Thirteen novel anticoagulation-resistance mutations uncovered
MedWire News: Researchers in Germany have identified 13 novel mutations in the vitamin K 2,3-epoxide reductase complex subunit 1 gene (VKORC1) that predispose patients to oral anticoagulation resistance (OACR).
In spite of the presence of these mutations, therapeutic international normalized ratio (INR) values can be achieved with increased OAC doses in some patients, remark Johannes Oldenburg (University Clinic Bonn) and colleagues.
"The tendency to abort OAC therapy for patients with high dosage requirements, despite approaching stable therapeutic INR values, represents a challenge for physicians treating patients with potential VKORC1 missense mutations," say the researchers who aimed to identify novel mutations in VKORC1, the molecular target of OACs.
They sequenced the VKORC1 gene in 626 individuals exhibiting partial or complete resistance to coumarin anticoagulants. In total, they identified 13 patients who each had a different, novel VKORC1 heterozygous mutation associated with OACR.
The 13 mutations resulted in the following amino acid substitutions: Ala26Thr, His28Gln, Asp36Gly, Ser52Trp, Ser56Phe, Trp59Leu, Trp59Cys, Val66Gly, Gly71Ala, Asn77Ser, Asn77Tyr, Ile123Asn, and Tyr139His.
A further 10 patients each had one of three previously reported VKORC1 mutations at Val29Leu (n=1), Asp36Tyr (n=6), and Val66Met (n=3).
Oldenburg and team note that increasing the OAC dose resulted in a stable therapeutic INR of 2.0-3.0 in 13 (56.5%) of the 23 patients, whereas OAC therapy was aborted in the 10 (43.5%) remaining patients.
Patients requiring OAC doses of more than double the high dosage threshold (42.2 mg/week phenprocoumon, 48.6 mg/week acenocoumarol, 99.6 mg/week warfarin, 277.2 mg/week fluindione) to reach therapeutic INR levels should be referred for detailed genetic analysis VKORC1, recommend the researchers.
"Identifying OACR patients with outlying OAC dosage requirements and specific VKORC1 missense mutations can potentially lead to successful treatment of these patients and would generate an important corpus of genotype/phenotype correlation data to aid understanding the molecular mechanisms of VKORC1-mediated OAC resistance," they conclude in the Journal of Thrombosis and Haemostasis.
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By Laura Dean