Elevated Levels of Factor VII Activity in the Postprandial State: Effect of the Factor VII Arg-GIn Polymorphism

1994 ◽  
Vol 72 (05) ◽  
pp. 734-739 ◽  
Author(s):  
Angela Silveira ◽  
Fiona Green ◽  
Fredrik Karpe ◽  
Margareta Blombäck ◽  
Steve Humphries ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Plasma Lipoproteins ◽  
Factor Vii ◽  
Percentage Increase ◽  
Fat Intake ◽  
Postprandial Lipaemia ◽  
Coagulation Factor Vii ◽  
Postprandial State ◽  
Activated Factor Vii ◽  
Before And After

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

scholarly journals Postprandial factor VII metabolism: the effect of the R353Q and 10 bp polymorphisms

2000 ◽  
Vol 83 (5) ◽  
pp. 467-472 ◽  
Author(s):  
Helen M. Roche ◽  
Irene L. Black ◽  
Enda Noone ◽  
Anne-Marie Tully ◽  
Alexander S. Whitehead ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Factor Vii ◽  
Strong Linkage Disequilibrium ◽  
Base Pairs ◽  
Postprandial Lipaemia ◽  
Strong Linkage ◽  
Coagulation Factor Vii ◽  
Activated Factor Vii ◽  
Increased Risk ◽  
Plasma Triacylglycerol

Elevated levels of coagulation factor VII activity (FVIIc) are associated with increased risk of CHD. FVIIc is strongly determined by two polymorphisms (R353Q and 0/10 base pairs (bp)) and plasma triacylglycerol (TAG) concentrations. The Q and 10 bp polymorphisms show strong linkage disequilibrium and have been associated with lower levels of fasting FVII, but there has been little investigation of the effect of these genotypes on the postprandial FVII metabolism. The present study demonstrated that fasting activated factor VII (FVIIa) and factor VII antigen (FVIIag) levels were significantly lower in the heterozygotes carrying the Q and 10 bp alleles (n12), than in the R/0 bp homozygotes (n12) (43·0 (SE 4·8)v. 23·9 (SE 6·5) mU/ml and 85·7 (SE 5·4)v. 71·6 (SE 7·5) % respectively). During postprandial lipaemia there was a significant increase in FVIIa in R/0 bp homozygotes but not in the heterozygotes carrying the Q and 10 bp alleles. The proportion of FVIIa (FVIIa : FVIIag) increased in the homozygotes but not in the heterozygotes (2·04 (SE 0·35)v. 1·20 (SE 0·26) respectively). Therefore possession of the relatively common Q and 10 bp alleles is not associated with postprandial activation of FVII, which may in turn have a protective effect against CHD.

scholarly journals Gene-based FVIIa prophylaxis modulates the spontaneous bleeding phenotype of hemophilia A rats

2019 ◽  
Vol 3 (3) ◽  
pp. 301-311 ◽  
Author(s):  
Shannon M. Zintner ◽  
Juliana C. Small ◽  
Giulia Pavani ◽  
Lynn Dankner ◽  
Oscar A. Marcos-Contreras ◽  
...  
Keyword(s):  
Statistical Power ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Spontaneous Bleeding ◽  
Coagulation Factor Vii ◽  
On Demand ◽  
Activated Factor Vii

Abstract A sizable proportion of hemophilia inhibitor patients fails immune tolerance induction and requires bypass agents for long-term bleed management. Recombinant human-activated coagulation Factor VII (rhFVIIa) is an on-demand bypass hemostatic agent for bleeds in hemophilia inhibitor patients. Prophylactic use of rhFVIIa may enable sustained hemostatic management of inhibitor patients, but the critical relationship of rhFVIIa circulating levels and clinical outcome in that setting remains unclear. To address this in vivo, we used the rat hemophilia A (HA) model that exhibits spontaneous bleeds and allows longitudinal studies with sufficient statistical power. We simulated activated Factor VII (FVIIa) prophylaxis by adeno-associated virus (AAV) gene transfer of a rat FVIIa transgene. Compared with naive HA animals, rat FVIIa continuous expression affected the overall observed bleeds, which were resolved with on-demand administration of recombinant rat FVIIa. Specifically, although 91% of naive animals exhibited bleeds, this was reduced to 83% and 33% in animals expressing less than 708 ng/mL (<14 nM) and at least 708 ng/mL (≥14 nM) rat FVIIa, respectively. No bleeds occurred in animals expressing higher than 1250 ng/mL (>25 nM). Rat FVIIa expression of at least 708 ng/mL was also sufficient to normalize the blood loss after a tail vein injury. Continuous, AAV-mediated rat FVIIa transgene expression had no apparent adverse effects in the hemostatic system of HA rats. This work establishes for the first time a dose dependency and threshold of circulating FVIIa antigen levels for reduction or complete elimination of bleeds in a setting of FVIIa-based HA prophylaxis.

