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A 12-year-old previously healthy male, with a family history of protein S deficiency, presented with confusion, aphasia, and right upper extremity weakness after a 10-day febrile illness. Imaging studies revealed sinovenous thrombosis and left parietal hemorrhagic stroke. On further investigation he was found to have both protein S and factor VII deficiencies.
As yet, there have been neither systematic reviews nor reports of randomized, controlled trials involving factor VII (FVII) deficiency. Hence, a picture of this disorder can only be drawn by reviewing and summarizing the data that is available. This article provides an overview of the understanding of this rare, inherited disorder of coagulation. In particular, the status of current knowledge of the disorder's prevalence, clinical presentation, diagnostic characteristics and molecular genetics is reviewed, followed by a summary of currently available options for its treatment and management.
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.
We investigated the molecular basis for factor VII (FVII) deficiency in Israel and found that 13 patients were homozygous and 10 heterozygous for a C to T substitution at nucleotide 10648 of the FVII gene. This predicted an Ala244Val change and was associated with decreased FVII activity and antigen level. Of the 36 Ala244Val positive alleles, 20 were observed in patients of Moroccan origin, 10 in Iranian-Jewish patients and 6 in patients of other origins. A computer model of the serine protease domain of FVII suggested that the Ala244Val substitution may cause distortion of the entire protein structure. Intragenic polymorphic sites analyses disclosed a founder effect for the Moroccan and Iranian-Jewish patients. A survey of the Ala244Val mutation revealed an allele frequency of 1:42.5 in Moroccan Jews and 1:40 in Iranian Jews. As Moroccan Jews have been separated from Iranian Jews for more than two millennia, the data suggest that the Ala244Val mutation occurred in ancient times.
We have characterized the molecular defect in two families with severe factor VII (FVII) deficiency. In family I, the proband was found to be homozygous for a novel 18 bp deletion in exon 8 (g.10896-10913del) resulting in the in-frame deletion of six amino acids in the serine protease domain. Molecular modelling suggests the deletion is likely to disrupt folding of the FVII molecule. The reduced FVII antigen (21 U/dl) and negligible activity (0.4 U/dl) in the patient's plasma indicated that the deletion affected both the secretion/stability and function of the mutant protein. In family II, the proband was found to be a compound heterozygote for a novel missense mutation (g.7884G>A; FVII G117R) in exon 5 encoding the EGF2 domain of FVII and a nonsense mutation (g.8960C>T; FVII R152X) in exon 6. Extensive sequence comparison in a wide evolutionary context suggested that the Gly117 residue is critical for structure of FVII. The grossly reduced FVII antigen (1.1 U/dl) and activity (0.4 U/dl) plasma values indicate the mutation primarily affected the folding/secretion or stability of the protein.
The case of a 57-year-old woman with no personal or family history of coagulopathy or blood dyscrasia who was found to be factor VII deficient by routine laboratory testing is reported. The patient was also found to have type 2 diabetes mellitus and adenocarcinoma of the uterus in the course of her hospitalization.
OBJECTIVE: To identify the genetic defect of coagulation factor VII in a Chinese family with hereditary FVII deficiency. METHODS: Peripheral blood samples were collected from the proband of hereditary FVII deficiency, female, aged 15, 4 members of her family, and 100 healthy persons. Genomic DNA was isolated. All the exons and exon-intron boundaries of FVII gene were amplified by PCR, then the PCR products were sequenced by direct sequencing. Restrictive endonuclease analysis was performed in all of the family members and the 100 healthy donors to exclude gene polymorphism. Biostructural analysis of the mutated FVII was completed by molecular modeling. RESULTS: Double heterozygous mutations in the proband were identified: A-->G mutation at position 10833 and C-->A mutation at position 9643, resulting in Met306Val and Thr181Asn substitution respectively. Heterozygosity for Met306Val was confirmed in the proband's mother and her elder sister; heterozygosity for Thr181Asn was confirmed in the proband's father. It was found by computer simulated molecular model that the Met306Val replacement, which was located on the surface of the FVII molecule, might cause steric hindrance and change the configuration and function of FVII protein. CONCLUSION: Double heterozygous mutations for Met306Val and Thr181Asn in FVII gene have been found in a proband with hereditary FVII deficiency. The Met306Val substitution in FVII gene is a novel mutation in hereditary FVII deficiency. The heterozygous mutation of FVII gene may change the configuration of FVII protein and result in FVII dysfunction.
