P13. Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man

Jb, Hansen; Pm, Sandset; Huseby, Kirsten Raanaas; Huseby, Nils‐Erik

doi:10.1097/00001721-199604000-00071

Cited by 11 publications

(16 citation statements)

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“…In addition, ECs treated with heparin for 4 hours failed to respond to a second challenge with heparin or calcium ionophore A23187, with the same release of TFPI as from control cells. In an in vivo study reporting the effect of repeated or continuous intravenous infusion of heparin on the release of TFPI in plasma, 49 Hansen et al 49 demonstrated depletion of intravascular pools of TFPI, with the major part of the decrease observed after 4 to 8 hours, and suggested that the constitutive synthesis of TFPI was overwhelmed by enhanced secretion of the inhibitor. From our analysis of the expression of TFPI message during the incubation of ECs with UFH or LMWH, we can suggest that the observed depletion might also be due to the decrease of TFPI mRNA, significantly manifested for the 1.4-kb transcript after 4 hours of heparin treatment.…”

Section: Lupu Et Al Effect Of Heparin On Tfpi In Cultured Ecs 2257mentioning

confidence: 99%

“…The enhanced secretion of TFPI induced by heparin and the modifications of cellular TFPI observed in human ECs in culture, if proven to take place in vivo also, may represent an important mechanism designed to mobilize TFPI from the endothelium to sites of TF exposure with ongoing thrombosis (eg, a damaged vessel wall or TF expressed on monocytes or in atherosclerotic plaque rupture areas) 49 or, probably more important, to confer highly regulatory anticoagulant properties to the intact endothelium.…”

Section: Lupu Et Al Effect Of Heparin On Tfpi In Cultured Ecs 2257mentioning

confidence: 99%

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Cellular Effects of Heparin on the Production and Release of Tissue Factor Pathway Inhibitor in Human Endothelial Cells in Culture

Lupu

Poulsen

Roquefeuil

et al. 1999

ATVB

112

113

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Abstract-Tissue factor pathway inhibitor (TFPI), the major downregulator of procoagulant activity of the tissue factor-factor VIIa complex (TF ⅐ FVIIa), is synthesized and constitutively secreted by endothelial cells (ECs). Here we describe the in vitro effects of heparin on the cellular localization, gene expression, and release of TFPI in human ECs in culture. Both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH; Fragmin) time-dependently induced a significant enhanced secretion of TFPI, paralleled by a redistribution and increase of TFPI on the cell surface and a decrease of intracellular TFPI. Immunogold electron microscopy showed the presence of clusters of TFPI, both on the plasmalemma proper and within cell-surface opened caveolae/enlarged caveolar profiles. Activation of FX by TF ⅐ FVIIa on ECs treated with endotoxin was inhibited by both heparins but to a higher extent by LMWH. Inhibition of protein synthesis by cycloheximide did not reduce the release of TFPI induced by heparin. Long-term incubation (48 hours) resulted in a time-dependent enhanced production of TFPI. After the first 4 to 8 hours, depletion of intracellular TFPI was observed, more significantly with UFH. Northern blot analysis of TFPI mRNA also showed a decrease of the 1.4-kb transcript after 4 hours of incubation with UFH, followed by recovery and an increase over the control level after 24 hours. Incubation of ECs with phorbol ester (PMA) significantly enhanced the secretion of TFPI and increased its activity on the cell surface, probably by preventing invagination of caveolae. Heparin-stimulated release of TFPI decreased significantly in the presence of PMA to a level that was 2.4 times lower than the expected additive value for PMA and UFH separately. Pretreatment of ECs with PMA suppressed a subsequent response to heparin. Altogether, our results suggest that the heparin-induced release of TFPI might involve a more specific mechanism(s) than the previously hypothesized simple displacement of TFPI from the cell surface glycocalyx. We assume that the increased secretion and redistribution of cellular TFPI induced by heparins in ECs in culture can play an important role in the modulation of the anticoagulant properties of the endothelium. Key Words: tissue factor pathway inhibitor Ⅲ human endothelial cells Ⅲ unfractionated heparin Ⅲ low-molecular-weight heparin Ⅲ caveolae E ndothelial cells (ECs) play a central role in the regulation of hemostasis by ensuring the cellular control of both procoagulant and anticoagulant mechanisms. The anticoagulant and profibrinolytic functions predominate in the quiescent state of the endothelium, thus maintaining blood fluidity (for a review, see References 1 and 2). Blood coagulation is initiated when factor VII/VIIa (FVII/VIIa) in plasma gains access to tissue factor (TF) at sites of blood vessel injury, and the resulting TF ⅐ FVIIa complex activates FX to Xa and FIX to IXa, leading to thrombin generation and the formation of a fibrin clot. 3 Although healthy ECs do not express ...

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Section: Lupu Et Al Effect Of Heparin On Tfpi In Cultured Ecs 2257mentioning

confidence: 99%

Section: Lupu Et Al Effect Of Heparin On Tfpi In Cultured Ecs 2257mentioning

confidence: 99%

Cellular Effects of Heparin on the Production and Release of Tissue Factor Pathway Inhibitor in Human Endothelial Cells in Culture

Lupu

Poulsen

Roquefeuil

et al. 1999

ATVB

112

113

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“…Because TFPI circulates in the blood, 7 we analyzed citrated plasma from 5 pigs for the presence of endogenous TFPI. Heparin (200 U/kg), which promotes the endothelial release of TFPI, 13 was administered to 3 pigs before blood was drawn. Plasma samples from 5 volunteers were tested as control.…”

Section: Gene Transfer Of Tfpi In a Porcine Carotid Balloon Injury Modelmentioning

confidence: 99%

Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor

et al. 2000

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Background-Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of factor Xa and the coagulant initiator complex tissue factor/factor VIIa. Methods and Results-To study the effects of TFPI gene transfer on thrombus formation, balloon-injured porcine carotid arteries were treated locally with an adenovirus encoding human TFPI (Ad-TFPI) or control virus. Gene transfer of TFPI was confirmed by detection of human TFPI in the conditioned medium of porcine carotid arteries kept in culture after in vivo transduction. When carotid flow was measured with Doppler probe 5 days after surgery, cyclic flow variations (CFVs) developed in 7 of 8 control pigs after constriction of the injured carotid artery by 40%, and all control-treated arteries occluded after 70% constriction. In contrast, CFVs were observed in only 1 of 8 Ad-TFPI-treated pigs after 40% constriction, and only 3 of 8 occluded after constriction by 70% (Pϭ0.0027 and Pϭ0.007, respectively).

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“…Recent studies have revealed that TFPI antigen and heparin-releasable TFPI are depleted during repeated and continuous intravenous infusion of heparin, but not during treatment with LMWHs [9,24]. Additionally, treatment with heparin by the subcutaneous route was also associated with depletion of TFPI but not with LMWHs [11].…”

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: 97%

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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P13. Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man

Cited by 11 publications

References 0 publications

Cellular Effects of Heparin on the Production and Release of Tissue Factor Pathway Inhibitor in Human Endothelial Cells in Culture

Cellular Effects of Heparin on the Production and Release of Tissue Factor Pathway Inhibitor in Human Endothelial Cells in Culture

Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor

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

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