High plasma levels of factor VIII (FVIII) and von Willebrand factor (VWF) have been indicated as independent risk factors for venous thromboembolism. However, the genetic factors responsible for their increase remain poorly known. In a large Italian family with high FVIII/VWF levels and thrombotic episodes, whole exome sequencing (WES) was performed on 12 family members to identify variants/genes involved in FVIII/VWF increase. Twenty variants spread over a 8300 Kb region on chromosome 5 were identified in 12 genes, including the low frequency rs13158382, located upstream of the MIR143/145 genes, which might affect miR-143/145 transcription or processing. The expression of miR-143/145 and VWF mRNA were evaluated in the peripheral blood mononuclear cells of six family members. Members with the variant (n = 3) showed lower levels of both miRNAs and higher levels of VWF mRNA compared to members without the variant (n = 3). An analysis of genetic and expression data from a larger cohort of individuals from the 1000 Genomes and GEUVADIS project confirmed a statistically significant reduction (p-value = 0.023) in miR-143 in heterozygous (n = 35) compared to homozygous wild-type individuals (n = 386). This family-based study identified a new genetic variant potentially involved in VWF increase by affecting miR-143/145 expression.

Factor VII deficiency (FVIID) is among the most common rare bleeding disorders. The ability of FVII coagulant activity (FVII:C) levels and genetic variants to predict clinical outcomes remain limited. We evaluated the discriminative performance of FVII:C levels, genotype-phenotype associations, and the accuracy of in silico tools in identifying pathogenic variants. In total, 422 patients from 3 international registries were analyzed. Overall, 61% experienced bleeding, predominantly spontaneous (73%); 20% had grade I, 27% had grade II, and 14% had grade III bleeding. Lower FVII:C levels showed a moderate inverse correlation with bleeding scores and were more common in individuals with spontaneous bleeding (r = −0.49; P< .0001). FVII:C levels showed moderate discrimination for asymptomatic status (area under the curve [AUC], 0.72) and strong discrimination for grade III bleeding (AUC, 0.84). Cutoffs of ≥19 IU/dLand <11 IU/dL identified asymptomatic individuals and those with grade III bleeding. We identified 90 variants, including 10 novel; 60% were missense, and 63% localized to the serine protease domain. According to the American College of Medical Genetics and Genomics criteria, 86% were pathogenic/likely pathogenic. The sensitivity of in silico tools was 96%, 85%, and 60% for REVEL, CADD, and AlphaMissense. Severe deficiency was more common in homozygous individuals (90%), whereas heterozygous individuals predominantly exhibited mild/moderate deficiency (92%). Consistently, bleeding phenotypes were frequent in individuals with homozygous/compound heterozygous variants, whereas most heterozygous variants were asymptomatic (71%). Overall, FVII:C levels moderately stratify bleeding severity. Homozygous/compound heterozygous variants are associated with lower FVII:C levels and more severe bleeding, whereas heterozygous variants are mostly asymptomatic. Among in silico tools, REVEL demonstrated the highest sensitivity.