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Quantification of heparin‐induced TFPI release: a maximum release at low heparin dose
Author(s) -
Kemme Michiel J. B.,
Burggraaf Jacobus,
Schoemaker Rik C.,
Kluft Cornelis,
Cohen Adam F.
Publication year - 2002
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2002.t01-1-01705.x
Subject(s) - heparin , tissue factor pathway inhibitor , pharmacokinetics , t plasminogen activator , pharmacology , medicine , plasminogen activator , chemistry , coagulation , tissue factor
Aims 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 µg 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.