Diurnal Rhythm in Anticoagulant Effect of Heparin during a Low Dose Constant Rate Infusion

Summary

The objective of the study was to investigate possible diurnal rhythms in coagulation tests during a continuous intravenous infusion of unfractionated heparin. Six volunteers participated in the study, which was divided in a treatment (500 U heparin/h for 30 h) and a control experiment. Under basal conditions, no rhythm was found in coagulation tests. During heparin treatment, APTT, thrombin clotting time and anti-Xa activity showed a greater anticoagulant effect at night, with a striking decrease in the morning.

In a search for the explanation of this phenomenon we looked for diurnal variations in the urinary excretion of heparin, in the plasma concentrations of antithrombin III and platelet factor 4, and in the effect of heparin added to the plasma samples in vitro. None of these studies provided the explanation.

• References

• 1 Decousus HA, Croze M, Levi FA, Jaubert JG, Perpoint BM, De Bonadona JF, Reinberg A, Queneau PM. Circadian changes in anticoagulant effect of heparin infused at a constant rate. Br Med J 1985; 290: 341-344
• 2 Toulon P, Vitoux JF, Leroy C, Lecomte T, Roncato M, Motobashi Y, Aiach M, Fiessinger JN. Circulating activities during infusion of heparin or a low molecular weight derivative (enoxaparine): failure to demonstrate any circadian variations. Thromb Haemostas 1987; 58: 1068-1072
• 3 Fagrell B, Arver S, Intaglietta M, Tsai AG. Changes of activated partial thromboplastin time during constant intravenous and fixed intermittent subcutaneous administration of heparin. J Intern Med 1989; 225: 257-260
• 4 Petralito A, Mangiafico RA, Gibiino S, Cuffari MA, Miano MF, Fiore CE. Daily modifications of plasma fibrinogen, platelets aggregation, Howell’s time, PTT, TT, and antithrombin II in normal subjects and in patients with vascular disease. Chronobiologia 1982; 9: 195-201
• 5 Haus E, Cusulos M, Sackett-Lundeen L, Swoyer J. Circadian variations in blood coagulation parameters, alpha-antitrypsin antigen and platelet aggregation and retention in clinically healthy subjects. Chronobiol Int 1990; 7: 203-216
• 6 Marshall J. Diurnal variation in occurrence of strokes. Stroke 1977; 78: 35-40
• 7 Tofler GH, Brezinski D, Schafter AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316: 1514-1518
• 8 Huber K, Rosc D, Resch I, Schuster E, Glogar DH, Kaindl F, Binder BR. Circadian fluctuations of plasminogen activator inhibitor and tissue plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction. Thromb Haemostas 1988; 60: 372-376
• 9 van den Besselaar AMHP, Meeuwisse-Braun J, Jansen-Grüter R, Bertina RM. Monitoring heparin therapy by the activated thromboplastin time- the effect of pre-analytical conditions. Thromb Haemostas 1987; 57: 226-231
• 10 Marciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin-III. Lancet 1977; ii: 581-584
• 11 Akiyama Y, Kazama M, Tahara C, Chisato S, Otake J, Kamei K, Nakatake T, Sakurai N, Yasumuro Y, Suzuki S, Maeba E, Nishida T. Reference values of hemostasis related factors of healthy Japanese adults: I: circadian fluctuation. Thromb Res 1990; 60: 281-289
• 12 Soulban G, Labrecque G. Circadian rhythms of blood clotting time and coagulation factors II, VII, IX and X in rats. Life Sci 1989; 45: 2485-2489
• 13 Mahadoo J, Hiebert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1978; 12: 79-90
• 14 Bleiberg I, MacGregor I, Aronson M. Heparin receptors on mouse macrophages. Thromb Res 1983; 29: 53-61
• 15 Shanberge JN, Gruhl M, Kitani T, Ambegaonkar S, Kambayashi J, Nakagawa M, Lenter D. Fractionated Tritium-labelled heparin studied in vitro and in vivo. Thromb Res 1978; 13: 767-783
• 16 De Swart CAM, Nijmeyer B, Andersson LO, Holmer E, Sixma JJ, Bouma BN. Elimination of intravenously administered radiolabelled antithrombin III and heparin in humans. Thromb Haemostas 1984; 52: 66-70
• 17 Decousus M, Gremillet E, Decousus H, Champailler A, Houzard C, Perpoint B, Jaubert J. Nycthemeral variations of ⁹⁹Tc^m-labelled heparin pharmacokinetic parameters. Nucl Med Commun 1985; 6: 633-640