B Brenner

Rambam Medical Center, H̱efa, Haifa, Israel

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Publications (140)535.03 Total impact

  • Inna Kogan · Dafna Chap · Ron Hoffman · Elena Axelman · Benjamin Brenner · Yona Nadir
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    ABSTRACT: Patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK-2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients.
    No preview · Article · Oct 2015 · Thrombosis and Haemostasis
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    ABSTRACT: In two recent studies based on the RIETE (Registro Informatizado de Enfermedad TromboEmbólica) registry, the presence of high D-dimer or low platelet count in cancer patients with venous thromboembolism (VTE) anticipated a worse clinical outcome. As elevated D-dimer and thrombocytopenia are two components of the DIC diagnosis, we assumed that the occurrence of DIC in cancer patients with VTE would lead to an unfavourable outcome. The use of a simple score, such as that provided by the ISTH, has the potential to identify patients in whom a more careful monitoring and treatment should be instituted in order to prevent the high risk of death imputable to the development of DIC.
    No preview · Article · Sep 2015

  • No preview · Article · Jul 2015 · Thrombosis and Haemostasis

  • No preview · Article · Jan 2015
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    ABSTRACT: Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. METHODS: Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. RESULTS: 1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p<0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p<0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p<0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02-229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03-2.06), with no differences in major bleeding rate. CONCLUSION: Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations.
    Full-text · Article · Nov 2014
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    ABSTRACT: Introduction Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. Methods Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. Results 1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p < 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p < 0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p < 0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02–229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03–2.06), with no differences in major bleeding rate. Conclusion Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations.
    Full-text · Article · Oct 2014 · European Journal of Internal Medicine
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    ABSTRACT: Background Heparanase is implicated in angiogenesis and tumor progression. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. It forms a complex and enhances the activity of the blood coagulation initiator- tissue factor (TF). Although increased heparanase antigen level in the plasma and biopsies of cancer patients was previously demonstrated, in the present study we evaluated, for the first time, the heparanase procoagulant activity in the plasma of patients with lung cancer. Materials and Methods Sixty five patients with non-small cell lung cancer at presentation and twenty controls were recruited. Plasma was studied for TF / heparanase procoagulant activity, TF activity and heparanase procoagulant activity using chromogenic assay and heparanase antigen levels by ELISA. Results Heparanase antigen levels were higher in the study group compared to control (P = 0.05). TF / heparanase activity, and even more apparent, heparanase procoagulant activity were significantly higher in the study group compared to controls (P = 0.008, P < 0.0001, respectively). No significant difference was observed in the TF activity between the groups. Survival of patients with heparanase procoagulant activity higher than 31 ng/ml predicted a mean survival of 9 ± 1.3 months while heparanase procoagulant activity of 31 ng/ml or lower predicted a mean survival of 24 ± 4 months (P = 0.001). Heparanase procoagulant activity was higher than 31 ng/ml in the four cases of thrombosis detected during the follow-up period. Conclusions Elevated heparanase procoagulant activity in patients with lung cancer reveals a new mechanism of coagulation system activation in malignancy. Heparanase procoagulant activity can potentially be used as a predictor for survival.
    No preview · Article · Sep 2014 · Thrombosis Research
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    ABSTRACT: Heparanase is implicated in cell invasion, tumour metastasis and angiogenesis. It forms a complex and enhances the activity of the blood coagulation initiator - tissue factor (TF). We describe new peptides derived from the solvent accessible surface of TF pathway inhibitor 2 (TFPI-2) that inhibit the heparanase procoagulant activity. Peptides were evaluated in vitro by measuring activated coagulation factor X levels and co-immunoprecipitation. Heparanase protein and/or lipopolysaccharide (LPS) were injected intra-peritoneally and inhibitory peptides were injected subcutaneously in mouse models. Plasma was analysed by ELISA for thrombin-antithrombin complex (TAT), D-dimer as markers of coagulation activation, and interleukin 6 as marker of sepsis severity. Peptides 5, 6, 7, 21 and 22, at the length of 11-14 amino acids, inhibited heparanase procoagulant activity but did not affect TF activity. Injection of newly identified peptides 5, 6 and 7 significantly decreased or abolished TAT plasma levels when heparanase or LPS were pre-injected, and inhibited clot formation in an inferior vena cava thrombosis model. To conclude, the solvent accessible surface of TFPI-2 first Kunitz domain is involved in TF/heparanase complex inhibition. The newly identified peptides potentially attenuate activation of the coagulation system induced by heparanase or LPS without predisposing to significant bleeding tendency.
    No preview · Article · Jul 2014 · Thrombosis and Haemostasis
  • A. Aharon · B. Brenner · G. Barsela · D. Loven