The In Vitro Analysis of the Coagulation Mechanism of Activated Factor VII Using Thrombelastogram

2002 ◽  
Vol 88 (11) ◽  
pp. 768-772 ◽  
Author(s):  
Chiharu Kawaguchi ◽  
Yae Hanesaka ◽  
Akira Yoshioka ◽  
Yukihiro Takahashi
Keyword(s):  
Platelet Rich Plasma ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Factor V ◽  
Coagulation Factor Vii ◽  
Activated Factor Vii ◽  
Coagulation Mechanism ◽  
Vitro Analysis ◽  
Hemostatic Effects

SummaryWe investigated the effects of addition of recombinant activated coagulation factor VII (rFVIIa) to coagulation factor-deficient plasma and whole blood, using thrombelastograms (TEGs). The addition of rFVIIa to factor II-or X-deficient plasma did not correct hemostatic parameters, whereas it produced partial responses in factor V-, VIII-or IX-deficient plasma and good responses in factor VII-, XI-or XII-deficient plasma. Furthermore, the addition of rFVIIa and platelets (30-100 X 103/µl) to platelet-poor plasma produced marked corrections, producing TEGs similar to those of platelet-rich plasma. These results indicate that factors II and X are essential for the hemostatic effects of rFVIIa, and that factors V and VIII promote these effects. We believe that TEGs are, at present, one of the most useful tools for evaluating in vitro hemostatic effects of rFVIIa.

Different effects of oral contraceptives containing levonorgestrel or desogestrel on plasma lipoproteins and coagulation factor VII

2002 ◽  
Vol 186 (1) ◽  
pp. 44-48 ◽  
Author(s):  
Marianne van Rooijen ◽  
Bo von Schoultz ◽  
Angela Silveira ◽  
Anders Hamsten ◽  
Katarina Bremme
Keyword(s):  
Oral Contraceptives ◽  
Coagulation Factor ◽  
Plasma Lipoproteins ◽  
Factor Vii ◽  
Coagulation Factor Vii

Coagulation factor VII variants resistant to inhibitory antibodies

2014 ◽  
Vol 112 (11) ◽  
pp. 972-980 ◽  
Author(s):  
Caroline Pfeiffer ◽  
Angelika Batorova ◽  
Muriel Giansily-Blaizot ◽  
Jean Schved ◽  
Guglielmo Mariani ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Factor Vii ◽  
Carboxyl Terminus ◽  
Recombinant Activated Factor Vii ◽  
Coagulation Factor Vii ◽  
Initiation Phase ◽  
Activated Factor Vii ◽  
Structural Differences ◽  
Inhibitory Antibodies ◽  
Maximal Binding

SummaryReplacement therapy is currently used to prevent and treat bleeding episodes in coagulation factor deficiencies. However, structural differences between the endogenous and therapeutic proteins might increase the risk for immune complications. This study was aimed at identifying factor (F)VII variants resistant to inhibitory antibodies developed after treatment with recombinant activated factor VII (rFVIIa) in a FVII-deficient patient homozygous for the p.A354V-p.P464Hfs mutation, which predicts trace levels of an elongated FVII variant in plasma. We performed fluorescent bead-based binding, ELISA-based competition as well as fluorogenic functional (activated FX and thrombin generation) assays in plasma and with recombinant proteins. We found that antibodies displayed higher affinity for the active than for the zymogen FVII (half-maximal binding at 0.54 ± 0.04 and 0.78 ± 0.07 BU/ml, respectively), and inhibited the coagulation initiation phase with a second-order kinetics. Isotypic analysis showed a polyclonal response with a large predominance of IgG1. We hypothesised that structural differences in the carboxyl-terminus between the inherited FVII and the therapeutic molecules contributed to the immune response. Intriguingly, a naturally-occurring, poorly secreted and 5-residue truncated FVII (FVII-462X) escaped inhibition. Among a series of truncated rFVII molecules, we identified a well-secreted and catalytically competent variant (rFVII-464X) with reduced binding to antibodies (half-maximal binding at 0.198 ± 0.003 BU/ml) as compared to the rFVII-wt (0.032 ± 0.002 BU/ml), which led to a 40-time reduced inhibition in activated FX generation assays. Taken together our results provide a paradigmatic example of mutation-related inhibitory antibodies, strongly support the FVII carboxyl-terminus as their main target and identify inhibitor-resistant FVII variants.

