Severe hereditary deficiency of factor VII during pregnancy. Evidence for the absence of transplacental diffusion of factor VII.
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Adult↗
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Purification and properties of human coagulation factor VII.
Blood coagulation Factor VII was purified 100,000-fold from fresh frozen human plasma to apparent homogeneity with a yield of 30% based on coagulation assay. The molecular weight estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis was 48,000. Factor VII is composed of a single polypeptide chain with the NH2-terminal sequence Ala-Asn-Ala-Phe-Leu-(Gla)-(Gla)-Leu-(Arg)-Pro. It is converted to a two-chain form (Factor VIIa) connected by disulfide bonds by the action of Factor Xa, in the presence of phospholipids and calcium, and by Factor XIIa without additional cofactors. This conversion is associated with a 20- to 25-fold increase in coagulation assay activity. Factors VII and VIIa were inhibited by 15 mM diisopropyl fluorophosphate with 50% inactivation in 160 and 60 min, respectively. The presence of tissue factor and CaCl2 accelerated the inactivation by approximated 5-fold. Neither Factor VII nor VIIa were inhibited by antithrombin III in the absence of heparin. However, with the addition of heparin, Factor VIIa was inhibited at a rate approximately 25 times that of Factor VII.
Amino Acid Sequence↗
Inhibition of the tissue factor-factor VII complex: involvement of factor Xa and lipoproteins.
Inhibition of the procoagulant activity of a tissue factor-Factor VII (TF-FVII) complex by Al(OH)3-adsorbed plasma (AP) was found to require the presence of Factor Xa (FXa). Inhibitory activity seems to be generated through the interaction of FXa with a component in AP rather than with the TF-FVII complex. Quantitation of inhibitor activity was carried out using an amidolytic assay for TF-FVII activity. Incubation of AP with various antisera demonstrated that the inhibition was mainly associated with the presence of apolipoprotein B (apo B) rather than alpha 2-macroglobulin or antithrombin III. Purified lipoprotein-rich fractions prepared from AP, using density gradient ultracentrifugation, all contained some inhibitory activity. Incubation with anti-apo B greatly reduced the inhibitor in the very low density lipoprotein (VLDL)- and low density lipoprotein (LDL)-rich fractions but had essentially no effect on inhibition by the high density lipoprotein (HDL) fraction, which was rich in apo A. The inhibitory activity of AP was 60% that of normal plasma and this correlated well with the relative apo A and apo B concentrations. It is proposed that inhibition requires the interaction of FXa with plasma lipoproteins or associated components and that the product of this interaction is then able to bind to and inhibit the TF-FVII complex.
Adsorption↗
Ca2+ in the first epidermal growth factor-like domain of activated factor VII.
Activated factor VII (FVIIa) needs to be bound to tissue factor (TF) to express biological activity, and biochemical and structural data show that the first epidermal growth factor (EGF)-like domain of FVIIa contributes essential contacts with TF. To investigate the role of Ca2+ binding to this domain in FVIIa we used site-directed mutagenesis to replace Asp46 and Asp63 by Asn, which abolished Ca2+ binding, and characterized the double mutant (D46,63N-FVIIa) with respect to its TF-binding properties and the functional status of its complex with TF. D46,63N-FVIIa had a lower amidolytic activity than FVIIa at optimal Ca2+ concentrations. A slightly lower amidolytic activity was also observed in complex with soluble TF, apparently due to a lower catalytic turnover rate of D46,63N-FVIIa. However, D46,63N-FVIIa and FVIIa bound to lipidated TF were equally efficient activators of factor X. The dissociation constant for the interaction between D46,63N-FVIIa and soluble TF, derived from amidolytic activity and direct binding measurements, was approximately 20-fold higher than that for the interaction between FVIIa and soluble TF. The same difference was observed in the affinity for lipidated TF. These findings suggest that a functional Ca2+-binding site in the first EGF-like domain adds approximately 7 kJ/mol to the total binding energy of the interaction with both lipidated and soluble TF.
Amino Acid Sequence↗
Prolonged prothrombin time, Factor VII and activated FVII levels in chronic liver disease are partly dependent on Factor VII gene polymorphisms.
