The EAHAD blood coagulation factor VII variant database

Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7 ). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus‐specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross‐species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity

Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs

Vitamin K antagonists (VKA) have long been the default drugs for anticoagulant management in venous thrombosis. While efficacious, they are difficult to use due to interpatient dose–response variability and the risks of bleeding. The approval of fondaparinux, a heparin-derived factor Xa (fXa) inhibitor, provided validation for the development of direct oral anticoagulants (DOAC), and currently such inhibitors of thrombin and fXa are in clinical use. These agents can be used without regular coagulation monitoring, but the inherent risk of bleeding complications associated with blocking the common coagulation pathway remains. Efforts are now underway to develop DOACs that inhibit components of the intrinsic and extrinsic coagulation cascades upstream of thrombin and fX. Evidence from humans and from transgenic animal models suggests that this strategy may provide a better therapeutic margin between antithrombotic and antihemostatic effects. Here the design of active-site inhibitors of S1A proteases involved in coagulation and fibrinolysis is summarized

The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers

Haemophilia published by John Wiley & Sons Ltd Introduction: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. Aim: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders. Results: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). Conclusion: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity

Hyperferritinemia without iron overload in patients with bilateral cataracts: a case series

Hepatologists and internists often encounter patients with unexplained high serum ferritin concentration. After exclusion of hereditary hemochromatosis and hemosiderosis, rare disorders like hereditary hyperferritinemia cataract syndrome should be considered in the differential diagnosis. This autosomal dominant syndrome, that typically presents with juvenile bilateral cataracts, was first described in 1995 and has an increasing number of recognized molecular defects within a regulatory region of the L-ferritin gene (FTL). CASE PRESENTATION: Two patients (32 and 49-year-old Caucasian men) from our ambulatory clinic were suspected as having this syndrome and a genetic analysis was performed. In both patients, sequencing of the FTL 5' region showed previously described mutations within the iron responsive element (FTL c.33 C > A and FTL c.32G > C). CONCLUSION: Hereditary hyperferritinemia cataract syndrome should be considered in all patients with unexplained hyperferritinemia without signs of iron overload, particularly those with juvenile bilateral cataracts. Liver biopsy and phlebotomy should be avoided in this disorder

Immune response to treatment in a severe factor VII deficient patient: characterization of the inhibitory antibody and epitope-mapping

-Background- At variance from Hemophilia, the development of inhibitory antibodies upon replacement therapy is very rare in coagulation factor VII (FVII) deficiency. So far, two cases have been reported and the inhibitory antibodies have not been characterized. Here, we investigate an anti-FVII inhibitory antibody that was developed at high titer (range 7-32 Bethesda Units) in a severe FVII deficient patient treated with rFVIIa or plasma-derived FVII. -Materials and Methods- Expression of recombinant FVII variants in BHK cells. Activated factor X (FXa) generation assays in plasma systems to assess FVII inhibition. ELISA-based assays to evaluate binding to FVII/FVIIa and competition. Bioplex 200 for IgG classification. -Results- The anti-FVII antibodies in patient’s plasma were polyclonal with a majority of IgG1. ELISA-based binding and competition assays showed that the antibodies recognized FVIIa (Kd 0.54±0.09 BU/ml) with higher affinity than FVII (Kd 0.77±0.07 BU/ml), thus pointing toward the hypothesis that rFVIIa was the major immunogen. Sequencing indicates that the patient was homozygous for the A294V-11125delC double mutation, which alters and extends the FVII carboxy-terminal sequence beyond position 404 and makes it different from that of the normal FVII. This information suggested the carboxyl terminal region of the normal molecule as a candidate epitope for the inhibitory antibodies. We therefore expressed the progressively truncated rFVII-406X, rFVII-405X and rFVII-404X variants that displayed a virtually normal specific activity. Upon incubation with the inhibitory antibodies the shortest variant showed the highest residual activity. As compared to that of rFVII-wt (12.4±0.8%), the FXa generation activity of the rFVII-406X, rFVII-405X and rFVII-404X variants were 28.1±8.9%, 25.1±9.9% and 56.5±6.7%, respectively. -Conclusions- This is the first characterization of an inhibitory antibody against FVII. The data obtained through the mutation-based approach support the carboxy-terminus region of FVII as a main functional epitope

Two new double mutant alleles of the F7 gene and a literature review on alleles with two mutations in FVII deficiency

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