Utility of ACMG classification to support interpretation of molecular genetic test results in patients with factor VII deficiency

BackgroundThe American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have introduced an internationally shared framework for variant classification in genetic disorders. FVII deficiency is a rare inherited autosomal recessive bleeding disorder with sparse data concerning ACMG classification.MethodsTo develop an approach which may improve the utility of molecular genetic test results, 129 patients with FVII deficiency were retrospectively assigned to six subgroups for exploratory analysis: F7 gene wildtype (group 1), ACMG 1 (benign variant) or ACMG 2 (likely benign variant), only (group 2), ACMG 3 (variant of uncertain significance) ± ACMG 1–2 heterozygous or not classified variant (group 3), ACMG 4 (likely pathogenic variant), or ACMG 5 (pathogenic variant) single heterozygous ± ACMG 1–3 single heterozygous (group 4), ACMG 4–5 homozygous or ≥2 ACMG 4–5 heterozygous or ≥1 ACMG 4–5 heterozygous plus either ACMG 1 c.1238G>A modifying variant homozygous or ≥2 ACMG 1–3 (group 5), FVII deficiency and another bleeding disorder (group 6).ResultsEleven of 31 patients (35.5%) in group 5 had abnormal ISTH-BS (n = 7) and/or history of substitution with recombinant factor VIIa (n = 5) versus 4 of 80 patients (5.0%, n = 1 abnormal ISTH-BS, n = 3 substitution) in groups 1 (n = 2/22), 2 (n = 1/29), 3 (n = 0/9), and 4 (n = 1/20). Four of 18 patients (22.2%) with FVII deficiency and another bleeding disorder (group 6) had an abnormal ISTH-BS (n = 2) and/or history of substitution with recombinant factor VIIa (n = 3).ConclusionPatients with a homozygous ACMG 4–5 variant or with specific combinations of heterozygous ACMG 4–5 ± ACMG 1–3 variants exhibited a high-risk bleeding phenotype in contrast to the remaining patients without another bleeding disorder. This result may serve as a basis to develop a genotype/phenotype prediction model in future studies

Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation

BACKGROUND Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient's age at the time of the first VTE. PATIENTS AND METHODS Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. RESULTS Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. CONCLUSIONS Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event

Low Allergenic Potential With Fondaparinux: Results of a Prospective Investigation

OBJECTIVE: To determine the incidence and causes of skin reactions to the synthetic pentasaccharide fondaparinux