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Rutger A Middelburg,1,2 M Sesmu Arbous,2,3 Judith G Middelburg,4 Johanna G van der Bom1,2 1Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Intensive Care Medicine, Leiden University Medical Center, Leiden, the Netherlands; 4Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands Abstract: Evidence-based medicine has become associated with a preference for randomized trials. Randomization is a powerful tool against both known and unknown confounding. However, due to cost-induced constraints in size, randomized trials are seldom able to provide the subgroup analyses needed to gain much insight into effect modification. To apply results to an individual patient, effect modification needs to be considered. Results from randomized trials are therefore often difficult to apply in daily clinical practice. Confounding by indication, which randomization aims to prevent, is caused by more severely ill patients being less or more likely to be treated. Therefore, the prognostic indicators that physicians use to make treatment decisions become confounders. However, these same prognostic indicators are also effect modifiers. This is in fact exactly why they are relevant to decision-making. We use simple, fictive numerical examples to illustrate these concepts. Then we argue that if we would record all relevant variables, it would simultaneously solve the problem of confounding by indication and allow quantification of effect modification. It has previously been argued that it is practically more feasible to “simply” randomize treatment allocation, than to adequately correct for confounding by indication. We will argue that, in the current age of evidence-based medicine and highly regulated randomized trials, this balance has shifted. We therefore call for better observational clinical research. However, careless acceptance of results from poorly performed observational research can lead clinicians seriously astray. Therefore, a more interactive approach toward the medical literature might be needed, where more room is made for scientific discussion and interpretation of results, instead of one-way reporting. Keywords: treatment, personalized, effectiveness, effect modification, risk factors, confounding by indication

Rutger A Middelburg,1,2 Jean-Louis H Kerkhoffs,1,3 Johanna G van der Bom1,2 1Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Hematology, Hagaziekenhuis, Den Haag, the Netherlands Background: Hematology–oncology patients often become severely thrombocytopenic and receive prophylactic platelet transfusions when their platelet count drops below 10×109 platelets/L. This so-called “platelet count trigger” of 10×109 platelets/L is recommended because currently available evidence suggests this is the critical concentration at which bleeding risk starts to increase. Yet, exposure time and lag time may have biased the results of studies on the association between platelet counts and bleeding risks.Methods: We performed simulation studies to examine possible effects of exposure time and lag time on the findings of both randomized trials and observational data.Results: Exposure time and lag time reduced or even reversed the association between the risk of clinically relevant bleeding and platelet counts. The frequency of platelet count measurements influenced the observed bleeding risk at a given platelet count trigger. A transfusion trigger of 10×109 platelets/L resulted in a severely distorted association, which closely resembled the association reported in the literature. At triggers of 0, 5, 10, and 20×109 platelets/L the observed percentages of patients experiencing bleeding were 18, 19, 19, and 18%. A trigger of 30×109 platelets/L showed an observed bleeding risk of 16% and triggers of 40 and 50×109 platelets/L both resulted in observed bleeding risks of 13%.Conclusion: The results from our simulation study show how minimal exposure times and lag times may have influenced the results from previous studies on platelet counts, transfusion strategies, and bleeding risk and caution against the generally recommended universal trigger of 10×109 platelets/L. Keywords: platelet transfusions, platelet counts, bleeding, simulation study, lag time, exposure time

Previous studies found exposure to red blood cell transfusions from female donors who have been pregnant reduces survival in male patients compared to exposure to male donor products, but evidence is not consistent. We postulate the previously observed association is modified by offspring sex, with an expected increased mortality risk for male patients receiving units from female donors with sons. Here, marginal structural models were used to assess the association between exposure to units from ever-pregnant donors, ever-pregnant donors with sons and ever-pregnant donors with daughters, and mortality. Clinical data were collected on first-ever transfusion recipients in the Netherlands and donor data were supplemented with information about offspring sex and date of birth. In this analysis, 56,825 patients were included, of whom 8,288 died during follow-up. Exposure to red blood cell units from ever-pregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR]=0.91, 95% confidence interval [CI]: 0.83-1.01). Exposure to ever-pregnant donors, irrespective of offspring sex, was associated with mortality in male patients aged between 18 and 50 years (ever-pregnant donors: HR=1.81, 95% CI: 1.31-2.51) compared to male donor units, but was protective in female patients. This study suggests that the observed increased mortality risk for exposure to red blood cell units from parous female donors does not depend on offspring sex. The increased risk of mortality seen in younger adult male patients is consistent with previous observations, but the underlying biological mechanism could not be identified in this study.

