[Application of heat-treated factor VII concentrates in a patient with congenital factor VII deficiency during labor].
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Adult↗
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Purification and properties of an abnormal blood coagulation factor IX (factor IXBm)/kinetics of its inhibition of factor X activation by factor VII and bovine tissue factor.
An abnormal blood coagulation factor IX has been isolated from the blood of a hemophilia B patient with a variant of the disease (hemophilia Bm) characterized by a normal concentration of factor IX antigen, negligible factor IX coagulant activity, and a prolonged prothrombin time with bovine tissue factor. The isolated protein (factor IXBm) had the same apparent molecular weight as normal factor IX (55,000) and the same mobility on two dimensional immunoelectrophoresis as normal factor IX. Factor IXBm underwent limited proteolysis induced by activated factor XI, in the presence of Ca2+ ions, or induced by the reaction product of tissue factor, factor VII and Ca2+ ions. A timecourse study showed that activated factor XI cleaved factor IXBm and factor IX at similar rates. However, in contrast to normal factor IX, the limited protelysis of factor IXBm did not generate procoagulant activity. In kinetic experiments purified factor IXBm behaved like a competitive inhibitor (Ki of 0.017 muM) of the activation of factor X by bovine tissue factor and factor VII. Normal factor IX was also found to inhibit the reaction but required a four-fold higher concentration to activate the same inhibitory effects as factor IXBm.
Animals↗
Prophylactic treatment of a small child with severe factor VII deficiency using repeat dosing from a single vial of recombinant activated factor VII.
We report our experience with a small child with severe factor VII deficiency and a history of frequent and spontaneous life-threatening hemorrhage. The patient has received several years of successful prophylactic treatment with an every 3-day infusion program in which she receives recombinant activated factor VII (rVIIa) using multiple doses from a single reconstituted vial over a 72-hr period. Comparison is made to prophylactic treatment in this same patient using plasma-derived factor VII (PDVII) using a prothrombin complex concentrate (PCC).
Blood Coagulation Factors↗
Homozygous 2bp deletion in the human factor VII gene: a non-lethal mutation that is associated with a complete absence of circulating factor VII.
We report the case of a 5-year-old boy with severe factor VII deficiency. The affected child presented at the age of 8 months and again at 18 months with bleeding from the gastrointestinal tract but the diagnosis of factor VII deficiency was not made until the age of 3 years. He was treated with fresh frozen plasma and subsequently factor VII concentrates and to date remains well. To identify the causative mutation, the factor VII gene was screened by SSCP and direct sequence analysis. A single homozygous 2 bp deletion (-CT) mutation was identified in exon 1a removing nucleotides 27/28 (codons 52/53). Both parents, who were first cousins, were heterozygous for the mutation. The mutation located in the prepropeptide of factor VII, results in a complete absence of factor VII in plasma. This case indicates that a complete absence of plasma factor VII is not necessarily a lethal condition.
Child, Preschool↗
Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors.
Recent prospective investigations have reported that higher plasma fibrinogen concentrations and higher factor VII coagulant activity are associated with greater risk of cardiovascular disease. To discover what characteristics may influence fibrinogen and factor VII, we analyzed data from the Atherosclerosis Risk in Communities Study obtained from over 12,000 men and women, aged 45-64 years, from four communities in December 1986 to June 1989. Fibrinogen was higher in blacks than whites and in women than men; in general, it increased with age, smoking, body size, diabetes, fasting serum insulin, LDL cholesterol, lipoprotein(a), leukocyte count, and menopause, and it decreased with ethanol intake, physical activity, HDL cholesterol, and female hormone use. Factor VII was higher in women than men and, in women, increased with age; in both sexes, it increased with body size, triglycerides, LDL cholesterol, and HDL cholesterol, and it decreased with ethanol intake. These findings indicate that elevations in fibrinogen and factor VII may be modifiable through appropriate lifestyle changes.
Body Constitution↗
Dietary oleic and palmitic acids and postprandial factor VII in middle-aged men heterozygous and homozygous for factor VII R353Q polymorphism.
