Genetic Landscape of Factor VII Deficiency: Insights from a Comprehensive Analysis of Pathogenic Variants and Their Impact on Coagulation Activity.

Congenital factor VII (FVII) deficiency is a rare genetic bleeding disorder characterized by deficient or reduced activity of coagulation FVII. It is caused by genetic variants in the F7 gene. We aimed to evaluate the rate of detection of pathogenic variants in the F7 gene in a large group of patients with FVII deficiency and investigate the correlations between the F7 genotype and FVII activity (FVII:C). Moreover, the influence of the common genetic variant rs6046: c.1238G>A; p.(Arg413Gln), designated as the M2 allele, on FVII:C was investigated. Genetic analysis of the F7 gene was performed on 704 index patients (IPs) using either direct Sanger- or next-generation sequencing. Genetic variants were detected in 390 IPs, yielding a variant detection rate (VDR) of 55%. Notably, the VDR exhibited a linear decline with increasing FVII:C levels. We identified 124 genetic variants, of which 48 were not previously reported. Overall, the frequency of the M2 allele was considerably higher in patients with mild deficiency (FVII:C > 20 IU/dl). Furthermore, IPs lacking an identified pathogenic variant exhibited a significantly higher prevalence of the M2 allele (69%) compared to IPs with a disease-causing variant (47%). These results strongly support the association of the M2 allele with decreased FVII:C levels. This study shows the utility of FVII:C as a predictive marker for identifying pathogenic variants in patients with FVII deficiency. The M2 allele contributes to the reduction of FVII:C levels, particularly in cases of mild deficiency.

Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients-A Single-Center Experience in Genetic Diagnosis.

BACKGROUND: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. METHODS: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. RESULTS: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K-dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority of patients exhibited bleeding symptoms while thrombotic events were uncommon. CONCLUSIONS: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis.

Transcatheter aortic valve implantation leads to a restoration of von Willebrand factor (VWF) abnormalities in patients with severe aortic stenosis - Incidence and relevance of clinical and subclinical VWF dysfunction in patients undergoing transfemoral TAVI.

BACKGROUND: In this study, we sought to analyze the incidence and relevance of von Willebrand factor (VWF) abnormalities in patients undergoing transcatheter aortic valve implantation (TAVI), especially on perioperative bleeding. Furthermore, we hypothesized that, similar to aortic valve surgery, TAVI results in a restoration of VWF abnormalities. METHODS AND RESULTS: We performed a prospective analysis of periinterventional VWF parameters in 74 patients (80±7years, female in 37.5%) undergoing transfemoral TAVI for severe symptomatic aortic valve stenosis. At baseline, VWF:Ag was 210±90IU/dl with a mean VWF activity of 166±106IU/dl; activity-to-antigen ratio was 0.85±0.45. Heyde's syndrome (severe aortic stenosis plus GI bleeding from angiodyplasia) was observed in 2/74 (2.7%). Whereas preprocedural loss of high-molecular-weight (HMW) VWF multimers was found in thirty-six patients (48.6%), none of the patients fulfilled criteria for possible acquired VW syndrome. After TAVI, an increase of both VWF:Ag and activity compared to baseline was observed (p<0.01). In patients with HMW multimer loss, post-interventional recovery of multimers occurred in all cases. In the two patients with Heyde's syndrome, a trend towards reduced VWF:Ag was seen, with loss of HMW multimers in one patient. Of interest, all patients suffering from periprocedural major bleeding (5/74; 6.8%) exhibited activity-to-antigen ratios <0.7, indicating subclinical VWF dysfunction. CONCLUSION: Whereas clinically relevant VWF dysfunction is rare, loss of HMW VWF multimers is common in TAVI patients. Similar to surgery, TAVI leads to a restoration of this loss. Furthermore, VWF parameters may be useful parameter to evaluate risk of periprocedural bleeding.