Background and Objectives: Donor characteristics have been implicated in transfusion-related adverse events. Uncertainty remains about whether sex, and specifically pregnancy history of the blood donor, could affect patient outcomes. Whether storage duration of the blood product could be important for patient outcomes has also been investigated, and a small detrimental effect of fresh products remains a possibility. Here, we hypothesize that fresh red blood cell products donated by ever-pregnant donors are associated with mortality in male patients., Materials and Methods: We used data from a cohort study of adult patients receiving a first transfusion between 2005 and 2015 in the Netherlands. The risk of death after receiving a transfusion from one of five exposure categories (female never-pregnant stored ≤10 days, female never-pregnant stored >10 days, female ever-pregnant stored ≤10 days, female ever-pregnant stored >10 days and male stored for ≤10 days), compared to receiving a unit donated by a male donor, which was stored for >10 days (reference), was calculated using a Cox proportional hazards model., Results: The study included 42,456 patients who contributed 88,538 person-years in total, of whom 13,948 died during the follow-up of the study (33%). Fresh units (stored for ≤10 days) from ever-pregnant donors were associated with mortality in male patients, but the association was not statistically significant (hazard ratio 1.39, 95% confidence interval 0.97-1.99). Sensitivity analyses did not corroborate this finding., Conclusion: These findings do not consistently support the notion that the observed association between ever-pregnant donor units and mortality is mediated by blood product storage., (© 2023 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Background: Intracranial hemorrhage is seen more frequently in acute leukemia patients compared to the general population. Besides leukemia-related risk factors, also risk factors that are present in the general population might contribute to hemorrhagic complications in leukemia patients. Of those, cardiovascular risk factors leading to chronic vascular damage could modulate the occurrence of intracranial hemorrhage in these patients, as during their disease and treatment acute endothelial damage occurs due to factors like thrombocytopenia and inflammation., Objectives: Our aim was to explore if cardiovascular risk factors can predict intracranial hemorrhage in acute leukemia patients., Methods: In a case-control study nested in a cohort of acute leukemia patients, including 17 cases with intracranial hemorrhage and 55 matched control patients without intracranial hemorrhage, data on cardiovascular risk factors were collected for all patients. Analyses were performed via conditional logistic regression., Results: Pre-existing hypertension and ischemic heart disease in the medical history were associated with intracranial hemorrhage, with an incidence rate ratio of 12.9 (95% confidence interval [CI] 1.5 to 109.2) and 12.1 (95% CI 1.3 to110.7), respectively., Conclusion: Both pre-existing hypertension and ischemic heart disease seem to be strong predictors of an increased risk for intracranial hemorrhage in leukemia patients., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: It has been suggested that children and infants can develop multisystem inflammatory syndrome in children (MIS-C) in response to a SARS-CoV-2 infection and that Black children are overrepresented among cases. The aim of the current study was to quantify the association between Black, Asian, or other non-White genetic background and COVID-19-related MIS-C in children and infants. Methods: Eight different research groups contributed cases of MIS-C, potentially related to SARS-CoV-2 infection. Several sensitivity analyses were performed, including additional data available from the literature. Analyses were stratified by geographical region. Results: Seventy-three cases from nine distinct geographical regions were included in the primary analyses. In comparison to White children, the relative risk for developing MIS-C after SARS-CoV-2 infection was 15 [95% confidence interval (CI): 7.1 to 32] for Black children, 11 (CI: 2.2 to 57) for Asian, and 1.6 (CI: 0.58 to 4.2) for other ethnic background. Conclusion: Pediatricians should be aware of the fact that the risk of COVID-19-related MIS-C is severely increased in Black children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Middelburg, Crijnen, D'Antiga, Verdoni, Chikermane, Garg, Acharyya, Pruccoli, Schnapp, Rauf and Middelburg.)

Background: Monitoring of symptoms and behavior may enable prediction of emerging COVID-19 hotspots. The COVID Radar smartphone app, active in the Netherlands, allows users to self-report symptoms, social distancing behaviors, and COVID-19 status daily. The objective of this study is to describe the validation of the COVID Radar., Methods: COVID Radar users are asked to complete a daily questionnaire consisting of 20 questions assessing their symptoms, social distancing behavior, and COVID-19 status. We describe the internal and external validation of symptoms, behavior, and both user-reported COVID-19 status and state-reported COVID-19 case numbers., Results: Since April 2nd, 2020, over 6 million observations from over 250,000 users have been collected using the COVID Radar app. Almost 2,000 users reported having tested positive for SARS-CoV-2. Amongst users testing positive for SARS-CoV-2, the proportion of observations reporting symptoms was higher than that of the cohort as a whole in the week prior to a positive SARS-CoV-2 test. Likewise, users who tested positive for SARS-CoV-2 showed above average risk social-distancing behavior. Per-capita user-reported SARS-CoV-2 positive tests closely matched government-reported per-capita case counts in provinces with high user engagement., Discussion: The COVID Radar app allows voluntarily self-reporting of COVID-19 related symptoms and social distancing behaviors. Symptoms and risk behavior increase prior to a positive SARS-CoV-2 test, and user-reported case counts match closely with nationally-reported case counts in regions with high user engagement. These results suggest the COVID Radar may be a valid instrument for future surveillance and potential predictive analytics to identify emerging hotspots., Competing Interests: Salaries of first and second authors were funded by the ZonMW grants. ORTEC provided support in the form of the salary of author MeB. The other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The restrictions on sharing of data are due to national legal regulations.

