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PubMed2000

Two novel factor VII gene mutations in a Chinese family with factor VII deficiency.

We report two novel factor VII (FVII) gene mutations in a Chinese family with FVII deficiency. The proband, a 55-year-old woman. was incidentally found to have right shoulder arthritis consistent with chronic haemophilic arthropathy. FVII studies showed a FVII activity of 0.02 iu/ml and a FVII antigen of 49%. Molecular analysis showed a double heterozygous state, with an exon 4 nonsense mutation (C6003-->A; Cys61-->Term) and an exon 8 missense mutation (T10902-->G; Cys329-->Gly) that disrupted a Cys310/Cys329 disulphide bond. The genotypes and phenotypes were correlated in the patient's daughters. Two daughters were heterozygous for the Cys61-->Term mutation and showed a type 1 FVII gene mutation phenotype consistent with a nonsense mutation. One daughter was heterozygous for the Csy329-->Gly mutation and showed a type 2 mutation phenotype consistent with a missense mutation. These are the first reported FVII gene mutations in the Chinese people.

China↗
PubMed1997

Congenital factor VII deficiency presenting as delayed bleeding following dental extraction. A review of the role of factor VII in coagulation.

Recent updated models of the coagulation mechanism suggest that factor VII/thromboplastin complex is the main initiator or trigger of coagulation. Factor VII activation of factor IX is likely to be an important activation pathway. Inhibition of factor VII by tissue factor pathway inhibitor may have a regulatory role in the initiation of coagulation. Defining factor VII's interactions in coagulation physiology may lead to answers for some clinical problems in both hemostasis and thrombosis. We describe a 15-year-old Chinese boy with factor VII deficiency and a factor VII level of 0.08 U/ml. His symptoms were recurrent epistaxis and moderate delayed bleeding post-dental extraction. Such specific symptoms have been reported previously in a study of 40 European patients. It is one diagnosis to consider if a patients main symptom is significant post-dental bleeding. It is possible that there is requirement for higher levels of factor VII at these anatomical sites making them the common sites for symptoms in patients with moderate deficiency. Case reports of rare clotting factor deficiencies will illustrate what may be important in vitro functions of clotting proteins. Therefore reporting should be encouraged, especially during review and reconsideration of models of the coagulation mechanism.

Adolescent↗
PubMed2001

Liver transplantation for factor VII deficiency.

Factor VII deficiency is a serious, potentially lethal disorder of blood coagulation caused by a defect in hepatic factor VII synthesis. We report two children, sisters, both with severe, recurrent hemorrhagic complications from factor VII deficiency, successfully treated with orthotopic liver transplantation. Postoperatively, they remain symptom free with normal coagulation profiles.

Child↗
PubMed1998

Severe factor VII deficiency due to a mutation disrupting an Sp1 binding site in the factor VII promoter.

We have identified a point mutation in the promoter of the factor VII gene responsible for a severe bleeding disorder in a patient from a large French-Canadian family with known consanguinity. The proband has an extremely low plasma level of factor VII antigen and factor VII coagulant activity (<1 percent of normal) and suffers from hemarthroses and chronic arthropathy. Sequencing of the patient's factor VII 5' flanking region, intron/exon junctions, and coding regions showed a homozygous point mutation, a C to G transversion at position -94 relative to the translation start site. We show here that this mutation prevented binding of transcription factor Sp1 and of other nuclear proteins to this region of the factor VII promoter and resulted in a 20-fold reduction in reporter gene expression in HepG2 cells. These data underscore the importance of this region of the factor VII promoter for in vivo expression of the factor VII gene.

Adult↗
PubMed1998

Factor VII coagulant activity (VIIc) and hypercoagulability in chronic renal disease and dialysis: relationship with dyslipidaemia, inflammation, and factor VII genotype.

