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PubMedDate not supplied

Fatal intracranial hemorrhage in a newborn with factor VII deficiency.

Factor VII deficiency is a rare congenital coagulopathy. Prolonged prothrombin time with normal partial thromboplastin time indicates factor VII deficiency. For the definitive diagnosis, the specific factor VII level should be investigated. We report a seven-day-old, male, full-term newborn who was admitted with the diagnosis of sepsis. Hematological tests revealed prolonged prothrombin time and a factor VII level of five percent. After antibiotic therapy and fresh frozen plasma replacement his clinical status improved but the prothrombin time continued to be prolonged. On the 14th day, just before the end of antibiotic therapy, the infant died of sudden intracerebral hemorrhage. In this article, the clinical features and management of factor VII deficiency are discussed.

Cerebral Hemorrhage↗
PubMed1986

The activity state of factor VII in plasma: two pathways for the cold promoted activation of factor VII.

The apparent amount of factor VII as determined in a one-stage test depends on the type of thromboplastin used: bovine thromboplastin only reacts with human factor VIIa whereas human thromboplastin interacts with unactivated human factor VII as well. Therefore the ratio factor VII activity as measured with bovine thromboplastin divided by the factor VII activity as assessed with human thromboplastin reflects the state of activation of factor VII in plasma. This approach was used to study the process of cold promoted factor VII activation and the involvement of different clotting factors therein. It could be shown that cold promoted activation does not occur in the absence of factors II and XII and is reduced for about 50% in factor IX deficient plasma. The other coagulation factors have a minor influence on the process. The results indicate that the cold promoted factor VII activation is the result of activation by both activated contact products and thrombin.

Adult↗
PubMed1994

Surface plasmon resonance studies of the interaction between factor VII and tissue factor. Demonstration of defective tissue factor binding in a variant FVII molecule (FVII-R79Q).

The blood coagulation cascade is initiated when vessel injury allows factor VII (FVII) to form a complex with tissue factor (TF). Complete deficiency of FVII causes a lethal bleeding diathesis, but individuals with moderately reduced FVII levels are often asymptomatic. Some of these individuals have circulating partially functional FVII, as a result of point missense mutations in critical parts of the molecule. One such mutation has been reported at position 79 in the first epidermal growth factor-like (EGF) domain of FVII, where an arginine residue has been replaced by glutamine. There is controversy as to whether or not this mutation reduces the affinity of the FVII/TF interaction compared to wild-type FVII. To address this problem, we have expressed recombinant FVII-R79Q and subjected it to detailed biochemical analysis. One-stage FVII:C assays show the variant FVII to have reduced activity with respect to the wild type. Rates of autoactivation and activation by FXa to the two-chain molecule were identical for wild-type and variant FVII. The Vmax for FX activation was lower for the mutant as measured using an amidolytic assay for FX activity. In contrast, the Km for FX was lower for the variant than the wild-type molecule. Peptidyl substrate hydrolysis was virtually identical for both variant and normal FVIIa in the presence and absence of TF. The variant has reduced affinity for TF as measured by surface plasmon resonance. FVII-R79Q has an association rate constant (kassoc) one-fifth of that of normal FVII, but a similar kdiss, resulting in a decrease in the affinity of the enzyme for its cofactor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in the factor VII promoter.

Although small deletions, splice site abnormalities, missense, and nonsense mutations have been identified in patients with factor VII deficiency, there have been no reports of mutations in the factor VII promoter. We investigated a girl with factor VII levels that were less than 1% of normal in association with a severe bleeding diathesis. The patient is homozygous for a T to G transversion that occurs 61 bp before the translation start site. This nucleotide is in a sequence that is an hepatocyte nuclear factor 4 (HNF-4) binding site within the factor VII promoter (ACTTTG AE-->ACGTTG). Using gel mobility shift assays, we show that the mutation disrupts the binding of HNF-4 to its cognate binding site. In growth hormone reporter gene assays, the activity of a plasmid containing the mutant promoter was 6.7% of the wild-type promoter plasmid. Although HNF-4 was able to transactivate the wild-type factor VII promoter 5.4-fold in HeLa cells, no transactivation could be shown with the mutant promoter. These findings indicate that HNF-4 exerts a major positive regulatory effect on factor VII expression and provides in vivo evidence that binding of this transcription factor is critical for normal factor VII expression.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2005

Lack of bleeding in patients with severe factor VII deficiency.