Aims: To investigate whether the Geriatric 8 (G8) score and the Timed Get Up and Go Test (TGUGT), together with clinical and demographic patient characteristics, are associated with survival and late toxicity after (chemo)radiation therapy, administered with curative intent in older patients with cancer., Materials and Methods: Four hundred and two patients aged ≥65 years (median age 72 years, range 65-96 years), diagnosed with either breast, non-small cell lung, prostate, head and neck, rectal or oesophageal cancer, and referred for curative (chemo)radiation therapy, took part in a multicentre prospective cohort study in eight radiotherapy centres in the Netherlands. The G8 and TGUGT scores were assessed before starting treatment. Other potential predictors and late toxicity were also recorded. Survival status and date of death, if applicable, were ascertained at the Dutch national death registry., Results: After 2.5 years, the overall survival was 83%. Survival was 87% for patients with high G8 scores and 55% for patients with low G8 scores (Log-rank P value < 0.0001). Survival was 77% for patients with good TGUGT results and 50% for patients with poor TGUGT results (Log-rank P value < 0.001). In multivariable analysis, in addition to age and type of primary tumour, the association of the G8 score with overall survival remained, with a hazard ratio of 2.1 (95% confidence interval 1.2-3.8) for low versus high scores., Conclusions: G8 was associated with overall survival in older patients with cancer irradiated with curative intent. This association was independent of the predictive value of age and primary tumour., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Renal failure and renal replacement therapy (RRT) affect the immune system and could therefore modulate red blood cell (RBC) alloimmunization after transfusion., Study Design and Methods: We performed a nationwide multicenter case-control study within a source population of newly transfused patients between 2005 and 2015. Using conditional multivariate logistic regression, we compared first-time transfusion-induced RBC alloantibody formers (N = 505) with two nonalloimmunized recipients with similar transfusion burden (N = 1010)., Results: Renal failure was observed in 17% of the control and 13% of the case patients. A total of 41% of the control patients and 34% of case patients underwent acute RRT. Renal failure without RRT was associated with lower alloimmunization risks after blood transfusion (moderate renal failure: adjusted relative rate [RR], 0.82 [95% confidence interval (CI), 0.67-1.01]); severe renal failure, adjusted RR, 0.76 [95% CI, 0.55-1.05]). With severe renal failure patients mainly receiving RRT, the lowest alloimmunization risk was found in particularly these patients [adjusted RR 0.48 (95% CI 0.39-0.58)]. This was similar for patients receiving RRT for acute or chronic renal failure (adjusted RR, 0.59 [95% CI, 0.46-0.75]); and adjusted RR, 0.62 [95% CI 0.45-0.88], respectively)., Conclusion: These findings are indicative of a weakened humoral response in acute as well as chronic renal failure, which appeared to be most pronounced when treated with RRT. Future research should focus on how renal failure and RRT mechanistically modulate RBC alloimmunization., (© 2020 The Authors. Transfusion published by Wiley Periodicals LLC. on behalf of AABB.)

We designed a study to describe the incidence of intracranial hemorrhage according to severity and duration of thrombocytopenia and to quantify the associations of platelet transfusions with intracranial hemorrhage in patients with acute leukemia. In this case-control study nested in a cohort of 859 leukemia patients, cases (n = 17) were patients diagnosed with intracranial hemorrhage who were matched with control patients (n = 55). We documented platelet counts and transfusions for seven days before the intracranial hemorrhage in cases and in a "matched" week for control patients. Three measures of platelet count exposure were assessed in four potentially important time periods before hemorrhage. Among these leukemia patients, we observed the cumulative incidence of intracranial hemorrhage of 3.5%. Low platelet counts were, especially in the three to seven days preceding intracranial hemorrhage, associated with the incidence of intracranial hemorrhage, although with wide confidence intervals. Platelet transfusions during the week preceding the hemorrhage were associated with higher incidences of intracranial hemorrhage; rate ratios (95% confidence interval) for one or two platelet transfusions and for more than two transfusions compared with none were 4.04 (0.73 to 22.27) and 8.91 (1.53 to 51.73) respectively. Thus, among acute leukemia patients, the risk of intracranial hemorrhage was higher among patients with low platelet counts and after receiving more platelet transfusions. Especially, the latter is likely due to clinical factors leading to increased transfusion needs.

