Comparative Tissue Factor Pathway Inhibitor Release Potential of Heparins

Töbü, Mahmut; Ma, Qing; Iqbal, Omar; Schultz, Christopher; Jeske, Walter; Hoppensteadt, Debra; Fareed, Jawed

doi:10.1177/107602960501100104

Cited by 9 publications

(10 citation statements)

References 22 publications

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“…No change in FVIIa and TFPI levels was found when they were compared with pre-CVVH values. The observed changes in TFPI and FVIIa in that study may represent the effects of heparin, rather than activation of the tissue factor/FVIIa-mediated pathway of coagulation, because the concentration of TFPI increases after administration of heparin [18], and because high TFPI levels may bind FVIIa. In our study CVVH was performed without administration of heparin, and no changes in markers of tissue factor/FVIIa-mediated coagulation were observed.…”

Section: Discussionmentioning

confidence: 99%

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et al. 2006

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Introduction The mechanism of coagulation activation during continuous venovenous hemofiltration (CVVH) has not yet been elucidated. Insight into the mechanism(s) of hemostatic activation within the extracorporeal circuit could result in a more rational approach to anticoagulation. The aim of the present study was to investigate whether CVVH using cellulose triacetate filters causes activation of the contact factor pathway or of the tissue factor pathway of coagulation. In contrast to previous studies, CVVH was performed without anticoagulation.

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Section: Discussionmentioning

confidence: 99%

Untitled

et al. 2006

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“…These findings indicate that there could be other factors contributing to anticoagulation in vivo. Heparin is known to release tissue factor pathway inhibitor (TFPI) from the vascular endothelium, thereby increasing its plasma concentration severalfold (42)(43)(44). Whereas heparin injection increased TFPI concentration in the plasma of a mouse ϳ2-fold over basal levels, two of the derivatives (RO.H, 100 NA-RO.H) were less efficient than heparin ( Table 2).…”

Section: Chemically Modified Heparin Derivatives Inhibit Selectinsmentioning

confidence: 99%

P‐selectin‐ and heparanase‐dependent antimetastatic activity of non‐anticoagulant heparins

et al. 2007

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Vascular cell adhesion molecules, P-and L-selectins, facilitate metastasis of cancer cells in mice by mediating interactions with platelets, endothelium, and leukocytes. Heparanase is an endoglycosidase that degrades heparan sulfate of extracellular matrix, thereby promoting tumor invasion and metastasis. Heparin is known to efficiently attenuate metastasis in different tumor models. Here we identified modified, nonanticoagulant species of heparin that specifically inhibit selectin-mediated cell-cell interactions, heparanase enzymatic activity, or both. We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC-38 colon carcinoma and B16-BL6 melanoma attenuates metastasis. Selectin-specific heparin derivatives attenuated metastasis of MC-38 carcinoma, but heparanase-specific derivatives had no effect, in accordance with the virtual absence of heparanase activity in these cells. Heparin derivatives had no further effect on metastasis in mice deficient in P-and L-selectin, indicating that selectins are the primary targets of heparin antimetastatic activity. Selectin-specific and heparanase-specific derivatives attenuated metastasis of B16-BL6 melanomas to a similar extent. When mice were injected with a derivative containing both heparanase and selectin inhibitory activity, no additional attenuation of metastasis could be observed. Thus, selectin-specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase. Here we identified modified, nonanticoagulant species of heparin that specifically inhibit selectin-mediated cell-cell interactions, heparanase enzymatic activity, or both. We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC-38 colon carcinoma and B16-BL6 melanoma attenuates metastasis. Selectin-specific heparin derivatives attenuated metastasis of MC-38 carcinoma, but heparanasespecific derivatives had no effect, in accordance with the virtual absence of heparanase activity in these cells. Heparin derivatives had no further effect on metastasis in mice deficient in P-and L-selectin, indicating that selectins are the primary targets of heparin antimetastatic activity. Selectin-specific and heparanase-specific derivatives attenuated metastasis of B16-BL6 melanomas to a similar extent. When mice were injected with a derivative containing both heparanase and selectin inhibitory activity, no additional attenuation of metastasis could be observed. Thus, selectin-specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase.-Hostettler, N., Naggi, A., Torri, G., IshaiMichaeli, R., Casu, B., Vlodavsky, I., Borsig, L. Pselectin-and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. FA...

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“…This may be associated with the anticoagulant properties of tissue factor pathway inhibitor (TFPI) which is not taken into account when measuring anti‐FXa activity. The LMWHs are known to increase the release of TFPI from endothelial cells and TFPI is responsible for one‐third of the anticoagulant effects of heparins by inhibiting FXa and FVIIa. Also, FIXa has also been shown to contribute to the anticoagulation mechanism of LMWH in an antithrombin‐independent way .…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, anti‐FXa activity is not a good predictor of bleeding during treatment with LMWH and may not correlate with the risk of recurring thromboembolism . This is because measuring anti‐FXa activity for the monitoring and adjustment of LMWH therapy has several limitations, such as the variation in relative anti‐FXa and anti‐FIIa activities between LMWH preparations, the noted importance of anti‐FIIa inhibition in kinetic studies, and the effects of LMWH on tissue factor pathway inhibitor (TFPI) released by endothelial cells . Measuring clotting time would be more clinically relevant, on the other hand assays such as the PT and APTT reflect the contribution of thrombin generated only during the initiation phase, while the vast majority of thrombin (> 95%) is generated during the propagation phase after initial coagulation and fibrin formation .…”

Section: Introductionmentioning

confidence: 99%