Factor VII deficiency, although rare, is now recognized as the most common autosomal recessive inherited factor deficiency. It is usually considered to be associated with bleeding only in the severely affected subject and heterozygotes (>10%) are not considered at risk. The general recommendation for surgery is to achieve a FVII level in excess of 15% (0.15 1U/mL). We present three cases of severe factor VII deficiency, each of whom appeared hemostatically competent based on clinical history. Subject 1 is a 33 year-old African-American female with a baseline FVII of <1%, who had a fractured tibia requiring open reduction with internal fixation without any FVII replacement and subsequently underwent successful laparoscopic knee surgery with a factor VII level measured at 6%. Subject 2 is a 58 year-old African-American female with a factor VII level of 9% who underwent an elective left total hip replacement without any factor replacement and had no excessive bleeding, but who sustained a pulmonary embolism postoperatively. Subject 3 is a 19-year-old African-American male with a baseline FVII of 1% with a history of active participation in football without noticeable injury and who underwent an emergent appendectomy without bleeding. These three cases represent individuals with the severe form of FVII deficiency who did not exhibit excessive bleeding when challenged with surgical procedures. The clinical history would appear the most valuable tool in predicting the likelihood of bleeding in these patients, and we suggest that the presumption that all patients with severe FVII deficiency should receive replacement therapy before surgical procedures may not be valid in all cases.

Adult↗
PubMed2000

A new mutation in the HNF4 binding region of the factor VII promoter in a patient with severe factor VII deficiency.

Investigation of the molecular basis of a severe factor VII (fVII) deficiency revealed compound heterozygosity in the fVII gene. On the paternal allele the patient had 3 structural gene abnormalities frequently associated with fVII deficiency. A new mutation, a C to T transition at position -55 relative to the translational start site, was found on the maternal allele. The study demonstrates that this mutation partially impeded binding of the transcriptional activator, hepatic nuclear factor 4, to the fVII promoter while greatly reducing reporter gene expression in hepatic cells. (Blood. 2000;96:4370-4372)

Adult↗
PubMed2003

Factor VII gene intronic mutation in a lethal factor VII deficiency: effects on splice-site selection.

In a patient with lethal factor VII (FVII) deficiency, 2 homozygous nucleotide substitutions were identified in the F7 gene: a IVS7+2T>G transversion involving the IVS7 donor splice site, followed by a mutation at nucleotide 10588 that would result in a missense variation (Arg224Gln). The mutated splice site, located within the first repeat of a minisatellite, is followed by a variable number of pseudo-sites, normally silent. To investigate the consequences of this mutation on F7 splicing, we designed normal and mutant minigenes, spanning exons 5 to 8. In cells transfected with the mutant construct, no normal splicing occurred. Only spliced transcripts including the first minisatellite repeat were observed, resulting from the activation of the most proximal wild-type pseudo-site, which would generate a truncated protein (stop codon upstream of nucleotide 10588). These findings, which suggest the existence of a mechanism selecting one single splice site among multiple cryptic sites, explain the patient's phenotype.

Animals↗
PubMed1986

Factor VII binding to tissue factor in reconstituted phospholipid vesicles: induction of cooperativity by phosphatidylserine.

The binding of factor VII and tissue factor produces a membrane-associated proteolytic complex which may be the primary biological initiator of coagulation. Homogeneous tissue factor, a glycoprotein purified from bovine brain, was reconstituted into phospholipid vesicles ranging from neutral (100% phosphatidylcholine) to highly charged (40% phosphatidylserine) with octyl glucoside. The vesicles were characterized with respect to size and tissue factor content and orientation. Employing data from protease digestion, we deduced that tissue factor is randomly oriented; thus, its effective concentration in these vesicles was half its total concentration. In all binding experiments, 1 mol of enzyme was bound per mole of available activator at saturation. This stoichiometry was not affected by the form of the enzyme employed or the phospholipid composition of the vesicles. With tissue factor incorporated into phosphatidylcholine vesicles, the Kd was 13.2 +/- 0.72 nM for factor VII and 4.54 +/- 1.37 nM for factor VIIa. Thus, the one-chain zymogen binds to the activator with only slightly less affinity than the more active two-chain enzyme. Active-site modification of factor VII and factor VIIa with diisopropyl fluorophosphate resulted in tighter binding of the derivatized molecules. Inclusion of phosphatidylserine in the vesicles altered the binding both quantitatively and qualitatively. With increasing acidic phospholipid, the concentration of enzyme required to occupy half the activator sites was decreased. In addition, positive cooperativity was observed, the degree of which depended on the vesicle charge and the form of the enzyme. An explicit two-site cooperative binding model is presented which fits these complex data. In this model, tissue factor is at least a dimer with two interacting enzyme binding sites.

Animals↗
PubMed1985

Monoclonal anti-human factor VII antibodies. Detection in plasma of a second protein antigenically and genetically related to factor VII.