Background: Different countries have adopted different containment and testing strategies for SARS-CoV-2. The difference in testing makes it difficult to compare the effect of different containment strategies. This study proposes methods to allow a direct comparison and presents the results., Design: Publicly available data on the numbers of reported COVID-19-related deaths between 01 January and 17 April 2020 were compared between countries., Results: The numbers of cases or deaths per 100,000 inhabitants gave severely biased comparisons between countries. Only the number of deaths expressed as a percentage of the number of deaths on day 25 after the first reported COVID-19-related death allowed a direct comparison between countries. From this comparison clear differences were observed between countries, associated with the timing of the implementation of containment measures., Conclusions: Comparisons between countries are only possible when simultaneously taking into account that the virus does not arrive in all countries simultaneously, absolute numbers are incomparable due to different population sizes, rates per 100,000 of the population are incomparable because not all countries are affected homogeneously, susceptibility to death by COVID-19 can differ between populations, and a death is only reported as a COVID-19-related death if the patient was diagnosed with SARS-CoV-2 infection. With the current methods, all these factors were accounted for and an unbiased direct comparison between countries was established. This comparison confirmed that early adoption of containment strategies is key in flattening the curve of the epidemic., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Haemato-oncological patients often receive platelet count driven prophylactic platelet transfusions to prevent bleeding. However, many prophylactically transfused patients still bleed. More knowledge on risk factors for bleeding is therefore needed. This will enable identification of bleeding risk profiles on which future transfusion policy can be optimised. The present BITE study (Bleeding In Thrombocytopenia Explained) aims to identify clinical conditions and biomarkers that are associated with clinically relevant bleeding events., Methods and Analysis: A matched case-control study nested in a cohort of haemato-oncological patients in the Netherlands. We collect a limited number of variables from all eligible patients, who together form the source population. These patients are followed for the occurrence of clinically relevant bleeding. Consenting patients of the source population form the cohort. Cases from the cohort are frequency matched to selected control patients for the nested case-control study. Of both case and control patients more detailed clinical data is collected., Study Population: Adult haemato-oncological patients, who are admitted for intensive chemotherapeutic treatment or stem cell transplantation, or who received such treatments in the past and are readmitted for disease or treatment-related adverse events., Statistical Analysis: Bleeding incidences will be calculated for the total source population, as well as for different subgroups. The association between potential risk factors and the occurrence of bleeding will be analysed using conditional logistic regression, to account for matching of case and control patients., Ethics and Dissemination: The study was approved by the Medical Research Ethics Committee Leiden Den Haag and Delft, and the Radboudumc Committee on Research Involving Human Subjects. Approval in seven other centres is foreseen. Patients will be asked for written informed consent and data is coded before analyses, according to Dutch privacy law. Results will be published in peer-reviewed journals., Trial Registration Number: NL62499.058.17. NCT03505086; Pre-results., Competing Interests: Competing interests: JJZ reports that the Leiden University Medical Center, his employer, is structurally compensated for his work on blood transfusion medicine by Dutch Blood Supply organisation Sanquin, also during the conduct of the study. The other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: To date, the effects of FFP and PC storage duration on mortality have only been studied in a few studies in limited patient subpopulations. The aim of the current study was to determine whether FFP and PC storage duration is associated with increased in hospital mortality risk across cardiac surgery, acute medicine, ICU and orthopaedic surgery patients., Materials and Methods: Two-stage individual patient data meta-analyses were performed to determine the effects of FFP and PC storage duration on in hospital mortality. Preset random effects models were used to determine pooled unadjusted and adjusted (adjusted for age, gender and units of product transfused) effect estimates., Results: The FFP storage duration analysis included 3625 patients across four studies. No significant association was observed between duration of storage and in hospital mortality in unadjusted analysis, but after adjusting for patient age, gender and units of product a small increased risk of in hospital mortality was observed for each additional month of storage (OR: 1·05, 95% CI: 1·01-1·08). This effect was no longer statistically significant when donor ABO blood group was incorporated into the random effects model on post hoc analyses. A total of 547 patients across five studies were incorporated in the PC storage duration analysis. No association was observed between PC storage duration and odds of in hospital morality (adjusted OR: 0·94, 95% CI: 0·79-1·11)., Conclusions: There is insufficient evidence to support shortening FFP or PC shelf life based on in hospital mortality., (© 2019 International Society of Blood Transfusion.)

