Publications by authors named "Benjamin Brenner"

222 Publications

Symmetrically dispersed spectroscopic single-molecule localization microscopy.

Light Sci Appl 2020 May 25;9(1):92. Epub 2020 May 25.

Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd., Evanston, IL, 60208, USA.

Spectroscopic single-molecule localization microscopy (sSMLM) was used to achieve simultaneous imaging and spectral analysis of single molecules for the first time. Current sSMLM fundamentally suffers from a reduced photon budget because the photons from individual stochastic emissions are divided into spatial and spectral channels. Therefore, both spatial localization and spectral analysis only use a portion of the total photons, leading to reduced precisions in both channels. To improve the spatial and spectral precisions, we present symmetrically dispersed sSMLM, or SDsSMLM, to fully utilize all photons from individual stochastic emissions in both spatial and spectral channels. SDsSMLM achieved 10-nm spatial and 0.8-nm spectral precisions at a total photon budget of 1000. Compared with the existing sSMLM using a 1:3 splitting ratio between spatial and spectral channels, SDsSMLM improved the spatial and spectral precisions by 42% and 10%, respectively, under the same photon budget. We also demonstrated multicolour imaging of fixed cells and three-dimensional single-particle tracking using SDsSMLM. SDsSMLM enables more precise spectroscopic single-molecule analysis in broader cell biology and material science applications.
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http://dx.doi.org/10.1038/s41377-020-0333-9DOI Listing
May 2020

Direct oral anticoagulants versus enoxaparin in patients with atrial fibrillation and active cancer.

Eur J Intern Med 2021 May 10. Epub 2021 May 10.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2021.04.002DOI Listing
May 2021

Improving spatial precision and field-of-view in wavelength-tagged single-particle tracking using spectroscopic single-molecule localization microscopy.

Appl Opt 2021 May;60(13):3647-3658

Spectroscopic single-molecule localization microscopy (sSMLM) generates super-resolution images of single molecules while simultaneously capturing the spectra of their fluorescence emissions. However, sSMLM splits photons from single-molecule emissions into a spatial channel and a spectral channel, reducing both channels' precisions. It is also challenging in transmission grating-based sSMLM to achieve a large field-of-view (FOV) and avoid overlap between the spatial and spectral channels. The challenge in FOV has further significance in single-molecule tracking applications. In this work, we analyzed the correlation between the spatial and spectral channels in sSMLM to improve its spatial precision, and we developed a split-mirror assembly to enlarge its FOV. We demonstrate the benefits of these improvements by tracking quantum dots. We also show that we can reduce particle-identification ambiguity by tagging each particle with its unique spectral characteristics.
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http://dx.doi.org/10.1364/AO.415275DOI Listing
May 2021

SARS-CoV-2 vaccine and thrombosis: Expert opinions.

Thromb Haemost 2021 May 4. Epub 2021 May 4.

Department of Internal Medicine and Clinical Immunology, Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière,, Paris, France.

Historically, the vaccination strategies developed in the second half of the 20th century have permitted to eradicate infectious diseases. From the onset of COVID-19 pandemic to March 2021, more than 141 million cases and 3 million deaths were documented worldwide with disruption of the economic and social activity, devastating material, physical and psychological consequences. Reports of unusual and severe thrombotic events, including cerebral and splanchnic venous thrombosis and other autoimmune adverse reactions such as immune thrombocytopenia or thrombotic microangiopathies (TMA) in connection with some of the SARS-CoV-2 vaccine have caused a great deal of concern within the population and the medical community. This report is intended to provide practical answers following an overview of our knowledge on these thrombotic events that are extremely rare but have serious consequences. Vaccine hesitancy threatens to reverse the progress made in controlling vaccine-preventable diseases. These adverse events must be put into perspective with an objective analysis of the facts and the issues of the vaccination strategy during this SARS-Cov-2 pandemic. Healthcare professionals remain the most pertinent advisors and influencers regarding vaccination decisions; they have to be supported in order to provide reliable and credible information on vaccines. We need to inform, reassure and support our patients when the prescription is made. Facing these challenges and these observations, a panel of experts express their insights and propose a tracking algorithm for vaccinated patients based on a10-point guideline for decision-making on what to do and not to do.
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http://dx.doi.org/10.1055/a-1499-0119DOI Listing
May 2021

Editorial: Thrombotic Disorders, Prothrombotic Abnormalities and COVID-19.

Front Med (Lausanne) 2021 15;8:676137. Epub 2021 Apr 15.

Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa, Israel.

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http://dx.doi.org/10.3389/fmed.2021.676137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081886PMC
April 2021

Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity.

