No abstract

A 30 year old black male required a 60 mg daily dose of warfarin to elicit a therapeutic anticoagulant response (normal warfarin dose 2.5-10 mg day-1; maximum 15 mg day-1). Hereditary warfarin resistance was suspected after compliance, diet, concurrent medication and any gastrointestinal disorder were eliminated as contributory causes. The disposition of vitamin K and vitamin K epoxide was examined in the propositus, his two sisters and 13 control black male subjects. Each subject was given an i.v. bolus dose (5 mg) of vitamin K prior to and after 2 weeks of warfarin therapy (5 mg day-1). The oral clearances of (S)- and (R)-warfarin were also measured in each subject during the last day of warfarin therapy. The mean (+/- s.d.) systemic clearance of vitamin K was similar in all subjects before (114 +/- 35 ml min-1) and after (112 +/- 40 ml min-1) warfarin therapy. The mean (+/- s.d.) AUC value for vitamin K epoxide was increased by warfarin treatment (6.5 +/- 5.4 micrograms ml-1 min before and 139 +/- 78 micrograms ml-1 min after) in all subjects. In the propositus, the oral clearance of (S)-warfarin (14.5 ml min-1) and the clearance ratio for (S)/(R)warfarin (2.6) differed by more than 7 standard deviations from the control group (4.3 +/- 1.1 ml min-1 and 1.2 +/- 0.2, respectively). In one sister of the propositus, the stereoselective disposition of warfarin was comparable with that of her brother ((S)-warfarin clearance = 16.2 ml min-1; and (S)/(R)-warfarin clearance ratio = 2.7).

We conclude that, at the dosages given, recombinant bovine aprotinin decreases surgical blood loss and transfusion requirements in patients undergoing coronary artery bypass grafting, but its use requires appropriate monitoring of heparin use during bypass. Whether higher dosages of aprotinin increase the risk of graft thrombosis must be further assessed with a larger patient sample.