Mutations in CYP2C9 and/or VKORC1 haplotype are associated with higher bleeding complications in patients with Budd–Chiari syndrome on warfarin
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Anticoagulation is universally recommended in Budd–Chiari syndrome [BCS]. Vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 are involved in the metabolism of warfarin. The present study was done to assess whether these mutations are associated with the risk of bleeding in patients with BCS receiving warfarin.
Patients and methods
Patients diagnosed with BCS underwent genotyping for three single nucleotide polymorphisms [SNPs]—two for the CYP2C9 and one for the VKORC1 haplotype. The patients were followed up for at least 12 months and all bleeding episodes were recorded. Patients with and without mutations were compared for bleeding complications and a crude odds ratio [crude OR] was derived for the association between bleeding and presence or absence of mutant alleles.
Eighty patients [mean (SD) age 27.47 (8.93) years, 35 male] with BCS underwent genetic testing. 37/80 (46.2%) patients had mutation of CYP2C9 and/or VKORC1; 22/80 (27.5%) had either of the mutant alleles of CYP2C9 and, similarly, 22/80 (27.5%) had the VKORC mutation. Over a median follow-up of 20 (range 12–96) months, 21/80 (26.3%) patients had bleeding complications. Patients with mutant SNPs had a higher risk of bleeding than those without [14/37 vs. 7/43, p = 0.04, crude OR (95% CI) 3.13 (1.1–8.9)].
The presence of mutations in VKORC1 or CYP2C9 is associated with increased risk of bleeding in patients with BCS on warfarin. Such patients with SNPs of CY2C9 or VKORC1 haplotype should be monitored intensively while receiving warfarin.
KeywordsPortal hypertension Varices Anticoagulation Cirrhosis Hemorrhage Hepatic venous outflow tract obstruction
Model for end-stage liver disease
Single nucleotide polymorphisms
Transjugular intrahepatic portacaval shunt
Vitamin K epoxide reductase complex 1
SA: conceptualized the study, protocol development, data collection, data interpretation, writing manuscript. JA: data collection, data analysis, writing manuscript. KV: data analysis, writing manuscript. BS: protocol development, laboratory work. GN: protocol development, supervision of laboratory work, data analysis and interpretation, writing manuscript. TU: protocol development, supervision of laboratory work, data interpretation, approval of manuscript. BS: protocol development, supervision of data collection, data interpretation, approval of manuscript.
Compliance with ethical requirements
Conflict of interest
Akash Shukla, Abhinav Jain, Vinit Kahalekar, Shital Bendkhale, Nithya Gogtay, Urmila Thatte and Shobna Bhatia have no conflict of interest to declare.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.
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