B Brenner

Rambam Medical Center, H̱efa, Haifa District, Israel

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Publications (146)911.18 Total impact

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    ABSTRACT: Venous thromboembolism is a frequent and serious complication in patients with cancer. It is an independent prognostic factor of death in cancer patients and the second leading cause of death, but physicians often underestimate its importance, as well as the need for adequate prevention and treatment. Management of venous thromboembolism in patients with cancer requires the coordinated efforts of a wide range of clinicians, highlighting the importance of a multidisciplinary approach. However, a lack of consensus among various national and international clinical practice guidelines has contributed to knowledge and practice gaps among practitioners, and inconsistent approaches to venous thromboembolism. The 2013 international guidelines for thrombosis in cancer have sought to address these gaps by critically re-evaluating the evidence coming from clinical trials and synthesizing a number of guidelines documents. An individualized approach to prophylaxis is recommended for all patients.
    Rambam Maimonides medical journal. 10/2014; 5(4):e0041.
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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.
    Thrombosis Research 09/2014; · 3.13 Impact Factor
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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.
    Thrombosis and Haemostasis 07/2014; 112(3). · 5.76 Impact Factor
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    ABSTRACT: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).
    New England Journal of Medicine 04/2014; 370(15):1402-11. · 54.42 Impact Factor
  • 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.
    Minerva medica 04/2013; 104(2):155-60. · 0.77 Impact Factor
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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.
    Journal of Thrombosis and Haemostasis 12/2012; · 6.08 Impact Factor
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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.
    Journal of Thrombosis and Haemostasis 12/2012; · 6.08 Impact Factor
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    ABSTRACT: One in every three patients with deep vein thrombosis (DVT) in the lower limbs may have silent pulmonary embolism (PE), but its clinical relevance has not been thoroughly studied. We used the RIETE Registry data to study patients with proximal DVT and no PE symptoms, but with a systematic search for PE. We compared the outcome of DVT patients with silent PE and those with no PE. Of 2375 patients with DVT, 842 (35%) had silent PE and 1533 had no PE. During the first 15 days of anticoagulation, patients presenting with silent PE had a higher incidence of symptomatic PE events than those with no PE (0.95% vs. 0.13%; P = 0.015), with a similar incidence of major bleeding (0.95% vs. 1.63%; P = 0.09). In patients with silent PE, the incidence of PE events during the first 15 days was equal to the incidence of major bleeding (eight events each), but in those with no PE the incidence of PE events was eight times lower (3 vs. 25 bleeding events). Multivariate analysis confirmed that DVT patients with silent PE had a higher incidence of symptomatic PE events during the first 15 days than those with no PE (odds ratio, 4.80; 95% CI, 1.27-18.1), with no differences in bleeding. DVT patients with silent PE at baseline had an increased incidence of symptomatic PE events during the first 15 days of anticoagulant therapy. This effect disappeared after 3 months of anticoagulation.
    Journal of Thrombosis and Haemostasis 01/2012; 10(4):564-71. · 6.08 Impact Factor
  • Autonomic Neuroscience-basic & Clinical - AUTON NEUROSCI-BASIC CLIN. 01/2011; 163(1):88-89.
  • Thrombosis Research - THROMB RES. 01/2011; 127.
  • Thrombosis Research - THROMB RES. 01/2011; 127.
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    ABSTRACT: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).
    New England Journal of Medicine 12/2010; 363(26):2499-510. · 54.42 Impact Factor
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    ABSTRACT: The efficacy and safety of anticoagulant treatment for patients with acute, symptomatic superficial-vein thrombosis in the legs, but without concomitant deep-vein thrombosis or symptomatic pulmonary embolism at presentation, have not been established. In a randomized, double-blind trial, we assigned 3002 patients to receive either fondaparinux, administered subcutaneously at a dose of 2.5 mg once daily, or placebo for 45 days. The primary efficacy outcome was a composite of death from any cause or symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis at day 47. The main safety outcome was major bleeding. The patients were followed until day 77. The primary efficacy outcome occurred in 13 of 1502 patients (0.9%) in the fondaparinux group and 88 of 1500 patients (5.9%) in the placebo group (relative risk reduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P<0.001). The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group, except for the outcome of death (0.1% in both groups). The rate of pulmonary embolism or deep-vein thrombosis was 85% lower in the fondaparinux group than in the placebo group (0.2% vs. 1.3%; 95% CI, 50 to 95; P<0.001). Similar risk reductions were observed at day 77. A total of 88 patients would need to be treated to prevent one instance of pulmonary embolism or deep-vein thrombosis. Major bleeding occurred in one patient in each group. The incidence of serious adverse events was 0.7% with fondaparinux and 1.1% with placebo. Fondaparinux at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with acute, symptomatic superficial-vein thrombosis of the legs and did not have serious side effects. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00443053.)
    New England Journal of Medicine 09/2010; 363(13):1222-32. · 54.42 Impact Factor
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    M Masoud, G Sarig, B Brenner, G Jacob
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    ABSTRACT: Prolonged standing activates the coagulation cascade by the activation of endothelial cells, and probably the haemoconcentration effect contributes to this "orthostatic hypercoagulability". It was the objective of this study to assess whether rehydration (haemodilution) prevents or attenuates orthostatic induced thrombin formation. Twelve healthy young subjects were studied during two separate visits. Haematocrit (Hct), total plasma protein, coagulation profile tests, including endothelial activation related factors, and protein C global pathway were studied at rest supine, and while standing at 15 and 30 minutes (min). During the second visit the study was repeated after intravenous 1.5 liter 0.9% saline. While in supine posture, intravenous rehydration resulted in Hct reduction of 14.2 +/- 2% (haemodilution), a decrease of 11.5 +/- 1.3% in total protein, as well as a significant dilutional effect on most of the coagulation parameters. Still standing for 30 min, with and without rehydration caused a comparable increase in tissue factor by 49.83 +/- 13.6%, and 35.34 +/- 8.55% (p>0.05), respectively and in von Willebrand factor (vWF) 9.5 +/- 2.4% and 13.59 +/- 2.17% (p>0.05), respectively. At 30 min standing, after intravenous rehydration, factor V and VIII activities, and fibrinogen rose by 22 +/- 1.9%, 31.2 +/- 6.2%, 9.15 +/- 2.64%, (p<0.002 for all), respectively. Prothrombin fragments 1+2 elevated by 84.84 +/- 15.3% (p<0.001). Comparable results were obtained with and without the rehydration. Additionally, protein C assay results decreased by 19.4 +/-1.7% and 17.5 +/- 2.6%, with and without fluids (p<0.05 for both). In healthy subjects, intravenous prophylactic rehydration with normal saline resulted in a haemodilution of all the coagulation parameters, but did neither attenuate nor prevent the orthostatic hypercoagulability.
    Thrombosis and Haemostasis 02/2010; 103(2):284-90. · 5.76 Impact Factor
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    ABSTRACT: Venous thromboembolism (VTE) is a leading cause of maternal death during pregnancy or postpartum, and in women using hormonal contraceptives. However, important issues concerning its natural history and therapy remain unsolved, and most of the protocols for treatment of VTE in this patient population are based on data extrapolated from other populations. RIETE is an ongoing registry of consecutive patients with objectively confirmed, symptomatic, acute VTE. We examined the clinical characteristics and three-month outcome of all enrolled women with pregnancy, postpartum or using hormonal contraceptives. As of December 2008, 173 pregnant women, 135 postpartum, and 798 contraceptive users were enrolled. Of these, 438 (40%) presented with pulmonary embolism (PE) and 668 with deep-vein thrombosis (DVT). Most women with acute PE had dyspnea (72%) or chest pain (75%), but only 2.0% had hypoxaemia. During the three-month study period, five women (0.45%; 95% CI: 0.17-1.00) died (3 had fatal PE), 13 (1.18%; 95% CI: 0.66-1.95) had VTE recurrences, and seven (0.63%; 95% CI: 0.28-1.25) major bleeding. Two of the three women with fatal PE died during the first few hours after arriving at the emergency ward, with no time to start any therapy. The outcome of pregnant or postpartum women with VTE is similar to that in contraceptive users, even though the treatment is different. The non-specific nature of PE signs may have caused some delay in PE diagnosis.
    Thrombosis and Haemostasis 02/2010; 103(2):306-11. · 5.76 Impact Factor
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    New England Journal of Medicine 01/2010; 363(13-363):1222-1232. · 54.42 Impact Factor
  • A. Aharon, B. Brenner
    Thrombosis Research - THROMB RES. 01/2010; 125.
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    Journal of Thrombosis and Haemostasis 04/2009; 7(6):1047-50. · 6.08 Impact Factor
  • Thrombosis Research 01/2009; 123. · 3.13 Impact Factor
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    01/2009;