Mol Ther 2021 05 9;29(5):1808-1820. Epub 2021 Feb 9.

Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA. Electronic address:

The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy: incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.
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http://dx.doi.org/10.1016/j.ymthe.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116608PMC
May 2021

Protein C global assay evaluation in naturally conceived vs. assisted reproduction-achieved twin pregnancies: a prospective longitudinal study.

Arch Gynecol Obstet 2021 Jun 9;303(6):1549-1555. Epub 2021 Feb 9.

Hematology Laboratory, Rambam Health Care Campus, Haifa, Israel.

Purpose: Protein C global assay tests the global function of the protein C pathway, the most clinically significant anticoagulant pathway in humans. The objective of this study is to assess the difference in protein C global assay levels, throughout twin gestation, in naturally conceiving and ART-treated women.

Methods: This is a prospective cohort longitudinal study of pregnant women with twin gestation. Protein C Global evaluation was performed on frozen blood samples. Ninety-eight women with twin pregnancy, thirty-eight naturally conceived and sixty following ART, were evaluated on four occasions: during the first, second, and third trimesters, and 6 weeks or later after delivery (baseline).

Results: Protein C global assay levels were lower throughout pregnancy as compared to basal levels in both the naturally conceived and ART-conceived groups. However, protein C global assay levels were similar between the ART-conceived and naturally conceived twin pregnancies in all three trimesters. Perinatal complications were associated with decreased protein C global assay levels during the third trimester, although no difference was encountered between naturally conceived and ART-complicated twin pregnancies.

Conclusion: While protein C global assay levels drop during twin pregnancy, there is no difference between ART-conceived and naturally conceived gestations. Decreased levels of protein C global assay during the third trimester were similarly associated with perinatal complications in both groups. Our results imply that twin pregnancy of itself is a more dominant factor for perinatal complications as compared to other factors, such as subfertility or the exposure to ART per se.
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http://dx.doi.org/10.1007/s00404-020-05959-8DOI Listing
June 2021

Relevance of Heparan Sulfate and Heparanase to Severity of COVID-19 in the Elderly.

Semin Thromb Hemost 2021 06 11;47(4):348-350. Epub 2021 Jan 11.

Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa, Israel.

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http://dx.doi.org/10.1055/s-0040-1722293DOI Listing
June 2021

COVID-19-Associated Hyper-Fibrinolysis: Mechanism and Implementations.

Front Physiol 2020 16;11:596057. Epub 2020 Dec 16.

Coagulation Research Laboratory Unit, Department of Hematology, Rambam Medical Center, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

The emerging novel coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 presents with high infectivity, morbidity and mortality. It presenting a need for immediate understanding of its pathogenicity. Inflammation and coagulation systems are over-activated in COVID-19. SARS-CoV-2 damages endothelial cell and pneumocyte, resulting in hemostatic disorder and ARDS. An influential biomarkers of poor outcome in COVID-19 are high circulating cytokines and D-dimer level. This latter is due to hyper-fibrinolysis and hyper-coagulation. Plasmin is a key player in fibrinolysis and is involved in the cleavage of many viruses envelop proteins, including SARS-CoV. This function is similar to that of TMPRSS2, which underpins the entry of viruses into the host cell. In addition, plasmin is involved in the pathophysiology of ARDS in SARS and promotes secretion of cytokine, such as IL-6 and TNF, from activated macrophages. Here, we suggest an out-of-the-box treatment for alleviating fibrinolysis and the ARDS of COVID-19 patients. This proposed treatment is concomitant administration of an anti-fibrinolytic drug and the anticoagulant.
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http://dx.doi.org/10.3389/fphys.2020.596057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772395PMC
December 2020

Extracellular Vesicles Reflect the Efficacy of Wheatgrass Juice Supplement in Colon Cancer Patients During Adjuvant Chemotherapy.

Front Oncol 2020 26;10:1659. Epub 2020 Aug 26.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

Introduction: Colorectal cancer (CC) is the third most common type of cancer, accounting for 10% of all cancer cases. Adjuvant chemotherapy is recommended in stages II-III CC. Wheatgrass juice (WGJ) from wheat seeds has high nutritional values, may induce synergistic benefits to chemotherapy and may attenuate chemotherapy-related side effects. Extracellular vesicles (EVs) are subcellular membrane blebs. EVs include exosomes (generated in the endosome, in size <150 nm) and microvesicles (shed from the plasma cell membrane) provide information on their parental cells and play a role in intercellular communication. We aimed to elucidate the effects of chemotherapy administration with supportive treatment of WGJ on CC patients' EVs characteristics.