Several murine monoclonal anti-human Factor VII antibodies were produced using hybridoma technology. Two noncompetitive monoclonal antibodies were used to examine by Western blotting the Factor VII cross-reactive material (CRM) in normal human plasma and three commercially available congenitally Factor VII-deficient plasmas, and to construct a facile "sandwich" immunoassay for plasma Factor VII. A second, previously undescribed, form of Factor VII CRM was detected in human plasma, which on Western blotting stained with an apparent intensity 5-8% that of Factor VII. This glycoprotein, tentatively called VII*, has a molecular weight 4,500 D less than Factor VII, lacks detectable Factor VII functional activity, does not bind to barium citrate, and is not recognized by a monoclonal antibody that recognizes Factor VII but not alpha-chymotrypsin-treated Factor VII. VII* was not proteolytically produced from Factor VII during in vitro coagulation or after infusion of human Factor VII into rabbits. As determined by Western blotting, the human hepatoma cell line, HepG2, cultured in the presence of vitamin K, secreted relatively greater levels of VII* in proportion to VII (75%) than that found in human plasma. Warfarin treatment of HepG2 cells decreased the quantity of VII secreted by 77%, whereas it only inhibited the secretion of VII* by 14%. Immunologic studies of the plasmas from a patient on chronic warfarin therapy and an individual given a short course of high dose warfarin therapy corroborated the in vitro synthetic studies obtained with HepG2 cells. The data are consistent with the production of VII* by posttranslational, proteolytic, modification of VII, that, at least in the HepG2 cells studied, occurs intracellularly. However, other mechanisms for the production of VII*, in particular, alternative RNA splicing of the transcript from a single gene, cannot be excluded.

Animals↗
PubMed2002

Perioperative pharmacokinetics of factor VII concentrate during liver surgery in a patient with congenital factor VII deficiency: an individual mathematical model.

A patient with congenital factor VII deficiency (baseline activity, 7%) underwent surgery for hepatocellular carcinoma. No literature reference was found concerning the management of this coagulation defect in patients requiring liver surgery. We report one such case, with special reference to the peri-operative management of factor VII replacement therapy and the pharmacokinetic behavior of factor VII. As a result of accidental suprahepatic vein lesion, a bleeding episode occurred. This was associated with an increase in factor VII clearance and volume of distribution values from 1.30 to 3.85 l/h, and from 6.51 to 13.2 l, respectively. After surgery, the patient continued to receive the concentrate every 8 h during the first nine post-operative days. No post-operative bleeding or thrombotic event was observed. The patient was discharged in good condition.

Aged↗
PubMed2001

Factor VII levels in patients undergoing coronary angiography: factor VII and coronary artery disease.

BACKGROUND: Factor VII (F VII) has been widely investigated as a risk factor for coronary atherosclerosis, however there is still debate about its role in the progression of coronary artery disease (CAD). In this study F VII levels were measured in patients with angiographically proven CAD and its relation with disease severity, coronary events and with other risk factors of coronary atherosclerosis were examined. METHODS: Consecutive patients referred to coronary angiography were divided in three groups: 1. CAD group--those with a significant lesion in one or more coronary arteries (n = 155), 2. High-risk group--patients with normal coronary arteries and with two or more risk factors (n = 54), 3. Controls--patients with normal coronary arteries and with no or one risk factor (n = 90). CAD group was also studied according to the number of vessels involved and to the history of coronary events. RESULTS: Mean F VII levels were not different between the three groups of patients. In CAD group, F VII increased parallel to the number of vessels involved (one vessel disease: 85 +/- 20%, two vessel disease: 92 +/- 23%, three vessel disease: 105 +/- 23%). Patients with a history of coronary events had significantly higher F VII levels than those without such a history (96 +/- 25% versus 89 +/- 22% respectively, P = 0.02). However, logistic regression analysis revealed no significant relation between F VII and either the presence of CAD or coronary events. CONCLUSIONS: F VII levels increase in patients with previous coronary events, but it is not an independent risk factor for the progression or for the severity of CAD.

Analysis of Variance↗
PubMed1993

The relationship between factor VII coagulant activity and factor XII activation induced in plasma by endogenous or exogenously added contact surface.

The contribution of various enzymes in the activation of factor VII, determined from the increase in factor VII coagulant activity (VIIc), was investigated following the exposure of citrated plasma to low temperature. The contact system of coagulation was initiated either by the contact surface present in certain plasmas (i.e. plasma from women in late pregnancy) or by micellar stearate added to plasma diluted with an equal volume of buffer (plasma from normal healthy subjects or from women in late pregnancy). With either of the contact surfaces, increase of VIIc and the concentration of enzymes derived from factor XII (XIIa) depended on the potency of the contact surface. The stearate-induced VIIc in diluted plasmas from women in late pregnancy or from normal subjects was inhibited by 60-70% in the presence of anti-factor IX monoclonal antibody. VIIc was not increased in XII-deficient plasma following the addition of stearate. The addition of purified human factor XII to this plasma restored the increase in VIIc and the activation of factor XII. In factor IX-deficient plasma, the stearate-induced increase in VIIc was only 38% of that seen in normal plasma and was restored by the addition of purified factor IX. Similarly in factor XI-deficient plasma, the stearate-induced increase in VIIc and the factor XII activation were 48% and 69% of that found in normal plasma. The addition of EDTA (2 mM) did not alter the extent of factor XII activation induced by contact surface, but it did inhibit the rise in VIIc. It is concluded that in the presence of contact surface the activation of factor XII and the sequential activation of factor XI and of factor IX results in the activation of factor VII. Activated factor IX is responsible for the major part of the factor VII activation whereas the rest may be through the direct activation by XIIa.

Antibodies, Monoclonal↗