Publications by authors named "Ron Hoffman"

41 Publications

The interRAI Suite of Mental Health Assessment Instruments: An Integrated System for the Continuum of Care.

Front Psychiatry 2019 17;10:926. Epub 2020 Jan 17.

LUCAS Center for Care Research and Consultancy & Academic Center for General Practice in the Department of Public Health and Primary Care, KU Leuven University, Leuven, Belgium.

The lives of persons living with mental illness are affected by psychological, biological, social, economic, and environmental factors over the life course. It is therefore unlikely that simple preventive strategies, clinical treatments, therapeutic interventions, or policy options will succeed as singular solutions for the challenges of mental illness. Persons living with mental illness receive services and supports in multiple settings across the health care continuum that are often fragmented, uncoordinated, and inadequately responsive. Appropriate assessment is an important tool that health systems must deploy to respond to the strengths, preferences, and needs of persons with mental illness. However, standard approaches are often focused on measurement of psychiatric symptoms without taking a broader perspective to address issues like growth, development, and aging; physical health and disability; social relationships; economic resources; housing; substance use; involvement with criminal justice; stigma; and recovery. Using conglomerations of instruments to cover more domains is impractical, inconsistent, and incomplete while posing considerable assessment burden. interRAI mental health instruments were developed by a network of over 100 researchers, clinicians, and policy experts from over 35 nations. This includes assessment systems for adults in inpatient psychiatry, community mental health, emergency departments, mobile crisis teams, and long-term care settings, as well as a screening system for police officers. A similar set of instruments is available for child/youth mental health. The instruments form an integrated mental health information system because they share a common assessment language, conceptual basis, clinical emphasis, data collection approach, data elements, and care planning protocols. The key applications of these instruments include care planning, outcome measurement, quality improvement, and resource allocation. The composition of these instruments and psychometric properties are reviewed, and examples related to homeless are used to illustrate the various applications of these assessment systems.
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http://dx.doi.org/10.3389/fpsyt.2019.00926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978285PMC
January 2020

BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study.

Blood Adv 2019 11;3(22):3740-3749

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

High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2 per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2 per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.
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http://dx.doi.org/10.1182/bloodadvances.2019000468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880904PMC
November 2019

Non-ST-Elevation Myocardial Infarction with Non-significant Coronary Artery Disease as a Symptom of Occult or New Malignancy.

Isr Med Assoc J 2019 Jun;21(6):381-385

Department of Internal Medicine C, Rambam Health Care Campus, Haifa, Israel.

Background: Malignancy is a known risk factor for venous thromboembolism; however, the association with arterial thromboembolic events remains unclear.

Objectives: To examine the association between non-ST-elevation myocardial infarction (NSTEMI) and non-significant coronary artery disease (CAD) and the presence of new or occult malignancy.

Methods: An observational cohort, single-center study was performed 2010-2015. Adult patients with NSTEMI, who underwent coronary angiography and had no significant coronary lesion, were included. Using propensity score matching, we created a 2:1 matched control group of adults with NSTEMI, and significant coronary artery disease. Risk factors for new or occult malignancy were assessed using multivariate backward stepwise logistic regression analysis. The primary outcome was new or occult malignancy, defined as any malignancy diagnosed in the 3 months prior and 6 months following the myocardial infarction (MI).

Results: During the study period, 174 patients who presented with MI with non-obstructive coronary arteries were identified. The matched control group included 348 patients. There was no significant difference in the group demographics, past medical history, or clinical presentation. The incidence of new or occult malignancy in the study group was significantly higher (7/174, 4% vs. 3/348, 0.9%, P = 0.019). NSTEMI with non-significant CAD was an independent risk factor for occult malignancy (odds ratio [OR] 4.6, 95% confidence interval [95%CI] 1.1-18.7). Other risk factors included active smoking (OR 11.2, 95%CI 2.5-49.1) and age (OR 1.1, 95%CI 1.03-1.17).