Methods: EVs were isolated from the blood samples of 15 healthy controls (HCs) and 50 CC patients post-surgery, treated by chemotherapy, with or without additional daily WGJ. Blood samples were taken before, during, and at the end of chemotherapy. EVs were characterized by size, concentration, membrane antigens and cytokine content using nanoparticle-tracking analysis, western blot, flow cytometry, and protein array methods.

Results: EVs were found to be similar by size and concentration with reduced levels of exosome markers (CD81) on samples at the end of combined treatment (chemotherapy and WGJ). Higher levels of endothelial EVs, which may indicate impairment of the vascular endothelial cells during treatment, were found in CC patients treated by chemotherapy only compared to those with chemotherapy and daily WGJ. Also, EVs thrombogenicity was lower in patients added WGJ compared to patients who had only chemotherapy (levels of tissue factor = 0.029 and endothelial protein C receptor = 0.005). Following treatments, levels of vascular endothelial growth factor receptors (VEGFR-1) and the majority of growth-factors/pro-inflammatory cytokines were higher in EVs of patients treated by chemotherapy only than in EVs obtained from patients with the combined treatment.

Conclusion: Daily consumption of WGJ during chemotherapy may reduce vascular damage and chemotherapy-related thrombogenicity, growth factors and cytokines, as reflected by the characteristics of patient's EVs.
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http://dx.doi.org/10.3389/fonc.2020.01659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479215PMC
August 2020

Immune-Mediated Coagulopathy in COVID-19 Infection.

Semin Thromb Hemost 2020 10 2;46(7):838-840. Epub 2020 Sep 2.

Proteomic and Clinical Flow Cytometry Unit, Bnai-Zion Medical Center, Haifa, Israel.

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http://dx.doi.org/10.1055/s-0040-1714272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645826PMC
October 2020

Thrombosis and Hemostasis Issues in Cancer Patients with COVID-19.

Semin Thromb Hemost 2020 10 12;46(7):785-788. Epub 2020 Aug 12.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

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http://dx.doi.org/10.1055/s-0040-1714275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645825PMC
October 2020

Thrombosis in hematological malignancies: mechanisms and implications.

Thromb Res 2020 07;191 Suppl 1:S58-S62

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.

A B S T R A C T Thrombotic events are a major cause of morbidity and mortality in cancer. While the association of venous thromboembolic events with cancer is well documented, in recent years arterial events (i.e. acute myocardial infarction and ischemic strokes) have also emerged as relatively common complications among cancer patients. In hematological malignancies incorporating a heterogeneous group of diseases, the prediction of thrombosis occurrence and/or recurrence is challenging, due to unique disease characteristics. Furthermore, the treatment of thrombosis in these patients is often complicated because of disease- or therapy-related thrombocytopenia. In addition, patients with hematological cancers are poorly represented in randomized control clinical trials; hence, evidence-based guidelines are limited. This review will discuss the incidence of venous and arterial thrombotic events in common myeloid and lymphoproliferative diseases. Several new mechanisms contributing to cancer- associated thrombosis will be elaborated. The complicated issue of risk assessment and management of venous thrombosis in patients with hematological malignancies will be delineated.
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http://dx.doi.org/10.1016/S0049-3848(20)30398-4DOI Listing
July 2020

Preface to the Proceedings of the 10 International Conference on Thrombosis and Hemostasis Issues in Cancer, 2020.

Thromb Res 2020 07;191 Suppl 1:S1-S2

Department of Hematology and Medical Oncology, Taussig Cancer Institute and Case Comprehensive Cancer Center, Cleveland Clinic, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1016/S0049-3848(20)30412-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386479PMC
July 2020

Management and outcomes of cancer patients with venous thromboembolism presenting with thrombocytopenia.

Thromb Res 2020 11 10;195:139-145. Epub 2020 Jul 10.

A full list of the RIETE investigators is given in the appendix.

Introduction: Treatment of venous thromboembolism (VTE) in cancer patients with thrombocytopenia is challenging due to perceived higher risk of bleeding.

Material And Methods: We used the RIETE registry to compare the 10- and 30-day outcomes in cancer patients with acute VTE, according to platelet count at baseline.