BACKGROUND: The R353Q genotype is a major determinant of factor VII coagulant (FVIIc) activity, which is associated with an increased risk of ischemic heart disease (IHD) and elevated plasma triacylglycerol concentrations. OBJECTIVE: The objectives were to 1) compare the effects of meals rich in palmitate or oleate with those of a meal low in fat on FVIIc in subjects with moderately elevated plasma nonfasting triacylglycerol concentrations and 2) determine whether the postprandial increase in FVIIc induced by dietary oleate differs in carriers of the Q allele. DESIGN: Fifty-two men aged >52 y with nonfasting plasma triacylglycerol concentrations between 2 and 5.5 mmol/L were randomly assigned to receive isoenergetic (5.1 MJ) meals providing 50 g high-oleate or high-palmitate oils or a low-fat meal providing 15 g high-oleate oil. In a second study, 17 men aged >52 y who were heterozygous for factor VII R353Q polymorphism were age-matched with subjects homozygous for the R allele and their responses to a 50-g, high-oleate meal were measured. RESULTS: FVIIc decreased by 11% after the low-fat meal. FVIIc increased by 9% and FVIIa (the activated form of FVII) increased by 55% after the high-oleate meal, whereas FVIIc did not change but FVIIa increased by 25% after the high-palmitate meal. Fasting FVIIc and FVIIa concentrations were 24% and 48% lower, respectively, in men with the RQ genotype than in men with the RR genotype but increased postprandially in both groups with no evidence of a genotype interaction. CONCLUSIONS: A high-fat meal rich in oleate increases FVIIa, whereas a low-fat meal does not, in men at high risk of IHD, independent of R353Q genotype.
Dietary Fats↗
Incomplete gamma carboxylation of human coagulation factor VII: differential effects on tissue factor binding and enzymatic activity.
The integrity of the gamma-carboxylic glutamic acid (GLA) residues of coagulation factor VII are thought to be essential for both the interaction of factor VII with its cell-surface lipoprotein receptor tissue factor and for the activated protein to manifest its serine protease activity. During the course of transiently expressing recombinant human factor VII in monkey COS cells it was noted that the factor VII synthesized in the absence of added vitamin K had <20% of expected procoagulant activity yet retained 65% of its binding activity to recombinant human tissue factor. Similar results were obtained when vitamin K was omitted from human 293 cell cultures permanently expressing recombinant factor VII. In contrast, both transient and permanent expression of factor VII in human 293 cell cultures containing physiological concentrations of vitamin K resulted in the synthesis of fully functional factor VII. Furthermore, factor VII in plasma samples from 24 patients undergoing warfarin therapy bound quantitatively to tissue factor whereas factor VII procoagulant activity averaged 65% of normal. Thus, data from both in vitro and in vivo situations indicated that factor VII molecules with suboptimal GLA content retained most of their ability to bind tissue factor but exhibited reduced procoagulant activity.
Cell Line↗
[Congenital factor VII deficiency; family investigation and physiological studies on factor VII].
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Factor VII↗
Alteration of factor VII activity by activated Fletcher factor (a plasma kallikrein): a potential link between the intrinsic and extrinsic blood-clotting systems.
Although surface contact is known to accelerate the one-stage prothrombin time of human plasma through the participation of Hageman factor (factor XII) and factor VII, it has not been clear whether Hageman factor interacts with factor VII directly or indirectly. Recently, Gjønnaess reported experiments suggesting that plasma kallikrein was an intermediate between Hageman factor and factor VII. The present study was undertaken to elucidate the interaction of plasma kallikrein and factor VII. Incubation of Fletcher-trait plasma (deficient in a plasma prekallikrein) with kaolin at 0 degrees C. did not induce shortening of the Thrombotest time or enhancement of factor VII activity, in contrast to studies of normal plasma. Monospecific rabbit antiserum against plasma kallikrein blocked the shortening of the Thrombotest time of normal plasma brought about by kaolin. Purified Hageman factor fragments (prekallikrein activator) induced an increase in factor VII activity in normal or Hageman-trait plasma, but not in Fletcher-trait plasma. A purified plasma kallikrein preparation enhanced factor VII activity in all plasmas, including that of Fletcher-trait plasma. The effect of the kallikrein preparation was blocked by soybean trypsin inhibitor, Trasylol, or rabbit antiserum against kallikrein, but not by lima bean trypsin inhibitor or antiserum against Hageman factor. The activity of partially purified factor VII was enhanced by purified kallikrein in the presence, but not in the absence of factor VII-deficient plasma. These results further support the idea that the enhancement of factor VII activity by surface contact is via Hageman factor and plasma kallikrein, suggesting a possible link between the intrinsic and extrinsic pathway of blood clotting. The significance of this phenomenon in hemostasis in vivo remains to be elucidated.
