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We report the plain film findings as knees and elbows in two patients with congenital coagulation factor VII deficiency. The radiographic features resemble hemophilia, although the joint manifestations are milder, appear later in life, and occur in both men and women.
BACKGROUND AND OBJECTIVES: Although a large number of gene mutations have been characterized in patients with factor VII (FVII) deficiency, few naturally occurring mutations have been described in epidermal growth factor (EGF)-like domains. We investigated a 6-year old Italian girl who had low functional and antigenic FVII plasma levels. DESIGN AND METHODS: Plasma levels of FVII activity and antigen were evaluated in the propositus and her relatives. Mutation screening was performed by sequencing the FVII gene. The effect of the identified FVII mutations was investigated by protein expression in transfected cells. RESULTS: The propositus was shown to be a compound heterozygote for a known (Arg110Cys) and a novel (Asp123Tyr) missense mutation both occurring in the second EGF-like domain. In transfected cells, expression of the Arg110Cys mutation reduced the amount of intracellular and secreted FVII protein (48% and 18%, respectively). Likewise, cells transfected with the Asp123Tyr mutation gave rise to low intracellular (40%) and extracellular (4%) FVII antigen levels. In conditioned media, FVII procoagulant activity was reduced accordingly (10% and <1%, respectively). INTERPRETATION AND CONCLUSIONS: Transient expression of the identified FVII mutations caused severely reduced but detectable FVII antigen and activity levels. The present findings suggest that the two naturally occurring missense mutations identified within the second EGF-like domain severely affect FVII protein handling, impairing the correct folding of FVII.
In the plasma of beagles known to be homozygotes for hereditary blood coagulation factor-VII deficiency, antibody neutralization assays indicate only slightly greater quantities of factor-VII related antigen than are detected by conventional assays of procoagulant activity. Plasma of one dog was depleted of factor-VII procoagulant activity by exposure to an immobilized antibody; the low level of activity originally present was then verified by titration with normal plasma. The plasma defect results from an incomplete deletion of synthesis.
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The liver is the primary site of synthesis for the majority of coagulation factors. There are published accounts of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia and factor XI deficiency. In this article, we report what we believe to be the first observation, of transmission of factor VII deficiency, a rare, autosomal recessive coagulation disorder, from an affected liver donor to a naive liver recipient. At 300 days after transplantation, the recipient remains with an isolated prolongation of the prothrombin time and a below-normal level of factor VII, and has had no bleeding complications.
We report on an 18-year-old woman who took an impulsive overdose of paracetamol. The admission international normalized ratio (INR) was prolonged which resulted in her being transferred to a specialist hepatology unit. Her clinical condition and laboratory parameters did not correlate; this prompted investigation into her coagulation profile, which revealed a factor VII deficiency and explained the observed abnormalities of an elevated INR, normal partial thromboplastin time and normal liver function. There are no other reports of factor VII deficiency being identified as a result of paracetamol overdose.
We have previously described a kindred with factor VII (FVII) deficiency whose members exhibited reduced procoagulant activity relative to FVII antigen concentration. In this report, the molecular genetic basis of the FVII defect has been determined to be a heterozygous substitution of Asp for Asn at position 57 in the first epidermal growth factor (EGF) domain. Recombinant FVII (N57D) cDNA was created by site-directed mutagenesis and transiently expressed in human 293 cells. The transfected cells synthesized an immunoprecipitable protein with an apparent molecular weight of 50 kD. Quantitation of expression by FVII enzyme-linked immunosorbent assay indicated that mutant protein yields were consistently low, typically 10% to 30% of wild-type FVII. FVII (N57D) protein did not accumulate intracellularly, and Northern blot analysis indicated equivalent FVII mRNA levels in 293 cells expressing either wild-type FVII or FVII (N57D). Secreted FVII (N57D) protein did not bind tissue factor, exhibited no procoagulant activity, and failed to bind a conformation-dependent monoclonal antibody specific for the first EGF domain of FVII. Molecular modeling of the first EGF domain of FVII predicted that the N57D amino acid substitution would disrupt tertiary bonding structure. We conclude that the N57D mutation affects folding of the first EGF domain of FVII resulting in decreased cellular secretion of a mutant FVII molecule, which is unable to bind tissue factor and is therefore biologically inactive.
