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study.
This paper describes the relationship of factor VII coagulant activity (FVIIc), FVII Arg/Gln353 genotype and risk of myocardial infarction (MI) in the ECTIM (Etude Cas Témoin sur l'Infarctus du Myocarde) study, a multi-centre case-control study on MI. FVIIc was significantly higher in controls from all four centres: Belfast, Lille, Strasbourg and Toulouse, perhaps because elevated FVIIc may predispose to fatal rather than non-fatal MI. Major influences on FVIIc were FVII Arg/Gln353 genotype, triglyceride and cholesterol levels. There was no significant effect of genotype on MI risk however there was a non-significant trend towards increased MI risk in FVII Arg353 homozygotes. Confirming previous observations, FVIIc was highest in FVII Arg353 homozygotes, intermediate in heterozygotes and lowest in FVII Gln353 homozygotes (except Toulouse cases) these differences being highly statistically significant (except Strasbourg cases P = 0.1). In Belfast, consistent with previous findings, there was significant interaction between FVII Arg/Gln353 genotype and triglyceride level in determining FVIIc, whilst this was absent in the French centres. In conclusion, FVII Arg/Gln353 genotype strongly determines FVIIc although neither factor has a strong impact on MI risk in the ECTIM study.
Adult↗
Factor-VIIcoag kinetics in factor-VII-CRM+ and factor-VII-CRM-deficiencies.
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Blood Coagulation↗
Low risk of viral infection after administration of vapor-heated factor VII concentrate or factor IX complex in first-time recipients of blood components. International Factor Safety Study Group.
BACKGROUND: Vapor-heated human factor VII concentrate and human factor IX complex are both obtained from prothrombin complex, undergo similar methods of manufacture, and are subjected to an identical two-step vapor-heating process for virus inactivation. STUDY DESIGN AND METHODS: Intermediate-purity vapor-heated human factor VII concentrate and vapor-heated human factor IX complex were monitored for safety with regard to viral infection in the context of an International Factor Safety Study, a prospective study that follows the revised recommendations from the International Congress of Thrombosis and Hemostasis (ICTH). Because the rarity of the respective hereditary deficiencies would have made separate analyses unrealizable, the results were combined for the final analysis. Entry required that patients have no history of transfusion with any blood derivative. After the first infusion of the study drug, patients were monitored for 6 months for the development of non-A, non-B hepatitis (NANBH) and infection with hepatitis B virus (HBV) and for 15 months for infection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). An event was defined as a positive result on any test for any infection. An alanine aminotransferase level more than 2.5 times the upper limit of normal on two consecutive occasions was defined as an event for NANBH. HBV infection was monitored with tests for three different HBV markers: the HBV surface antigen, antibody against the HBV surface antigen, and antibody against HBV core antigen. HCV and HIV infection were monitored with tests for HCV and HIV antibodies. RESULTS: The 25 patients who completed the study (1 has not completed the study and 1 dropped out) received a total of 434 infusions comprising 17 different production lots of the concentrates. Twenty patients were analyzable for NANBH and 25 for HCV and HIV infection. Since most patients had been given HBV vaccination, only 4 patients were analyzable for this end point. None of the patients showed evidence of having developed an event. These data satisfy ICTH criteria when the products are considered together, but vapor-heated factor VII concentrate does not qualify alone because there were only five patients in this group. CONCLUSION: Vapor-heated factor VII concentrate and vapor-heated factor IX complex are associated with a low risk of viral infection. Preliminary results are also presented, indicating that the concentrates are safe with regard to inhibitor development.
Adult↗
Pharmacokinetic evaluation of recombinant, activated factor VII in patients with inherited factor VII deficiency.
