Quantification of heparin‐induced TFPI release: a maximum release at low heparin dose

Abstract

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 m 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 antiIIa 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.

Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides

“…It has been suggested that the deletion of TFPI by heparin is due to its inability to maintain the pools of both circulating TFPI and heparin-releasable TFPI [24]. This hypothesis is supported by the recent study showing that the maximum TFPI release was achieved at low heparin doses [25]. In the case of C3, a gradually increased TFPI release might be due to its containing fewer high molecular weight components, which contribute to the depletion of TFPI, and relatively long half-life.…”

Antithrombin supplementation during extracorporeal membrane oxygenation: study protocol for a pilot randomized clinical trial

“…The heparin/AT also inhibits factor Xa and to a lesser extent other activated coagulation factors (Xa, IXa, XIa, and XIIa) [18]. Another possible anticoagulant mechanism of heparin includes the release of tissue factor pathway inhibitor from endothelial cells [19]. Although AT is needed by heparin to properly exploit its anticoagulant activity, there is no consensus on AT supplementation during ECMO.…”

Antithrombin Supplementation during Extracorporeal Membrane Oxygenation: Study Protocol for a Pilot Randomized Clinical Trial

“…Another possible anticoagulant mechanism of heparin includes the release of tissue factor pathway inhibitor from endothelial cells (19). Although AT is needed by heparin to properly exploit its anticoagulant activity, there is no consensus on AT supplementation during ECMO.…”