Conclusions: NSTEMI with non-significant CAD may be a presenting or early marker of malignancy and warrants further investigation.
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June 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

Hemostasis and Thrombosis in the Oldest Old.

Semin Thromb Hemost 2018 Oct 19;44(7):624-631. Epub 2018 Jun 19.

Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.

There is a growing proportion of the elderly population in the Western world, and these individuals require special considerations regarding a broad variety of aspects, including treatment approaches to illnesses that affect all age groups. The hemostatic system in individuals changes considerably with aging. Specifically, changes in levels of procoagulant and natural anticoagulant factors along with thrombopathy simultaneously create a hypercoagulable state and hemostatic difficulties. Underlying morbidities, such as congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and cancer, increase the risk for venous and arterial thrombosis. This population is also increasingly affected by acquired bleeding disorders, including acquired hemophilia and acquired von Willebrand syndrome, as well as mild congenital bleeding disorders. Real-life data demonstrate that recurrent and fatal venous thromboembolism is the major hemostatic concern in the elderly. The fact that treatment of thrombotic complications increases the bleeding risk also has to be taken into consideration, particularly in the older age group. This remains true in the era of direct oral anticoagulants. In conclusion, maintaining a delicate balance between thrombosis and bleeding risks is the key issue in providing qualified treatment to elderly patients.
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http://dx.doi.org/10.1055/s-0038-1657779DOI Listing
October 2018

Clinical significance of prothrombin G20210A mutation in homozygous patients.

Am J Hematol 2017 Oct 17;92(10):E618-E620. Epub 2017 Aug 17.

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

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http://dx.doi.org/10.1002/ajh.24859DOI Listing
October 2017

Does molecular analysis increase the efficacy of bronchoalveolar lavage in the diagnosis and management of respiratory infections in hemato-oncological patients?

Int J Infect Dis 2016 Sep 30;50:48-53. Epub 2016 Jul 30.

Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objectives: The identification of the specific pathogen responsible for a respiratory infection in patients with hematological malignancies (HM) would ensure relevant treatment and prevent toxicity associated with anti-infective therapy. This large-scale study aimed to explore the clinical impact of fiberoptic bronchoscopy with bronchoalveolar lavage (FOB-BAL) in conjunction with molecular analysis on the diagnosis and management of respiratory infections in hemato-oncological patients.

Methods: All consecutive patients with HM and pulmonary infiltrates, who underwent FOB-BAL between January 2008 and January 2013, were included in the analysis. Clinical characteristics, FOB-BAL results, and treatment adjustments were recorded, and factors predicting a positive BAL were assessed.

Results: Four hundred and twenty-five FOB-BAL procedures were analyzed. BAL revealed a specific diagnosis in 219 (51.5%) patients, 208 of them with a pulmonary infection. Infectious etiological agents found were mainly Aspergillus spp (n=142), bacterial species (n=44), and Pneumocystis jirovecii (n=34). Multivariate analysis showed that a lymphoproliferative disease, ≥2 symptoms (dyspnea/cough/hemoptysis/pleuritic pain), and less than 4 days between symptom appearance and FOB-BAL, predicted a positive FOB-BAL result. BAL results prompted a treatment modification in 48% of subjects.

Conclusions: FOB-BAL in conjunction with molecular assays is efficient in the rapid detection of life-threatening infections, allowing for adjustment of anti-infective therapy, which may result in better outcomes and reduce treatment-related toxicity.
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http://dx.doi.org/10.1016/j.ijid.2016.07.011DOI Listing
September 2016

Dehydration as a Possible Cause of Monthly Variation in the Incidence of Venous Thromboembolism.

Clin Appl Thromb Hemost 2016 Sep 19;22(6):569-74. Epub 2016 May 19.

Department of Hematology, Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa, Israel The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

Background: Monthly or seasonal changes in the incidence of venous thromboembolism (VTE) were previously reported; however, the mechanism of such variability is not completely understood.