BACKGROUND AND OBJECTIVES: Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleedings occurring in hemophiliacs with inhibitors. Very few reports exist on the use of rFVIIa in patients with inherited FVII deficiency. Pharmacokinetic studies on rFVIIa have been performed exclusively in hemophiliacs, patients with cirrhosis or volunteers pretreated with acenocoumarol. The aim of this study was to evaluate the kinetics of rFVIIa in patients naturally deficient of FVII. DESIGN AND METHODS: A single dose kinetic study with rFVIIa was performed in 5 patients affected by severe congenital deficiency of factor VII in order to evaluate the true kinetic parameters of rFVIIa without the interference of FVII. Two dosages, 15 and 30 microg/kg, were used in a crossover schedule. FVII:C and FVIIa concentration/time curves were analyzed by a model-independent method. Antithrombin (AT), prothombin fragment 1+2 (F1+2) and tissue factor pathway inhibitor (TFPI) were assayed. RESULTS: No differences emerged between the dosages with respect to dose-independent parameters [total body clearance (CL), volume of distribution area (VdArea), mean residence time (MRT)]. No significant changes of AT, TFPI, and F1+2 were observed. Comparing the results with those of other studies performed in adult hemophiliacs, in patients affected by cirrhosis or in volunteers on oral anticoagulant therapy (OAT), CL and VdArea of rFVIIa were definitely higher and in vivo recovery was lower. INTERPRETATION AND CONCLUSIONS: These findings suggest that the kinetics of rFVIIa are not dose-dependent. In the absence of FVII, the changes of VdArea and CL may be in agreement with a mechanism of competition between FVII and rFVIIa for tissue factor binding.
Adult↗
Association of beta-fibrinogen and factor VII polymorphism with plasma fibrinogen and factor VII levels, and no association of PAI-1 polymorphism with plasma PAI-1 levels in hemodialysis patients.
AIMS: Recent studies have stressed the roles of genetic factors on the plasma levels of hemostatic markers and on cardiovascular complications. We investigated the association of DNA polymorphisms for beta-fibrinogen, factor VII, and PAI-1 with plasma levels of these factors and with ischemic heart disease (IHD) and cerebral infarction (CI) in patients undergoing hemodialysis (HD). METHODS: beta-fibrinogen G/A-455, factor VII R353Q and PAI-1 4G/5G polymorphisms were determined by PCR-RFLP in 149 HD patients and in 100 controls. The plasma levels of fibrinogen, factor VII and PAI-1 were also measured. RESULTS: The allele frequencies and the genotype frequencies of these 3 polymorphisms were not different between HD patients and controls. In HD patients, plasma fibrinogen levels were significantly lower in the GG genotype than in the GA genotype, and plasma factor VII activity was significantly higher in the RR genotype than in the RQ genotype. Multiple regression analysis disclosed that CRP and beta-fibrinogen polymorphism were the significant determinants of fibrinogen levels. Plasma PAI-1 levels were not different among the 3 genotypes. The frequency of the A-455 allele was significantly higher in HD patients with CI than in those without CI, and the genotype distribution for beta-fibrinogen differed significantly between the 2 groups. Between the same 2 groups, however, significant differences were found neither in the frequency of the 353Q or 4G allele nor in the genotype distribution for factor VII and PAI-1. No significant differences in the frequency of the G-455, 353Q or 4G alleles, or in the genotype distribution for beta-fibrinogen, factor VII and PAI-1 were observed between patients with IHD and those without IHD. Multiple logistic regression analysis demonstrated that neither polymorphism was associated with CI or IHD. CONCLUSIONS: In HD patients, beta-fibrinogen and factor VII polymorphisms affected plasma levels of fibrinogen and factor VII, respectively. Beta-fibrinogen polymorphism was not an independent but a possible risk factor for CI in HD patients. Further study will be needed to confirm the precise role of 5-fibrinogen polymorphisms in the pathogenesis of CI in HD patients.
Adult↗
Characterization and comparison of immune-depleted and hereditary factor-VII-deficient plasmas as substrate plasmas for factor VII assays.
The functional activity of coagulation factors usually is determined using bioassays dependent on substrate plasmas deficient in the factor being measured. These are obtained most often from patients with hereditary deficiency and are frequently poorly characterized. The authors characterized seven commercially available hereditary Factor-VII-deficient substrate plasmas in terms of Factor VII activity and antigen level, and then compared them with a Factor-VII-deficient plasma prepared by immunoadsorption. All of the hereditary Factor-VII-deficient plasmas contained significant quantities of Factor VII antigen (120-217 ng/mL; normal, 250-600 ng/mL). One of the commercial substrate plasmas showed significant factor VII coagulant activity with a human thromboplastin. The sensitivity of the Factor VII assay system was dependent on both the source of Factor-VII-deficient plasma and the origin of the thromboplastins; human thromboplastin was more sensitive than rabbit thromboplastin, and immune-depleted plasma gave the most sensitive assay with each thromboplastin. These results indicate that immunoadsorbed plasma may be a superior reagent for coagulation factor assays.
Blood Coagulation Tests↗
Considerations on combined factor VII and factor VIII defect.
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Factor VII Deficiency↗