Plasma levels of total and free tissue factor pathway inhibitor (TFPI) as individual pharmacological parameters of various heparins

The release of circulating tissue factor pathway inhibitor (TFPI) into plas ma by heparins is thought to contribute to their overall antithrombotic act ivity. In the presented study in healthy volunteers, we measured the hepari n-induced increase of circulating total and free TFPI antigen and the aXa- and aIIa activity after subcutaneous (s.c.) injection of 9000 aXa-U of four different heparins: unfractionated heparin (UFH) (13.0 kDa), a medium mole cular weight (MW) heparin with a narrow MW range (HF) (10.5 kDa). certopari n (6.0 kDa) and enoxaparin (4.5 kDa). Based on the administration of equi-a ctive aXa doses, certoparin induced the highest increase in total TFPI dete rmined as AUC (p <0.01). The lowest effect was observed for UFH (p <0.0001) . However, the AUC of released free TFPI significantly increased in the ord er: enoxaparin < UFH < certoparin < HF, showing MW dependency with the exce ption of UFH. Comparing the effects of equi-gravimetric heparin doses. the MW dependency becomes even more pronounced. The mismatch of UFH may be due to its poor bioavailability, which becomes obvious from its low ex vivo aXa activity. In contrast to the TFPI releasing potency, the ex vivo aXa activ ity continuously decreased with increasing MW. Although the ex vivo aIIa ac tivity of the heparins increased in the same order like the release of free TFPI, there was no clear correlation. This is attributed to the fact that the aIIa activity of heparin is not only dependent on the MW, but, in contr ast to its TFPI releasing effect. also on the percentage of material with h igh affinity to AT. In conclusion, besides the aXa-and aIIa activity, the T FPI releasing effect of heparins is an additional parameter of their indivi dual pharmacological profile.