Warfarin dose requirement in patients having severe thrombosis or thrombophilia

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.

DOI: 10.1111/bcp.13948

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