Results: As of December 2018, 15,337 cancer patients with VTE were included: 166 (1.1%) had <50 × 10 platelets/L (severe thrombocytopenia), 711 (4.6%) had 50-99 × 10/L (mild thrombocytopenia) and 14,460 (94.3%) had ≥100 × 10/L (normal count). Most patients in all subgroups received initial therapy with low-molecular-weight heparin (LMWH), but 62% of those with severe thrombocytopenia received <150 IU/kg/day LMWH, 42% received <100 IU/kg/day. The mortality rate progressively decreased with increasing platelet counts (12%, 9.4% and 3.3% respectively at 10 days, 27%, 18% and 9.4% at 30 days), but the major bleeding rates did not (1.2%, 2.5% and 1.3% respectively at 10 days, 2.4%, 4.4% and 2.2% at 30 days). On multivariable analysis, patients with severe thrombocytopenia had a similar risk for major bleeding at 10 days (OR 0.84; 95%CI 0.20-3.49) and at 30 days (OR 0.90; 95%CI 0.32-2.49), but those with mild thrombocytopenia were at increased risk both at 10 days (OR 2.11; 95%CI 1.27-3.49) and at 30 days (OR 1.91; 95%CI 1.29-2.84).

Conclusions: Cancer patients with acute VTE and baseline thrombocytopenia often receive initial lower-than recommended doses of LMWH. Although caution is required, this practice seems to be safe in patients with severe thrombocytopenia. Nonetheless, there was an inverse correlation between baseline platelet count and mortality.
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http://dx.doi.org/10.1016/j.thromres.2020.07.021DOI Listing
November 2020

Extracellular Vesicles of Alzheimer's Disease Patients as a Biomarker for Disease Progression.

Mol Neurobiol 2020 Oct 17;57(10):4156-4169. Epub 2020 Jul 17.

Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Alzheimer's disease (AD) is a progressive neurodegenerative brain pathology and the most common form of dementia. Evidence suggests that extracellular vesicles (EVs) containing cytokines and microRNA are involved in inflammation regulation. The current study aimed to explore a potential impact of AD patients' EVs on disease progression. Blood samples were collected after obtaining signed informed consent (No. 0462-14-RMB) from 42 AD patients at three stages of disease severity and from 19 healthy controls (HC). EV size and concentration were studied by nanotracking analysis. EV membrane antigens were defined by flow cytometry and Western blot; EV protein contents were screened by protein array; the miRNA content was screened by nanostring technology and validated by RT-PCR. HC and AD patients' EVs consisted of a mixture of small (< 100 nm) and larger vesicles. The myelin oligodendrocyte glycoprotein (MOG) expression on EVs correlated with disease severity. EVs of patients with moderate and severe AD had significantly higher levels of MOG, compared with mild AD patients. Levels of EVs expressing the axonal glycoprotein CD171 were significantly higher in severe AD patients than in HC. Increase in endothelial EVs was observed in AD patients. An above twofold increase was found in the content of inflammatory cytokines and > 50% decrease in growth factors in AD patients' EVs compared with HC-EVs. Levels of let-7g-5p, miR126-3p, miR142-3p, miR-146a-5p, and mir223-3p correlated with disease severity. Neural damage, specific miRNA downregulation, and inflammatory cytokine upregulation, found in patients' EVs, might be used as a biomarker reflecting AD severity.
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http://dx.doi.org/10.1007/s12035-020-02013-1DOI Listing
October 2020

Symmetrically dispersed spectroscopic single-molecule localization microscopy.

Light Sci Appl 2020 25;9:92. Epub 2020 May 25.

Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd., Evanston, IL 60208 USA.

Spectroscopic single-molecule localization microscopy (sSMLM) was used to achieve simultaneous imaging and spectral analysis of single molecules for the first time. Current sSMLM fundamentally suffers from a reduced photon budget because the photons from individual stochastic emissions are divided into spatial and spectral channels. Therefore, both spatial localization and spectral analysis only use a portion of the total photons, leading to reduced precisions in both channels. To improve the spatial and spectral precisions, we present symmetrically dispersed sSMLM, or SDsSMLM, to fully utilize all photons from individual stochastic emissions in both spatial and spectral channels. SDsSMLM achieved 10-nm spatial and 0.8-nm spectral precisions at a total photon budget of 1000. Compared with the existing sSMLM using a 1:3 splitting ratio between spatial and spectral channels, SDsSMLM improved the spatial and spectral precisions by 42% and 10%, respectively, under the same photon budget. We also demonstrated multicolour imaging of fixed cells and three-dimensional single-particle tracking using SDsSMLM. SDsSMLM enables more precise spectroscopic single-molecule analysis in broader cell biology and material science applications.
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http://dx.doi.org/10.1038/s41377-020-0333-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248114PMC
May 2020

Psychotropic Drugs and Outcome in Patients Receiving Anticoagulant Therapy for Venous Thromboembolism.

Thromb Haemost 2020 Apr 14;120(4):620-626. Epub 2020 Apr 14.

Department of Internal Medicine, Hospital Germans Trias i Pujol, Universidad Autónoma de Barcelona, Badalona, Barcelona, Spain.