Background: Reports on the clinical consequences of longer storage time of platelet concentrates are contradictory. The objective of this study was to assess whether longer storage times are associated with a higher risk of transfusion reactions., Study Design and Methods: We gathered storage times of pooled platelet concentrates related to transfusion reactions reported to the national hemovigilance office from 2004 to 2015. These were combined with storage times of platelet concentrates in the reference population to compare incidences of transfusion-associated circulatory overload, transfusion-related acute lung injury, allergic reactions, febrile nonhemolytic reactions, and "other" reactions between storage time categories., Results: A total of 567,053 platelet concentrates and 1870 transfusion reactions were analyzed. Among platelet additive solution (PAS)-B platelet recipients, the odds ratio of a storage time of 4 to 5 days compared to 1 to 3 days was 1.60 (95% confidence interval [CI], 1.17-2.18) for allergic, and 1.47 (1.09-1.98) for febrile reactions. For PAS-C platelet recipients, the odds ratio for allergic reactions was 3.78 (95% CI, 1.31-10.9) for 4 to 5 days, and 4.57 (95% CI, 1.57-13.4) for 6- to 7-day-old platelets when compared to 1- to 3-day-old units. In all other studied reaction types, no statistically significant association was observed in platelets in plasma, PAS-B, and PAS-C., Conclusions: In plasma platelets, longer storage time was not associated with a higher incidence of transfusion reactions. In PAS platelets, longer storage time was associated with higher transfusion reaction incidences, in particular for allergic reactions with both PAS fluids and febrile reactions with PAS-B. This indicates that the effect of storage time is different for different reaction types and depends on the storage fluid., (© 2019 AABB.)

Infants with haemolytic disease of the fetus and newborn (HDFN) often require erythrocyte transfusions in the first 3 months of life. We aimed to evaluate the incidence, timing and potential predictors of transfusion-dependent anaemia. An observational cohort of 298 term and near-term infants with severe HDFN treated with or without intrauterine transfusion (IUT) was evaluated. Transfusions were administered to 88% (169/193) of infants with IUT and 60% (63/105) without IUT. The following potential predictors were associated with less anaemia: K compared to D immunisation [odds ratio (OR) 0·13, 95% confidence interval (CI): 0·03-0·55], higher reticulocyte count at birth [per 10 parts per thousand (‰) higher, OR 0·99, CI: 0·97-1·00] and exchange transfusion (OR 0·11, 95% CI: 0·03-0·50). Without IUT, these variables were: lower reticulocyte count at birth (per 10‰ lower, OR 1·02, 95% CI: 1·00-1·03), lower maximum bilirubin after birth (per 10 μmol/l lower, OR 1·01, 95% CI: 1·01-1·02) and exchange transfusion (OR 0·07, 95% CI: 0·01-0·20). In conclusion, potential predictors for anaemia in infants with severe HDFN varied between infants treated with and without IUT and are useful for selecting subgroups of infants at increased risk of anaemia., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Storage of platelet concentrates (PCs) results in reduced recovery and survival of transfused platelets (PLTs). Upon storage PLTs develop storage lesion that can be monitored by several laboratory tests. However, correlation of these descriptive tests with corrected count increments (CCIs), a marker frequently used to establish the effectiveness of PLT transfusions, is limited or unknown. This study investigated to what extent a functional test or a combined in vitro rating score improves the correlation of laboratory tests with 1-hour CCI., Study Design and Methods: PCs were analyzed using six different laboratory tests (n = 123) before transfusion in a prophylactic setting to 74 hematooncologic patients. Linear regression and Spearman correlation were used to determine associations between descriptive (either separately or combined in an in vitro rating score) or functional test results and 1-hour CCIs obtained after transfusion., Results: CD62P expression (r = -0.45), annexin V binding (r = -0.36), the updated in vitro rating score (r = 0.50), and PLT responsiveness after thrombin receptor activator for peptide-6 (TRAP) (r = 0.43-0.57) or adenosine diphosphate stimulation (r = 0.11-0.51) significantly correlated to 1-hour CCIs obtained after transfusion, whereas lactate concentration, ThromboLUX score, and thromboelastography measurements did not. The strongest correlations were observed for in vitro rating score and PLT responsiveness after TRAP stimulation and these tests could explain 24 and 33% of the observed variation in 1-hour CCI, respectively., Conclusion: Combining descriptive markers in one in vitro rating score improved correlation to 1-hour CCI compared to the tests separately. Of all tests investigated, mean PLT responsiveness after TRAP stimulation showed the strongest clinical correlation and was best able to predict the 1-hour CCI., (© 2019 AABB.)

