VARIATIONS IN PROTHROMBIN TIME AND INTERNATIONAL NORMALIZED RATIO OVER 24 HOURS IN WARFARIN-TREATED PATIENTS

Study Objective. To determine the variation of prothrombin times and i nternational normalized ratio (INR) over 24 hours in humans. Design. P rospective, parallel study. Setting. University-affiliated general cli nical research center. Patients. Six patients receiving long-term warf arin therapy and six sex-matched controls. Interventions. Warfarin was administered to the patients at 6:00 P.M. Measurements and Main Resul ts. Prothrombin times and INR were determined every 2 hours over 24 ho urs. Time of study entry, meals, and sleep cycles were controlled. A s ignificant cosinor rhythm for prothrombin times and INR (p less than o r equal to 0.03) occurred in warfarin-treated patients, suggesting tha t diurnal variation occurs. The mean difference between the peak and t rough prothrombin times was 1.8 +/- 0.9 seconds (range 0.8-3 sec) with a mean change of 9.3% +/- 3.7%. The peak prothrombin time and INR val ues occurred between 4:00 A.M. and 8:00 A.M. in five patients, and tro ugh values between 6:00 P.M. and midnight in five. No significant cosi nor rhythm was noted for controls (p>0.5). Conclusion. Significant var iations in prothrombin time and INR occurred in patients receiving war farin therapy, with the highest values occurring in the morning and th e lowest in the evening. These results may have clinical implications for patients receiving either high- or low-intensity warfarin therapy.