Background:  The influence (if any) of the use of psychotropic drugs on outcome in patients receiving anticoagulant therapy for venous thromboembolism (VTE) has not been consistently evaluated.

Methods:  We used data from the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the risk for VTE recurrences, major bleeding, or death during the course of anticoagulant therapy, according to the use of psychotropics at baseline.

Results:  Among 49,007 patients with VTE enrolled from February 2009 to September 2019, total 5,230 (11%) were using psychotropics at baseline: antidepressants 3,273 (6.7%), antipsychotics 1,588 (3.2%), and anticholinesterases 369 (0.7%). During the course of anticoagulation, 1,259 patients developed VTE recurrences, 1,231 bled, and 3,988 died (fatal pulmonary embolism 269 and fatal bleeding 187). On multivariable analysis, patients using psychotropics at baseline had a similar risk for VTE recurrences (adjusted hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.58-1.12), a nonsignificantly higher risk for major bleeding (adjusted HR: 1.15; 95% CI: 0.97-1.35), and a higher risk for intracranial bleeding (adjusted HR: 1.83; 95% CI: 1.32-2.53) or death (adjusted HR: 1.44; 95% CI: 1.32-1.57) compared with those not using psychotropics. When separately analyzed, the highest risk for intracranial bleeding was found in patients using antidepressants (adjusted HR: 1.60; 95% CI: 1.08-2.37) or antipsychotics (adjusted HR: 2.02; 95% CI: 1.17-3.49) but not in those on anticholinesterases (adjusted HR: 1.69; 95% CI: 0.62-4.60).

Conclusion:  During the course anticoagulation for VTE, patients using psychotropics at baseline were at increased risk for intracranial bleeding.
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http://dx.doi.org/10.1055/s-0040-1708482DOI Listing
April 2020

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.

N Engl J Med 2020 04 29;382(17):1599-1607. Epub 2020 Mar 29.

From the Internal Vascular and Emergency Medicine-Stroke Unit, University of Perugia, Perugia (G.A., C.B., M.V.), Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti (FADOI) Research Center, Milan (G.G.), the Department of Medicine, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara (M.C.), the Department of Medicine, Buon Consiglio-Fatebenefratelli Hospital, Naples (A.F.), and Internal Medicine, Azienda Ospedale-Università, Padua (G.V.) - all in Italy; Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, and INNOVTE, Saint-Etienne (G.M.) - both in France; Instituto de Investigatión Sanitaria Gregorio Marañon, Universidad Complûtense, Madrid (A.M.); the Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands (M.V.H.); the Hematology Division, Brigham and Women's Hospital, and Harvard Medical School, Boston (J.M.C.); Guy's and St. Thomas' NHS Foundation Trust Hospital, King's College London, London (A.C.); the Department of Vascular Medicine, Darmstadt, and Center for Thrombosis and Hemostasis, University of Mainz, Mainz (R.B.) - both in Germany; the Institute of Hematology and Bone Marrow Transplantation Unit, Rambam Health Care Campus Technion, Israel Institute of Technology, Haifa (B.B.); the Departments of Pulmonary Circulation, Thromboembolic Diseases, and Cardiology, Center for Postgraduate Medical Education, Europejskie Centrum Zdrowia, Otwock, Poland (A.T.); the Surgical Oncology Department, Institut Português de Oncologia do Porto, Porto, Portugal (M.R.S.); and Cliniques Universitaires Saint-Luc, Brussels (C.L.).

Background: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use.

Methods: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding.

Results: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60).

Conclusions: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).
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http://dx.doi.org/10.1056/NEJMoa1915103DOI Listing
April 2020

Comparison of international societal guidelines for the diagnosis of suspected pulmonary embolism during pregnancy.

Lancet Haematol 2020 Mar;7(3):e247-e258

Department of Medicine, Northwell Health, Manhasset, NY, USA; Center for Health Innovations and Outcomes Research, Feinstein Institutes for Medical Research and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.

Pregnancy-associated pulmonary embolism is one of the leading causes of maternal mortality. Diagnosis of pulmonary embolism in pregnancy is challenging, with symptoms of pulmonary embolism mimicking those of pregnancy. Several key components such as clinical prediction tools, risk stratification, laboratory tests, and imaging widely used for diagnosis of pulmonary embolism in the non-pregnant population show limitations for diagnosis in pregnancy. Further, because of the difficulty of studying pregnant patients, high-quality research evaluating the performance of these diagnostic components in pregnancy is scarce. Seven international medical society guidelines present clinical diagnostic pathways for evaluation of pulmonary embolism in pregnancy that show conflicting recommendations on the use of these diagnostic components. This Review assesses all key components of diagnostic clinical pathways recommended by guidelines for evaluation of pulmonary embolism in pregnancy, reviews current evidence, compares the guideline recommendations with respect to each key component, and provides our preferred diagnostic pathway. It provides the guidelines and available data needed for informed decision making to diagnose pulmonary embolism in pregnancy.
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http://dx.doi.org/10.1016/S2352-3026(19)30250-9DOI Listing
March 2020

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in at-risk patient groups: pregnancy, elderly and obese patients.