Animals↗
Factor VII inhibitor.
Factor VII inhibitor activity was identified in a 66 year old man with probable bronchogenic carcinoma. Initial studies indicated a normal partial thromboplastin time (PTT) and a prothrombin time (PT) prolongation which increased with incubation. PT correction failed to occur with 50 per cent normal plasma in vitro and 2 U of fresh frozen plasma in vivo, indicating inhibitor activity. Specific factor assay levels fell within normal limits except for a factor VII level of 30 per cent. Subsequent evaluation with antiglobulin studies suggested an inhibitor of immunoglobulin G [IgG] origin.
Aged↗
Molecular characterisation and three-dimensional structural analysis of mutations in 21 unrelated families with inherited factor VII deficiency.
Factor VII (FVII) is a four-domain glycoprotein that plays a critical role in the initiation of blood coagulation. Hereditary deficiencies of this plasma protein results in a bleeding diathesis that varies in severity amongst affected patients. We have analysed the FVII gene in 27 patients with FVII deficiency from 21 unrelated families predominantly of Middle-Eastern extraction. A total of 19 different mutations were identified, of which 12 were novel and 7 had been previously reported. Nine of the 12 novel mutations were missense mutations located in the Gla domain (Ser23Pro), the second epidermal growth factor domain (Cys135Arg) and the catalytic serine protease domain (Arg247Cys, Arg277Cys, Ser282Arg, Pro303Thr, Ser363Ile, Trp364Cys, Trp364Phe), of which five are homozygous. Three novel splice mutations were identified in intron 1a (IVS1a+5), intron 2 (IVS2+1) and intron 6 (IVS6+1). Of the seven previously reported mutations, five were missense mutations of which three are homozygous (Gln100Arg, Arg152Gln, Arg304Gln, Cys310Phe and Thr359Met), one was a 17 bp deletion (10585del117bp) and one was a splice site mutation within intron 7 (IVS7+7). This study has significantly extended the current database of FVII mutations, including the number of known homozygous mutations. Conformational analyses of crystal structures for FVIIa and the FVIIa-tissue factor complex provided likely explanations for the effect of the missense mutations on FVIIa secretion or function. In particular, since 23 missense mutations were located to the serine protease domain, mostly to the region between the catalytic triad and the contact surface with tissue factor, this showed that the orientation of the serine protease domain relative to bound tissue factor in the complex is crucial for functional activity.
Adolescent↗
Molecular analysis of the genotype-phenotype relationship in factor VII deficiency.
Factor VII (FVII) deficiency is a rare haemorrhagic condition, normally inherited as an autosomal recessive trait, in which clinical presentation is highly variable and correlates poorly with laboratory phenotype. The FVII (F7) gene was sequenced in 48 unrelated individuals with FVII deficiency, yielding a total of 23 novel lesions including 15 missense mutations, 2 micro-deletions, 5 splice junction mutations and a single base-pair substitution in the 5' untranslated region. Family studies were performed in order to distinguish the contributions of individual mutant F7 alleles to the clinical and laboratory phenotypes. Specific missense mutations were evaluated by molecular modelling in the context of the FVIIa-tissue factor crystal structure. Single base-pair substitutions in splice sites and the 5' untranslated region were studied by in vitro splicing assay and luciferase reporter gene assay, respectively. All probands were also typed for four previously reported F7 polymorphisms. In the majority of cases of FVII deficiency studied here, consideration of both mutational and polymorphism data permitted the derivation of plausible explanations for the FVII activity and antigen levels measured in the laboratory. Inter-familial variation in FVII activity and the antigen levels of heterozygous relatives of probands was found to be significantly higher than intra-familial variation, consistent with the view that the nature of the F7 gene lesion(s) segregating in a given family is a prime determinant of laboratory phenotype. Although no relationship could be discerned between laboratory phenotype and polymorphism genotype, the frequencies of the A2 and M2 polymorphic alleles were significantly higher in the FVII-deficient individuals tested than in controls. This suggests that the presence of these alleles may have served to increase the likelihood of pathological F7 gene lesions coming to clinical attention.
