Major Bleeding Caused by Warfarin in a Genetically Susceptible Patient

Abstract

A 90-year-old woman was hospitalized for gastrointestinal bleeding. Although she had been receiving only warfarin 5 mg/day, her international normalized ratio (INR) was 66. Warfarin was discontinued, and her INR fell to 3.7 after transfusion of fresh-frozen plasma. However, it rose again spontaneously to 7.5. Eleven days after the last dose of warfarin had been administered, it was still detectable in the patient's plasma, indicating that impaired warfarin clearance may have caused an enhanced anticoagulation effect. Genetic analysis of the cytochrome P450 (CYP) isoenzyme 2C9, which mediates the major deactivating pathway of S-warfarin, revealed that the patient was a compound heterozygote carrying two variant alleles: CYP2C9*2 and CYP2C9*3. The patient's enhanced sensitivity to warfarin 5 mg/day can be ascribed to decreased clearance of S-warfarin secondary to genetic alteration of the gene encoding CYP2C9, resulting in a life-threatening complication.

CYP2C9 Genotype-guided Warfarin Prescribing Enhances the Efficacy and Safety of Anticoagulation: A Prospective Randomized Controlled Study

“…This is why most loading protocols recommend the use of low starting warfarin doses (usually 5 mg) during the initial days of therapy 34 . This widely used approach does not eliminate the risk of bleeding 35 and unnecessarily prolongs the loading period for the majority of patients.…”

Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status

“…For warfarin, the most frequently used coumarin anticoagulant worldwide, it has been demonstrated that the presence of one of the CYP2C9 polymorphic alleles, CYP2C9*2 or CYP2C9*3, results in a reduced dose need and more bleeding complications and overanticoagulation. [2][3][4][5][6][7][8][9] For acenocoumarol, several studies indicate that the presence of the CYP2C9*3 allele, but not the CYP2C9*2 allele, is associated with a reduced maintenance dose and an increased risk of severe overanticoagulation. [10][11][12][13][14][15][16] Surprisingly little is known regarding the role of CYP2C9 in the metabolism of phenprocoumon, a coumarin anticoagulant that is frequently used in European countries.…”

Extreme sensitivity to acenocoumarol therapy in patient with both VKORC.-1639 A/A and CYP2C9*1/*3 genotypes

“…A several studies confirmed that CYP2C9*3 variant allele is the only to have an effect on dose requirements in patient on acenocoumarol therapy, while the effect of CYP2C9*2 did not seem to be clinically relevant [10][11][12]. Isolated cases of extreme sensitivity to warfarin have been reported in homozygous CYP2C9*3 patients [13,14] as well as in one compound heterozygous CYP2C9*2/*3 patient [15]. Verstuyft et al reported case of two patients with early acenocoumarol over-anticoagulation who were carriers of CYP2C9*3 (homozygous), but without bleeding complications.…”