Partial depletion of tissue factor pathway inhibitor during subcutaneous administration of unfractionated heparin, but not with two low molecular weight heparins

Bendz, Bjørn; Jb, Hansen; To, Andersen; Østergaard, Per; Pm, Sandset

doi:10.1046/j.1365-2141.1999.01791.x

Cited by 37 publications

(30 citation statements)

References 45 publications

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“…Since the differential effect of UFH and LMWH could also be explained by the different mode of administration in these studies, we performed a direct comparison of putative equivalent doses of UFH and two different LMWHs (dalteparin and enoxaparin) given by the subcutaneous route [48]. This study again found a significant depletion of TFPI associated with UFH but not with the two LMWHs.…”

Section: Differential Effect Of Ufh and Lmwhmentioning

confidence: 80%

“…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: Differential Effect Of Ufh and Lmwhmentioning

confidence: 80%

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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“…Additionally, treatment with heparin by the subcutaneous route was also associated with depletion of TFPI but not with LMWHs [11]. The effects of C3 on plasma TFPI levels were investigated after repeated subcutaneous administration.…”

Section: Discussionmentioning

confidence: 99%

“…Subcutaneous administration of a LMWH (enoxaparin) resulted in larger increases in circulating TFPI levels than heparin [7]. In addition, plasma free TFPI antigen and heparin releasable TFPI were depleted during repeated or continuous treatment with heparin, but not during subcutaneous treatment with LMWHs [8,9,11]. In a recent study [10] with two different LMWHs, a clear dose-response relationship has been noted for dalteparin and enoxaparin on the release of endogenous TFPI.…”

Section: Introductionmentioning

confidence: 96%

Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides

Töbü

Schultz

et al. 2007

Thrombosis Research

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Heparin and low molecular weight heparins exert their vascular effects by mobilizing tissue factor pathway inhibitor (TFPI) from the vascular endothelium into the blood circulation. We compared the influence of molecular weight on the TFPI release by heparin and its fractions in a non-human primate model. Primates were treated with unfractionated heparin, a low molecular weight heparin (gammaparin), or a heparin-derived oligosaccharide mixture (C3). Endothelial TFPI release was determined using both immunologic and functional assays. After intravenous administration, all agents significantly increased TFPI levels ( p < 0.05) in a dose dependent manner. The increase produced by unfractionated heparin and gammaparin was greater than that by C3 at an equal dosage (p < 0.05). With subcutaneous injection, all agents produced less TFPI release. Repeated administration of heparin-derived oligosaccharides gradually increased TFPI release. A 1.89 fold increase in TFPI levels was observed 4 days after C3 treatment (2.5 mg/ kg). Our findings indicated that TFPI release is dependent on the molecular weight of heparin and its derivatives. Heparin oligosaccharides exert their vascular effects through increased TFPI release after longterm repeated administration.

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“…LMWH confers the additional advantage of facilitating studies on extended therapy, since LMWH may be administered on an outpatient basis. Theoretical advantages include superior ability of LMWH (enoxaparin) to attenuate von Willebrand factor and increase TFPI [19].…”

Section: Rationale For Use In Acsmentioning

confidence: 99%

Low-Molecular-Weight Heparin in Acute Coronary Syndromes

O’Donnell¹,

Turpie²

2004

Heart Drug

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Acute coronary syndrome (ACS) may be divided into two distinct conditions on the basis of the electrographical presence or absence of significant ST-segment elevation. Coronary arterial plaque rupture with subsequent thrombus formation is usually responsible for the development of ACS. A number of antithrombotic therapies have been developed to inhibit key steps in the sequential process of thrombus formation. Thrombin generation is of critical importance in the creation of intracoronary thrombosis. Heparins, in therapeutic doses, reduce the risk of death and myocardial infarction by about 50% in aspirin-treated patients presenting with ACS with non-ST-segment elevation. Low-molecular-weight heparin (LMWH) primarily targets the inhibition of factor Xa (and to a lesser extent thrombin) by binding with antithrombin. A number of well-designed, large randomized controlled trials have shown that LMWHs have at least comparable efficacy and safety to unfractionated heparin, but their superior practical advantages have made them a mainstay therapy in the treatment of ACS with non-ST-segment elevation. More recently, the role of LMWH in the treatment of ACS with ST elevation has been evaluated in a large randomized trial.

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Partial depletion of tissue factor pathway inhibitor during subcutaneous administration of unfractionated heparin, but not with two low molecular weight heparins

Cited by 37 publications

References 45 publications

Physiological Function of Tissue Factor Pathway Inhibitor and Interaction with Heparins

Physiological Function of Tissue Factor Pathway Inhibitor and Interaction with Heparins

Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides

Low-Molecular-Weight Heparin in Acute Coronary Syndromes

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