Observational studies address packed red blood cell effects at the end of shelf life and have larger sample sizes compared to randomized control trials. Meta-analyses combining data from observational studies have been complicated by differences in aggregate transfused packed red blood cell age and outcome reporting. This study abrogated these issues by taking a pooled patient data approach. Observational studies reporting packed red blood cell age and clinical outcomes were identified and patient-level data sets were sought from investigators. Odds ratios and 95% confidence intervals for binary outcomes were calculated for each study, with mean packed red blood cell age or maximum packed red blood cell age acting as independent variables. The relationship between mean packed red blood cell age and hospital length of stay for each paper was analyzed using zero-inflated Poisson regression. Random effects models combined paper-level effect estimates. Extremes analyses were completed by comparing patients transfused with mean packed red blood cell aged less than ten days to those transfused with mean packed red blood cell aged at least 30 days. sixteen datasets were available for pooled patient data analysis. Mean packed red blood cell age of at least 30 days was associated with an increased risk of in-hospital mortality compared to mean packed red blood cell of less than ten days (odds ratio: 3.25, 95% confidence interval: 1.27-8.29). Packed red blood cell age was not correlated to increased risks of nosocomial infection or prolonged length of hospital stay., (Copyright© 2018 Ferrata Storti Foundation.)

Introduction: Electronic health care data offers the opportunity to study rare events, although detecting these events in large datasets remains difficult. We aimed to develop a model to identify leukemia patients with major hemorrhages within routinely recorded health records., Methods: The model was developed using routinely recorded health records of a cohort of leukemia patients admitted to an academic hospital in the Netherlands between June 2011 and December 2015. Major hemorrhage was assessed by chart review. The model comprised CT-brain, hemoglobin drop, and transfusion need within 24 hours for which the best discriminating cut off values were taken. External validation was performed within a cohort of two other academic hospitals., Results: The derivation cohort consisted of 255 patients, 10,638 hospitalization days, of which chart review was performed for 353 days. The incidence of major hemorrhage was 0.22 per 100 days in hospital. The model consisted of CT-brain (yes/no), hemoglobin drop of ≥0.8 g/dl and transfusion of ≥6 units. The C-statistic was 0.988 (CI 0.981-0.995). In the external validation cohort of 436 patients (19,188 days), the incidence of major hemorrhage was 0.46 per 100 hospitalization days and the C-statistic was 0.975 (CI 0.970-0.980). Presence of at least one indicator had a sensitivity of 100% (CI 95.8-100) and a specificity of 90.7% (CI 90.2-91.1). The number of days to screen to find one case decreased from 217.4 to 23.6., Interpretation: A model based on information on CT-brain, hemoglobin drop and need of transfusions can accurately identify cases of major hemorrhage within routinely recorded health records., Competing Interests: The authors have declared that no competing interests exist.

Background: Platelets (PLTs) stored in PLT additive solution (PAS) are associated with fewer allergic reactions than plasma-stored PLTs. However, earlier studies could not provide conclusive evidence on febrile reactions and did not analyze other transfusion reactions separately due to limited sample size. We therefore compared incidences of all transfusion reactions of PAS-B-PLTs, PAS-C-PLTs, and plasma-PLTs., Study Design and Methods: In this observational study, all transfusion reactions reported to the national hemovigilance office of the Netherlands from 2006 to 2015 were included., Results: During the study period, a total of 2407 transfusion reactions after PLT transfusions were reported. In that period 553,267 pooled buffy coat-derived PLT units were issued, of which 83,884 were stored in PAS-B, 45,728 in PAS-C, and 423,655 in plasma. Regarding transfusion-related circulatory overload, transfusion-related acute lung injury, and "other reactions" no significant differences were observed between the PLT products. When PAS-B-PLT transfusions were compared to plasma-PLT transfusions, the overall relative risk (RR; 95% confidence interval [CI]) of transfusion reactions was 0.99 (0.88-1.11); for allergic and febrile nonhemolytic transfusion reactions (FNHTRs) it was 0.66 (0.55-0.80) and 1.54 (1.27-1.86), respectively. When PAS-C-PLTs were compared to plasma-PLTs, the RR (95% CI) was 0.56 (0.46-0.68) for all transfusion reactions, 0.38 (0.28-0.52) for allergic reactions, and 0.82 (0.59-1.13) for FNHTRs. When PAS-C-PLTs were compared to PAS-B-PLTs, for all reactions the RR (95% CI) was 0.56 (0.45-0.70) for allergic reactions 0.58 (0.40-0.82), and for FNHTRs 0.53 (0.37-0.75)., Conclusions: PAS-C-PLTs are associated with fewer transfusion reactions compared to plasma-PLTs and compared to PAS-B-PLTs., (© 2018 AABB.)

