Physiological Function of Tissue Factor Pathway Inhibitor and Interaction with Heparins

Abstract

Tissue factor pathway inhibitor (TFPI) is now recognized as a major physiological anticoagulant. Its main role is to modulate factor VIIa/tissue factor catalytic activity. Another important role is to potentiate the effect of heparins. TFPI is released from the vascular endothelium after injection of either unfractionated heparin (UFH) or low-molecular-weight heparins (LMWHs), which may then provide high concentrations of TFPI at sites of tissue damage and ongoing thrombosis. In dilute prothrombin-time-based assays, released TFPI contributes approximately one-third to the anticoagulant effect of heparin, the remaining being accounted for by antithrombin. Released TFPI, but not plasma TFPI, contains the basic carboxy-terminal tail which is important for the anticoagulant effect. UFH and LMWH exert differential effects on intravascular TFPI. UFH, but not LMWH, given in therapeutic doses, is associated with a progressive depletion of TFPI, which is associated with a strong rebound activation of coagulation after cessation of treatment. Such depletion may explain the apparent superior efficacy of LMWH observed in clinical trials.

Trousseau's syndrome: multiple definitions and multiple mechanisms

“…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.…”

“…[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.…”

Long-Term Use of Low-Molecular-Weight Heparin in Hemodialysis Patients: A 7-Year Experience

“…Third, there is the conservative effect of EN on tissue factor pathway inhibitor (TFPI). It is known that both UFH and LMWH bind to vascular endothelial cells and mobilize TFPI into the circulation [13] . TFPI is a potent inhibitor of the extrinsic coagulation pathway that is triggered by tissue factor, neutralizing both factor Xa and the activated factor VIIa/ tissue factor complex [13] .…”

“…It is known that both UFH and LMWH bind to vascular endothelial cells and mobilize TFPI into the circulation [13] . TFPI is a potent inhibitor of the extrinsic coagulation pathway that is triggered by tissue factor, neutralizing both factor Xa and the activated factor VIIa/ tissue factor complex [13] . The TFPI-mediated action of heparin contributes more than one third to its total anticoagulant effect.…”

Emerging concepts in thromboprophylaxis

“…Released TFPI, but not plasma TFPI, contains the basic carboxy-terminal, which is important for the anticoagulant effect. Experimental studies demonstrate that UFH and LMWH exert differential effects on intravascular TFPI [9]. UFH, but not LMWH, given in therapeutic doses, is coupled with a progressive depletion of TFPI, Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com which is in turn associated with a strong rebound activation of coagulation after cessation of treatment.…”