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

Ma, Qing; Töbü, Mahmut; Schultz, Christopher; Jeske, Walter; Hoppensteadt, Debra; Walenga, Jeanine M.; Cornelli, Umberto; Lee, John; Linhardt, Robert J.; Hanin, Israel; Fareed, Jawed

doi:10.1016/j.thromres.2006.05.007

Cited by 21 publications

(15 citation statements)

References 29 publications

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“…25,26 Several previous studies have reported on the release of TFPI after the administration of heparin and LMWHs prepared from porcine intestinal mucosa. [25][26][27][28] Due to the potential shortage of porcine heparin there has been an interest to use bovine and ovine heparins as an additional source for heparin production. The anticoagulant effects at equigravemetric dosages of these preparations have been previously reported.…”

Section: Discussionmentioning

confidence: 99%

Studies on Tissue Factor Pathway Inhibitor Antigen Release by Bovine, Ovine and Porcine Heparins Following Intravenous Administration to Non-Human Primates

Kouta

Hoppensteadt

Bontekoe

et al. 2020

Clin Appl Thromb Hemost

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Unfractionated heparin (UFH) is a sulfated glycosaminoglycan that consists of repeating disaccharides, containing iduronic acid (or glucuronic acid) and glucosamine, exhibiting variable degrees of sulfation. UFHs release tissue factor pathway inhibitor (TFPI) which inhibits the extrinsic pathway of coagulation by inactivating factor Xa and the factor VIIa/TF complex. Most heparins used clinically are derived from porcine intestinal mucosa however, heparins can also be derived from tissues of bovine and ovine origin. Currently there are some concerns about the shortage of the porcine heparins as they are widely used in the manufacturing of the low molecular weight heparins (LMWHs). Moreover, due to cultural and religious reasons in some countries, alternative sources of heparins are needed. Bovine mucosal heparins (BMH) are currently being developed for re-introduction to the US market for both medical and surgical indications. Compared to porcine mucosal heparin (PMH), BMH exhibits a somewhat weaker anti-coagulant activity. In this study, we determined the TFPI antigen level following administration of various dosages of UFHs from different origins. These studies demonstrated that IV administration of equigravemetric dosages of PMH and ovine mucosal heparin (OMH) to non-human primates resulted in comparable TFPI antigen release from endothelial cells. In addition, the levels of TFPI were significantly higher than TFPI antigen levels observed after BMH administration. Potency adjusted dosing resulted in comparable TFPI release profiles for all 3 heparins. Therefore, such dosing may provide uniform levels of anticoagulation for the parenteral indications for UFHs. These observations warrant further clinical validation in specific indications.

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Section: Discussionmentioning

confidence: 99%

Studies on Tissue Factor Pathway Inhibitor Antigen Release by Bovine, Ovine and Porcine Heparins Following Intravenous Administration to Non-Human Primates

Kouta

Hoppensteadt

Bontekoe

et al. 2020

Clin Appl Thromb Hemost

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“…We found that colorectal patients with high TF expression showed a poorer oncologic outcome than those with low TF expression, suggesting that TF can be a potential target in cancer therapy. Various TF-directed therapeutic agents are being devel-oped, including TF antagonists such as recombinant TF pathway inhibitors and anti-TF antibodies, and other agents that act indirectly on TF expression, such as vitamin D3, retinoids, and heparin [26][27][28]. Preclinical studies have shown that some of these agents have antitumor and antiangiogenic effects [29].…”

Section: Discussionmentioning

confidence: 99%

Tissue factor expression is associated with recurrence in patients with non-metastatic colorectal cancer

Jung

Kim

Kaneko

et al. 2018

Korean J Clin Oncol

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Previous studies have addressed the role of the hypercoagulable state in the pathogenesis of cancer progression and metastasis. In this study, we investigated the association between coagulation factors, including tissue factor (TF) expression, platelet count, and fibrinogen level, and disease recurrence in patients with non-metastatic colorectal cancer. Methods: Patients who underwent curative resection for stage II or III colorectal cancer between 2000 and 2007 were included in this study. Data from a prospectively maintained database were retrospectively reviewed. TF expression was determined by immunohistochemistry using an anti-TF monoclonal antibody. The Kaplan-Meier method was used to estimate 5-year disease-free survival. Results: TF was highly expressed in 257 of 297 patients (86.5%). TF expression was not significantly associated with the platelet counts (P=0.180) or fibrinogen level (P=0.281). The 5-year disease-free survival rate was lower in patients with high TF expression than in patients with low TF expression (72.3% vs. 83.9%, P=0.074). In Cox hazard analysis, high TF expression was an independent risk factor for tumor recurrence (hazard ratio [HR] 2.446; 95% confidence interval [CI], 1.054-5.674; P=0.037). Undifferentiated histologic type (HR, 2.911; 95% CI, 1.308-6.481; P =0.009), venous invasion (HR, 2.784; 95% CI, 1.431-5.417; P =0.003), and lymph node metastasis (HR, 2.497; 95% CI, 1.499-4.158; P<0.001), were also significantly associated with disease recurrence. Conclusion: TF expression is associated with a recurrence in patients with non-metastatic colorectal cancer. However, further studies are required to clarify the underlying mechanisms relating TF expression with oncologic outcomes and its potential role as a therapeutic target.

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“…26 The interaction between proteins and heparins, for example, selectins and growth factors, on the cell surface is nonspecific, which poses limitations on these molecules, given that anticancer proteins, such as TFPI, may be simultaneously secreted. 27 Thus, the nonselective target of heparins could diminish the advantage of their use as anticancer agents. The commonly employed unfractionated heparin (UFH) along with its derivatives low-molecular-weight heparins (LMWHs) possess anticoagulant activity that is an apparent benefit as these drugs attenuate the level of additional activated coagulation factors, including fibrin and thrombin.…”

Section: Antitumor Effects Of Heparinsmentioning

confidence: 99%

Decreasing Tumor Growth and Angiogenesis by Inhibition of Coagulation

Nadir

2019

Semin Thromb Hemost

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Data regarding the effect of coagulation proteins on enhancing angiogenesis and tumor growth are ample. Thus, inhibition of the coagulation system in an attempt to reduce tumor growth and metastasis seems appealing. However, such molecules as direct oral anticoagulants, warfarin and heparins, may impose a bleeding tendency, limiting the treatment dose that can be used. The heparanase protein, as a cofactor for tissue factor (TF) activity, enhances activation of the coagulation system and in addition has several nonhemostatic effects increasing tumor growth. The molecules currently investigated in the field of cancer and coagulation are heparin mimetics and inhibitors of heparanase derived from TF pathway inhibitor 2. Both groups of molecules are inhibitors of heparanase and in addition pose a low bleeding tendency. Hence, interfering in heparanase activity seems to be a promising target for development of antitumor drugs.

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

Cited by 21 publications

References 29 publications

Studies on Tissue Factor Pathway Inhibitor Antigen Release by Bovine, Ovine and Porcine Heparins Following Intravenous Administration to Non-Human Primates

Studies on Tissue Factor Pathway Inhibitor Antigen Release by Bovine, Ovine and Porcine Heparins Following Intravenous Administration to Non-Human Primates

Tissue factor expression is associated with recurrence in patients with non-metastatic colorectal cancer

Decreasing Tumor Growth and Angiogenesis by Inhibition of Coagulation

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