    No preview · Article · May 2014 · Thrombosis Research
  • B. Brenner · A. Aharon · I. Tzoran-Rosenthal

    No preview · Article · May 2014 · Thrombosis Research
  • G. Saharov · Y. Nadir · I. Zoran · A. Keren · B. Brenner · T. Shochat

    No preview · Article · Dec 2013 · Sleep Medicine
  • J.S. Younis · M. Ben-Ami · I. Izhaki · B. Brenner · G. Sarig

    No preview · Article · Sep 2013 · Fertility and Sterility
  • I Tzoran · B Brenner · R Hoffman
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    ABSTRACT: Multiple myeloma (MM) is a hematological malignancy with high risk for thrombosis. While venous thromboembolism is more common, myeloma patients can also present with arterial thrombosis. Risk factors responsible for this complication can be patient-related, myeloma- and treatment-related. Thromboprophylaxis is indicated along with specific therapeutic regimens employed in myeloma patients. This review will cover potential risk factors for thrombosis in patients with multiple myeloma, prevention recommendations and treatment strategies in this clinical setting.
    No preview · Article · Apr 2013 · Minerva medica
  • G. Saharov · Y. Nadir · A. Keren · B. Brenner · T. Shochat
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    ABSTRACT: Hemostatic markers and sleep quality among shift work and day work female nurses Background: The haemostatic system has a significant impact on cardiovascular morbidity. Epidemiologic studies indicate an increased risk of cardiovascular diseases amongst shift workers. Such risk may be attributed to circadian misalignment of haemostatic markers and restricted sleep time. To reveal some of the underlying mechanisms of cardiovascular morbidity in the shift-work population, we performed a comparison of the profiles of haemostatic markers among healthy shift working vs. daytime working female nurses. It was hypothesized that alterations in the haemostatic system may underlie the increased risk for cardiovascular illness in shift workers. Accordingly it was predicted, that haemostatic markers would be elevated in rotating shift workers compared to regular day workers, and that sleep quality would serve as a mediator in this relationship. Methods: Thirty shift working and thirty day working female nurses were recruited at Rambam Health-Care Campus (total n=60). For each participant, blood was drawn at 07:00 in the morning for the measurement of 6 markers of coagulation, including PAI-1, Heparanase procoagulant activity, tissue factor + heparanase complex, protein C, D-dimer and fibrinogen. Sleep quality was assessed by self report (Pittsburgh Sleep Quality Index, PSQI). Results: PAI-1 levels were significantly higher among shift work nurses compared to day work group (36.6 ng/ml vs 24.3 ng/ml, p<0.05). In shift workers, Heparanase procoagulant activity was 2-fold and tissue factor + heparanase complex was 1.5-fold compared to day work nurses (both p<0.05). Sleep quality was significantly lower for shift compared to day workers(p<0.001). No group differences were found for Protein C, D-dimer and fibrinogen. Concusions: PAI-1 and heparanase markers were significantly elevated and sleep quality reduced in shift-work compared to day-work nurses. Such alterations in healthy shift workers point at disturbances in haemostatic system, which may contribute to cardiovascular morbidity in the future.
    No preview · Article · Jan 2013 · Thrombosis Research
  • J.S. Younis · M. Ben-Ami · I. Izhaki · G. Sarig · B. Brenner

