Molecular Weight-Dependent Influence of Heparin on the Form of Tissue Factor Pathway Inhibitor Circulating in Plasma

Abstract

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.

Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study

“…It is well established that f-TFPI plasma levels are affected by heparin treatment [28][29][30]. In the present study, individuals with UFH but not those with LMWH exhibited higher plasma levels of f-TFPI than those without heparin treatment.…”

“…In the present study, individuals with UFH but not those with LMWH exhibited higher plasma levels of f-TFPI than those without heparin treatment. This result underlines that the specific potency of heparin to mobilize TFPI from the vessel wall increases with its molecular weight [30]. Unfortunately, information on the dose of heparin and on the delay between heparin injection and blood drawing was not available, leading us to exclude patients under UFH treatment for all analyses on f-TFPI.…”

P‐selectin‐ and heparanase‐dependent antimetastatic activity of non‐anticoagulant heparins

“…These findings indicate that there could be other factors contributing to anticoagulation in vivo. Heparin is known to release tissue factor pathway inhibitor (TFPI) from the vascular endothelium, thereby increasing its plasma concentration severalfold (42)(43)(44). Whereas heparin injection increased TFPI concentration in the plasma of a mouse ϳ2-fold over basal levels, two of the derivatives (RO.H, 100 NA-RO.H) were less efficient than heparin ( Table 2).…”

Trousseau's syndrome: multiple definitions and multiple mechanisms

“…[89][90][91] Moreover, LMWHs selectively inhibit factor Xa without affecting thrombin and may be less likely to deplete TFPI pools over time. 79,80,82,92,93 Thus, there have been several reports in which LMWHs have been successfully substituted for unfractionated heparin in managing Trousseau's syndrome. 64,94 However, it should be noted that the ability of some LMWHs to mediate some of the heparin actions indicated in Figure 1 may not be equivalent.…”

“…Meanwhile, tissue factor pathway inhibitor (TFPI) is released from the vascular endothelium by heparin, perhaps delivering higher concentrations of this potent anticoagulant to the sites of ongoing thrombosis. [79][80][81][82][83] The effects of heparin on fibrinolysis are more complex, because both activators and inhibitors can be affected. 84,85 Heparin can also bind and potentially neutralize a wide variety of cytokines and chemokines.…”