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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. Source


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. Source


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. Source


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. Source


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. Source

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