Thromb J 2019 27;17:24. Epub 2019 Dec 27.

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China.

Background: Venous thromboembolism (VTE) accounts for an estimated 900,000 cases per year in the US alone and constitutes a considerable burden on healthcare systems across the globe.

Objective: To understand why the burden is so high, qualitative and quantitative research was carried out to gain insights from experts, guidelines and published studies on the unmet clinical needs and therapeutic strategies in VTE prevention and treatment in three populations identified as being at increased risk of VTE and in whom VTE prevention and treatment were regarded as suboptimal: pregnant women, the elderly and obese patients.

Methodology: A gap analysis methodology was created to highlight unmet needs in VTE management and to discover the patient populations considered most at risk. A questionnaire was devised to guide qualitative interviews with 44 thrombosis and haemostasis experts, and a review of the literature on VTE in the specific patient groups from 2015 to 2017 was completed. This was followed by a Think Tank meeting where the results from the research were discussed.

Results: This review highlights the insights gained and examines in detail the unmet needs with regard to VTE risk-assessment tools, biomarkers, patient stratification methods, and anticoagulant and dosing regimens in pregnant women, the elderly and obese patients.

Conclusions: Specifically, in pregnant women at high risk of VTE, low-molecular-weight heparin (LMWH) is the therapy of choice, but it remains unclear how to use anticoagulants when VTE risk is intermediate. In elderly patients, evaluation of the benefit of VTE prophylaxis against the bleeding risk is particularly important, and a head-to-head comparison of efficacy and safety of LMWH versus direct oral anticoagulants is needed. Finally, in obese patients, lack of guidance on anticoagulant dose adjustment to body weight has emerged as a major obstacle in effective prophylaxis and treatment of VTE.
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http://dx.doi.org/10.1186/s12959-019-0214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935082PMC
December 2019

Incidence of major adverse cardiovascular events among patients with provoked and unprovoked venous thromboembolism: Findings from the Registro Informatizado de Enfermedad Tromboembólica Registry.

J Vasc Surg Venous Lymphat Disord 2020 05 26;8(3):353-359.e1. Epub 2019 Nov 26.

Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; Department of Internal Medicine, Universidad Católica de Murcia, Murcia, Spain.

Objective: Overlap exists between the risk factors for coronary artery disease and venous thromboembolism (VTE). However, a paucity of data is available on the incidence of major acute cardiovascular events (MACE) and major adverse limb events (MALE) among patients presenting with VTE. Moreover, it is unknown whether the rate of cardiovascular outcomes differs among patients with unprovoked vs provoked VTE.

Methods: We analyzed the data from 2009 to 2017 in the Registro Informatizado de Enfermedad Tromboembólica registry, an ongoing, multicenter, international registry of consecutive patients with a diagnosis of objectively confirmed VTE. The query was restricted it to patients with data entry for the arterial outcomes. The baseline prevalence of coronary artery disease risk factors was compared between patients with provoked (ie, immobility, cancer, surgery, travel >6 hours, hormonal causes) and unprovoked VTE. After the initial VTE event, we followed up patients for the composite primary outcome of incident MACE (ie, stroke, myocardial infarction, unstable angina) and/or MALE (ie, major limb events). We used the χ test for baseline associations and a Cox proportional hazard for multivariate analysis. We used IBM SPSS, version 24 (IBM Corp, Armonk, NY) for statistical analysis. A P value of <.05 was considered statistically significant.

Results: We analyzed the data from 41,259 patients with VTE, of whom 22,633 (55.6%) had experienced a provoked VTE. During follow-up, the patients with provoked VTE were more likely to develop MACE or MALE than were patients with unprovoked VTE (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5). The association of arterial events with recent immobility (HR, 1.4; 95% CI, 1.5-12.1) and cancer (HR, 1.7; 95% CI, 1.4-1.9) was strong. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE, compared with unprovoked VTE, was significantly associated with an increased hazard for MACE (HR, 1.4; 95% CI, 1.1-1.7). Cancer remained a significant adjusted predictor for both MACE (HR, 1.7; 95% CI, 1.4-2.1) and MALE (HR, 2.1; 95% CI 1.01-4.6) in those with provoked VTE.

