Effects of anti-Xa activity monitoring on the outcome of high-risk pregnancies treated with a prophylactic dose of low-molecular-weight heparin.

OBJECTIVE: To evaluate if anti-Xa level monitoring and dose adjustment in women using a prophylactic dose of enoxaparin can decrease placenta-mediated pregnancy complications. METHODS: This retrospective observational cohort study included pregnant women receiving enoxaparin prophylaxis, who were followed at the Thrombosis and Hemostasis Outpatient clinic between 2010 and 2017. The dose was adjusted according to enoxaparin anti-Xa levels in the study group or the weight of individuals in the control group. RESULTS: Of 585 women surveyed, 110 met the inclusion criteria; 63 of them were included in the study group and 47 in the control group. Mean starting dose was 46 versus 43 mg (p = .25), mean final dose was 52 mg versus 45 mg (p = .03) and dose adjustment was required in 37% versus 11% (p = .002) in the study and control groups, respectively. Twenty-eight percent of anti-Xa measurements in the second trimester were beneath the prophylactic threshold, compared to 11% and 16% in the first and third trimesters, respectively (p = .02). Labors ended with live birth in 91% versus 94% of cases (p = .5), 85% versus 68% of pregnancies were term (p = .05), 11% versus 23% of newborns were low birth weight (p = .1) and placenta-mediated pregnancy complications were documented in 9% versus 19%, (p = .17) in the study group relative to controls, respectively. CONCLUSIONS: The most prominent decrease in anti-Xa levels was observed in the second trimester. Monitored women had significantly more term deliveries and demonstrated a trend toward higher birth weight and fewer placenta-mediated pregnancy complications. Larger studies are needed to confirm improved pregnancy outcome in monitored women.

Management of patients receiving novel antithrombotic treatment in endodontic practice: Review and clinical recommendations.

Cardiovascular diseases are a major component of non-communicable diseases and death, with thrombosis constituting the most common underlying pathosis of the three major cardiovascular disorders: ischaemic heart disease (acute coronary syndrome), stroke and venous thromboembolism (VTE). The introduction of direct oral anticoagulants (DOACs) in recent years has necessitated a more complex approach to periprocedural and perioperative anticoagulation management and the need for revised management strategies and protocols. Currently, patients taking classic oral anticoagulants are advised to stop taking the drugs and have their INR values checked 72 h prior to dental surgery (e.g., apical surgery, tooth extraction, and periodontal surgery) and checked again 24 h prior to the procedure to ensure it is within the therapeutic range. However, the current incorporation of these novel DOACs in routine medical practice requires changes in the way patients are managed preoperatively in dentistry, and specifically in endodontic surgery. The methodology applied in this review included searching for relevant articles in the PubMed database using keywords listed in the Entree Terms databases. Articles published on human blood clotting mechanism, antithrombotic drugs, as well as treatment guidelines and recommendations for dentistry were retrieved. In addition, textbooks and guidelines that may not have surfaced in the online search were searched manually. The aim of this paper was to review the mechanisms of action of classic and novel antithrombotic medications and their impact on endodontic treatment and the management of local haemostasis in endodontics.

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

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.

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

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.

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

Hemostasis and Thrombosis in the Oldest Old.

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.

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

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.

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

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.

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

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.

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

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.

An outbreak of severe coagulopathy in northern Israel among users of illicit synthetic cannabinoids adulterated with brodifacoum.

