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The increase of circulating tissue factor pathway inhibitor (TFPI) in plasma by heparins is thought to contribute to their overall antithrombotic activity. In a clinical study in healthy volunteers, we recently found that the specific potency of a heparin to mobilize TFPI from the vessel wall increases with its molecular weight (MW). The released TFPI originally is not associated with lipoproteins, but it is not known whether it remains free circulating in plasma. A further question is whether the MW of heparin influences not only the release of TFPI but also its potential association with lipoproteins. In the present study, the release of free TFPI was compared with the release of total TFPI after application of four heparins with different MWs. Only the TFPI released by unfractionated heparin (UFH) circulated completely as free TFPI. With decreasing heparin MW, the percentage of released free TFPI on released total TFPI decreased to 57%. As a consequence, the longer the heparin chains are, the better they are at preventing the binding of the released, originally free, TFPI to plasma lipoproteins. Because only free TFPI is known to exhibit anticoagulant activity, the activity of released TFPI is better the higher the MW of the applied heparin is. In conclusion, in addition to the potency of heparin to mobilize TFPI, there is its influence on the circulating form, and thus the anticoagulant activity of the released TFPI depends on its MW.