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Twenty-three patients with congenital factor VII (FVII) deficiency, belonging to 9 kindreds were studied. Immunological variants were classified according to the relationship between FVII coagulant activity (FVIIC) and the level of FVII antigen (FVIIAg), considering 3 previously described groups: VII-, VII+ and VIIR. Activation variants were determined by the reactivity pattern with three different thromboplastins. One patient was classified as VII-, 16 as VII+, and 6 as VIIR. Three patients belonging to the same kindred showed a Padua 2 FVII deficiency, and 1 patient showed a Padua 1 variant. There was no correlation between antigenic or activation variants and severity of bleeding tendency. Classical autosomal recessive mode of inheritance was observed in VII- and VII+ families. Nevertheless, a possible autosomal dominant trait was observed in VII+ kindreds.
During preoperative blood coagulation testing the factor VII (FVII) deficiency was found in two patients. No liver disease or cardiac insufficiency was found. No history of bleeding episodes existed. The latent (mild) deficiency of the FVII was diagnosed. The treatment with vitamin K (Vitacon) was administered in order to exclude vitamin K deficiency. The treatment showed no impact on the level of the FVII. Mixing study corrected the deficit (normal PT was found). Both patients underwent cardiac surgery with extracorporeal circulation. The epsilon-aminocapronic acid and fresh frozen plasma were used to prevent bleeding. The postoperative bleeding was compared to average of the year. No difference was found. The patients with mild FVII deficiency may safely undergo cardiac surgery with extracorporeal circulation.
Hepatocyte transplantation has been investigated in patients with liver-based metabolic disorders and acute liver failure. We report the first use of hepatocyte transplantation in two brothers with severe inherited coagulation factor VII deficiency. Patient 1 received a total of 1.09x10(9) cryopreserved hepatocytes, and patient received 2.18x10(9) fresh and cryopreserved hepatocytes through a Hickman line inserted in the inferior mesenteric vein. Infusion of isolated human hepatocytes improved the coagulation defect and markedly decreased the requirement for exogenous recombinant factor VII (rFVIIa) to approximately 20% of that before cell transplantation. In both patients, episodes of line sepsis were associated with an increase in rFVIIa requirement. Six months posthepatocyte transplantation, higher rFVIIa doses were required, suggesting loss of transplanted hepatocyte function. Because of increasing problems with venous access and long-term uncertainty of the efficacy of hepatocyte transplantation, orthotopic liver transplantation was performed successfully in both cases.
A 33 year old female with a congenital deficit in factor VII underwent four operations, all without any haemorrhage. One of then was carried out using substitutive therapy. She had a non-A non-B hepatitis one month after this treatment. Substitutive therapy depends on the assessment of the risk of haemorrhage, which can be estimated by the concentration of factor VII, the severity of spontaneous haemorrhage, the surgical history, and the planned operation. Since the risk of transmitting viruses with freeze-dried blood products would appear to be virtually nil, since 1985, fresh frozen plasma should be avoided for this type of indication. The doses of concentrated factor VII to be used lie between 20 IU.kg-1 every 4 h and 40 IU.kg-1 every 8 h. Such a dose should be administered in either one or several injections, according to whether the risk of haemorrhage is important or not. Substitutive therapy should be continued as long as the risk persists. Using a test dose of factor VII and, afterwards, measuring its biological activity can help to determine the best time for starting the treatment in order to obtain a level of factor VII greater than the minimum required for surgical haemostasis (10%).
BACKGROUND AND OBJECTIVES: Arginine 315 in factor VII (FVII) belongs to a solvent-exposed loop involved in direct interaction with the co-factor (tissue factor, TF), in transmission of TF-induced effects and potentially in FVIIa inactivation. Natural FVII variants at position 315 provide peculiar models for structure-function studies. DESIGN AND METHODS: We characterized a mild coagulation FVII deficiency associated with reduced FVII activity (26%) and antigen (67%). Mutations were searched by FVII gene sequencing. FVII variants were created by mutagenesis of FVII cDNA and characterized through expression in HEK293 cells followed by functional studies. FVII antigen in media was estimated by immunoassay while FVII activity was assessed by prothrombin-time based and FXa generation assays. FVII variants were injected into mice to investigate their recovery and half-life. One-way ANOVA was used to test statistical significance. RESULTS: The patient was double heterozygous for a novel R315W mutation and for the R304Q substitution (FVII Padua) previously demonstrated to impair TF binding. The recombinant 315W-FVII was normally expressed in medium but showed a markedly reduced coagulant function (52%) and activity towards factor X (FX) in plasma (34%). Moreover, the 315W-FVII showed significantly decreased recovery of the protein (20%) and a slightly shorter half-life (8.6 min) as compared to wt-FVII (50% and 10.7 min). We also studied the conservative R315K change that was responsible for low recovery (20%) and a decreased half-life (7 min) of a FVII variant with virtually normal FVII antigen and activity levels. INTERPRETATION AND CONCLUSIONS: These findings suggest a dual role of R315 for FVII function and clearance, and indicate that substitutions at this position have appreciable effects on human FVII biology, compatible with residual FVII function and thus with mild FVII deficiency.
