Variant VKORC1 and CYP2C9 alleles in patients with diffuse alveolar hemorrhage caused by oral anticoagulants.
BACKGROUND
Diffuse alveolar hemorrhage (DAH) is a life-threatening bleeding complication that can occur as a result of oral anticoagulation therapy.


OBJECTIVE
We hypothesized that in patients treated with coumarins, alveolar hemorrhage is associated with vitamin K epoxide reductase (VKORC1) and cytochrome P450 (CYP) 2C9 (CYP2C9) variant alleles. In addition, in the case of acenocoumarol use, CYP2C19 allelic variants also play a role.


METHODS
During a 7-year period, data on patients using coumarins with confirmed DAH were gathered. Of 173 confirmed DAH cases, 75 received oral anticoagulants, and 63 (84%) of these 75 patients were included because their DNA was available. For genotyping the CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP2C19*3 (636G>A), VKORC1 (-1639G>A), and VKORC1 (1173C>T) single nucleotide polymorphisms (SNPs), real-time PCRs were performed.


RESULTS
In 62 (98.4%) of 63 patients with DAH, variant alleles were found. In 51 (81.0%) of the 63 patients, VKORC1 allelic variants (20 homozygotes and 31 heterozygotes) were present. In 31 (49.2%) of the 63 DAH cases, CYP2C9 allelic variants (three homozygotes, 26 heterozygotes, and two compound heterozygotes) were observed, and in 20 (32.0%) of the 63 patients, variant alleles of both genes were observed.


CONCLUSIONS
Genotyping of four SNPs for VKORC1 and CYP2C9 polymorphisms is useful in predicting a high probability of the occurrence of DAH in patients receiving oral anticoagulants. Early and timely use of genotyping is recommended to prevent a fatal outcome and to provide safer and more individualized anticoagulant therapy.
Wijnen
Petal A
PA
Department of Clinical Chemistry, Maastricht University Medical Centre, Maastricht, the Netherlands.
Linssen
Catharina F
CF
Haenen
Guido R
GR
Bekers
Otto
O
Drent
Marjolein
M
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003374:Coumarins / Q000008:administration & dosage / Q000009:adverse effects; D065729:Cytochrome P-450 CYP2C9; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D003374:Coumarins; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases