Circadian variations in natural coagulation inhibitors protein C, protein S and antithrombin in healthy men: A possible association with interleukin-6

Recent observations describe an increase in platelet aggregability and a de crease in fibrinolytic activity in the early morning hours. To determine wh ether anticoagulant proteins also show such a circadian variation we measur ed protein C (PC), protein S (PS), antithrombin (AT) and heparin cofactor-I I (HC-II) levels on venous plasma samples taken from 10 healthy men at thre e-hour intervals throughout a 24-hour period. To investigate the possible t emporal mapping of circadian periodicity, we also measured plasma levels of beta-thromboglobulin (beta-TG) as an indicator of platelet activation, and interleukin-6 (IL-6) as one of the possible regulatory factors that drive this rhythm. Blood samples were drawn at 6 a.m., 9 a.m., noon, 3 p.m., 6 p.m., 9 p.m, an d midnight. PC, IL-6 and beta-TG were measured by ELISA; PS and AT by latex immune assay and HC-II by chromogenic substrate method. A significant circ adian variation was found in PC, PS, AT, beta-TG and IL-6, but not in HC-II levels. PC, PS, IL-6 and beta-TG were at their peaks at 6 a.m:, and nadirs at a time from noon to midnight. AT peak was at 6 p.m. and nadir at noon. The regression of PS on IL-6 was significant, Although the fluctuations of PS and AT were within the normal ranges during the day, some PC levels of t wo subjects were below the lower normal limit (0.70). These data indicate that PC, PS, and AT show a marked circadian periodicity as the other components of the blood coagulation and fibrinolytic system d o. The similar trends in plasma concentrations of PC, PS, beta-TG and IL-6 may be coincidental, but could reflect a common regulatory mechanism or an effect on each other. The clinical implications of these physiological chan ges in coagulation inhibitors and the role of IL-6 in the anticoagulant res ponse deserve further studies.