BACKGROUND: Prothrombin time is a benchmark for functional assessment in cirrhosis and Factor VII levels (FVII), crucial in determining the prothrombin time, are genetically determined. METHODS: We have evaluated the prothrombin time, a number of haemostatic variables synthesised by the liver (FII, FV, FVII and activated FVII, AT and fibrinogen) and two polymorphisms of the FVII gene (5'F7 and 353R/Q) in: (a) patients with liver cirrhosis (n=118), (b) patients with chronic hepatitis (n=102) and (c) controls (n=100). RESULTS: By one-way analyses of variance, the prothrombin time and the mean levels of the FII, FV, FVIIc, FVIIa, and AT were statistically different between cirrhotics, chronic hepatitis patients and controls. The allele frequency of the FVII polymorphisms did not differ between the three groups. Those rare patients (4.6%) who were homozygous for the type 2 alleles had markedly reduced FVIIc and FVIIa levels. The analysis carried out taking into account Child class versus FVII genotype showed that the mean FVIIc levels were comparable for different genotypes within each Child's class, with the exception of the patients homozygous for the type 1 allele. CONCLUSION: Our findings help to explain the not infrequent finding of a severely prolonged prothrombin time in patients who are otherwise in a good functional class.
Alleles↗
Sphingosine inhibits monocyte tissue factor-initiated coagulation by altering factor VII binding.
Tissue factor is a lipoprotein, expressed on the surface of cells, which binds coagulation Factor VII or VIIa, leading to activation of Factors X and IX with subsequent fibrin generation. Cellular tissue factor activity is important in pathophysiologic processes such as inflammation and disseminated intravascular coagulation. In this study, the long-chain base sphingosine inhibited coagulation initiated by lipopolysaccharide-stimulated intact human monocytes. Sphingosine (5-100 microM) also profoundly inhibited thromboplastin-initiated coagulation (greater than 90% decrease in thromboplastin activity). This inhibition was dose- and time-dependent. Sphingosine inhibited neither the intrinsic pathway of coagulation nor thrombin generation of fibrin. The sphingosine analogues sphingomyelin, ceramide, or N-acetylsphingosine did not affect thromboplastin activity, suggesting that the polar head of sphingosine was necessary for interaction of the molecule with the coagulation system. Investigation of the biochemical mechanism revealed that sphingosine (5-50 microM), but neither sphingomyelin nor ceramide, inhibited specific binding of radiolabeled Factor VII to lipopolysaccharide-stimulated intact monocytes. The results suggest that sphingosine may regulate monocyte tissue factor-initiated coagulation by modulating Factor VII binding to tissue factor. Sphingosine may represent a new class of inhibitors of hemostasis.
Blood Coagulation↗
The direct binding of human factor VII in plasma to recombinant human tissue factor.
The extrinsic pathway of coagulation is initiated when zymogen factor VII binds to its cell surface receptor tissue factor. Recently recombinant human tissue factor has become available and therefore in this study the direct binding of human factor VII in plasma to recombinant tissue factor was explored. Factor VII binding was quantitated by a standard ELISA protocol using monospecific polyclonal rabbit anti-human factor VII as the primary antibody and goat anti-rabbit IgG conjugated to alkaline phosphatase as the second antibody. Both the oxidation state of the recombinant tissue factor and calcium ion concentration were found to be critical for the efficient binding of factor VII. A linear relationship was observed between absorbance and factor VII concentration when normal pooled human plasma was diluted in the range 1:25 to 1:1000 (factor VII concentration 0.5-20 ng/ml). Evidence is provided to show that binding is both specific for human coagulation factor VII and can be utilized to detect factor VII molecular variants with impaired tissue factor binding.
Binding, Competitive↗
[Fibrinogen and factor VII: 2 risk factors for arterial thrombosis].
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Cardiovascular Diseases↗
Cooperative interaction between factor VII and cell surface-expressed tissue factor.