BACKGROUND: Factor VII coagulant activity (VIIc) is implicated in cardiovascular disease (CVD) risk in the general population. VIIc is correlated with hyperlipidaemia and influenced by a polymorphism of the factor VII gene and could contribute to thrombotic risk in patients with renal disease. METHODS: We studied VIIc in 100 patients with chronic renal disease or on maintenance dialysis and examined its relationship with dyslipidaemia, a marker of coagulation activation prothrombin fragment F1+2 (F1+2), the acute-phase reactant and coagulation factor fibrinogen, a mediator of the inflammatory response interleukin-6 (IL6), and the factor VII R353Q polymorphism. RESULTS: VIIc (186+/-58 vs 140+/-37, % standard, P<0.0001) and F1+2 (0.51 vs 0.30 nM, median, P<0.0001) were increased in the patients with renal disease compared with the control group, consistent with a hypercoagulable state. Patients and controls heterozygous for the factor VII R353Q polymorphism, had 35% lower VIIc than homozygotes for the R353 allele, indicating that the Q353 allele could confer genetic protection from thrombotic risk. There was a significant correlation between VIIc and F1+2 (r=0.26, P<0.05), total and VLDL cholesterol, and triglycerides, but the correlation with lipids did not differ by genotype. VIIc and F1+2 also correlated with increased concentration of IL6 and fibrinogen, and inversely with albumin, suggesting that a persistent inflammatory response could contribute to a hypercoagulable state, possibly via cytokine induced activation of the endothelium, or by induction of monocytes to express tissue factor. Patients with CVD complications or a history of myocardial infarction did not have higher VIIc or F1+2 than those without CVD. CONCLUSIONS: VIIc was significantly increased in renal disease states and strongly influenced by a common polymorphism of the factor VII gene, but the increase in VIIc and its correlation with lipids was not genotype specific. VIIc correlated with evidence of increased coagulation activation and persistence of an inflammatory response. A persistent inflammatory response and the dyslipidaemia of renal disease may contribute to coagulation activation and increased cardiovascular risk. Prospective studies are required to evaluate increased VIIc as a thrombotic risk factor in chronic renal disease.

Adult↗
PubMed1995

The strong positive correlation between factor VII clotting activity using bovine thromboplastin and the activated factor VII level.

We compared factor VII clotting activity (FVIIc) assays using different thromboplastins to determine which is the most sensitive for activated FVII (FVIIa) or for FVII antigen (FVIIag). FVIIc levels were measured using thromboplastins derived from bovine brain (FVIIc Bov), human placenta (FVIIc Hum), and rabbit brain (FVIIc Rab). FVIIa levels were measured by fluorogenic assays using human soluble tissue factor (rsTF) or bovine rsTF. We also measured FVII activity by an amidolytic assay (FVIIc:am Hum) using human thromboplastin and a chromogenic substrate for thrombin. FVIIag levels were determined by ELISA. In the FVIIa assay, the reaction time obtained from using bovine rsTF was shorter than that with human rsTF, suggesting that the interaction of plasma FVIIa with bovine rsTF was stronger than with human rsTF. The plasma FVIIa levels measured using human rsTF and bovine rsTF were almost the same (r = 0.947, p < 0.0001). Among the three FVIIc assays, FVIIc Bov had the strongest positive correlation with the plasma FVIIa level (r = 0.886, p < 0.0001), but had no correlation with FVIIag. An increase of 1 ng/ml in the plasma FVIIa level yielded a 27.9% increase of FVIIc Bov. Plasma FVIIc Hum and FVIIc:am Hum showed moderate correlations with both FVIIa (r = 0.520, p < 0.02 and r = 0.569, p < 0.01, respectively) and FVIIag (r = 0.438, p < 0.05 and r = 0.468, p < 0.05, respectively). FVIIc Rab had the lowest correlation with FVIIa (r = 0.367, p < 0.1), but had a moderate correlation with FVIIag (r = 0.436, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Factor VII deficiency and its treatment in delivery with recombinant factor VII.

The authors present two cases of pregnant women with coagulation disorders--one with inherited deficiency of factor VII and the second with chronic hepatitis. Both cases were successfully treated with recombinant activated factor VII of coagulation (NovoSeven) in delivery. The advantages of using this product are discussed.

Adult↗
PubMed2001

Novel mutations in the Factor VII gene of Taiwanese Factor VII-deficient patients.

The genetic defects of four Taiwanese patients with factor VII (FVII) deficiency were studied. FVII activity and antigen levels were < 1 u/dl and 125.7 u/dl (patient I), < 1 u/dl and < 1 u/dl (patient II), 3.4 u/dl and 5.9 u/dl (patient III), and 1.2 u/dl and 30.4 u/dl (patient IV) respectively. The 5' flanking region, and all exons and junctions were amplified using polymerase chain reaction and sequenced. Patient I was homozygous for a 10824C-->A transversion with Pro303-->Thr mutation in exon 8. In patient II, a heterozygous transversion, 9007+1G-->T at the IVS6, a heterozygous decanucleotide insertion polymorphism at -323 (both mutations present in his father) and a heterozygous deletion, del TC (26-27) in exon 1A (originating from his mother) were identified. Patient III had a homozygous 10961T-->G transversion with His348-->Gln mutation in exon 8. Patient IV had a heterozygous 10902T-->G transversion with Cys329-->Gly mutation in exon 8 (transmitted to her second son) and a heterozygous decanucleotide insertion polymorphism at -323 (transmitted to her third son). All but one of the FVII gene mutations detected in the four patients have not been previously reported. In conclusion, four novel mutations of the FVII gene in Taiwanese, including two missense mutations in exon 8, one point mutation at the exon 6 splice site and one deletion in exon 1A, were identified.

