[PATIENT BLOOD MANAGEMENT - IT IS IMPOSSIBLE TO IGNORE THIS POLICY].

INTRODUCTION: Anemia is common and is an independent risk factor for morbidity and mortality, especially in pre- (30-40% of patients undergoing major surgery) or post-operative anemia (up to 80-90%). Using World Health Organization (WHO) criteria, in 2010 one quarter of the global population was anemic (1.9 billion people) and iron deficiency anemia (IDA( was and still remains the most common type of anemia worldwide, accounting for more than half of the total anemia burden. In a systematic analysis for the Global Burden of Disease Study 2016, IDA was the fourth leading cause of years lived with disability, particularly in women, thus highlighting prevention and treatment of IDA as a major public health goal. Red blood cells (RBC) transfusion is a common therapeutic intervention with considerable variation in clinical practice. More than 85 million units packed RBC (PRBC) are transfused annually worldwide. The principal indication for blood transfusion (BT) is anemia, yet a significant percentage of RBC transfusions are inappropriately overused. For many physicians and clinicians, across many different specialties, BT is still considered to be the first-line treatment when facing anemia. The Joint Commission along with the American Medical Association has included BT in a list of the five most overused therapeutic procedures in the United States. Restrictive blood transfusion (RBT) is an evidence-based policy, at least as effective, if not superior to the liberal policy of BT. Patient blood management (PBM) is a patient-centered systematic, evidence-based approach, supported by RBT. In this article we analyze the factors which influence the implementation of PBM.

Humanitarian Outpatient Pediatric Endeavor (HOPE): A Novel Specialist Ambulatory Health-Care Concept in Conflict Areas.

With the collapse of the medical system in Syria, Israel began providing Syrians with humanitarian aid, first to the war-injured and then general medical treatment. We developed a novel specialist ambulatory care concept to provide medical care for Syrian children. Children with their caregivers were transported by bus across the border from Syria to our medical center in Israel for day-stay outpatient-clinic advanced evaluation and treatment due to coordination between Syrian, Red Cross, and Israeli authorities, including Israeli Defense Forces. This retrospective field report includes 371 Syrian children treated as outpatients at Galilee Medical Center between January 2016 and September 2018. In our experience, this novel pediatric ambulatory care concept has been feasible, efficient, and successful in providing specialist care for children in a crisis region devoid of access to health care. We believe it can also serve adult patients and be implemented in other crises and disasters scenarios.

Increased serum level of alpha-2 macroglobulin and its production by B-lymphocytes in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL), the most common adult's leukemia in the western world, is caused in 95% of the cases by uncontrolled proliferation of monoclonal B-lymphocytes. The complement system in CLL is chronically activated at a low level via the classical pathway (CP). This chronic activation is induced by IgG-hexamers, which are formed after binding to alpha-2-macroglobulin (A2M). The study investigated for the first time the serum levels of A2M in CLL patients, their association with the disease severity, and A2M production by the malignant B-lymphocytes. Blood samples were collected from 65 CLL patients and 30 normal controls (NC) subjects, and used for quantifications of the A2M levels, the complement activation marker (sC5b-9), the complement components C2, C3 and C4, and clinical biochemistry and hematology parameters. The production of A2M was studied in B-lymphocytes isolated from blood samples as well as in CLL and non-CLL cell lines.The serum A2M levels were significantly higher in CLL patients vs NCs, showing values of 3.62 ± 0.22 and 1.97 ± 0.10 mg/ml, respectively. Within the CLL group, A2M levels correlated significantly with the disease stage, with sC5b-9, and with clinical indicators of the disease severity. Increased A2M production was showed in three out of four CLL B-lymphocytic lines that were studied, as compared to non-CLL lines, to a non-lymphocytic line, and to blood-derived primary B-lymphocytes. A2M production was further increased both in primary cells and in the CLL cell-line after incubation with CLL sera, compared to NC sera. This study shows for the first time that serum A2M levels in CLL are significantly increased, likely due to A2M production by the malignant B-lymphocytes, and are correlated with the disease severity and with chronic complement activation. The moderate change in A2M production after incubation with NC sera in-vitro supports the hypothesis that inhibition of excess A2M production can be achieved, and that this may potentially down-regulate the IgG-hexamerization and the resulting chronic CP activation. This may also help restore complement system activity, and eventually improve complement activity and immunotherapy outcomes in CLL.

Reasons underlying the intention to vaccinate children aged 5-11 against COVID-19: A cross-sectional study of parents in Israel, November 2021.