Plasma transfusions may result in transfusion reactions. We used the International Surveillance of Transfusion-Associated Reactions and Events (ISTARE) database, containing yearly reported national annual aggregate data on transfusion reactions from participating countries, to investigate risks of plasma transfusion reactions and compare transfusion reaction risks for different plasma types. We calculated risks for plasma transfusion reactions and compared transfusion reaction risks between plasma types using random effects regression on repeated measures. The ISTARE database contains data from 23 countries, reporting units issued and/or transfused and transfusion reactions observed for some portion of 7 years (2006-2012). Interquartile ranges (IQRs) of plasma transfusion reaction risks were: allergic reactions (5·6-72·2 reactions/10 5 units transfused); febrile non-haemolytic transfusion reactions (0-9·1); transfusion-associated circulatory overload (0-1·9); transfusion related acute lung injury (TRALI) (0-1·2); and hypotensive reactions (0-0·6). Apheresis plasma was associated with more allergic reactions [odds ratio (OR) = 1·29 (95% confidence interval: 1·19-1·40)] and hypotensive reactions [OR = 2·17 (1·38-3·41)] than whole blood-derived plasma. Pathogen-inactivated plasma was associated with fewer transfusion reactions than untreated plasma., (© 2018 John Wiley & Sons Ltd.)

Background and Objectives: Evidence-based guidelines on optimal triggers for red blood cell (RBC) transfusion in patients with haematological malignancies exist, but the evidence is weak. Secondary iron overload is an often overlooked chronic complication of RBC transfusions, and also here, guidelines are either lacking or lack international consensus. Our aim was to evaluate the triggers for RBC transfusion support and management of secondary iron overload among haematologists in the Netherlands., Materials and Methods: For this cross-sectional study, all haematologists and haematologists in training in the Netherlands were sent a web-based, 25-question survey including three clinical scenarios. The survey distribution took place between 19 November 2015 and 26 January 2016., Results: Seventy-seven responses were received (24%), well distributed among community and university hospitals. A wide variation in haemoglobin triggers existed: 5·6-9·5 g/dl (median: 8·0 g/dl). Personalization of this trigger was mostly based on (estimated) cardiopulmonary compensation capacity of patients. About 65% of respondents reported two RBC units per transfusion episode (range 1-3). For monitoring secondary iron overload, serum ferritin was most frequently measured (97%), while a value of 1000-1500 μg/l was the most common cut-off to initiate treatment (39%). For 81% of respondents, phlebotomies were the first choice of treatment, although often the haemoglobin level was considered a limiting factor., Conclusion: Our results confirm large reported variation in daily practice among haematologists in the Netherlands regarding RBC transfusion support and management of secondary iron overload. Future studies providing better evidence are needed to improve guidelines specific for patients with haematological malignancies., (© 2017 International Society of Blood Transfusion.)

Background: Concern of transfusion-transmitted bacterial infections has been the major hurdle to extend shelf life of platelet (PLT) concentrates. We aimed to investigate the association between storage time and risk of positive blood cultures at different times after transfusion., Study Design and Methods: We performed a nationwide cohort study among PLT transfusion recipients in Denmark between 2010 and 2012, as recorded in the Scandinavian Donations and Transfusions (SCANDAT2) database. Linking with a nationwide database on blood cultures (MiBa), we compared the incidence of a positive blood culture among recipients of PLTs stored 6 to 7 days (old) to those receiving fresh PLTs (1-5 days), using Poisson regression models. We considered cumulative exposures in windows of 1, 3, 5, and 7 days., Results: A total of 9776 patients received 66,101 PLT transfusions. The incidence rate ratio (IRR) of a positive blood culture the day after transfusion of at least one old PLT concentrate was 0.77 (95% confidence interval [CI], 0.54-1.09) compared to transfusion of fresh PLT concentrates. The incidence rate of a positive blood culture was lower the day after receiving one old compared to one fresh PLT concentrate (IRR, 0.57; 95% CI, 0.37-0.87). Three, 5, or 7 days after transfusion, storage time was not associated with the risk of a positive blood culture., Conclusion: Storage of buffy coat-derived PLT concentrates in PAS-C up to 7 days seems safe regarding the risk of a positive blood culture. If anything, transfusion of a single old PLT concentrate may decrease this risk the following day., (© 2017 AABB.)