Adolescent↗
PubMed1998

Exclusion of the first EGF domain of factor VII by a splice site mutation causes lethal factor VII deficiency.

We have studied a family with homozygous lethal, blood coagulation factor VII (FVII) deficiency. To identify the mutation responsible for the deficiency, exons 2 to 8 and the intron-exon junctions of their FVII genes were amplified from peripheral white blood cell DNA by polymerase chain reaction and screened by single-strand conformational polymorphism analysis. The fragment showing aberrant mobility was cloned and sequenced. We detected a single point mutation, a homozygous G to A substitution at nucleotide position 6070, in the invariant GT dinucleotide at the 5' splice site of intron 4. Homozygosity was confirmed by loss of a site for the restriction endonuclease Mlu I. Analysis of the splicing pattern of ectopic transcripts in lymphocytes in the parents revealed that this mutation is associated with skipping of exon 4, which produces an mRNA encoding FVII with an in-frame deletion of the first epidermal growth factor-like domain (EGF 1). Transient transfection of COS-7 cells with an expression vector containing the triangle upEGF 1 FVII cDNA shows that this mutant protein is not expressed. The identification of the molecular basis of the FVII deficiency in this family allowed mutation-specific prenatal diagnosis to be performed in a subsequent pregnancy. In this family complete FVII deficiency is associated with a severe bleeding diathesis but no developmental abnormalities, lending weight to the hypothesis that fetal FVII is not required for the putative angiogenic functions of tissue factor in humans.

Animals↗
PubMed2002

Residual factor VII activity and different hemorrhagic phenotypes in CRM(+) factor VII deficiencies (Gly331Ser and Gly283Ser).

Two cross-reacting material-positive (CRM(+)) factor VII (FVII) mutations, associated with similar reductions in coagulant activity (2.5%) but with mild to asymptomatic (Gly331Ser, c184 [in chymotrypsin numbering]) or severe (Gly283Ser, c140) hemorrhagic phenotypes, were investigated. The affected glycines belong to structurally conserved regions in the c184 through c193 and c140s activation domain loops, respectively. The natural mutants 331Ser-FVII and 283Ser-FVII were expressed, and in addition 331Ala-FVII and 283Ala-FVII were expressed because 3 functional serine-proteases bear alanine at these positions. The 331Ser-FVII, present in several asymptomatic subjects, showed detectable factor Xa generation activity in patient plasma (0.7% +/- 0.2%) and in reconstituted system with the recombinant molecules (2.7% +/- 1.1%). The reduced activity of recombinant 283Ala-FVII (7.2% +/- 2.2%) indicates that the full function of FVII requires glycine at this position, and the undetectable activity of 283Ser-FVII suggests that the oxydrile group of Ser283 participates in causing severe CRM(+) deficiency. Furthermore, in a plasma system with limiting thromboplastin concentration, 283Ser-FVII inhibited wild-type FVIIa activity in a dose-dependent manner.

Adult↗
PubMed2000

Continuous infusion of recombinant activated factor VII during caesarean section delivery in a patient with congenital factor VII deficiency.

Recombinant activated factor VII (rFVIIa) can be used as an alternative therapy in patients with FVII deficiency. However, as the drug has a very short half-life, continuous infusion could be a meaningful administration modality. We report the case of a 30-year-old woman with moderate FVII deficiency and human immunodeficiency virus infection who underwent a caesarean section delivery. She was treated with a continuous infusion of rFVIIa and did not suffer any bleeding complication. The continuous infusion of rFVIIa was a safe and effective therapeutic approach for our patient, maintaining her levels of FVII:C and avoiding bleeding during caesarean section and afterwards.

Adult↗
PubMed1994

Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration.