Vaccination is a key tool to mitigate impacts of the COVID-19 pandemic. In Israel, COVID-19 vaccines became available to adults in December 2020 and to 5-11-year-old children in November 2021. Ahead of the vaccine roll-out in children, we aimed to determine whether surveyed parents intended to vaccinate their children and describe reasons for their intentions. We collected information on parental socio-demographic characteristics, COVID-19 vaccine history, intention to vaccinate their children against COVID-19, and reasons for parental decisions using an anonymous online survey. We identified associations between parental characteristics and plans to vaccinate children using a logistic regression model and described reasons for intentions to vaccinate or not. Parental non-vaccination and having experienced major vaccination side effects were strongly associated with non-intention to vaccinate their children (OR 0.09 and 0.18 respectively, p < .001). Parents who were younger, lived in the socio-economically deprived periphery, and belonged to the Arab population had lower intentions to vaccinate their children. Reasons for non-intention to vaccinate included concerns about vaccine safety and efficacy (53%, 95%CI 50-56) and the belief that COVID-19 is a mild disease (73%, 95%CI 73-79), while a frequent motive for vaccination was the return to normal social and educational life (89%, 95%CI 87-91). Understanding rationales for COVID-19 vaccine rejection or acceptance, as well as parental demographic data, can pave the way for intentional educational campaigns to encourage not only vaccination against COVID-19, but also regular childhood vaccine programming.

Parental intention to vaccinate children aged 5-11 is much lower than vaccine coverage in parental age groupsBeing unvaccinated and having experienced side effects following vaccination were the greatest negative predictors in parents of intention to vaccinate their childrenParents were more likely to accept a COVID-19 vaccine for their children to allow them to return to daily social life and to ensure economic security in the familyParents were more likely to reject a COVID-19 vaccination for health reasons such as safety concerns or due the belief that COVID-19 was a mild disease in children.

Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness.

OBJECTIVE: Studies have demonstrated a potential correlation between low vitamin D status and both an increased risk of infection with SARS-CoV-2 and poorer clinical outcomes. This retrospective study examines if, and to what degree, a relationship exists between pre-infection serum 25-hydroxyvitamin D (25(OH)D) level and disease severity and mortality due to SARS-CoV-2. PARTICIPANTS: The records of individuals admitted between April 7th, 2020 and February 4th, 2021 to the Galilee Medical Center (GMC) in Nahariya, Israel, with positive polymerase chain reaction (PCR) tests for SARS-CoV-2 (COVID-19) were searched for historical 25(OH)D levels measured 14 to 730 days prior to the positive PCR test. DESIGN: Patients admitted to GMC with COVID-19 were categorized according to disease severity and level of 25(OH)D. An association between pre-infection 25(OH)D levels, divided between four categories (deficient, insufficient, adequate, and high-normal), and COVID-19 severity was ascertained utilizing a multivariable regression analysis. To isolate the possible influence of the sinusoidal pattern of seasonal 25(OH)D changes throughout the year, a cosinor model was used. RESULTS: Of 1176 patients admitted, 253 had records of a 25(OH)D level prior to COVID-19 infection. A lower vitamin D status was more common in patients with the severe or critical disease (<20 ng/mL [87.4%]) than in individuals with mild or moderate disease (<20 ng/mL [34.3%] p < 0.001). Patients with vitamin D deficiency (<20 ng/mL) were 14 times more likely to have severe or critical disease than patients with 25(OH)D ≥40 ng/mL (odds ratio [OR], 14; 95% confidence interval [CI], 4 to 51; p < 0.001). CONCLUSIONS: Among hospitalized COVID-19 patients, pre-infection deficiency of vitamin D was associated with increased disease severity and mortality.

Patient Involvement in the Transfusion Decision-Making Can Change Patient Blood Management Practice for Better or Worse.