5' Untranslated Regions↗
The significance of published polymorphisms in 14 cases of mild factor VII deficiency.
Factor VII (FVII) plays a critical role in the initiation of blood coagulation, and patients with dysfunctional or reduced levels of this protein are susceptible to mucosal bleeding. There is poor correlation between the clinical presentation and the phenotypic data; and in cases of a mild bleeding tendency, mild to moderate reductions in both FVII antigen and activity may be overlooked. The prevalence of FVII deficiency may therefore be underestimated. Polymorphic differences throughout the FVII gene are associated with variations in plasma FVII antigen and activity levels. This study highlights the significance of mild FVII deficiency, and examines the importance of seven previously published polymorphisms in such patients.
Adolescent↗
Coupled amidolytic assay for factor VII: its use with a clotting assay to determine the activity state of factor VII.
A coupled amidolytic assay for factor VII (VII) has been developed that when used with a clotting assay for VII enables detection of activated VII. In the assay, VII in a test material determines generation of factor Xa in a mixture of purified factor X, tissue factor, and calcium; factor Xa is measured with a chromogenic substrate. Factor VII activity in the coupled amidolytic assay (VIIam) correlated well with VII activity in a one-stage clotting assay (VIIc) in 57 healthy subjects, 5 patients with hereditary VII deficiency, and 11 patients with liver disease. Activation of plasma VII by kaolin, clotting, or cold strikingly increased VIIc but not VIIam levels. Thus the ratio VIIc/VIIam (VII activity ratio) is a measure of VII activation. In 27 warfarin-treated patients the mean VII activity ratio was significantly decreased, reflecting a greater decline in VIIc than in VIIam. This probably stems from partially carboxylated VII being able to act during the 3-min incubation of the amidolytic assay but unable to act rapidly enough to affect the clotting assay. Measurement of VIIc/VIIam should enable evaluation of the activity state of VII in thrombotic disorders and in components for transfusion therapy.
Blood Preservation↗
Efficacy and safety of continuous infusion of factor VII concentrate in a factor VII-deficient patient at high risk for arterial thrombosis.
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Angina Pectoris↗
STUDIES ON PROCONVERTIN (FACTOR VII). VII. FURTHER STUDIES ON THE BIOSYNTHESIS OF FACTOR VII IN RAT CELL SUSPENSIONS.
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Adenosine Triphosphate↗
Activation of human factor VII in the initiation of tissue factor-dependent coagulation.
We have used activation peptide release assays to compare factor VII and activated factor VII (VIIa) activation of factor X, normal factor IX (IXN), and a variant factor IX (IXBmLE), which, after activation, is unable to back-activate factor VII. In purified systems, factor VII and VIIa each rapidly activated factor X, but after a one minute lag for factor VII. VIIa also readily activated both IXN and IXBmLE. Factor VII initially failed to activate substantial amounts of either IXN or IXBmLE; on further incubation factor VII activated IXN but not IXBmLE. Activation of IXN began when approximately 10% of factor VII had been converted to VIIa, as measured by 125I-factor VII radioactivity profiles. Adding factor VII to VIIa slowed its activation of IXBmLE. However, in the presence of factor X, factor VII alone rapidly activated IXBmLE. Unlike purified systems, 1 nmol/L VIIa added to factor VII-deficient plasma failed to activate factor IX. Increasing factor VII to 10 nmol/L (plasma concentration) either as native VII or VIIa yielded similar activation curves for factor IX and similar activation curves for factor X. Adding 5% VIIa to factor X-deficient plasma and to factor XII-deficient plasma substantially shortened the dilute tissue factor clotting time of only the former. These data support the hypothesis that factor VII/tissue factor complex initiates tissue factor-dependent clotting through a minimal generation of Xa. This Xa then rapidly back-activates a small amount of factor VII, following which the rates of activation of both factors IX and X increase dramatically.
Blood Coagulation↗
Factor IX variants of hemophilia B. The effect of activated factor XI and the reaction product of factor VII and tissue factor on the abnormal factor IX molecules.
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Animals↗