We have previously reported a homozygous Cys329Gly mutation in a Chinese patient with factor VII (FVII) deficiency. Others have found a heterozygous Cys329Gly mutation in the F7 gene from patients of three different pedigrees. However, none of the reports included the expression and characterization of the mutant FVII in vitro. To investigate the effect of Cys329Gly on FVII function, we carried out transient transfections of baby hamster kidney cells (BHK-21) with a mutant FVII construct and compared the results to those obtained using a wild-type FVII construct and vector control. The results demonstrate that the level of FVII:Ag secreted into the medium by transfected BHK-21 cells with mutant construct was not affected, but the coagulation activity of the mutant FVII was undetectable. We conclude that Cys329 is critical to FVII coagulation, and the replacement of cysteine 329 by glycine leads to the loss of coagulation activity in the patients, possibly the molecular basis for FVII deficiency in the patients.
The prevalence of factor VII (FVII) deficiency in 267 Brazilian patients was estimated to be 4.1%, including one patient with significant bleeding, five with minor bleeding and five patients asymptomatic. Only one novel mutation 8926G <-- T (I140S) was seen in one patient. The other mutations were 10828G <-- A (R304Q) in three patients, 10846G <-- T (C310F) in one patient, and 10909G <-- A (G331D) in one patient. Except for one homozygous patient (C310F) with a severe deficiency, only one allele was affected in all other instances. An inverse association between F7 polymorphisms and FVII activity were found in these patients, as those with higher levels of FVII activity presented the genotype described in the literature as related to reduced FVII activity. As the R304Q mutation was the most frequent in these patients, and may be associated with an asymptomatic form of the disease, particularly in Blacks, we examined this mutation and FVII activity in 49 Blacks and 49 Caucasian blood donors with no clinical bleeding. None of the individuals showed the R304Q mutation, and FVII activity was normal in all of them, thus indicating that FVII deficiency is not common in normal individuals of these two ethnic groups in Brazil. This is the first study in South America to examine the prevalence and molecular basis of FVII deficiency, including the description of a novel mutation.
To investigate the relationship between clinical phenotype, clotting activity (FVIIc) and FVII genotype, a multi-center study of factor VII (FVII) congenital deficiency with centralized genotyping and specific functional assays was carried out. FVII mutations characterized in patients (n=313) were extremely heterogeneous (103 different, 22 novel). Clinical phenotypes ranged from asymptomatic condition, including 15 homozygotes and 14 double heterozygotes, to patients with a severe disease characterized by life-threatening and disabling symptoms (CNS, GI bleeding and hemarthrosis) strongly associated with an early age of presentation. Based on type and number of symptoms we classified 90 'severe' (median FVIIc 1.4%, IQR [Interquartile Range] 0.9-3.8), 83 'moderate' (FVIIc 3%, IQR 1-21.7), and 140 'mild' bleeders (FVIIc 14%, IQR 3-31). The significantly different FVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%), moderate (84%) and mild (56%) bleeders, further support our classification. The excess of females among moderate bleeders (female/male ratio = 2.6) is attributable to menorrhagia. There was no evidence for modulation of clinical features by frequent functional polymorphisms. Homozygotes for the same mutation (Ala294Val; 11125delC) with similar FVIIc and FXa generation levels, showed striking differences in clinical phenotypes. Our study depicts the ample clinical picture of this rare disorder, proposes a severity classification and provides arguments for the early management of the disease in the severe cases. Genotype-phenotype relationships indicate the presence of major environmental and/or extragenic components modulating expressivity of FVII deficiency.
In homocystinuria, thrombosis is frequent (50% of the cases). The authors report a case of cystathionine-synthetase deficiency-induced homocystinuria associated with thrombosis of a common iliac vein. This patient presented with a blood coagulation disorder which was related to severe factor VII deficiency and which was corrected by treatment. Homocystinuria was pyridoxine independent as witnessed by the fact that Brand's reaction remained positive with vitamin B6 therapy and cystathionine. Cystathionine-synthetase activity measured in cultured fibroblasts increased only slightly with pyridoxine therapy. Treatment (Betaine, folic acid, vitamin B 12) induced the disappearance of plasma methionine. Clinically, the patient whose treatment came late in the course of her disease, was only slightly improved. Hypotheses about etiopathogenic mechanisms of this disease are discussed. Difficulties of treatment and diet are reviewed. The relative inefficacy of therapy, even in case with early treatment, makes antenatal diagnosis preferable to neonatal diagnosis.
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