BACKGROUND: Red blood cell transfusion (RBCT) is a therapeutic procedure with important and undesirable secondary effects. Inappropriate overuse of RBCT is significant, and a significant percentage of physicians prescribe RBCT unnecessarily. Patient involvement in treatment decision-making is poor worldwide. Shared (with the patient) transfusion decision-making (TrDM) can temper a "quick finger on the trigger" of blood transfusion (BT). The objective of this study was to determine patients' preferences surrounding their involvement in the TrDM process as well as physicians' willingness to involve the patient in TrDM. The study also determined the role of patient age, gender, ethnicity, and schooling years in the TrDM process. METHODS: This cross-sectional study was conducted in a variety of departments, with 123 patients over 18 years old, who received a BT for the first time. The patients completed an anonymous questionnaire which included demographic characteristics (age, gender, ethnicity, and schooling years) and 2 questions linked to potential willingness to participate in the decision to transfuse. RESULTS: The questionnaire response rate was 100%. The data showed that 60% of patients (especially younger patients), independent of ethnicity, preferred a passive role in TrDM and 40% preferred to share the decision. CONCLUSIONS: The majority of patients, especially younger patients, prefer a passive role in TrDM, possibly due to insufficient information about the need for BT and its significance. We feel that active involvement on the part of the patient can provoke a more judicious thought process about the real need of BT on the part of the physician and have a positive influence on patient blood management.

Is There a Predictive Value of High Mean Platelet Volume in Early Diagnosis of Venous Thromboembolism?

BACKGROUND: Venous thromboembolism (VTE) is a serious disease, which demands a fast accurate diagnosis to begin suitable treatment. It presents a major problem in the emergency department (ED), and its confirmation requires adequate evaluation. OBJECTIVES: To evaluate a potential role of mean platelet volume (MPV) in differentiating VTE from other potential diagnosis in patients with suspected VTE. METHODS: We conducted a retrospective case-controlled study of 440 consecutive patients who presented to the ED of our hospital with clinical VTE, but only 316 with proven VTE. A control group was composed of patients (124) who presented with clinical VTE but without proven VTE. We checked the MPV value in all 440 patients and the correlation with VTE occurrence in the study group vs. control group. RESULTS: Statistical analysis of the acquired results indicated that MPV value could not aid in determining the difference of real VTE vs. patients with VTE-like clinical picture presenting to the ED. We found an inverse correlation between MPV value and proven VTE, in contrast to most researchers who have studied the same issue. CONCLUSIONS: Although MPV can be a useful diagnostic marker in many diseases, we found no definite association between low MPV and VTE.

Vaccine hesitancy due to vaccine country of origin, vaccine technology, and certification.

Vaccine hesitancy is a global health threat which may hinder the widespread acceptance of several COVID-19 vaccines. Following the collection of 2470 responses from an anonymous questionnaire distributed between October and November 2020 across Israel, we analyzed the responses of physicians, life science graduates (biology, virology, chemistry, etc.), and the general public to whether they would obtain a COVID-19 vaccine with particular vaccine characteristics such as vaccine country of origin, technology, side effect profile, efficacy, and other attributes. Physicians and life science graduates were least likely to accept a vaccine based on mRNA technology (30%) while the general population seemed to adopt any vaccine technology if the declared efficacy is above 90% and the country of manufacturing is the USA/UK rather than China or Russia. However, current inoculation rates in Israel far outpace our predicted rate. Our results highlight the importance of tailored vaccine educational campaigns based on population demographic details and specific vaccine concerns.

Blood Myths and Ethnic-Cultural Background as Impediments in Patient Blood Management Education.

A significant percentage of red blood cell transfusions (RBCTs) are the result of overuse. The implementation of patient blood management (PBM) is challenging. We examined whether blood-linked myths and ethnic-cultural background factors are impediments to PBM education and implementation. Data about the influence of blood myths and diverse ethnic-cultural communities were collected from physicians in our medical center via an anonymous questionnaire which contained questions about myths as well as knowledge of blood transfusion. No statistical differences were found between ethnic and cultural groups regarding blood myths and cultural background influence, although the Jewish participants were less influenced by myths than their Arab colleagues. The influence of blood myths concerning the decision to transfuse exists in both studied ethnic groups. With regard to the association between knowledge and myths influence, we found that the greater the knowledge of the participant, the lower was the myths influence. In a significant proportion of our physician cohort, blood myths and cultural-ethnic status influenced their approach toward RBCT and can be considered an impediment in PBM education. A high knowledge level is associated with less myths influence. The myths and cultural-ethnic background may play a role in PBM education.

Cell-free IgG-aggregates in plasma of patients with chronic lymphocytic leukemia cause chronic activation of the classical complement pathway.

