Reduced Factor V Concentration and Altered FV1/FV2 Ratio do not fully Explain R2-associated APC-resistance

 

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Summary

Carriership of the factor V (FV) R2 haplotype is associated with mild APC-resistance, moderately reduced FV levels and a relative increase of the more thrombogenic FV isoform, FV₁. Since low FV levels and increased FV₁ can theoretically cause APC-resistance, we investigated whether these alterations can quantitatively account for R2-associated APC-resistance. In order to determine the effect of FV concentration and FV isoform composition on the APC-response, we reconstituted FV-deficient plasma with purified FV₁ and FV₂ in different molar ratios and to varying FV concentrations. APC sensitivity ratios (APCsr) were determined with the Coatest^® APC^TM Resistance V, which probes the effect of APC on both FV-a and FVIIIa-inactivation, and with the Immunochrom^® APC response test, which only quantifies the effect of APC on FVIII(a)-inactivation. In both assays, low FV concentrations and/or high relative amounts of FV₁ rendered plasma samples more resistant to APC. APCsr were also determined in FVdeficient plasma reconstituted with purified FV at levels and isoform ratios observed in R2-homozygotes (98% FV, 42% FV₁) and agematched controls (119% FV, 26% FV₁). In both tests the APCsr of reconstituted control plasma was the same as that of plasma from controls, whereas reconstituted R2-plasma was less APC-resistant than plasma from homozygous carriers of the R2 haplotype. We conclude that the low FV levels and altered FV isoform ratio cannot fully explain R2-associated APC-resistance.

• References

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