Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII

Nadir, Yona; Brenner, Benjamin; Fux, Liat; Shafat, Itay; Attias, Judith; Vlodavsky, Israël

doi:10.3324/haematol.2010.023713

Cited by 67 publications

(78 citation statements)

References 32 publications

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“…In line with our previous findings, 24,25 endothelial heparanase overexpression observed in aged mice was paralleled by elevated plasma factor Xa activity levels. Moreover, transgenic mice overexpressing human heparanase exhibited shortened time to arterial thrombosis following vascular injury and increased in-stent thrombosis.…”

Section: Discussionsupporting

confidence: 80%

“…Aged End.p53-WT mice exhibited significantly higher plasma factor Xa levels compared with their adult counterparts, whereas a similar age-dependent increase was not observed in End.p53-KO mice ( Figure 4A). In line with the role of heparanase in factor X activation, as previously shown by our group, 24,25 western blot analysis revealed significantly increased heparanase expression in primary endothelial cells isolated from lungs of aged compared with adult WT mice ( Figure 4B; representative western blot findings in Figure 4E). Protein levels of Egr1, involved in the transcriptional regulation of p53 26 and heparanase, 27,28 also were higher in endothelial cells of aged mice ( Figure 4C,E).…”

Section: Deletion Of P53 In Endothelial Cells Protects Aged Mice Agaisupporting

confidence: 62%

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The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Bochenek

Bauer

Gogiraju³

et al. 2018

Blood Advances

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Key Points• Deletion of p53 in endothelial cells prevents venous thrombosis in aged, but not in adult, mice.• Neutralization of heparanase in aged mice using TFPI2 peptides restores the thrombotic phenotype of adult mice. End.p53-KO mice were protected from vein thrombosis. Analysis of primary endothelial cells from aged mice or human vein endothelial cells after induction of replicative senescence revealed significantly increased early growth response gene-1 (Egr1) and heparanase expression, and plasma factor Xa levels were elevated in aged End.p53-WT, but not in End.p53-KO mice. Increased endothelial Egr1 and heparanase expression also was observed after doxorubicin-induced p53 overexpression, whereas p53 inhibition using pifithrin-a reduced tissue factor (TF) expression. Importantly, inhibition of heparanase activity using TF pathway inhibitor-2 (TFPI2) peptides prevented the enhanced venous thrombus formation in aged mice and restored it to the thrombotic phenotype of adult mice.Our findings suggest that p53 accumulation and heparanase overexpression in senescent endothelial cells are critically involved in mediating the increased risk of venous thrombosis with age and that heparanase antagonization may be explored as strategy to ameliorate the prothrombotic endothelial phenotype with age.

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Section: Discussionsupporting

confidence: 80%

Section: Deletion Of P53 In Endothelial Cells Protects Aged Mice Agaisupporting

confidence: 62%

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Bochenek

Bauer

Gogiraju³

et al. 2018

Blood Advances

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“…However, enzymatically inactive heparanase (proenzyme) did not have an effect on heparanase-activated partial pro-thrombin time or platelet aggregation. Recent reports have also suggested that heparanase may act through alteration of TF and activated factor X (24,25). Together these results suggest that heparanase has only a moderate effect on the hypercoagulability of the blood (overexpression of TF with compensation by TF pathway inhibitor).…”

Section: Discussionmentioning

confidence: 99%

Heparanase Regulates Thrombosis in Vascular Injury and Stent-Induced Flow Disturbance

Baker

Gibson

Kolachalama

et al. 2012

Journal of the American College of Cardiology

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Objectives The purpose of this study was to examine the role of heparanase in controlling thrombosis following vascular injury or endovascular stenting. Background The use of endovascular stents are a common clinical intervention for the treatment of arteries occluded due to vascular disease. Both heparin and heparan sulfate are known to be potent inhibitors of thrombosis. Heparanase is the major enzyme that degrades heparan sulfate in mammalian cells. This study examined the role of heparanase in controlling thrombosis following vascular injury and stent-induced flow disturbance. Methods This study used mice overexpressing human heparanase and examined the time to thrombosis using a laser-induced arterial thrombosis model in combination with vascular injury. An ex vivo system was used to examine the formation of thrombus to stent-induced flow disturbance. Results In the absence of vascular injury, wild type and heparanase overexpressing (HPA Tg) mice had similar times to thrombosis in a laser-induced arterial thrombosis model. However, in the presence of vascular injury, the time to thrombosis was dramatically reduced in HPA Tg mice. An ex vivo system was used to flow blood from wild type and HPA Tg mice over stents and stented arterial segments from both animal types. These studies demonstrate markedly increased thromboses on stents with blood isolated from HPA Tg mice in comparison to blood from wild type animals. We found that blood from HPA Tg animals had markedly increased thrombosis when applied to stented arterial segments from either wild type or HPA Tg mice. Conclusions Taken together, this study’s results indicate that heparanase is a powerful mediator of thrombosis in the context of vascular injury and stent-induced flow disturbance.

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“…Up-regulation of TF adds another example of the multiple non-enzymatic functions of heparanase. Recently, we have demonstrated that heparanase may serve as a cofactor of TF, suggesting that heparanase is directly involved in activation of the coagulation cascade 17. The findings were supported by experiments indicating that heparanase increases the level of factor Xa in the presence of TF/VIIa and the effect is enzymatically independent.…”

Section: Heparanase As a Cofactor To Tissue Factor Activitymentioning

confidence: 57%

“…Heparanase was recently revealed as an important modulator of blood coagulation 13,17,18,27. Generating peptides inhibiting heparanase procoagulant activity36 strengthens the role of heparanase as a new procoagulant factor in the coagulation cascade.…”

Section: Resultsmentioning

confidence: 98%

Heparanase and Coagulation–New Insights

Nadir¹

2014

Rambam Maimonides Med J

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Heparanase, a β-D-endoglucuronidase abundant in platelets that was discovered 30 years ago, is an enzyme that cleaves heparan sulfate side chains on the cell surface and in the extracellular matrix. It was later recognized as being a pro-inflammatory and pro-metastatic protein. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. We had shown that heparanase up-regulated the expression of the blood coagulation initiator tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we have demonstrated that heparanase directly enhanced TF activity which led to increased factor Xa production and subsequent activation of the coagulation system. Recently, heparanase inhibitory peptides derived of TFPI-2 were demonstrated by us to inhibit heparanase procoagulant activity and attenuate sepsis in mouse models.

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Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII

Cited by 67 publications

References 32 publications

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Heparanase Regulates Thrombosis in Vascular Injury and Stent-Induced Flow Disturbance

Heparanase and Coagulation–New Insights

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