Labrecque G, Soulban G
Ecole de Pharmacie, Centre Hospitalier de l'Université Laval, Québec, Canada.
Chronobiol Int. 1991;8(5):361-72. doi: 10.3109/07420529109059172.
This article reviews the current knowledge on time-dependent variations in the physiology of blood coagulation and in the anticoagulant effect of heparin and warfarin. Animal data indicated that the shortest blood clotting time and the highest levels of coagulation factors II, VII, and IX were recorded during the resting period of the animal. These circadian rhythms were not altered by modifications of the lighting regimens. In healthy volunteers, the prothrombin time was longer at the end of the afternoon than early in the morning; the acrophases of activated partial thromboplastin time and thrombin time occurred in the evening or during the night. The acrophases of fibrinogen, factors II, VII, VIII, and a-1-antitrypsin were obtained in the morning. There is no agreement on the chronobiology of platelet aggregation, and differences can be found in the time of maximal aggregability. The chronopharmacological studies of heparin infused at a constant rate to patients with thromboembolic diseases suggested that maximal effectiveness occurred at 04:00, while it was minimal at 08:00. Animal data indicated that oral administration of warfarin at the end of the activity period of rats produced maximal inhibition of vitamin K-dependent factors. This was the time of day when warfarin interference with the vitamin K cycle of the liver was highest. Further studies are needed to determine the clinical significance of biological rhythms in the physiology and pharmacology of blood coagulation.
本文综述了目前关于血液凝固生理学以及肝素和华法林抗凝作用随时间变化的相关知识。动物数据表明，在动物休息期间，血液凝固时间最短，凝血因子II、VII和IX水平最高。这些昼夜节律不会因光照方案的改变而改变。在健康志愿者中，下午晚些时候的凝血酶原时间比清晨时长；活化部分凝血活酶时间和凝血酶时间的高峰相位出现在晚上或夜间。纤维蛋白原、因子II、VII、VIII和α-1-抗胰蛋白酶的高峰相位出现在早晨。关于血小板聚集的时间生物学尚无定论，最大聚集性出现的时间存在差异。对血栓栓塞性疾病患者持续输注肝素的时间药理学研究表明，最大疗效出现在04:00，而在08:00时最小。动物数据表明，在大鼠活动期结束时口服华法林对维生素K依赖因子产生最大抑制作用。这是一天中华法林对肝脏维生素K循环干扰最高的时间。需要进一步研究以确定生物节律在血液凝固生理学和药理学中的临床意义。