Methods: In the present retrospective single-center analysis, consecutive patients with proximal deep vein thrombosis and/or pulmonary embolism (PE) diagnosed between January 2009 and December 2013 were evaluated.

Results: The study population included 1496 patients, 48% men, mean age 63 ± 18 years. Most (82%) cases with VTE were provoked and 39% of patients had active cancer. Four months of peak incidence (3, 7, 10 and 11) were compared with 4 months of the lowest incidence (4, 5, 6, and 12), showing a significant difference in VTE numbers (597 vs 405 cases/year, P = 0.001). In all subgroup analyses, including gender, provoked or unprovoked event and presence or absence of cancer, significant differences between the months of peak and lowest incidence remained. Blood urea nitrogen (BUN)-creatinine ratio was significantly higher in all cases in the peak incidence group compared to the lowest incidence group (24 ± 1.5 vs 21 ± 1.6, P = 0.03). In patients with unprovoked VTE (n = 269), levels of BUN and hematocrit were significantly increased in the peak incidence group compared to lowest incidence group (19.5 ± 0.8 mg/dL vs 16 ± 1.1 mg/dL, P = 0.03; 39.2 ± 0.3% vs 37.4 ± 0.5%, P = 0.01, respectively).

Conclusions: The current study demonstrates that occurrence of VTE exhibits monthly variation also existing in patients with provoked events and even in those with cancer. Dehydration is suggested as a potential explanation to the month-related variation in incidence of VTE.
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http://dx.doi.org/10.1177/1076029616649435DOI Listing
September 2016

The use of a brief mental health screener to enhance the ability of police officers to identify persons with serious mental disorders.

Int J Law Psychiatry 2016 Jul-Aug;47:28-35. Epub 2016 Apr 1.

Division of Forensic Psychiatry, Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R, Canada; Waypoint Centre for Mental Health Care, 500 Church Street, Penetanguishene, Ontario L9M 1G3, Canada.

Police agencies in Canada and elsewhere have received much criticism over how they respond to persons with serious mental disorders. The adequacy of training provided to police officers on mental health issues and in particular on recognizing indicators of serious mental disorders has been a major concern. This paper describes the process that led to the development of a new brief mental health screener (interRAI Brief Mental Health Screener, BMHS) designed to assist police officers to better identify persons with serious mental disorders. The interRAI BMHS was developed in collaboration with interRAI, an international, not-for-profit consortium of researchers. The government of Ontario had previously partnered with interRAI to develop and implement the Resident Assessment Instrument for Mental Health (RAI-MH), the assessment system mandated for use on all persons admitted into inpatient psychiatric care in the province. Core items on the interRAI BMHS were obtained through analysis (N=41,019) of RAI-MH data together with input from representatives from health care, police services, and patient groups. Two police services in southwestern Ontario completed forms (N=235) on persons thought to have a mental disorder. Patient records were later accessed to determine patient disposition. The use of summary and inferential statistics revealed that the variables significantly associated with being taken to hospital by police included performing a self-injurious act in the past 30days, and others being concerned over the person's risk for self-injury. Variables significantly associated with being admitted included abnormal thought process, delusions, and hallucinations. The results of the study indicate that the 14-variable algorithm used to construct the interRAI BMHS is a good predictor of who was most likely to be taken to hospital by police officers and who was most likely to be admitted. The instrument is an effective means of capturing and standardizing police officer observations enabling them to provide more and better quality information to emergency department (ED) staff. Teaching police officers to use the form constitutes enhanced training on major indicators of serious mental disorders. Further, given that items on the interRAI BMHS are written in the language of the health system, language acts as common currency between police officers and ED staff laying the foundation for a more collaborative approach between the systems.
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http://dx.doi.org/10.1016/j.ijlp.2016.02.031DOI Listing
January 2018

Finding Your Way™: a collaborative approach to increase awareness of missing person events among persons with dementia.

