Method-dependent influence of certain polymorphisms in the factor VB-domain on the response to activated protein C

The factor V (FV) B-domain is extremely important to the cofactor function of native FV for activated protein C (APC) in the inactivation of factor VI II (FVIII). In a previous study, we found that in the B-domain coding porti on of DNA, the polymorphisms at nucleotide positions 2391, 2663, 2684, and 2863 were associated. In the major allele, all bases are A (A allele) and t hose in the minor allele are G (G allele). This study concerns itself with the question of whether or not there are differences in the APC response be tween the A allele and the G allele in plasma samples from persons without the FV Leiden. The APC ratios of homozygous carriers of the major A allele and the minor G allele do not differentiate themselves in classical activat ed partial thromboplastin time-based assays. In contrast, a test based on t he deactivation of FVIII in the tenase complex in homozygous carriers of th e minor G allele showed significantly lower APC ratios (P = 0.001) in compa rison with the major A allele. The results of the investigation after modif ication of the test indicate that mutative changes in the B-domain apparent ly influence the interaction among phospholipids, APC, FV, and protein S, A n increase in FVIII through the introduction of the FVIII concentrate Kogen ate (R) to the plasma samples was associated with a drop in the APC ratios of both genotypes. After defining 59 age- and sex-based matched pairs witho ut the FV Leiden, the observed frequency of the minor G allele was higher i n the non-thrombotic group (33.0%) than in the thrombotic group (22.8%). Ho wever, the difference did not reach the level of significance (odds ratio, 0.53; 95% confidence interval, 0.26-1.12). It does, nevertheless, appear po ssible that a homozygous condition for the minor allele in combination with a defect known to be associated with thrombophilia represents an additiona l thrombogenetic risk factor, Blood Coagul Fibrinolysis 11:519-527 (C) 2000 Lippincott Williams & Wilkins.