Coagulation Factor VII in Middle-aged Women with and without Coronary Heart Disease

2001 ◽  
Vol 85 (05) ◽  
pp. 787-792 ◽  
Author(s):  
Angela Silveira ◽  
Kristina Orth-Gomér ◽  
Anders Hamsten ◽  
Karin Schenck-Gustafsson ◽  
Margita Eriksson-Berg
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Plasma Concentrations ◽  
Coagulation Factor ◽  
Epidemiological Studies ◽  
Factor Vii ◽  
Community Based ◽  
Coagulation Factor Vii ◽  
Activated Factor Vii ◽  
Control Study

SummaryEpidemiological studies of coagulation factor VII as a risk factor for coronary heart disease (CHD), mainly conducted in men, have shown discrepant results. We examined the associations of coagulation factor VII antigen (VIIag) and activated factor VII (VIIa) with manifest CHD in a community-based case-control study of women aged ≤65 years. Mean plasma concentrations of VIIag and VIIa in patients and controls were 443 ± 108 and 418 ± 89 ng/L (p <0.01) and 5.26 ± 2.21 and 4.90 ± 1.65 ng/L (NS), respectively. The odds ratio (OR) for CHD for the highest versus the lowest quartile of VIIag was 1.75 (95% CI, 1.05 to 2.92). The adjusted OR was 0.76 (95% CI, 0.28-1.98) after controlling for other cardiovascular risk factors. The corresponding ORs for VIIa were non-significant. In conclusion, the plasma concentration of VIIa was not significantly increased in a large group of women with precocious CHD, and VIIag levels, although elevated, were not independently associated with manifest disease.

Inhibition of Activated Coagulation Factor VII by Normal Human Plasma

1982 ◽  
Vol 48 (03) ◽  
pp. 253-256 ◽  
Author(s):  
P E Dahl ◽  
U Abildgaard ◽  
M L Larsen ◽  
L Tjensvoll
Keyword(s):  
Gel Filtration ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Test System ◽  
Factor Vii ◽  
Coagulation Factor Vii ◽  
Activated Factor Vii ◽  
Normal Plasma ◽  
Total Inhibition ◽  
Blocking Antibodies

SummaryAn amidolytic assay system with tissue thromboplastin (Tpl), purified coagulation factors VII and X, and the chromogenic substrate S-2222 was developed. Antithrombin III (AT) accounts for about one third of the total inhibition exerted by normal plasma in this test system. This effect of AT was prevented by adding purified AT blocking antibodies. Normal plasma and serum showed approximately similar inhibitory effects. The inhibition was probably directed against activated factor VII (F VIIa). Gel filtration of adsorbed normal plasma on Ultrogel AcA 34 showed three inhibitory peaks which were different from AT.

scholarly journals An engineered human albumin enhances half-life and transmucosal delivery when fused to protein-based biologics

2020 ◽  
Vol 12 (565) ◽  
pp. eabb0580
Author(s):  
Malin Bern ◽  
Jeannette Nilsen ◽  
Mattia Ferrarese ◽  
Kine M. K. Sand ◽  
Torleif T. Gjølberg ◽  
...  
Keyword(s):  
Half Life ◽  
Coagulation Factor ◽  
Human Albumin ◽  
Factor Vii ◽  
Coagulation Factor Vii ◽  
Activated Factor Vii ◽  
Extended Plasma ◽  
Albumin Variant ◽  
Transcellular Delivery ◽  
Plasma Half Life

Needle-free uptake across mucosal barriers is a preferred route for delivery of biologics, but the efficiency of unassisted transmucosal transport is poor. To make administration and therapy efficient and convenient, strategies for the delivery of biologics must enhance both transcellular delivery and plasma half-life. We found that human albumin was transcytosed efficiently across polarized human epithelial cells by a mechanism that depends on the neonatal Fc receptor (FcRn). FcRn also transported immunoglobulin G, but twofold less than albumin. We therefore designed a human albumin variant, E505Q/T527M/K573P (QMP), with improved FcRn binding, resulting in enhanced transcellular transport upon intranasal delivery and extended plasma half-life of albumin in transgenic mice expressing human FcRn. When QMP was fused to recombinant activated coagulation factor VII, the half-life of the fusion molecule increased 3.6-fold compared with the wild-type human albumin fusion, without compromising the therapeutic properties of activated factor VII. Our findings highlight QMP as a suitable carrier of protein-based biologics that may enhance plasma half-life and delivery across mucosal barriers.

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