Heparin induces release of extrinsic: Coagulation pathway inhibitor (EPI)

Sandset, Per Morten; Abildgaard, Ulrich; Kobæk-Larsen, Morten

doi:10.1016/0049-3848(88)90340-4

Cited by 412 publications

(276 citation statements)

References 15 publications

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“…This lipoprotein-bound TFPI is variably C-terminally truncated and is therefore not as effective an anticoagulant in one-stage clotting assays as the full-length protein [5]. Full-length TFPI seems to be associated with the endothelium and is released into the circulating blood after the infusion of heparin, which increases the plasma TFPI concentration 2-4-fold [6,7]. Individuals with abetalipoproteinaemia possess greatly decreased circulating TFPI concentrations but normal amounts of heparin-releasable TFPI.…”

Section: Introductionmentioning

confidence: 99%

Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor

Mast

Higuchi

Huang

et al. 1997

Biochemical Journal

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Tissue factor pathway inhibitor (TFPI) is a primary regulator of the initiation of blood coagulation. TFPI is internalized and degraded by HepG2 cells through the low-density-lipoprotein receptor-related protein (LRP) but also binds another molecule present on the cell surface at approx. 10-fold the abundance of LRP [Warshawsky, Broze and Schwartz (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 6664-6668]. When HepG2 cells are washed with heparin or dextran sulphate, a substance that binds TFPI is removed from the cell surface and can be detected in a slot-blot assay. Preincubation with trypsin destroys the reactivity of the TFPI-binding component in the slot-blot assay, suggesting that it is a protein. In addition, when the sulphation of glycosaminoglycans (GAGs) is prevented by growing the HepG2 cells in the presence of 30 mM sodium chlorate, TFPI binding is unaffected, whereas the binding of bovine lipoprotein lipase, a protein known to associate with cell-surface GAGs, falls to 50% of control levels. Dextran sulphate washes of HepG2 cells grown in sodium chlorate have an equal reactivity in slot-blot experiments to that of non-treated cells, suggesting that GAGs are not totally responsible for the binding activity observed. By using the slot blot to follow binding activity and conventional protein purification techniques, a protein species that migrates at 40 kDa after reduction was identified in the HepG2 cell wash. The binding of this protein to TFPI was confirmed with immobilized TFPI. Amino acid sequence analysis identified this protein species as a proteolytic fragment of glypican-3 (also called OCI-5), a member of the glypican family of glycosylphosphatidylinositol-anchored proteoglycans.

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Section: Introductionmentioning

confidence: 99%

Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor

Mast

Higuchi

Huang

et al. 1997

Biochemical Journal

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“…Both heparin and LMWHs are known to release TFPI from vascular endothelium by displacing the TFPI from endothelial cell surface glycosaminoglycans with subsequent release into the circulation [6,14,16]. In addition, it has been reported that heparin and LMWHs are capable of binding to TFPI to form heparin-TFPI complexes and promoting a synergistic anticoagulant action [16].…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence has indicated that enhancement of TFPI activity may contribute to the antithrombotic effect of both LMWHs and heparin [6]. Additionally, TFPI may be involved in the non-anticoagulant actions of heparins, such as its anti-inflammatory effect and modulation of arteriosclerosis [26].…”

Section: Discussionmentioning

confidence: 99%

“…Levels of TFPI activity in primate plasma samples were measured using an amidolytic assay based on that of Sandset et al [6]. In this assay, 300 to 400 μL of test plasma was heated in a plastic test tube at 56 °C in a water bath for 15 min to inactivate endogenous coagulation enzymes and to precipitate fibrinogen.…”

Section: Tfpi Assaymentioning

confidence: 99%

“…Sand-set demonstrated that TFPI levels increased markedly after intravenous heparin administration, whereas subcutaneous administration gave lower but prolonged increases in TFPI activity [6]. Subcutaneous administration of a LMWH (enoxaparin) resulted in larger increases in circulating TFPI levels than heparin [7].…”

Section: Introductionmentioning

confidence: 99%

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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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Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives

et al. 1999

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Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P < 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1&2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.

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Heparin induces release of extrinsic: Coagulation pathway inhibitor (EPI)

Cited by 412 publications

References 15 publications

Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor

Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor

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

Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives

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