Conclusions: Among patients with VTE, provoked cases, specifically those with cancer-associated VTE, have an increased risk of major arterial events.
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http://dx.doi.org/10.1016/j.jvsv.2019.03.011DOI Listing
May 2020

2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.

Lancet Oncol 2019 10 3;20(10):e566-e581. Epub 2019 Sep 3.

Department of Medicine, McMaster University, Hamilton ON, Canada.

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.
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http://dx.doi.org/10.1016/S1470-2045(19)30336-5DOI Listing
October 2019

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in high-risk patient groups: cancer and critically ill.

Thromb J 2019 15;17. Epub 2019 Apr 15.

9Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China.

Background: Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups.

Objective: To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill.

Methodology: To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts.

Results: The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment.

Conclusions: Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins.
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http://dx.doi.org/10.1186/s12959-019-0196-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466798PMC
April 2019

[ACQUIRED HEMOPHILIA A AND THE TIMING OF IMMUNOMODULATORY THERAPY].

Harefuah 2019 Mar;158(3):165-167

Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa, Israel.

Introduction: Acquired hemophilia A is an autoimmune disease affecting men and women equally and is idiopathic in 50% of the cases. As the mortality rate reaches 50%, prompt diagnosis and treatment are needed. Diagnosis is made in a patient with a bleeding manifestation and prolonged PTT (partial thromboplastin time) that is not corrected in a mixing study with normal plasma. The level of antibodies in the plasma is measured by Bethesda units and a level above 5 units is considered high. Patients with a high titer of antibodies are treated with factor VIII, prothrombin complex, recombinant factor VIIa and tranexamic acid, in combination with immunomodulatory therapy, including steroids, cyclophosphamide, rituximab and immunoglobulins. The timing of rituximab therapy remains debatable. To date, it has not been established whether to use it as a first-line or second-line therapy. According to the currently available literature that relies on a database, the use of rituximab as a first-line modality increased survival without increasing the rate of infections, compared to steroids alone or steroids combined with cyclophosphamide. The current article describes a 79-year old woman who presented with diffuse hematomas in the limbs. A rapid diagnosis and treatment, including factor VIII, tranexamic acid, steroids, cyclophosphamide and rituximab as a first-line therapy, facilitated her complete recovery at a one-year follow-up.
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March 2019

[EXPERIENCE IN DIAGNOSTIC ASSAYS FOR HEPARIN-INDUCED THROMBOCYTOPENIA - EXPERIENCE OF A TERTIARY HOSPITAL IN ISRAEL].

Harefuah 2019 Mar;158(3):160-164

Hematology Laboratory, Rambam Health Care Campus, Haifa, Israel.

Aims: To analyze the experience of a tertiary medical center in clinical and laboratory diagnosis of suspected HIT.

Background: The diagnosis of heparin-induced thrombocytopenia (HIT) requires clinical data and laboratory detection of platelet activating factor 4/heparin (PF4/H) antibodies by immunological or functional assays. Although antigen screening assays are widely used, the functional assays are performed only by several expert labs.

Methods: A retrospective review of the Hematology Laboratory database on patients evaluated between the years 2008-2016 at Rambam, identified 412 individuals with clinical suspicion of HIT. Till 2011, 135 cases were screened using particle gel PaGIA (Biorad) and between the years 2012-2016, a total of 277 cases were screened by lateral flow Milenia (Biotec GmbH). All patients diagnosed with HIT were treated with Fondaparinux (Arixtra). Functional assay with heparin/LMWH induced platelet aggregation was performed using light transmission aggregometry (Helena AggRAM) to validate borderline or positive results in indistinct cases.

Results: From the tested samples, 63% vs. 75% were negative in PaGIA and Milenia, respectively (P=0.03), and were considered negative for HIT. During 2008-2011, only 38% of cases with non-negative immunoassay results underwent functional aggregation, whereas, in 2012-2016, 83% of such cases were further evaluated. None of the borderline PaGIA samples was positive in the functional assay compared to 13.3% borderline Milenia results; 25% of positive PaGIA and 51.7% of positive Milenia were confirmed by a positive functional HIT assay (P=N.S.). The survival rate among 14 patients with a positive functional assay was 42.7 % (6 patients).

Conclusions: The Milenia assay introduced at our lab in 2012, has improved the screening process. The functional assay provides a more accurate HIT diagnosis. The combined approach of an optimal laboratory and clinical investigation is crucial to obtain a precise HIT diagnosis.
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March 2019

Extracellular vesicles of multiple myeloma cells utilize the proteasome inhibitor mechanism to moderate endothelial angiogenesis.

