Tuukka A Helin1, Lotta Joutsi-Korhonen1, Heidi Asmundela2, Mikko Niemi3, Arto Orpana4, Riitta Lassila1,2. 1. Coagulation Disorders Unit, Clinical Chemistry, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland. 2. Coagulation Disorders Unit, Hematology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland. 3. Department of Clinical Pharmacology, Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland. 4. Genetics and Clinical Chemistry, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
Abstract
AIMS: Warfarin dose requirement varies significantly. We compared the clinically established doses based on international normalized ratio (INR) among patients with severe thrombosis and/or thrombophilia with estimates from genetic dosing algorithms. METHODS: Fifty patients with severe thrombosis and/or thrombophilia requiring permanent anticoagulation, referred to the Helsinki University Hospital Coagulation Center, were screened for thrombophilias and genotyped for CYP2C9*2 (c.430C>T, rs1799853), CYP2C9*3 (c.1075A>C, rs1057910) and VKORC1 c.-1639G>A (rs9923231) variants. The warfarin maintenance doses (target INR 2.0-3.0 in 94%, 2.5-3.5 in 6%) were estimated by the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) algorithms. The individual warfarin maintenance dose was tailored, supplementing estimates with comprehensive clinical evaluation and INR data. RESULTS: Mean patient age was 47 years (range 20-76), and BMI 27 (SD 6), 68% being women. Forty-six (92%) had previous venous or arterial thrombosis, and 26 (52%) had a thrombophilia, with 22% having concurrent aspirin. A total of 40% carried the CYP2C9*2 or *3 allele and 54% carried the VKORC1-1639A allele. The daily mean maintenance dose of warfarin estimated by the Gage algorithm was 5.4 mg (95% CI 4.9-5.9 mg), and by the IWPC algorithm was 5.2 mg (95% CI 4.7-5.7 mg). The daily warfarin maintenance dose after clinical visits and follow-up was higher than the estimates, mean 6.9 mg (95% CI 5.6-8.2 mg, P < 0.006), with highest dose in patients having multiple thrombophilic factors (P < 0.03). CONCLUSIONS: In severe thrombosis and/or thrombophilia, variation in thrombin generation and pharmacodynamics influences warfarin response. Pharmacogenetic dosing algorithms seem to underestimate dose requirement.
AIMS: Warfarin dose requirement varies significantly. We compared the clinically established doses based on international normalized ratio (INR) among patients with severe thrombosis and/or thrombophilia with estimates from genetic dosing algorithms. METHODS: Fifty patients with severe thrombosis and/or thrombophilia requiring permanent anticoagulation, referred to the Helsinki University Hospital Coagulation Center, were screened for thrombophilias and genotyped for CYP2C9*2 (c.430C>T, rs1799853), CYP2C9*3 (c.1075A>C, rs1057910) and VKORC1 c.-1639G>A (rs9923231) variants. The warfarin maintenance doses (target INR 2.0-3.0 in 94%, 2.5-3.5 in 6%) were estimated by the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) algorithms. The individual warfarin maintenance dose was tailored, supplementing estimates with comprehensive clinical evaluation and INR data. RESULTS: Mean patient age was 47 years (range 20-76), and BMI 27 (SD 6), 68% being women. Forty-six (92%) had previous venous or arterial thrombosis, and 26 (52%) had a thrombophilia, with 22% having concurrent aspirin. A total of 40% carried the CYP2C9*2 or *3 allele and 54% carried the VKORC1-1639A allele. The daily mean maintenance dose of warfarin estimated by the Gage algorithm was 5.4 mg (95% CI 4.9-5.9 mg), and by the IWPC algorithm was 5.2 mg (95% CI 4.7-5.7 mg). The daily warfarin maintenance dose after clinical visits and follow-up was higher than the estimates, mean 6.9 mg (95% CI 5.6-8.2 mg, P < 0.006), with highest dose in patients having multiple thrombophilic factors (P < 0.03). CONCLUSIONS: In severe thrombosis and/or thrombophilia, variation in thrombin generation and pharmacodynamics influences warfarin response. Pharmacogenetic dosing algorithms seem to underestimate dose requirement.
Authors: Mark J Rieder; Alexander P Reiner; Brian F Gage; Deborah A Nickerson; Charles S Eby; Howard L McLeod; David K Blough; Kenneth E Thummel; David L Veenstra; Allan E Rettie Journal: N Engl J Med Date: 2005-06-02 Impact factor: 91.245
Authors: Stephen E Kimmel; Benjamin French; Scott E Kasner; Julie A Johnson; Jeffrey L Anderson; Brian F Gage; Yves D Rosenberg; Charles S Eby; Rosemary A Madigan; Robert B McBane; Sherif Z Abdel-Rahman; Scott M Stevens; Steven Yale; Emile R Mohler; Margaret C Fang; Vinay Shah; Richard B Horenstein; Nita A Limdi; James A S Muldowney; Jaspal Gujral; Patrice Delafontaine; Robert J Desnick; Thomas L Ortel; Henny H Billett; Robert C Pendleton; Nancy L Geller; Jonathan L Halperin; Samuel Z Goldhaber; Michael D Caldwell; Robert M Califf; Jonas H Ellenberg Journal: N Engl J Med Date: 2013-11-19 Impact factor: 91.245
Authors: Anne M Holbrook; Jennifer A Pereira; Renee Labiris; Heather McDonald; James D Douketis; Mark Crowther; Philip S Wells Journal: Arch Intern Med Date: 2005-05-23