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Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found., Summary: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance., (© 2018 International Society on Thrombosis and Haemostasis.)

Background: Little research has been performed regarding the psychological consequences of knowing that one is at an increased risk for venous thrombosis., Objectives: The aim of this study was to explore attitudes toward genetic testing for protein C deficiency., Methods: Questionnaires about genetic testing attitudes, dispositional anxiety, risk perception, and thrombosis-related worry were completed by 168 asymptomatic members of a North-American kindred with a high incidence of heritable protein C deficiency conferring a high lifetime risk of venous thrombosis. A total of 76 subjects (45%) had not been tested for protein C deficiency before participating in our study whereas the other 92 subjects (55%) had been tested prior to filling in the questionnaire, of whom 34 people had protein C deficiency, while 58 did not., Results: Family members with protein C deficiency perceived a higher risk of suffering venous thrombosis and scored higher on thrombosis-related worry than family members without protein C deficiency. Participants who had not been tested did not report excessive thrombosis-related worry. Participants with protein C deficiency reported a belief in the psychological and health benefits of testing, and felt that they experienced low psychological distress following the genetic test. High psychological distress following the test was related to dispositional anxiety and thrombosis-related worry. Participants without protein C deficiency were relieved after finding out that they did not have the deficiency., Conclusion: There seem to be few negative psychological consequences of knowing that one is at an increased risk for venous thrombosis, except in vulnerable individuals.