INTRODUCTION: Adulteration of illicit drugs is a well-known phenomenon that may expose consumers to unexpected adverse effects. We report a large outbreak of severe coagulopathy in northern Israel during nine months in 2021-2022 among users of synthetic cannabinoids adulterated with a long-acting anticoagulant, brodifacoum. METHODS: We performed a retrospective cohort study based on data extracted from the Israeli National Poison Information Center database and from electronic medical patient records at three participating hospitals. Confiscated drug samples and blood samples obtained at admission in a subgroup of patients were tested for the presence of long-acting anticoagulants. RESULTS: We identified 98 patients affected by the outbreak. All patients had a prolonged international normalized ratio on admission, and in 69%, the blood was non-coagulating. For patients treated in the three participating centers (n = 72), the presenting complaint was overt bleeding in 79% of patients, most commonly in the urinary (53%) and gastrointestinal tracts (50%). The most severe complications were intracranial bleeding (4%), hemothorax (3%), pericardial bleeding (1%), and four patients died. Brodifacoum was detected in all available blood samples (median concentration 207 µg/L, interquartile range 112-349 µg/L, range 45-1,118 µg/L), and the drug samples contained both brodifacoum and the synthetic cannabinoid ADB-BUTINACA. All patients were treated with high-dose phytomenadione (vitamin K1) and additionally by packed red blood cell transfusions, fresh frozen plasma, and/or 4-factor prothrombin complex concentrate when indicated. The most frequent phytomenadione (vitamin K1) dose regimen was initially 20 mg intravenously every eight hours, and at discharge, 20 mg orally three times daily. CONCLUSIONS: Outbreaks of severe coagulopathies in users of synthetic cannabinoids adulterated with a long-acting anticoagulant continue to erupt in different regions of the world. Rapid recognition of an outbreak requires a high index of suspicion when confronting young, otherwise healthy subjects with otherwise unexplained severe coagulopathy.

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

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.

Using the interRAI brief mental health screener to identify persons with mental disorders having repeat contact with police.

Repeat contacts between persons with serious mental disorder (PSMD) and police officers are costly to both police services and hospitals in terms of service utilization and can be viewed as a direct indicator of unmet needs and gaps in service provision. The intent of the current study was to examine the demographic and clinical characteristics of PSMD who had repeat contact with police officers in London, Ontario from 2016 to 2019 using data collected using the interRAI Brief Mental Health Screener (BMHS). Negative binomial regression was used on a sample of 4143 cases to develop a model predictive of repeat police contacts. The most parsimonious model predicting police contact based on items on the BMHS included age, command hallucinations, lack of insight, verbal abuse, known to possess weapons and family, friends and caregivers expressing concern over the possibility of self harm. Delusions were also independently significantly associated with repeat encounters. Unique to this study is the observation that possessing a weapon in the past 12 months was included in the predictive model. The results of the study add to the sparse research devoted to identifying the characteristics of PSMD who have repeat contact with police officers. Recommendations include integrating the findings into police training to ensure police officers flag those who have the potential for repeat encounters and refer them to appropriate community mental health service providers for proactive outreach services.

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

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.

Costs and Savings Associated With the Police Use of the interRAI Brief Mental Health Screener.

Background: The police response to calls for service identified as being related to mental health continues to be highly controversial. Strategies to improve the police response include Crisis Intervention Team (CIT) training and various forms of co-response models neither of which have been subjected to comprehensive evaluations, particularly as to cost-efficiency. A new approach is the use of the interRAI Brief Mental Health Screener to enhance police officer ability to identify persons with serious mental disorders. The purpose of the current study is to evaluate the costs and cost efficiency of the police response to mental health calls using the interRAI Brief Mental Health Screener. Method: Secondary data was analyzed from the use of the screener from 2018 to 2020 by police officers in a mid-sized Canadian city. Changes were measured in the overall number of interactions police officers had with persons with mental health disorders, the number of incidents where police officers referred the person to hospital, and the time officers remained in the emergency department. Results: A total of 6,727 assessments were completed with involuntary referrals decreasing by 30%, and voluntary referrals by 34%. The overall time police officers were involved in involuntary referrals decreased from 123 min in 2018 to 113 min in 2020. The average emergency department wait time for voluntary referrals dropped from 41 min in 2018 to 27 min in 2020, while involuntary referrals decreased from 61 min in 2018 to 42 min in 2020. Each averted involuntary referral to the emergency department resulted in a savings of $81, on average during the study period. Conclusion: An analysis of the costs and costs savings associated with the use of the screener demonstrate that it is a worthwhile investment for police services. An additional benefit is its ability to collect mental health statistics that may be useful to police leaders to justify budgets. Future studies should attempt to devise some method of collecting pre-implementation data that would reveal the true costs and cost-efficiency of using the BMHS, which have been shown to be significant in the current study however, undoubtedly are under-estimated.

Coagulation and anticoagulation in pulmonary arterial hypertension.

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.

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

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.

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

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.