Angiogenesis 2019 02 1;22(1):185-196. Epub 2018 Nov 1.

Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Bone marrow microenvironment is known to support angiogenesis, thus contributing to progression of multiple myeloma (MM). Bortezomib, a proteasome inhibitor (PI) widely used in MM treatment, has anti-angiogenic activity. Extracellular vesicles (EVs), shedding from cell surface, serve as mediators in cell-to-cell communication. We have hypothesized that MM cells (MMCs) treated with bortezomib generate EVs that could diminish angiogenesis, thus limiting MM progression. In the present study, EVs were obtained from MMCs (RPMI-8226), untreated (naïve) or pre-treated with bortezomib. EVs were outlined using NanoSight, FACS, protein arrays and proteasome activity assays. The impact of MMC-EVs on endothelial cell (EC) functions was assessed, employing XTT assay, Boyden chamber and Western blot. A high apoptosis level (annexin V binding 70.25 ± 16.37%) was observed in MMCs following exposure to bortezomib. Compared to naïve EVs, a large proportion of bortezomib-induced EVs (Bi-EVs) were bigger in size (> 300 nm), with higher levels of annexin V binding (p = 0.0043).They also differed in content, presenting with increased levels of pro-inflammatory proteins, reduced levels of pro-angiogenic growth factors (VEGFA, PDGF-BB, angiogenin), and displayed lower proteasome activity. Naïve EVs were found to promote EC migration and proliferation via ERK1/2 and JNK1/2/3 phosphorylation, whereas Bi-EVs inhibited these functions. Moreover, Bi-EVs appeared to reduce EC proteasome activity. EVs released from apoptotic MMCs following treatment with bortezomib can promote angiogenesis suppression by decreasing proliferation and migration of EC. These activities are found to be mediated by specific signal transduction pathways.
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http://dx.doi.org/10.1007/s10456-018-9649-yDOI Listing
February 2019

Hemostasis and Thrombosis in Extreme Physiological and Pathological Conditions.

Semin Thromb Hemost 2018 Oct 25;44(7):615-616. Epub 2018 Sep 25.

Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1055/s-0038-1666826DOI Listing
October 2018

Extracellular Vesicle Characteristics in β-thalassemia as Potential Biomarkers for Spleen Functional Status and Ineffective Erythropoiesis.

Front Physiol 2018 30;9:1214. Epub 2018 Aug 30.

The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

β-thalassemia major (β-TM) is a therapeutically challenging chronic disease in which ineffective erythropoiesis is a main pathophysiological factor. Extracellular vesicles (EVs) are membrane-enclosed vesicles released by cells into biological fluids; they are involved in intercellular communication and in multiple physiological and pathological processes. The chaperone heat-shock protein 70 (HSP70), which is released from cells via EVs, aggravates ineffective erythropoiesis in β-TM. We propose that β-TM EVs may show specific signatures, reflecting disease mechanisms, stages and severity. Our study aims were to define EV profiles in β-TM patients, investigate the influence of hypersplenism and splenectomy on EV features, and explore the association of circulating EVs with ineffective erythropoiesis and iron-overload parameters. We characterized circulating EVs in 35 transfusion-dependent β-thalassemia patients and 35 controls using several techniques. Nanoparticle-tracking analysis revealed increased EV concentration in patients vs. controls ( = 0.0036), with smaller EV counts and sizes in patients with hypersplenism. Flow cytometry analysis showed lower levels of RBC and monocyte EVs in patients vs. controls. RBC-EV levels correlated with patient hematocrit, reflecting degree of anemia. The procoagulant potential of the EVs evaluated by flow cytometry revealed lower levels of endothelial protein C receptor-labeled EVs in patients vs. controls, and increased tissue factor-to-tissue factor pathway inhibitor-labeled EV ratio in splenectomized patients, suggesting a hypercoagulable state. Protein content, evaluated in EV pellets, showed increased levels of HSP70 in patients ( = 0.0018), inversely correlated with transfusion requirement and hemoglobin levels, and positively correlated with reticulocyte, erythropoietin and lactate dehydrogenase levels. This first description of EVs in patients with hypersplenism reveals the spleen's importance in EV physiology and clearance. Circulating EV-HSP70 levels were associated with markers of ineffective erythropoiesis, hemolysis and hematological disease severity. EV analysis in β-TM-reflecting spleen status, hypercoagulability state and ineffective erythropoiesis-may serve as a biomarker of disease dynamics, supporting both anticipation of the risk of complications and optimizing treatment.
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http://dx.doi.org/10.3389/fphys.2018.01214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125348PMC
August 2018