Clinical phenotypes and factor VII genotype in congenital factor VII deficiency

Abstract

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.

Gene therapy-based prophylaxis to rescue the “prima ballerina”

“…Indeed FVII deficiency, despite its modest frequency, is one of the most extensively investigated bleeding disorders. The first mutations in FVII deficiency have been described 25 years ago in Italian patients (11) and registers (12) and database (13) reporting FVII genotyping in more than 1,000 subjects are now available. The clinical symptomatology of FVII deficiency does not completely overlap with that of other more frequent conditions, as Hemophilia A and Hemophilia B.…”

Thrombin generation in different cohorts: Evaluation of the haemostatic potential

“…The laboratory finding of an isolated, spontaneously prolonged PT-INR either by chance or during investigation of a patient with bleeding symptoms triggers the suspicion of a vitamin K-dependent factor deficiency if the liver function is normal [132] and there is no deficiency of vitamin K. The prolongation of PT-INR in patients with FVII deficiency is variable and usually dependent on the level of FVII [154]. FVII deficiency is not believed to be associated with complete absence of functional FVII, as the results from studies in knockout mice suggest that a complete lack of FVII is incompatible with life [155].…”

“…The bleeding symptoms in patients with FVII deficiency are characterized by clinical heterogeneity and are not predicted by the levels of FVII [154]. Thirty per cent of the patients with FVII deficiency are asymptomatic [154].…”

“…Thirty per cent of the patients with FVII deficiency are asymptomatic [154]. The remainder have symptoms that vary from mild, mimicking the symptoms of patients with platelet function disorders (epistaxis, easy bruising, gum bleeding) to more severe symptoms (haemarthrosis, muscle haematomas, central nervous system bleeding, gastrointestinal bleeding) [156].…”

Factor VII Deficiency in Pregnancy and Labour: A Case Report

“…Symptoms vary from mild to severe and do not necessarily correlate with factor VII levels. A multicenter European study of patients with congenital factor VII deficiency showed that clinical symptoms did not vary with the frequency of functional polymorphisms and that homozygotes with the same mutation presented with striking differences in severity of bleeding [3].…”