Method-dependent influence of certain polymorphisms in the factor V B-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 VIII (FVIII). In a previous study, we found that in the B-domain coding portion 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 those 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 between 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 activated partial thromboplastin time-based assays. In contrast, a test based on the deactivation of FVIII in the tenase complex in homozygous carriers of the minor G allele showed significantly lower APC ratios (P = 0.001) in comparison with the major A allele. The results of the investigation after modification of the test indicate that mutative changes in the B-domain apparently influence the interaction among phospholipids, APC, FV, and protein S. An increase in FVIII through the introduction of the FVIII concentrate Kogenate 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 without the FV Leiden, the observed frequency of the minor G allele was higher in the non-thrombotic group (33.0%) than in the thrombotic group (22.8%). However, the difference did not reach the level of significance (odds ratio, 0.53; 95% confidence interval, 0.26-1.12). It does, nevertheless, appear possible that a homozygous condition for the minor allele in combination with a defect known to be associated with thrombophilia represents an additional thrombogenetic risk factor.
Siegert
G
G
Institute for Clinical Chemistry and Laboratory Medicine, Carl Gustav Carus Medical Faculty of the Dreseden Technical University, Germany. Gabriele.Siegert@mailbox.tu-dresden.de
Kostka
H
H
Gehrisch
S
S
Schwarz
T
T
Schellong
S
S
Jaross
W
W
D020016:Activated Protein C Resistance / Q000235:genetics*; D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005165:Factor V / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D020246:Venous Thrombosis / Q000235:genetics
D000925:Anticoagulants; D005165:Factor V