Neurodegener Dis Manag 2016 Apr 1;6(2):107-18. Epub 2016 Apr 1.

Mental Health Training, Ontario Police College, Ministry of Community Safety & Correctional Services, Faculty of Applied & Professional Studies, School of Criminology & Criminal Justice, Nipissing University, 100 College Drive, Box 5002, North Bay, P1B 8L7, Canada.

Aim: To describe an innovative community-wide program aimed at increasing awareness of risks of missing person events among persons with dementia targeting various cultural groups and to present preliminary evaluation findings.

Methods: Review of program records to describe program implementation and a community partner survey.

Results: Over 23 months, 386 partnerships were established to implement the program; 941 awareness-raising sessions were conducted reaching 23,495 individuals. There is an upward trend in number of sessions conducted in various languages and attendance. Community partners' (>85%) responded positively to the program and consultation process.

Conclusion: This partnership experience demonstrates the effectiveness of a collaborative approach to the development and widespread dissemination of information and resource materials aimed at ensuring the safety of a vulnerable population.
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http://dx.doi.org/10.2217/nmt.15.72DOI Listing
April 2016

JAK-2 V617F mutation increases heparanase procoagulant activity.

Thromb Haemost 2016 Jan 22;115(1):73-80. Epub 2015 Oct 22.

Yona Nadir, MD, PhD, Thrombosis and Hemostasis Unit,, Rambam Health Care Campus, Haifa, Israel, Tel.: +972 4 8453520, Fax: +972 4 8543886, E-mail:

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.
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http://dx.doi.org/10.1160/TH15-04-0320DOI Listing
January 2016

Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the "3 + 7" induction regimen for acute myeloid leukemia.

Am J Hematol 2015 Dec 17;90(12):1159-64. Epub 2015 Nov 17.

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

Evaluation of early response during induction therapy for acute myeloid leukemia (AML) is used for prognostication and re-induction strategy, yet the optimal evaluation time point is unknown. Clearance of bone marrow (BM) blasts by day 14 of therapy does not ensure remission; thus, some patients requiring re-induction are neglected. This study aimed to examine the role of earlier BM evaluation during induction for predicting remission and overall survival. Results of BM testing on the 5th and 14th day of intensive induction were prospectively compared in 127 adult patients with AML. Re-induction was given, based on Day 14 results, to 25 patients. Reduction of the BM blast count to <5% as early as by the fifth day of induction was more specifically associated with the achievement of remission compared to Day 14 (88.2% vs. 60%, respectively). Rapid responders have a better 3-year overall survival (OS). Day 5 results are a stronger predictor of OS by multivariate analysis and better segregate long-term survivors than the Day 14th BM count (66% vs. 30%, P = 0.0001 and 48% vs. 37%, respectively, P = 0.04). The Day 5 evaluation of BM carries significant clinical information. The benefit of prescribing re-induction based on such early evaluation should be prospectively studied.
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http://dx.doi.org/10.1002/ajh.24207DOI Listing
December 2015

A novel mutation of antithrombin deficiency in six family siblings and the clinical combat.

Thromb Haemost 2015 Oct 16;114(4):859-61. Epub 2015 Jul 16.

Yona Nadir, MD, PhD, Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa 31096, Israel, Tel.: +972 4 7773520, Fax: +972 4 7773886, E-mail:

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http://dx.doi.org/10.1160/TH15-01-0040DOI Listing
October 2015

A protocol to reduce police wait times in the emergency department.

Healthc Manage Forum 2015 Jul 1;28(4):134-8. Epub 2015 Jun 1.

University of Waterloo, Waterloo, Ontario, Canada.