Publication Stats

3k Citations
911.18 Total Impact Points

Institutions

  • 1986–2009
    • Rambam Medical Center
      • • Department of Hematology
      • • Department of Obstetrics and Gynecology A
      • • Department of Internal Medicine D
      H̱efa, Haifa District, Israel
  • 2005–2006
    • Ministry of Health (Israel)
      Yerushalayim, Jerusalem District, Israel
  • 1997–2005
    • Sheba Medical Center
      • Department of Pathology
      Gan, Tel Aviv, Israel
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 1986–2005
    • Technion - Israel Institute of Technology
      • • Rambam Medical Center
      • • Ruth and Bruce Rappaport Faculty of Medicine
      H̱efa, Haifa District, Israel
  • 1996–2000
    • Schneider Children's Medical Center of Israel
      Petah Tikva, Central District, Israel
  • 1993
    • Carmel Medical Center
      H̱efa, Haifa District, Israel
    • Bank Of Israel
      Yerushalayim, Jerusalem District, Israel
  • 1989–1992
    • Tel Aviv Sourasky Medical Center
      Tell Afif, Tel Aviv, Israel
  • 1988–1989
    • University of Vienna
      • • Universitätsklinik für Innere Medizin I
      • • Institute of Social Medicine
      Vienna, Vienna, Austria