Heparanase and Coagulation–New Insights

Nadir, Yona

doi:10.5041/rmmj.10165

Cited by 11 publications

(11 citation statements)

References 56 publications

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“…Heparanase is an endo--D-glucuronidase capable of cleaving heparan sulfate (HS) side chains, both in extracellular space and within the cells, regulating several biological activities. Indeed, in addition to its well characterized role in cancer, Heparanase activity may play a role in the pathogenesis of several inflammatory disorders, promoting migration of vascular endothelial cells and activation of immune system cells [10,11]. Heparanase generates soluble HS fragments that control inflammatory responses at multiple levels, including release of cytokines/chemokines in the extracellular space, modulation of leukocyte interactions with endothelial cells and extracellular matrix and initiation of innate immune responses through interactions with Toll-like receptor 4 (TLR-4) [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Capozzi

Riitano

Recalchi

et al. 2020

Preprint

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Anti-phospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity associated with the presence of “anti-phospholipid antibodies”. Thrombosis may be the result of a hypercoagulable state related to activation of endothelial cells and platelets by anti-2-glycoprotein I (β2-GPI) antibodies. Anti-β2-GPI antibodies induce a proinflammatory and procoagulant phenotype in these cells that, after activation, express Tissue Factor (TF), the major initiator of the clotting cascade, playing a role in thrombotic manifestations. Moreover, TF expression may also be induced by Heparanase, an endo--D-glucuronidase, that generates heparan sulfate fragments, regulating inflammatory responses. In this study we analyzed, in human platelets and endothelial cells, the effect of a new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivative (RDS3337), able to inhibit Heparanase activity, on signal transduction pathway leading to TF expression triggered by anti-β2-GPI. Platelets and endothelial cells were incubated with affinity purified anti-β2-GPI after pretreatment with RDS3337. Cell lysates were analyzed for phospho-interleukin-1 receptor-associated kinase 1 (IRAK1), phospho-p65 nuclear factor kappa B (NF-κB) and TF by Western blot. IRAK phosphorylation and consequent NF-κB activation, as well as TF expression, triggered by anti-β2-GPI treatment were significantly prevented by previous pretreatment with RDS3337. In the same vein, pretreatment with RDS3337 prevented platelet aggregation and ATP release triggered by anti-β2-GPI antibodies. These findings support the view of Heparanase involvement in a prothrombotic state related to APS syndrome, suggesting a novel target to regulate overexpression of procoagulant protein(s).

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Section: Introductionmentioning

confidence: 99%

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Capozzi

Riitano

Recalchi

et al. 2020

Preprint

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“…On the other hand, heparanase also exerts functions independently of its enzymatic activity. Hence, it has been described that heparanase affects the hemostatic system in a non-enzymatic manner, by directly enhancing TF activity and up-regulating its expression[ 23 ]. This results in an increased factor Xa production and leads to dissociation of TFPI from the endothelial membrane surface, thus activating the coagulation system[ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…This results in an increased factor Xa production and leads to dissociation of TFPI from the endothelial membrane surface, thus activating the coagulation system[ 24 ]. A potential role of heparanase in coagulation has also been suggested based on the high expression of this protein during the pro-thrombotic state of most neoplasms [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site

et al. 2016

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Heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is over-expressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by degradation of heparan sulphate proteoglycans of the extracellular matrix. Heparanase may also affect the hemostatic system in a non-enzymatic manner, up-regulating the expression of tissue factor, which is the initiator of blood coagulation, and dissociating tissue factor pathway inhibitor on the cell surface membrane of endothelial and tumor cells, thus resulting in a procoagulant state. Trying to check the effect of heparanase on heparin, a highly sulphated glycosaminoglycan, when it activates antithrombin, our results demonstrated that heparanase, but not proheparanase, interacted directly with antithrombin in a non-covalent manner. This interaction resulted in the activation of antithrombin, which is the most important endogenous anticoagulant. This activation mainly accelerated FXa inhibition, supporting an allosteric activation effect. Heparanase bound to the heparin binding site of antithrombin as the activation of Pro41Leu, Arg47Cys, Lys114Ala and Lys125Alaantithrombin mutants was impaired when it was compared to wild type antithrombin. Intrinsic fluorescence analysis showed that heparanase induced an activating conformational change in antithrombin similar to that induced by heparin and with a KD of 18.81 pM. In conclusion, under physiological pH and low levels of tissue factor, heparanase may exert a non-enzymatic function interacting and activating the inhibitory function of antithrombin.

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“…These tissue factor-bearing microparticles are associated with a heightened risk of venous thrombeombolism (49, 50). The regulation of tissue factor activation is complex and incompletely understood (42, 51, 41, 52). The reduction of an allosteric disulfide bond converting “cryptic” TF to the active form may serve as a key regulatory step (51).…”

Section: Hypercoagulability Of Cancer and Potential Interface With Pdimentioning

confidence: 99%

“…This disulfide bond reduction may be mediated by PDI, which is also overexpressed and secreted by cancer cells (34, 44), but this hypothesis has not been proven and remains controversial (51, 53, 54). PDI can alter TF activity indirectly through PS exposure (16, 41, 55) or through the enzyme heparanase which increases the procoagulant activity of tissue factor by preventing the binding of tissue factor pathway inhibitor (TFPI) (52, 56). Heparanase requires disulfide bond oxidation for activation and was identified as a potential substrate for extracellular PDI (8, 57).…”

Section: Hypercoagulability Of Cancer and Potential Interface With Pdimentioning

confidence: 99%

The intersection of protein disulfide isomerase and cancer associated thrombosis

Stopa¹,

Zwicker²

2018

Thrombosis Research

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The mechanisms underlying the hypercoagulability of cancer are complex and include the upregulation coagulation factors or procoagulant proteins, shedding of microparticles, and direct activation of vascular cells. Protein disulfide isomerase (PDI) is a thiol isomerase secreted from activated platelets and endothelial cells and plays a critical role in both platelet aggregation and fibrin generation. A number of potential intravascular targets of PDI have been identified including cell surface receptors (e.g. β-integrins and glycoprotein Ib), receptor ligands (e.g. fibrinogen and von Willebrand factor), serine proteases (e.g. cathepsin G and kallekrein-14), and coagulation factors (e.g. factor XI and factor V). Recent clinical studies demonstrated that a small molecule inhibitor of PDI, isoquercetin, decreases platelet-dependent thrombin generation and PDI activity in plasma following oral administration. This review explores the mechanistic overlap between the molecular drivers of cancer associated thrombosis and the potential roles PDI plays in mediating thrombosis. These molecular insights provide rationale for clinical trials targeting PDI to prevent thrombosis in cancer patients.

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Heparanase and Coagulation–New Insights

Cited by 11 publications

References 56 publications

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site

The intersection of protein disulfide isomerase and cancer associated thrombosis

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