Healthcare organizations are increasingly tasked with implementing change initiatives that improve the patient experience and target priorities such as Emergency Department (ED) volumes. This article describes the development, implementation, and outcomes of a collaborative protocol between the Niagara Health System and the Niagara Regional Police Service that resulted in a 57% reduction in police wait times in the ED. Six critical success factors contributed to the outcomes that were achieved and are detailed for those organizations interested in engaging in a similar change initiative.
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http://dx.doi.org/10.1177/0840470415581257DOI Listing
July 2015

Heparanase procoagulant activity, factor Xa, and plasminogen activator inhibitor 1 are increased in shift work female nurses.

Ann Hematol 2015 Jul 7;94(7):1213-9. Epub 2015 Mar 7.

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

Epidemiologic studies indicate on an increased risk of cardiovascular disease and cancer in shift workers, although the underlying mechanism is obscure. Heparanase directly enhances tissue factor (TF) activity leading to increased factor Xa production and subsequent activation of the coagulation system. In the present study, a comparison of coagulation markers among healthy shift working (SW) vs. healthy daytime working (DW) female nurses was performed. Thirty SW and 30 DW female nurses were enrolled. For each of the 60 participants, blood was drawn between 7:00 and 8:00 a.m. and at least 8 h after the last work shift. Plasma was studied for coagulation marker that included TF/heparanase procoagulant activity, TF activity, heparanase procoagulant activity, heparanase level, factor Xa level, plasminogen activator inhibitor 1 (PAI-1), plasminogen, α2-antiplasmin, fibrinogen, global protein C, von Willebrand factor, and D-dimer by chromogenic assays and enzyme-linked immunosorbent assays (ELISAs). Sleep quality was assessed by self-report according to the Pittsburgh Sleep Quality Index. The heparanase procoagulant activity increased by 2-fold and the TF/heparanase procoagulant activity increased by 1.5-fold in SW nurses compared to DW nurses (P < 0.05). Factor Xa levels and PAI-1 levels were significantly higher among SW nurses compared to the DW group (22 vs. 18 ng/ml, P < 0.05, and 32 vs. 22 ng/ml, P < 0.005, respectively). No significant differences were found in the other tested coagulation markers between the study groups. Heparanase procoagulant activity, factor Xa level, and PAI-1 level were significantly higher in SW nurses compared to the DW group. These alterations of blood coagulation activation may potentially contribute to cardiovascular and cancer morbidity.
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http://dx.doi.org/10.1007/s00277-015-2345-8DOI Listing
July 2015

Can we program VTE prevention in pregnancy?

Intern Emerg Med 2015 Mar 30;10(2):123-4. Epub 2015 Jan 30.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, P.O. Box 9602, Haifa, 31096, Israel,

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http://dx.doi.org/10.1007/s11739-014-1184-2DOI Listing
March 2015

Open-label study of oral CEP-701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2-V617F mutation.

Br J Haematol 2014 Jan 28;164(1):83-93. Epub 2013 Oct 28.

University of Pennsylvania, Philadelphia, PA, USA.

JAK2-V617F is central to the pathogenesis of myeloproliferative neoplasms. We examined whether lestaurtinib decreased JAK2-V617F allele burden and evaluated its clinical benefits and tolerability in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET). This phase 2, open-label, multicentre study was designed to detect ≥15% reduction in JAK2-V617F allele burden in 15% of patients. Eligible patients received lestaurtinib 80 mg twice daily for 18 weeks and could participate in a 1-year extension phase of treatment. Of 39 enrolled patients, 27 (69%) had PV; 12 (31%) had ET. While the pre-specified responder rate of 15% was not met, lestaurtinib modestly reduced JAK2-V617F allele burden and reduced spleen size in a subset of patients. Of 37 patients in the full efficacy analysis, 5 (14%) responded clinically. Every patient had ≥1 adverse event, most commonly gastrointestinal (95%). Fifteen patients (38%) experienced serious adverse events; 23 (59%) withdrew due to adverse events. This is the first reported study of JAK2-inhibitor treatment in patients with PV/ET and highlights both the need for further studies to assess the role of JAK2 inhibition in treatment of PV/ET and the use of JAK2-V617F as a biomarker for response. This trial was registered at www.clinicaltrials.gov as NCT00586651.
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http://dx.doi.org/10.1111/bjh.12607DOI Listing
January 2014

Coagulopathy unmasking hepatic failure in a child with ornithine transcarbamylase deficiency.