Ischemic heart disease is caused by a combination of and interaction between a number of genetic and environmental factors. In a study of a group of healthy men from the United Kingdom, such an interaction was identified between the levels of plasma triglycerides and genetic variation determining plasma levels of factor VII, a clotting factor that is associated with risk of ischemic heart disease. We previously reported a common genetic polymorphism of the factor VII gene that changes arginine at residue 353 to a glutamine (Arg353-->Gln) and showed that healthy men who carry the allele for Gln353 had lower plasma levels of factor VII coagulant activity. This association is strongly confirmed in a new sample. Compared with 301 men with the allele for Arg353, 63 men with one or two alleles for Gln353 had levels of factor VII coagulant activity that were 20% lower (97.8% [95% confidence interval (CI), 95.2% to 100.4%] and 78.2% [CI, 73.8% to 82.9%], respectively; P < .0001), with similar genotype-associated differences observed for levels of factor VII antigen. The 6 men who were homozygous for the Gln353 allele had mean levels of factor VII coagulant activity and antigen that were lower by 40% and 50%, respectively. In an assay using bovine thromboplastin, which is specific for the cleaved (activated) form of factor VII, they had levels lower by 60%, suggesting that the major effect of the Gln353 substitution is to reduce the proportion of the circulating zymogen that is activated.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed2002

Effects of coagulation Factor VII polymorphisms on the coronary artery disease in Japanese: Factor VII polymorphism and coronary disease.

We investigated the relationships among Factor VII coagulant activity (FVIIc), genetic polymorphisms of Factor VII (FVII) and coronary artery disease (CAD) in 380 unrelated Japanese individuals (mean 64 years) who underwent coronary angiography and whose cholesterol levels were within normal range. CAD subjects were defined as those in whom one of the three major coronary arteries showed >50% narrowing after nitroglycerin administration. FVIIc was measured and the following polymorphisms of FVII were determined: R353Q polymorphism (M1, M2 alleles), -323 0/10 bp polymorphism (0, 10 alleles), hypervariable region 4 of intron 7 (HVR4; H5, H6, H7 alleles). FVIIc was slightly lower in M1M2/M2M2 than M1M1 (89.5+/-8.9%, 93.4+/-17.8%). Those with M2 and/or 10 allele have less chance of developing CAD (M2: OR 0.36, 95% CI 0.18-0.69, 10: OR 0.50, 95% CI 0.26-0.97). However, both alleles did not associate with myocardial infarction (MI). HVR4 was unrelated with CAD, nor with MI. In conclusion, M2 and/or 10 allele has protective effects on the developing CAD in individuals with a normal cholesterol level.

Aged↗
PubMed2000

Influence of fatty acid chain length and cis/trans isomerization on postprandial lipemia and factor VII in healthy subjects (postprandial lipids and factor VII).

Exaggerated postprandial lipemia is believed to be atherogenic and to influence risk of thrombosis. The postprandial effects on plasma triacylglycerol concentration, factor VII coagulant activity (FVII(c)) and activated FVII concentration (FVII(a)) of five high fat meals (5.2 MJ, 90 g fat) enriched with medium triacylglycerols (MCT, 8:0+10:0), palmitate(16:0), stearate (18:0), elaidate(18:1 trans) and oleate(18:1 cis) were compared with those following a low fat meal (5.2 MJ,10 g fat) in 16 healthy subjects using a randomized crossover design. Postprandial lipemia measured as the area under the curve (AUC arbitrary units) for plasma triacylglycerol concentration (mean+/-SE) was greater following the oleate (5.8+/-1. 05), elaidate (4.3+/-0.79) and palmitate (4.1+/-0.64) meals compared with stearate (2.0+/-0.45) and MCT (1.1+/-0.47) meals. Fatty acid analyses of the chylomicron lipids suggested that approximately one fifth of the dietary stearate was not absorbed. FVII(c) increased following the oleate, elaidate and palmitate meals and fell following the low fat meal; the increase in FVII(c) was correlated with the AUC for plasma TAG (r=0.34; P=0.001). FVII(a) concentration increased following all high fat meals but not following the low fat meal. The increase in FVII(a) at 7 h was greater after the oleate meal than after the stearate and MCT meals. These results do not support the hypothesis that dietary stearate and elaidate are responsible for the postprandial increases in FVII associated with high fat intakes.

Adolescent↗
PubMed1976

Biological control of factor VII.

The tissue factor pathway is initiated by factor VII in the presence of tissue factor. The first proteolytic reaction involves cleavage of factor X by factor VII. Activated factor X, the product of this reaction, can activate factor VII by cleavage of a specific bond. The apparent coagulant activity of factor VII then rises about 60-fold. Activated factor X can also inactivate factor VII by catalyzing the cleavage of a second bond which results in a three chain molecule. Fragments of Hageman factor and perhaps kallikrein can also activate factor VII. Hageman factor, however, does not catalyze the inactivating cleavage of factor VII at a significant rate. Recent data showing that the tissue factor pathway can activate the intrinsic system are discussed. We have shown that activated factor X, which can be generated by the tissue factor pathway, can feed back and activate factor IX in a calcium and phospholipid requiring reaction.

Binding Sites↗