CIRCADIAN CHANGES IN ANTICOAGULANT EFFECT OF HEPARIN INFUSED AT A CONSTANT RATE

Six patients with venous thromboembolism were treated with heparin, administered i.v. by a constant infusion pump. The initial daily dose of heparin was adjusted to keep the activated partial thromboplastin time, sampled at 0800 h, between 1.5 and 2.5 times the control level. Once that level was obtained, this dose was kept constant. Anticoagulation was thereafter measured, every 4 h for 48 h, by activated partial thromboplastin time, thrombin time and coagulation factor Xa inhibition assay. The results of all 3 coagulation tests showed a circadian variation in the 6 patients. Maximum values were achieved at night and minimum values in the morning. These circadian variations were reproduced for 2 consecutive days. Differences between night and morning values reached almost 50% for activated partial thromboplastin time, 60% for thrombin time and 40% for factor Xa inhibition assay. This circadian variation resulted from 2 rhythms, a circadian rhythm lasting 24 h and an ultradian rhythm lasting 12 h, which were detected by cosinor analysis for each coagulation test (P < 0.01). A circadian rhythm was detected individually in most of the patients for each coagulation test (P < 0.05). All patients had a nocturnal peak in activated partial thromboplastin time on both days. In 4 patients this peak exceeded the upper desired limit of activated partial thromboplastin time. These rhythms should be taken into account when evaluating the dosage of heparin to be administered.