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Matan M.,University of Sfax | Axelman E.,Thrombosis and Hemostasis Unit | Brenner B.,Thrombosis and Hemostasis Unit | Nadir Y.,Thrombosis and Hemostasis Unit
Human Reproduction | Year: 2013

STUDY QUESTIONWhat is the effect of estrogen on heparanase procogulant activity?SUMMARY ANSWEREstrogen increases heparanase procoagulant activity.WHAT IS KNOWN ALREADYEstrogen therapy increases the risk of thrombosis and was previously found to up-regulate heparanase expression. Heparanase is involved in angiogenesis and metastasis, and has been shown to form a complex with tissue factor (TF) and also shown to enhance the generation of factor Xa.STUDY DESIGN, SIZE, DURATIONA case-control study. Thirty-four healthy women using oral contraceptives (OC) and 41 women not using hormonal therapy and not pregnant per history were enrolled, over a 5-month period, at the Rambam Medical Center, Haifa, Israel. In vitro, estrogen receptor-positive (MCF-7) and -negative (MDA-231) cell lines were incubated with estrogen, tamoxifen and ICI-182.780 a pure estrogen receptor antagonist. The cell medium was evaluated for TF/heparanase complex activity, TF activity and heparanase procoagulant activity by chromogenic substrate.PARTICIPANTS/MATERIALS, SETTING, METHODSExclusion criteria included age <18 years, post-menopausal women, concomitant medications other than supplement minerals and vitamins, acute or chronic illness.MAIN RESULTS AND THE ROLE OF CHANCEThe study demonstrates increased risk of high heparanase procoagulant activity in OC users. When a cutoff level of 0.25 (absorbance 405-490 nm) was set, the odds ratio was 131 (P < 0.0001). When all results were studied by quartiles, in quartiles 3 and 4 the results were almost exclusively of the OC users (P < 0.0001). In cell cultures, estrogen and tamoxifen increased heparanase procoagulant activity in the medium of estrogen receptor-positive (MCF-7) cells.LIMITATIONS, REASONS FOR CAUTIONThe main limitation of the current study is that the two estrogens given to the women and cell cultures, ethinyl estradiol (EE) and 17-β-estradiol (E2), respectively, may have different effects on the coagulation system, although an increase in heparanase procoagulant activity was demonstrated in both of them. Although the sample size of the study group was limited, significant differences in the activation of the extrinsic coagulation pathway were demonstrated.WIDER IMPLICATIONS OF THE FINDINGSThe clinical relevance of the heparanase procoagulant activity assay as a screening tool in thrombophilia work-up should further be elucidated. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Baudo F.,Thrombosis and Hemostasis Unit | Collins P.,University of Cardiff | Huth-Kuhne A.,SRH Kurpfalzkrankenhaus Heidelberg GmbH | Levesque H.,University of Rouen | And 5 more authors.
Blood | Year: 2012

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%). © 2012 by The American Society of Hematology.


Hamed S.,Rambam Health Care Campus | Hamed S.,Technion - Israel Institute of Technology | Brenner B.,Technion - Israel Institute of Technology | Brenner B.,Thrombosis and Hemostasis Unit | Roguin A.,Technion - Israel Institute of Technology
Cardiovascular Research | Year: 2011

Diabetes mellitus type-2 (DM-2) contributes to atherogenesis by inducing endothelial cell injury and dysfunction. Endothelial progenitor cells (EPCs) are essential to blood vessel formation, can differentiate into mature endothelial cells, and promote the repair of damaged endothelium. In DM-2, the circulating EPC count is low and their functionality is impaired. The mechanisms that underlie this reduced count and impaired functionality are poorly understood. Nitric oxide (NO) is a short-lived signalling molecule that is produced by vascular endothelial cells and participates in the maintenance of vascular tone. NO is also known to participate in other physiological processes, such as cell survival, proliferation, and migration. The bioavailability of NO is reduced in EPCs from DM-2 patients. Interestingly, an inverse relationship exists between the reduction in NO bioavailability in EPCs and the patients plasma glucose and glycated haemoglobin levels. In addition, NO bioavailability in EPCs correlates with plasma oxidized low-density lipoprotein levels in DM-2. Although this reduction in NO bioavailability could be attributed to oxidative stress in DM-2 patients, it also may be due to impairment of one or more members of the protein signalling cascades that are responsible for NO production. The stimulation of NO production or its signalling cascades in EPCs may increase their numbers and improve their function, thus attenuating endothelium damage, independent of the vasodilatory effects of NO. This review summarizes the metabolic alterations that underlie the molecular mechanisms that may be responsible for EPC decrease and dysfunction in DM-2 with emphasis on the involvement of the NO system. © 2011 The Author.


Papadakis E.,Pappagergiou Hospital | Hoffman R.,Thrombosis and Hemostasis Unit | Brenner B.,Thrombosis and Hemostasis Unit
Blood Reviews | Year: 2010

Myeloproliferative disorders are commonly associated with thrombohemorrhagic manifestations. The current review highlights recent advances in understanding the epidemiology and pathogenetic mechanisms of thrombotic and bleeding complications. Therapeutic modalities and prophylactic interventions corresponding to the specific disease states are also discussed. © 2010 Elsevier Ltd.


