Quantification of heparin-induced TFPI release: a maximum release at low heparin dose.
OBJECTIVE
Heparin releases tissue factor pathway inhibitor (TFPI) from the endothelium and this release may decrease after repeated high dose heparin administration. The primary aim was to investigate and quantify this phenomenon during a short low dose heparin infusion. Also, the effects of heparin on tissue plasminogen activator (t-PA) were studied.


METHODS
Nine healthy, nonsmoking, male volunteers (range 19-23 years) received a continuous heparin infusion (2000 IU) over 40 min. The endothelial TFPI release rate was estimated from the total TFPI concentration profile using a pharmacokinetic model.


RESULTS
Mean +/- s.d. total and free TFPI increased from 62.9 +/- 9.4/8.3 +/- 2.1 ng ml-1 at baseline to 237.2 +/- 40.9/111.0 +/- 19.9 ng ml-1 after 40 min infusion. The relationship between heparin concentration (anti-IIa activity) and TFPI concentration followed a maximum effect model and a clockwise loop (proteresis) was observed. The TFPI release rate rapidly increased to maximum of 200 +/- 45 micro g min-1 after 17.5 min heparin infusion but did not increase further although heparin concentrations further doubled. In contrast to TFPI, t-PA antigen decreased from 5.6 +/- 1.0 at baseline to 4.5 +/- 1.0 ng ml-1 at the end of infusion (t = 40 min) (difference of 1.1 ng ml-1 (95% confidence interval; 0.9, 1.3).


CONCLUSIONS
Our application of concentration-effect models and pharmacokinetic principles to these haemostatic variables showed that endothelial TFPI release has a maximum that is already reached at low heparin dose, corresponding with an anti-IIa activity of 0.08 IU ml-1. The relationship between anti-IIa activity and TFPI release rate showed signs of acute tolerance (clockwise loop) indicating exhaustion of endothelial TFPI pools. These findings may be of importance for the heparin dose used in conditions such as unstable angina, in which the favourable effects of heparin have been ascribed to its ability to release TFPI.
Kemme
Michiel J B
MJ
Centre for Human Drug Research and Gaubius Laboratory TNO-PG, Leiden, The Netherlands. mk@CHDR.nl
Burggraaf
Jacobus
J
Schoemaker
Rik C
RC
Kluft
Cornelis
C
Cohen
Adam F
AF
D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000097:blood / Q000494:pharmacology*; D006493:Heparin / Q000008:administration & dosage* / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D008074:Lipoproteins / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D010959:Tissue Plasminogen Activator / Q000032:analysis
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D010959:Tissue Plasminogen Activator