Dose-dependent release of endogenous tissue factor pathway inhibitor by different low molecular weight heparins

Bendz, Bjørn; To, Andersen; Pm, Sandset

doi:10.1097/00001721-200006000-00005

Cited by 21 publications

(14 citation statements)

References 18 publications

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“…However, in a recent study from our own laboratory, direct head-to-head comparisons of different doses of two LMWHs (dalteparin and enoxaparin) failed to demonstrate any large differences in the release of TFPI by putative equivalent doses [49]. The effect on anti-factor Xa and anti-factor IIa activities were markedly different for the two species, and the differential effect on the release of TFPI may thus not explain a possible difference in antithrombotic potential between these two LMWHs.…”

Section: Introductionmentioning

confidence: 87%

“…The release of TFPI results in a two-fold to fivefold increase in total TFPI activity [44,45], a three-fold to ten-fold increase in TFPI total antigen levels [33], and an eight-fold to fifteen-fold increase in TFPI free antigen levels [46,47]. After subcutaneous injection of either UFH or LMWH, the release is maximal after only 30-60 min as compared with the maximal anti-factor Xa and anti-factor IIa activities after 3-5 h [35, [47][48][49]. This rapid release of TFPI may involve rapid absorption of heparin fragments without anti-factor Xa and anti-factor IIa activities, but with retained ability to release TFPI.…”

Section: Introductionmentioning

confidence: 99%

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Physiological Function of Tissue Factor Pathway Inhibitor and Interaction with Heparins

Sandset

Bendz²,

Hansen³

2000

Pathophysiol Haemos Thromb

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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.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Physiological Function of Tissue Factor Pathway Inhibitor and Interaction with Heparins

Sandset

Bendz²,

Hansen³

2000

Pathophysiol Haemos Thromb

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“…[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.…”

Section: Alternative Approaches To the Management Of Trousseau's Syndmentioning

confidence: 99%

Trousseau's syndrome: multiple definitions and multiple mechanisms

Varki

2007

Blood

704

548

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In 1865, Armand Trousseau noted that unexpected or migratory thrombophlebitis could be a forewarning of an occult visceral malignancy. An analysis by Sack and colleagues in 1977 extended the term Trousseau's syndrome to include chronic disseminated intravascular coagulopathy associated with microangiopathy, verrucous endocarditis, and arterial emboli in patients with cancer, often occurring with mucin-positive carcinomas. In recent times the term has been ascribed to various clinical situations, ranging all the way from these classic descriptions to any kind of coagulopathy occurring in the setting of any kind of malignancy. These multiple definitions of Trousseau's syndrome are partly the consequence of multiple pathophysiologic mechanisms that apparently contribute to the hypercoagulability associated with cancer. Even the classic syndrome probably represents a spectrum of disorders, ranging from exaggerated fluid-phased thrombosis dependent on prothrombotic agents such as tissue factor to a platelet-and endotheliumum-based selectin-dependent microangiopathy associated with mucinproducing carcinomas, along with thrombin and fibrin production. Also considered here are recent hypotheses about genetic pathways within tumor cells that might trigger these thrombotic phenomena, and the reasons why therapy with heparins of various kinds remain the preferred treatment, probably because of their salutary actions on several of the proposed pathologic mechanisms.(Blood.

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“…The peak TFPI activity is reached Ϸ4 h after s.c. administration. TFPI activity is also elevated in the plasma from heparin-treated animals, albeit to a lesser extent, whereas enoxaparin (or dalteparin) resulted in a minimal increase of plasma TFPI activity (33). These results strongly suggest that the administration of rdLMWH-1 or -2 is associated with superior mobilization of TFPI from the endothelium as compared with other heparin-derived molecules.…”

Section: -O-sulfated Tetrasaccharide As An Indicator Of Anticoagulanmentioning

confidence: 76%

Rational design of low-molecular weight heparins with improved in vivo activity

Sundaram

Shriver

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Heparin and low-molecular weight heparins (LMWHs), complex, sulfated polysaccharides isolated from endogenous sources, are potent modulators of hemostasis. Heparin and LMWHs interact with multiple components of the coagulation cascade to inhibit the clotting process. Pharmaceutical preparations of these complex polysaccharides, typically isolated from porcine intestinal mucosa, are heterogeneous in length and composition and, hence, highly polydisperse. Because of the structural heterogeneity of heparin and LMWHs, correlating their activity with a particular structure or structural motif has been a challenging task. Herein, we demonstrate a practical analytical method that enables the measurement of a structural correlate to in vivo anticoagulant function. With this understanding we have developed LMWHs with increased anticoagulant activity and decreased polydispersity. In addition to the pronounced anti-Xa and anti-IIa activity of these LMWHs, we also demonstrate that they possess desirable in vivo pharmacokinetic properties, the ability to cause the release of tissue factor pathway inhibitor (TFPI) from the endothelium, complete bioavailability through s.c. delivery, and the ability to inhibit both venous and arterial thromboses. Importantly, from a clinical safety point of view, unlike LMWHs presently used in the clinic, we show that these LMWHs are rapidly and completely neutralized by protamine. Together, the findings presented herein demonstrate a facile approach for the creation of designer LMWHs with optimal activity profiles.

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Dose-dependent release of endogenous tissue factor pathway inhibitor by different low molecular weight heparins

Cited by 21 publications

References 18 publications

Physiological Function of Tissue Factor Pathway Inhibitor and Interaction with Heparins

Physiological Function of Tissue Factor Pathway Inhibitor and Interaction with Heparins

Trousseau's syndrome: multiple definitions and multiple mechanisms

Rational design of low-molecular weight heparins with improved in vivo activity

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