Isr Med Assoc J 2013 Dec;15(12):777-9

Department of Pediatrics B, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel.

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December 2013

The promise of novel direct oral anticoagulants.

Best Pract Res Clin Haematol 2012 Sep 31;25(3):351-60. Epub 2012 Jul 31.

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

The standard effective treatment of venous and arterial thromboembolism includes unfractionated and low-molecular weight heparin as well as warfarin, which have major disadvantages. In recent years, new anticoagulants have been developed in an attempt to overcome the known limitations of established treatment and develop improved therapies. This chapter reviews pharmacological properties of the new anticoagulants, the most recent trials assessing their safety and efficacy as well as potential advantages and disadvantages of using these novel drugs in real life.
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http://dx.doi.org/10.1016/j.beha.2012.06.004DOI Listing
September 2012

Quantitative real-time monitoring of chemical reactions by autosampling flow injection analysis coupled with atmospheric pressure chemical ionization mass spectrometry.

Anal Chem 2012 Sep 21;84(17):7547-54. Epub 2012 Aug 21.

Mass Spectrometry Center, Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996-1600, United States.

Although qualitative and/or semiquantitative real-time monitoring of chemical reactions have been reported with a few mass spectrometric approaches, to our knowledge, no quantitative mass spectrometric approach has been reported so far to have a calibration valid up to molar concentrations as required by process control. This is mostly due to the absence of a practical solution that could well address the sample overloading issue. In this study, a novel autosampling flow injection analysis coupled with an atmospheric pressure chemical ionization mass spectrometry (FIA/APCI-MS) system, consisting of a 1 μL automatic internal sample injector, a postinjection splitter with 1:10 splitting ratio, and a detached APCI source connected to the mass spectrometer using a 4.5 in. long, 0.042 in. inner diameter (ID) stainless-steel capillary, was thus introduced. Using this system together with an optional FIA solvent modifier, e.g., 0.05% (v/v) isopropylamine, a linear quantitative calibration up to molar concentration has been achieved with 3.4-7.2% relative standard deviations (RSDs) for 4 replicates. As a result, quantitative real-time monitoring of a model reaction was successfully performed at the 1.63 M level. It is expected that this novel autosampling FIA/APCI-MS system can be used in quantitative real-time monitoring of a wide range of reactions under diverse reaction conditions.
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http://dx.doi.org/10.1021/ac3017136DOI Listing
September 2012

Evaluation of direct analysis in real time mass spectrometry for onsite monitoring of batch slurry reactions.

Rapid Commun Mass Spectrom 2011 Dec;25(23):3575-80

Mass Spectrometry Center, Department of Chemistry, University of Tennessee, Knoxville, TN 37996-1600, USA.

Batch slurry reactions are widely used in the industrial manufacturing of chemicals, pharmaceuticals, petrochemicals and polymers. However, onsite monitoring of batch slurry reactions is still not feasible in production plants due to the challenge in analyzing heterogeneous samples without complicated sample preparation procedures. In this study, direct analysis in real time mass spectrometry (DART-MS) has been evaluated for the onsite monitoring of a model batch slurry reaction. The results suggested that automation of the sampling process of DART-MS is important to achieve quantitative results. With a sampling technique of manual sample deposition on melting point capillaries followed by automatic sample introduction across the helium beam, relative standard deviation (RSD) of the protonated molecule signals from the reaction product of the model batch slurry reaction ranged from 6 to 30%. This RSD range is improved greatly over a sampling technique of manual sample deposition followed by manual sample introduction where the RSDs are up to 110%. Furthermore, with the semi-automated sampling approach, semi-quantitative analysis of slurry samples has been achieved. Better quantification is expected with a fully automated sampling approach.
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http://dx.doi.org/10.1002/rcm.5269DOI Listing
December 2011

Anticoagulants and chronic kidney disease.

