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Warfarin dose requirement in patients having severe thrombosis or thrombophilia

Tuukka A Helin, Lotta Joutsi-Korhonen, Heidi Asmundela, Mikko Niemi, Arto Orpana, Riitta Lassila
British Journal of Clinical Pharmacology 2019 April 1

AIMS: Warfarin dose requirement varies significantly. We compared the clinically established international normalized ratio (INR) -based doses 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.


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