Assembly of the extrinsic pathway on cell surfaces was investigated by studying the binding and activity of factor VII on the bladder carcinoma cell line J82 which expressed 18,800 milliunits of tissue factor activity/10(6) cells. In binding studies, the association of factor VII to monolayers of cells was time-, temperature-, and calcium-dependent. The ligand binding was specific, reversible, and saturable. This interaction was inhibited by a monoclonal antibody to human brain tissue factor. Factor VII added to the cells was recovered as factor VII rather than factor VIIa when incubated in the presence of factor X neutralizing antibodies, suggesting that these cells produced factor X. Specific factor VII binding to the cell revealed a sigmoidal binding isotherm with half-maximal binding occurring at 314 +/- 145 pM to 38,300 +/- 14,300 sites/cell. Hill plots of the binding data indicated an average slope of 2.1. Binding parameters were also determined kinetically. At maximal factor VII-tissue factor complex formation the apparent Km for factor X was 274 nM, the Vmax was 4.15 nM/min, and the kcat was estimated to be 14 s-1. In the presence of excess tissue factor and factor X, increasing amounts of factor VII added to the J82 cells demonstrated a sigmoidal relationship with the rate of factor Xa formation. Hill plots indicated a slope of 2.0 at the lower factor VII concentrations which changed to 1.0 at the higher input amounts of factor VII. Hanes plots were used to determine the apparent dissociation constant of the interaction (222 +/- 85 pM). The Vmax was 5.54 +/- 1.04 nM/min for the cleavage of factor X. These data are consistent with factor VII binding to at least two sites on tissue factor (receptor) with positive cooperativity. Because at saturation the stoichiometry of the factor VII-tissue factor complex is 1:1, tissue factor must be expressed as a dimer on the surface of the J82 cells.
Antibodies, Monoclonal↗
Reduction of factor VII coagulant activity (VIIC), a risk factor for ischaemic heart disease, by fixed dose warfarin: a double blind crossover study.
An increase in factor VII coagulant activity is known to be an important risk factor for ischaemic heart disease. Four hundred and eight healthy male Post Office workers were screened in an occupational survey. Sixty eight (16.5%) of these had values of factor VII coagulant activity greater than 1.0 SD above the age related mean. A randomised double-blind crossover study was undertaken to investigate the effect of a fixed daily minidose of warfarin (1 mg) on the high activities of factor VII in these men. Forty two agreed to enter the study and 40 completed it. Their mean factor VII coagulant activity before warfarin treatment was 135.9%. Treatment with a fixed minidose of warfarin significantly reduced factor VII coagulant activity to 124.6%; there was no change on placebo. The prothrombin time was also significantly prolonged on active treatment although all the results remained within the normal range. These findings suggested a fixed minidose warfarin regime might be useful in the primary prevention of ischaemic heart disease by reducing high activities of factor VII.
Adolescent↗
Complete nucleotide sequence of the cDNA encoding rabbit coagulation factor VII.
Rabbit coagulation factor VII cDNA has been cloned and sequenced. Two rabbit liver cDNA libraries in lambda gt11 were screened using both random-primed, 32p-labelled, factor VII cDNAs and polymerase chain reaction technology. Three overlapping cDNA clones were isolated comprising a sequence of 1572 base pairs of DNA encoding an open-reading-frame of 443 amino acids. Mature circulating rabbit factor VII is predicted to contain 404 amino acids, two less than its human counterpart and three less than bovine factor VII.
Amino Acid Sequence↗
Factor VII in liver cirrhosis.
Factor VII activity and factor VII cross-reacting material (CRM) in plasma of patients with liver cirrhosis have been studied before and after vitamin K1 parenteral administration. Subjects were divided into two groups according to the absence (group I) or the presence (group II) of the following clinical findings: ascites, portal hypertension, encephalopathy. Factor VII activity and CRM show a statistically significant correlation (p less than 0.001) in all patients. In group II, significantly reduced levels of both activity and CRM were found as compared to the reference and the group I values. No variations were found after vitamin K administration. Different thromboplastins, investigated with respect to their sensitivity for factor VII, acted differently. Patients with normal albumin levels also showed normal levels of factor VII activity and antigen. No correlation was found in group II. The data discussed suggest that in liver cirrhosis with unknown aetiology no immunologically detectable precursor of factor VII is present.