Thromb Res 2011 Oct 6;128(4):305-6. Epub 2011 Jul 6.

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http://dx.doi.org/10.1016/j.thromres.2011.06.014DOI Listing
October 2011

Emerging options in the treatment of deep vein thrombosis and pulmonary embolism.

Blood Rev 2011 Sep 24;25(5):215-21. Epub 2011 May 24.

Department of Hematology, Rambam Health Care Campus, Haifa, Israel.

The incidence of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasing and the disease has been found to account for over 500,000 annual deaths in the European Union. VTE is associated with increased mortality and may lead to serious long-term complications. Unfractionated heparin (UFH), low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) have remained standard of care for many years. Recent trials of novel anticoagulants have indicated that new therapeutical options may soon become available. Studies on the role of new agents in VTE prevention in patients undergoing orthopaedic surgery have provided the evidence suggesting potential value of these drugs for the management of acute events. At present, investigation of new anticoagulants has reached the stage when phase III clinical studies on some novel agents have been completed and others are in progress. Of those furthest along are the direct Factor Xa inhibitors, rivaroxaban and apixaban, and the direct thrombin inhibitor, dabigatran. Findings of ongoing trials are expected to determine potential impact of these agents on current clinical practice.
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http://dx.doi.org/10.1016/j.blre.2011.04.003DOI Listing
September 2011

Thrombohemorrhagic complications of myeloproliferative disorders.

Blood Rev 2010 Nov;24(6):227-32

Department of Hematology, Pappagergiou Hospital, Thessaloniki, Greece.

Myeloproliferative disorders are commonly associated with thrombohemorrhagic manifestations. The current review highlights recent advances in understanding the epidemiology and pathogenetic mechanisms of thrombotic and bleeding complications. Therapeutic modalities and prophylactic interventions corresponding to the specific disease states are also discussed.
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http://dx.doi.org/10.1016/j.blre.2010.08.002DOI Listing
November 2010

Coagulation and anticoagulation in pulmonary arterial hypertension.

Isr Med Assoc J 2009 Jun;11(6):376-9

Division for Pulmonary Medicine, Rambam Health Care Campus, Haifa, Israel.

Pulmonary arterial hypertension is a complex pulmonary vascular disease with a broad range of abnormal vascular abnormalities. Vasoconstriction, remodeling and thrombosis contribute to some extent to increased pulmonary vascular resistance and pressure. This review presents current knowledge on the role of the thrombotic process in the pathogenesis of PAH and evaluates the rationale for anticoagulation therapy.
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June 2009

Corpus luteum hemorrhage in women with bleeding disorders.

Womens Health (Lond) 2009 Jan;5(1):91-5

Thrombosis & Haemostasis Unit, POB 9602, Rambam, Health Care Campus, Haifa, Israel.

Bleeding into the corpus luteum following ovulation rarely has clinical significance in healthy women, but may lead to life-threatening hemorrhage in women with congenital or acquired bleeding disorders. Women who are at an increased risk for corpus luteum hemorrhage (CLH) can be divided in two categories; first, those taking anticoagulants because of a thrombotic disorder; and second, women with congenital bleeding disorders. The management and prevention of CLH is still unsettled and the literature dealing with this problem is based on case reports only. This review focuses on the pathophysiology, clinical presentation, diagnosis and treatment options of an acute bleeding event and prevention modalities of CLH in women with bleeding disorders.
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http://dx.doi.org/10.2217/17455057.5.1.91DOI Listing
January 2009

Transfusion medicine during the summer of 2006: lessons learned in northern Israel.

Transfus Med Rev 2008 Jan;22(1):70-6

Blood Bank and Apheresis Unit, Rambam Health Care Campus, P.O. Box 9602, Haifa, Israel.

