Possible impact of factor V Leiden genotype on warfarin induced bleeding.

Sir,

We read with interest the report, recently published by Nahar et al.[1] on the prevalence of warfarin sensitive alleles in factor V Leiden (FVL) mutation carriers. The study provides preliminary evidence for the need of pre-prescription genotyping of warfarin sensitive polymorphisms (CYP2C9*2, *3 and Vitamin-K epoxide reductase complex subunit1 [VKORC1]-1639G/A) in patients who are at risk of thrombosis (carriers of thrombophilic marker) and require anticoagulation therapy.

The authors have reported that 55.6% of the patients who carry FVL mutation also carry warfarin sensitive genotypes; thus, it is important that all patients with thrombophilia need warfarin genotyping prior to prescription with warfarin. The prevalence of these genotypes are however, not significantly different in few other studies including ours [Table 1], where the allele frequencies were studied in warfarin anticoagulated patients, as well as normal healthy controls.[23] FVL mutation has however, not been studied in these cases.

Table 1

Genotype and allele frequencies of CYP2C9 and VKORC1 in few studies from India

In our study, which included 145 warfarin treated patients (blinded to FVL or other thrombophilic marker carrier status), nearly 44.14% patients were found to be carriers for one or more variant genotype(CYP2C9*2, *3 and VKORC1-1639G/A). Out of these warfarin sensitive genotype carrier patients, 67.18% patients faced over anticoagulation (INR > 4) while on warfarin. Indicating that genotyping of warfarin sensitive markers will be beneficial in all the patients prior to the initiation of anticoagulation therapy.[3]

Another important aspect of coinheritance of thrombophilia is its impact on the bleeding phenotype. Several studies, both in vitro and case series have shown that FVL mutation modulates the clinical severity in hemophilia and other rare bleeding disorders.[45] We therefore premise that FVL carrier patients should be at lower risk of over anticoagulation than the FVL non-carrier patients. This would be confirmed by undertaking studies in large series of anticoagulated patients with the long duration follow-up analysis for over anticoagulation and risk of bleeding in carriers of thrombophilia marker versus non-carriers.