    No preview · Article · Jan 2013 · Thrombosis Research
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    ABSTRACT: BACKGROUND: Although long term indwelling central venous catheters (CVC) may lead to pulmonary embolism (PE) and loss of the CVC, there is lack of consensus on management of CVC related thrombosis (CRT) in cancer patients and heterogeneity in clinical practices worldwide. OBJECTIVES: To establish common international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer patients. METHODS: An international working group of experts was set up to develop GCPG according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the treatment of established CRT in cancer pts, we found no prospective randomized study, 2 non-randomized prospective studies and 1 retrospective study examining the efficacy and safety of Low Molecular Weight Heparin (LMWH) plus vitamin K antagonists (VKA). One retrospective study evaluated the benefit of CVC removal and 2 small retrospective studies on thrombolytic drugs. For the treatment of symptomatic CRT, anticoagulant treatment (AC) is recommended for a minimum of 3 months; in this setting, LMWH are suggested. VKA can be also be used, in the absence of direct comparisons of these two types of anticoagulants in this setting [Guidance]. The CVC can be kept in place if it is functional, well-positioned, non-infected and there is good resolution under close surveillance; whether the CVC is kept or removed, no standard approach in terms of AC duration is established [Guidance]. For the prophylaxis of CRT in cancer patients, we found 6 randomized studies investigating the efficacy and safety of VKA vs placebo or no treatment, 1 on the efficacy and safety of Unfractionnated Heparin, 6 on the value of LMWH, one double-blind randomized and 1 non randomized study on thrombolytic drugs with 6 meta-analyses of AC and CVC thromboprophylaxis. Type of catheter (open-ended like the Hickman(®) catheter versus closed-ended catheter with a valve like the Groshong(®) catheter), its position (above, below or at the junction of the superior vena cava and the right atrium), and method of placement may influence the onset of CRT on the basis of 6 retrospective, 4 prospective non-randomized trials, 3 randomized trials and 1 meta-analysis. In light of these data: Use of AC for routine prophylaxis of CRT is not recommended [1A]; CVC should be inserted on the right side, in the jugular vein, and distal extremity of the CVC should be located at the junction of the superior vena cava and the right atrium [1A]. CONCLUSION: Dissemination and implementation of these international GCPG for the prevention and treatment of CRT in cancer patients at each national level is a major public health priority, needing worldwide collaboration. © 2012 International Society on Thrombosis and Haemostasis.
    Full-text · Article · Dec 2012 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: BACKGROUND: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. OBJECTIVES: To establish a common international consensus addressing practical, clinically relevant questions in this setting. METHODS: An international consensus working group of experts was set up to develop guidelines according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the initial treatment of established VTE: low-molecular-weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case-by-case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long-term (beyond 3 months) treatment of established VTE, LMWH for a minimum of three months are preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3 to 6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit-risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: 1) switch from VKA to LMWH when treated with VKA; 2) increase in LMWH dose when treated with LMWH, and 3) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started. 12-2 hours preoperatively and continued for at least 7-10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (four weeks) after major laparotomy may be indicated in cancer patients with a high VTE risk and low bleeding risk [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with L-asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low bleeding risk; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low-dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl <30 mL/min), thrombocytopenia and pregnancy. Guidances are provided in these contexts. CONCLUSIONS: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority. © 2012 International Society on Thrombosis and Haemostasis.
    Full-text · Article · Dec 2012 · Journal of Thrombosis and Haemostasis
  • L. Issman · A. Aharon · B. Brenner · Y. Talmon

    No preview · Article · Apr 2012 · Thrombosis Research
  • G. Sarig · A. Meir · M. Wollner · I. Shafat · B. Brenner · N. Haim

    No preview · Article · Apr 2012 · Thrombosis Research

  • No preview · Article · Apr 2012 · Thrombosis Research

Publication Stats

3k Citations
535.03 Total Impact Points

Institutions

  • 1986-2015
    • Rambam Medical Center
      • • Department of Hematology
      • • Department of Ophthalmology
      • • Faculty of Medicine
      H̱efa, Haifa, Israel
  • 1986-2013
    • Technion - Israel Institute of Technology
      • • Ruth and Bruce Rappaport Faculty of Medicine
      • • Rambam Medical Center
      H̱efa, Haifa, Israel
  • 1992-2005
    • Sheba Medical Center
      • Department of Pathology
      Gan, Tel Aviv, Israel
  • 1993
    • Bank Of Israel
      Yerushalayim, Jerusalem District, Israel
  • 1988-1991
    • University of Vienna
      • Institute of Social Medicine
      Wien, Vienna, Austria