Variant VKORC1 and CYP2C9 Alleles in Patients with Diffuse Alveolar Hemorrhage Caused by Oral Anticoagulants
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ORIGINAL RESEARCH ARTICLE
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Variant VKORC1 and CYP2C9 Alleles in Patients with Diffuse Alveolar Hemorrhage Caused by Oral Anticoagulants Petal A. Wijnen,1,2 Catharina F. Linssen,3 Guido R. Haenen,2,4 Otto Bekers1,2 and Marjolein Drent2,5 1 2 3 4 5
Department of Clinical Chemistry, Maastricht University Medical Centre, Maastricht, the Netherlands ild care center, Maastricht University Medical Centre, Maastricht, the Netherlands Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, the Netherlands Department of Pharmacology and Toxicology, University of Maastricht, Maastricht, the Netherlands Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
Abstract
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. Conclusion: 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.
Background Coumarin-based oral anticoagulants act as vitamin K antagonists. They are the most commonly prescribed drugs for therapy (such as in venous thrombosis or pulmonary embolism) or for prophylaxis (as in chronic atrial fibrillation, prosthetic heart valves, and other cardiovascular diseases) of thromboembolic conditions. The primary goal of coumarin administration is to prevent clot formation and its expansion while carefully avoiding unintended adverse drug reactions (ADRs) from over-anticoagulation.[1] The effect of the therapy is monitored by the prothrombin-time international
normalized ratio (INR). An INR of 20%) in br
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