We describe the clinical history of a 35-year-old woman with severe cross-reacting-material-negative factor VII deficiency. Because of a severe hemophilic arthropathy of the hips, reconstructive surgery was indicated. After advice was obtained from 11 clinical hemostasis experts it was decided to use plasma for factor VII replacement during and after surgery and to use pneumatic boots to prevent thrombosis. Volume overload was treated with plasmapheresis and diuretics. The operation was carried out without abnormal blood loss and the patient recovered without thromboembolic complications. We conclude that continuous infusion of plasma is a suitable way to replace factor VII provided adequate venous access is available for plasmapheresis.
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.
BACKGROUND: Unbalanced chromosomal translocations may present with a variety of clinical and laboratory findings and provide insight into the functions of genes on the involved chromosomal segments. CASE PRESENTATION: A 9 year-old boy presented to our clinic with Factor VII deficiency, microcephaly, a seizure disorder, multiple midline abnormalities (agenesis of the corpus callosum, imperforate anus, bilateral optic nerve hypoplasia), developmental delay, hypopigmented macules, short 5th fingers, and sleep apnea due to enlarged tonsils. Cytogenetic and fluorescence in situ hybridization analyses revealed an unbalanced translocation involving the segment distal to 16p13 replacing the segment distal to 13q33 [46, XY, der(13)t(13;16)(q33;p13.3)]. Specific BAC-probes were used to confirm the extent of the 13q deletion. CONCLUSION: This unique unbalanced chromosomal translocation may provide insights into genes important in midline development and underscores the previously-reported phenotype of Factor VII deficiency in 13q deletions.
BACKGROUND AND OBJECTIVES: Inherited factor VII (FVII) deficiency is a rare bleeding disorder characterized by a poor relationship between reported FVII clotting activity (FVII:C) and bleeding tendency. Our study was aimed at defining biological parameters that are possibly predictive for bleeding risk in this condition. DESIGN AND METHODS: Forty-two FVII-deficient patients (FVII:C <30%) were classified into two opposite clinical groups defined as severe and non-or-mild bleeders. For each patient, plasma samples were collected and then investigated for FVII:C (using a sensitive method and human recombinant thromboplastin as the reagent), FVII antigen, activated FVII coagulant activity (FVIIa:C) and the free-form of tissue factor pathway inhibitor. RESULTS: None of these tests could be used as highly accurate predictors of bleeding. Nevertheless, both FVII:C and FVIIa:C differed significantly between the two clinical groups. Using ROC-curve analysis, two critical values of 8% and 3mIU/mL for FVII:C and FVIIa:C, respectively, could be proposed to discriminate between severe bleeders and non-or-mild bleeders. INTERPRETATION AND CONCLUSIONS: A highly accurate diagnostic test for predicting bleeding tendency in inherited FVII deficiency still eludes definition, highlighting the fact that factors other than FVII itself interfere with the expression of bleeding phenotypes in this condition. Nevertheless, potential critical values using sensitive FVII:C and FVIIa:C methods may be useful in clinical laboratories for FVII-deficient patients. Those patients with FVII:C levels higher than 8% FVII:C or FVIIa:C higher than 3 mIU/mL, with no other hemostatic defect, seem to have a minimal risk of severe bleeding. Extended clinical studies are needed to support these findings.
The molecular basis of severe type I factor (F)VII deficiency was investigated in two Algerian patients. One patient, a 13-year-old-girl who has suffered from severe bleeding since birth, was homozygous for a 7-bp deletion (nt 7774-7780) and a 251-bp insertion (nt 7773-7781) of mitochondrial origin, in IVS 4 acceptor splice site. The other patient, an infant who died from massive intracranial haemorrhage, was homozygous for a transversion in the IVS 7 donor splice site (T9726+2-->G) and a missense mutation in exon 8 (G10588-->A; Arg224-->Gln). In both cases, the deleterious mutations are probably the splice site junction abnormalities impairing mRNA processing. These three lesions have not yet been reported.
A 1(1/2)-month-old baby with seizures, lethargy and refusal of feeds was diagnosed to have intracranial hemorrhage due to factor VII deficiency. MRI also demonstrated the unusual presence of a hemorrhagic infarct. The case underscores the importance of carrying out neuroimaging and appropriate hematological studies even in the absence of obvious external bleeding. Hypothesis for increased propensity for intra-cranial hemorrhage is discussed.