title: Phenotypic APC resistance in carriers of the A20210 prothrombin mutation is associated with an increased risk of venous thrombosis.
abstract: We hypothesized that increased prothrombin levels associated with G20210A prothrombin gene mutation could affect the results of activated protein C (APC) resistance phenotype and increase the risk of venous thrombosis (VT). The increasing addition of purified prothrombin in plasma of 90 normal subjects resulted in a parallel significant increase of APC resistance. Significantly different mean n-APC-SR in 879 GG20210 subjects compared to 27 heterozygous carriers of isolated G20210A mutation was observed (1.0 +/- 0.12 vs. 0.95 +/- 0.11; P = 0.02) in a random sample of 906 normal population subjects. Twenty-seven families with VT and isolated G20210A mutation consecutively diagnosed during 1998-1999 were evaluated. Mean n-APC-SR was significantly lower in the 80 G20210A carriers compared to 58 GG 20210 relatives investigated, even after sex and age adjustment (0.92 +/- 0.08 vs. 1.05 +/- 0.13; P < 0.0001). A strong relationship between plasma prothrombin level and n-APC-SR was observed in the families. When n-APC-SR values were grouped in tertiles, the odds ratio for VTE, after exclusion of the index cases and adjustment for 20210 status, for subjects in the lowest tertile (n-APC-SR 0.73-0.90) was 4.58 (95% CI 0.78-26.88) compared to upper tertile (n-APC-SR 1.01-1.30). In conclusion, in subjects with G20210A mutation APC resistance is significantly increased, correlates with plasma prothrombin level and the carriers with the lowest APC resistance values have an increased risk of VTE.
authors.affiliation: Department of Hematology and Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza, Italy. castaman@hemato.ven.it
authors.forename: G
authors.initials: G
authors.lastname: Castaman
authors.forename: A
authors.initials: A
authors.lastname: Tosetto
authors.forename: M
authors.initials: M
authors.lastname: Simioni
authors.forename: M
authors.initials: M
authors.lastname: Ruggeri
authors.forename: D
authors.initials: D
authors.lastname: Madeo
authors.forename: F
authors.initials: F
authors.lastname: Rodeghiero
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020016:Activated Protein C Resistance / Q000235:genetics*; D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016017:Odds Ratio; D010641:Phenotype; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011516:Prothrombin / Q000032:analysis / Q000235:genetics*; D012307:Risk Factors; D012494:Sampling Studies; D019851:Thrombophilia / Q000235:genetics*; D020246:Venous Thrombosis / Q000453:epidemiology* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D011516:Prothrombin