In July 2006 a Hizballah attack erupted at the Lebanon-Israel border. Reported here is the experience of the Rambam Health Care Campus--a level I trauma center--during 33 days of warfare. Two hundred ninety-five soldiers and 209 civilians were admitted to the emergency department (ED). Forty-eight wounded soldiers (16%) and 12 civilians (6%) had transfusion. Twenty soldiers and 1 civilian had massive transfusions. The ratio between packed red blood cells and fresh frozen plasma (FFP) used for patients who had massive transfusion was 3:2. In these patients, the median prothrombin time international normalized ratio and partial thromboplastin time increased during the first 2 hours after admission from 1.29 to 1.51 and from 33.6 to 39 seconds, respectively. Twenty patients who had massive transfusion survived. Patients with an injury severity score of at least 16 had a higher need for blood products than others, with a lower severity score, with a mean packed red blood cells unit transfusion of 7 vs 4 (P = .03) and FFP transfusion of 13 vs 1.5 (P = .002), respectively. In conclusion, we observed that early transfusion of FFP to casualties with penetrating wounds requiring massive transfusion is needed to overcome the coagulopathy present. The presence of a transfusion service representative on-site in the ED is recommended to ensure proper identification and labeling of blood samples. Real-time consultations provided by a transfusion medicine physician in the operation theater was also found to be essential.
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http://dx.doi.org/10.1016/j.tmrv.2007.09.005DOI Listing
January 2008

Prospective evaluation of patients hospitalized with venous thromboembolism: comparison between cancer and non-cancer patients.

Isr Med Assoc J 2006 Dec;8(12):848-52

Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Medical Center, Haifa, Israel.

Background: Little is known about the epidemiology of venous thromboembolism in hospitalized patients in Israel. Also, a direct comparison of the clinical and laboratory features between cancer and non-cancer patients has not yet been reported.

Objectives: To investigate and compare the epidemiologic, clinical and laboratory characteristics of cancer and non-cancer patients hospitalized with venous thromboembolism in a large referral medical center in Israel.

Methods: Between February 2002 and February 2003, patients diagnosed at the Rambam Medical Center as suffering from VTE (deep vein thrombosis and/or pulmonary embolism), based on diagnostic findings on Doppler ultrasonography, spiral computed tomography scan or lung scan showing high probability for pulmonary embolism, were prospectively identified and evaluated. In addition, at the conclusion of the study period, the reports of spiral chest CT scans, performed during the aforementioned period in this hospital, were retrospectively reviewed to minimize the number of unidentified cases. Blood samples were drawn for evaluation of the coagulation profile.

Results: Altogether, 147 patients were identified and 153 VTE events diagnosed, accounting for 0.25% of all hospitalizations during the study period. The cancer group included 63 patients (43%), most of whom had advanced disease (63%). The most common malignancies were cancer of the lung (16%), breast (14%), colon (11%) and pancreas (10%). Of 122 DVT events (with or without pulmonary embolism) there were 14 upper extremity thromboses (12%). The most common risk factors for VTE, except malignancy, were immobilization (33%), surgery/trauma (20%) and congestive heart failure (17%). There was no difference in prevalence of various risk factors between cancer and non-cancer patients. During an acute VTE event, D-dimer levels were higher in cancer patients than non-cancer patients (4.27 +/- 4.04 vs. 2.58 +/- 1.83 mg/L respectively, P = 0.055). Relatively low values of activated protein C sensitivity ratio and normalized protein C activation time were observed in both cancer and non-cancer groups (2.05 +/- 0.23 vs. 2.01 +/- 0.33 and 0.75 +/- 0.17 vs. 0.71 +/- 0.22, respectively). These values did not differ significantly between the groups.

Conclusion: The proportion of cancer patients among patients suffering from VTE was high. Their demographic, clinical and laboratory characteristics (during an acute event) were not different from those of non-cancer patients, except for higher D-dimer levels.
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December 2006