Nadir Y.,Thrombosis and Hemostasis Unit | Brenner B.,Thrombosis and Hemostasis Unit
Thrombosis Research | Year: 2014

Heparanase is an endo-β-D-glucuronidase that is capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans on cell surfaces and the extracellular matrix, activity that is strongly implicated in tumor metastasis and angiogenesis. Apart of its well characterized enzymatic activity, heparanase was noted to exert also enzymatic-independent functions. Among these are the up-regulation of vascular endothelial growth factor (VEGF)-A, VEGF-C and activation of intra-cellular signaling involved in cell survival and proliferation. 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. Taking into account the prometastatic, pro-angiogenic and pro-coagulant functions of heparanase, over-expression in human malignancies and abundance in platelets, implies that heparanase is potentially a good target for cancer therapy. © 2014 Elsevier Ltd. All rights reserved. © 2014 Elsevier Ltd.


Nadir Y.,Thrombosis and Hemostasis Unit | Brenner B.,Thrombosis and Hemostasis Unit
Thrombosis Research | Year: 2012

Heparanase that was cloned from and is abundant in the placenta is implicated in cell invasion, tumor metastasis and angiogenesis. We have recently demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. Heparanase was shown to up-regulate tissue factor (TF) expression and interact with tissue factor pathway inhibitor (TFPI) on cell surface, leading to dissociation of TFPI from cell membrane of endothelial and tumor cells, resulting in increased cell surface coagulation activity. We have lately shown that heparanase directly enhances TF activity resulting in increased factor Xa production and activation of the coagulation system. Data indicate increased plasma levels of heparanase suggesting its possible involvement in pregnancy vascular complications. Elevation in heparanase levels and procoagulant activity was also documented in orthopedic surgery patients receiving prophylactic doses of enoxaparin. Taking into account the pro-metastatic and pro-angiogenic functions of heparanase, with over-expression in human malignancies and abundance in platelets and placenta, its involvement in the coagulation machinery is an intriguing novel platform for further research. © 2012 Elsevier Ltd.


Nadir Y.,Thrombosis and Hemostasis Unit
Thrombosis research | Year: 2010

Heparanase is an endo-beta-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPG) on cell surfaces and the extracellular matrix, activity that is strongly implicated in tumor metastasis and angiogenesis. Evidence was provided that heparanase over-expression in cancer cells results in a marked increase in tissue factor (TF) levels. Likewise, TF was induced by exogenous addition of recombinant heparanase to tumor cells and primary endothelial cells, induction that was mediated by p38 phosphorylation and correlated with enhanced procoagulant activity. TF induction was further confirmed in heparanase over-expressing transgenic mice and correlated with heparanase expression levels in leukemia patients. Heparanase was also found to be involved in the regulation of tissue factor pathway inhibitor (TFPI). A physical interaction between heparanase and TFPI was demonstrated, suggesting a mechanism by which secreted heparanase interacts with TFPI on the cell surface, leading to dissociation of TFPI from the cell membrane and increased coagulation activity, thus further supporting the local pro-thrombotic function of heparanase. Data indicate a possible involvement of heparanase in early miscarriages and point to a regulatory effect on TFPI and TFPI-2 in trophoblasts. As heparins are strong inhibitor of heparanase, in view of the effect of heparanase on TF, the role of heparins anticoagulant-activity may potentially be expanded. Taking into account the pro-metastatic and pro-angiogenic functions of heparanase, its over-expression in human malignancies and abundance in platelets, its involvement in the coagulation machinery is an intriguing novel arena for further research.


Nadir Y.,Thrombosis and Hemostasis Unit | Brenner B.,Technion - Israel Institute of Technology
Blood Reviews | Year: 2012

Thrombotic complications are common in stem cell transplantation (SCT) recipients and endothelial cell injury is a dominant contributing factor to the hemostatic impairments. Endothelial cells line the vascular bed and each vascular bed has a unique structural and functional properties. Therefore, understanding of these properties may hold important clues to site-specific diagnostics and therapeutics. The two most common thrombotic manifestations related to SCT, veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA), are characterized by small vessel thrombosis in the microcirculation. In diffuse alveolar hemorrhage (DAH), although the clinical presentation is hemorrhagic, autopsy findings and mice experiments imply a thrombotic etiology. In the present review, the pathogenesis and treatment options of these three microcirculation thromboses are discussed. © 2012 Elsevier Ltd.


Aharon A.,Thrombosis and Hemostasis Unit | Aharon A.,Technion - Israel Institute of Technology | Brenner B.,Thrombosis and Hemostasis Unit | Brenner B.,Technion - Israel Institute of Technology
Thrombosis Research | Year: 2011

Microparticles (MPs) are shed from cell membranes of a variety of cells, promote thrombus formation, mediate pro-inflammatory effects and may cause endothelial dysfunction. Normal pregnancy is characterized by increased levels of MPs compared to non-pregnant healthy women but the prevalence, cell origin and the role of MPs in pregnancy-related complications remain controversial. Normal pregnancy is an acquired hyper-coagulable state due to an increase in procoagulants and decrease in natural anticoagulants. Pregnancy-related complications such as preeclampsia, intrauterine fetal growth restriction (IUGR) and fetal loss are associated with placental dysfunction and may cause significant maternal and fetal morbidity and mortality. This article highlights the role of microparticles in maternal placental crosstalk and the interplay between microparticles, thrombosis and pregnancy complications. © 2010 Elsevier B.V. All rights reserved.


Kuperman A.,Thrombosis and Hemostasis Unit
Harefuah | Year: 2010

Bleeding in patients on oral anticoagulant treatment is not uncommon, but hemarthrosis has been described only in few patients. This is a case report of a patient on warfarin due to recurrent venous and arterial thromboembolism, with congenital thrombophilia and Behcet's disease. This report presents knee hemarthrosis during warfarin therapy, reviews the literature and discusses this issue.

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