Adult↗
In vivo dissociation of factor VII (AHF) activity and factor VII-related antigen in von Willebrand's disease.
Using monospecific rabbit antihuman factor VIII antiserum, we have examined the amounts of factor VIII-related antigen and compared these to the levels of factor VIII procoagulant activity in normal subjects and patients with von Willebrand's disease. We have observed that even without transfusion all nine probands with von Willebrand's disease and 20 of their 34 relatives possessed a significantly elevated factor VIII activity/factor VIII-related antigen ratio when compared to that of 55 normal subjects. It is suggested that an elevated factor VIII activity/factor VIII-related antigen ratio may be used for detection of the carriers of von Willebrand's disease.
Animals↗
Fibrinogen and factor VII as risk factors in vascular disease.
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Adult↗
Development of a subdural vein thrombosis following aggressive factor VII replacement for postnatal intracranial haemorrhage in a homozygous factor VII-deficient infant.
Congenital factor VII deficiency is a rare (1:500,000) autosomally recessive coagulopathy with variable expression and high penetration. In infants the most devastating presentation is that of intracranial haemorrhage. An infant is described with severe factor VII deficiency who developed postnatal intracranial haemorrhage. The baby was treated with factor VII concentrate (ImmunoA.G., Vienna, Austria). Three weeks after the haemorrhage he developed a dural venous sinus thrombosis. Although factor VII-deficient patients may need treatment with factor VII concentrate, this needs to be carefully monitored because of the thrombotic risk.
Cerebral Hemorrhage↗
"Off-license" use of recombinant activated factor VII.
Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleeding episodes in haemophiliac patients with inhibitors. In haemostatic circles it has also been assessed in reversing oral anticoagulant therapy. Over the last few years, it has been used "off-label" in patients with uncontrolled bleeding due to haemostatic abnormalities due to trauma and/or massive blood loss, thrombocytopenia, platelet dysfunction or liver dysfunction. This review examines the proposed mechanism of action of rFVIIa in the context of current concepts of haemostasis and its pharmacological properties. The "off-license" use of rFVIIa is reviewed. The latter are reported mainly as case reports, case series. There is an overwhelming need for randomized controlled trials to assess rFVIIa's efficacy, dosing and safety in current "off-license" use.
Blood Coagulation Disorders↗
Factor VII deficiency in beagle dog plasma and its use in the assay of human factor VII.
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Animals↗
Molecular interaction between factor VII and tissue factor.
Complex formation between serine protease factor VIIa (VIIa) and tissue factor (TF) dramatically enhances the catalytic activity of VIIa, leading to the initiation of extrinsic blood coagulation. The recently determined crystal structure of the complex formed between VIIa and the extracellular domain of TF has revealed in detail the interacting surfaces of the two molecules. Mutational and biochemical studies have further identified regions of VIIa and/or those of TF essential for the high affinity interaction. These studies indicate that the regions extending from the gamma-carboxyglutamic acid domain through the first epidermal growth factor-like domain and protease domain of VIIa are involved separately in the interaction with the distinct sites of TF. The interaction of TF with the protease domain of VIIa apparently induces a conformational transition of the VIIa active site. Studies of the chemical modification of VIIa provided a model for the mechanism of TF-mediated acceleration of VIIa activity. In this model, the protease domain of VIIa exists in equilibrium between minor active and dominant zymogen-like inactive conformational states, and preferential binding of TF to the active state leads to a shift in equilibrium into the active state, thereby accelerating VIIa activity. Overall docking of TF with VIIa in the presence of phospholipids further supports a recognition of macromolecular substrates, such as factors IX and X. Therefore, single VIIa-TF interaction contains several distinct mechanisms for enhancing the coagulant activity of VIIa, which may be important for the initiation of coagulation specifically mediated by TF. Studies of the interaction between VIIa and TF provide not only a detailed understanding of the regulated initiation of blood coagulation but also the potential to design novel anticoagulants for the treatment of thrombotic diseases.
Amino Acid Sequence↗