Therapy regimens for Chronic lymphocytic leukemia (CLL) commonly include chemotherapy and immunotherapy, which act through complement-mediated-cytotoxicity (CDC) and other mechanisms. CDC depends on several factors, including the availability and activity of the complement classical pathway (CP). Recently, a significant decrease in CP activity was shown to be associated with an immunoglobulin-C5a complex (Ig-C5a) and other markers of chronic CP activation in 40% of the patients. The study focused on the involvement of IgG-hexamers, an established CP activator, in the mechanism of chronic CP activation in CLL. Sera from 51 naïve CLL patients and 20 normal controls were collected. CP and alternative pathway (AP) activities were followed by the complement activity marker sC5b-9. Serum high molecular weight (HMW) proteins were collected by gel-filtration chromatography and their complement activation capacity was assessed. The levels of IgM, another established CP activator, were measured. Data were associated with the presence of Ig-C5a. Baseline levels of activation markers negatively correlated with CP and the AP activities, supporting chronic complement activation. In patients with Ig-C5a, HMW proteins that are not IgM, activated the complement. HMW proteins were identified as IgG-aggregates by affinity binding assays and Western blot analysis. The data indicate chronic CP activation, mediated by cell-free IgG-hexamers as a cause of decreased CP activity in part of the CLL population. This mechanism may affect immunotherapy outcomes due to compromised CP activity and CDC.

The Role of Alpha 2 Macroglobulin in IgG-Aggregation and Chronic Activation of the Complement System in Patients With Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. One of the treatments offered for CLL is immunotherapy. These treatments activate various cellular and biochemical mechanisms, using the complement system. Recently it was shown that the complement system in CLL patients is persistently activated at a low level through the classical pathway (CP). The mechanism of chronic CP activation involves the formation of IgG-hexamers (IgG-aggregates). According to recent studies, formation of ordered IgG-hexamers occurs on cell surfaces via specific interactions between Fc regions of the IgG monomers, which occur after antigen binding. The present study investigated the formation of IgG-hexamers in CLL patients and normal (non-malignant) controls (NC), their ability to activate complement, their incidence as cell-free and cell-bound forms and the identity of the antigen causing their formation. Sera from 30 patients and 12 NC were used for separation of IgG- aggregates. The obtained IgG- aggregates were measured and used for assessment of CP activation. For evaluation of the presence of IgG- aggregates on blood cells, whole blood samples were stained and assessed by flow cytometry. Serum levels of IgG- aggregates were higher in CLL and they activated the complement system to a higher extent than in NC. Alpha 2 macroglobulin (A2M) was identified as the antigen causing the hexamerization/aggregation of IgG, and was found to be part of the hexamer structure by mass spectrometry, Western blot and flow cytometry analysis. The presence of A2M-IgG-hexamers on B-cells suggests that it may be formed on B cells surface and then be detached to become cell-free. Alternatively, it may form in the plasma and then attach to the cell surface. The exact time course of A2M-IgG-hexamers formation in CLL should be further studied. The results in this study may be useful for improvement of current immunotherapy regimens.

Sex Differences in Plasma MicroRNA Biomarkers of Early and Complicated Diabetes Mellitus in Israeli Arab and Jewish Patients.

MicroRNAs play functional roles in the etiology of type 2 diabetes mellitus (T2DM) and complications, and extracellular microRNAs have attracted interest as potential biomarkers of these conditions. We aimed to identify a set of plasma microRNAs, which could serve as biomarkers of T2DM and complications in a mixed Israeli Arab/Jewish patient sample. Subjects included 30 healthy volunteers, 29 early-stage T2DM patients, and 29 late-stage T2DM patients with renal and/or vascular complications. RNA was isolated from plasma, and the levels of 12 candidate microRNAs were measured by quantitative reverse transcription and polymerase chain reaction (qRT-PCR). MicroRNA levels were compared between the groups and correlated to clinical measurements, followed by stepwise regression analysis and discriminant analysis. Plasma miR-486-3p and miR-423 were respectively up- and down-regulated in T2DM patients compared to healthy controls. MiR-28-3p and miR-423 were up-regulated in patients with complicated T2DM compared to early T2DM, while miR-486-3p was down-regulated. Combined, four microRNAs (miR-146a-5p, miR-16-2-3p, miR-126-5p, and miR-30d) could distinguish early from complicated T2DM with 77% accuracy and 79% sensitivity. In male patients only, the same microRNAs, with the addition of miR-423, could distinguish early from complicated T2DM with 83.3% accuracy. Furthermore, plasma microRNA levels showed significant correlations with clinical measurements, and these differed between men and women. Additionally, miR-183-5p levels differed significantly between the ethnic groups. Our study identified a panel of specific plasma microRNAs which can serve as biomarkers of T2DM and its complications and emphasizes the importance of sex differences in their clinical application.