title: Diurnal changes in heparin effect during continuous constant-rate infusion. A study in nine patients with venous thromboembolism.
abstract: OBJECTIVE
  To evaluate the importance of diurnal variations in the effect of a continuous infusion of unfractionated heparin.
  
  
  METHODS
  Twenty-four-hour follow-up.
  
  
  METHODS
  Tertiary referral centre.
  
  
  METHODS
  Patients (five male, four female) with acute venous thromboembolic diseases.
  
  
  METHODS
  Two-hourly measurement of anti-IIa activity, anti-Xa activity, APTT (Cephotest and automated APTT), antithrombin III and cortisol for 24 h.
  
  
  RESULTS
  The maximum anticoagulant effect was found at 04.00-06.00 hours, and the minimum effect at 12.00 hours. The difference was 0.40 U ml-1 for anti-IIa activity (95% confidence interval (CI) 0.03-0.78; P < 0.05), 0.36 U ml-1 for anti-Xa activity (95% CI-0.05-0.72; not significant [NS]), 15.1 s for Cephotest APTT (95% CI 3.3-26.9; P < 0.03), and 112.9 s for automated APTT (95% CI 7.8-218.0; P < 0.05). Antithrombin III decreased from 97.9% at the start to 82.6% 24 h later (P = 0.001). Cortisol showed a typical diurnal rhythm. Expressed as a percentage of the individual 24-h mean, a maximum was found at 04.00 hours (anti-IIa activity), 06.00 hours (both APTTs), and 08.00 hours (anti-Xa activity) and a minimum at 12.00 hours (all variables). The difference was 26% for anti-IIa activity (P < 0.05) and anti-Xa activity (NS), 22% for APTT (Cephotest; P < 0.03), and 44% for APTT (automated APTT; P < 0.05).
  
  
  CONCLUSIONS
  A continuous intravenous infusion of unfractionated heparin has a maximum anticoagulant effect between 04.00 and 8.00 hours and a minimum effect at noon. For individual patients the moment of minimum and maximum effect varies widely. Because the most impressive changes occur between 06.00 and 08.00 hours, laboratory control can best be performed at fixed times, e.g. at 10.00 and at 22.00 hours.
authors.affiliation: Department of General Internal Medicine, University Hospital, Leiden, The Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: Krulder
authors.forename: A M
authors.initials: AM
authors.lastname: Van den Besselaar
authors.forename: F J
authors.initials: FJ
authors.lastname: Van der Meer
authors.forename: A E
authors.initials: AE
authors.lastname: Meinders
authors.forename: E
authors.initials: E
authors.lastname: Briët
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000187:drug effects*; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013923:Thromboembolism / Q000097:blood* / Q000188:drug therapy*
chemical_list: D006493:Heparin