Phenotypic APC resistance in carriers of the A20210 prothrombin mutation is associated with an increased risk of venous thrombosis.
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.
Castaman
G
G
Department of Hematology and Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza, Italy. castaman@hemato.ven.it
Tosetto
A
A
Simioni
M
M
Ruggeri
M
M
Madeo
D
D
Rodeghiero
F
F
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
D020413:3' Untranslated Regions; D011516:Prothrombin