Background: Storage time of platelet (PLT) concentrates has been negatively associated with clinical efficacy outcomes. The aim of this study was to quantify the association between storage time of PLT concentrates and interval to the next PLT transfusion for different types of PLT components, stored for up to 7 days and transfused to transfusion-dependent hematooncology patients with thrombocytopenia., Study Design and Methods: From a cohort of patients from 10 major Dutch hospitals, patients were selected whose transfusion patterns were compatible with PLT transfusion dependency due to hematooncologic disease. Mean time to the next transfusion and mean differences in time to the next transfusion for different storage time categories (i.e., fresh, <4 days; intermediate, 4-5 days; and old, >5 days) were estimated, per component type, using multilevel mixed-effects linear models., Results: Among a cohort of 29,761 patients who received 140,896 PLT transfusions we selected 4441 hematooncology patients who had received 12,724 PLT transfusions during periods of PLT transfusion dependency. Transfusion of fresh, compared to old, buffy coat-derived PLTs in plasma was associated with a delay to the next transfusion of 6.2 hours (95% confidence interval [CI], 4.5-8.0 hr). For buffy coat-derived PLTs in PAS-B and -C this difference was 7.7 hours (95% CI, 2.2-13.3 hr) and 3.9 hours (95% CI, -2.1 to 9.9 hr) while for apheresis PLTs in plasma it was only 1.8 hours (95% CI, -3.5 to 7.1 hr)., Conclusion: Our results indicate that the time to the next transfusion shortens with increasing age of transfused buffy coat-derived PLT concentrates. This association was not observed for apheresis PLTs., (© 2017 AABB.)

Importance: Transfusion of red blood cells from female donors has been associated with increased mortality in male recipients., Objective: To quantify the association between red blood cell transfusion from female donors with and without a history of pregnancy and mortality of red blood cell recipients., Design, Setting, and Participants: Retrospective cohort study of first-time transfusion recipients at 6 major Dutch hospitals enrolled from May 30, 2005, to September 1, 2015; the final follow-up date was September 1, 2015. The primary analysis was the no-donor-mixture cohort (ie, either all red blood cell transfusions exclusively from male donors, or all exclusively from female donors without a history of pregnancy, or all exclusively from female donors with a history of pregnancy). The association between mortality and exposure to transfusions from ever-pregnant or never-pregnant female donors was analyzed using life tables and time-varying Cox proportional hazards models., Exposures: Red blood cell transfusions from ever-pregnant or never-pregnant female donors, compared with red blood cell transfusions from male donors., Main Outcomes and Measures: All-cause mortality during follow-up., Results: The cohort for the primary analyses consisted of 31 118 patients (median age, 65 [interquartile range, 42-77] years; 52% female) who received 59 320 red blood cell transfusions exclusively from 1 of 3 types of donors (88% male; 6% ever-pregnant female; and 6% never-pregnant female). The number of deaths in this cohort was 3969 (13% mortality). For male recipients of red blood cell transfusions, all-cause mortality rates after a red blood cell transfusion from an ever-pregnant female donor vs male donor were 101 vs 80 deaths per 1000 person-years (time-dependent "per transfusion" hazard ratio [HR] for death, 1.13 [95% CI, 1.01-1.26]). For receipt of transfusion from a never-pregnant female donor vs male donor, mortality rates were 78 vs 80 deaths per 1000 person-years (HR, 0.93 [95% CI, 0.81-1.06]). Among female recipients of red blood cell transfusions, mortality rates for an ever-pregnant female donor vs male donor were 74 vs 62 per 1000 person-years (HR, 0.99 [95% CI, 0.87 to 1.13]); for a never-pregnant female donor vs male donor, mortality rates were 74 vs 62 per 1000 person-years (HR, 1.01 [95% CI, 0.88-1.15])., Conclusions and Relevance: Among patients who received red blood cell transfusions, receipt of a transfusion from an ever-pregnant female donor, compared with a male donor, was associated with increased all-cause mortality among male recipients but not among female recipients. Transfusions from never-pregnant female donors were not associated with increased mortality among male or female recipients. Further research is needed to replicate these findings, determine their clinical significance, and identify the underlying mechanism.

Background: Hyperfibrinolysis has been observed in patients heavily transfused with solvent/detergent-treated pooled plasma (S/D plasma). We compared coagulation and fibrinolytic variables in blood containing S/D plasma with blood containing fresh-frozen plasma (FFP), with and without α2-antiplasmin or tranexamic acid (TXA) supplementation., Study Design and Methods: Whole blood samples were reconstituted from red blood cells, platelet (PLT) concentrates, and varying mixtures of FFP and S/D plasma. Hematocrit and PLT count of reconstituted whole blood samples were varied. For a subset of runs, α2-antiplasmin or TXA was added to S/D plasma whole blood samples. Thromboelastography (TEG) analysis was performed to assess 50% clot lysis time (CLT 50% ), maximum amplitude (MA), and initial clotting time (R-time)., Results: The change in CLT 50% of whole blood as the plasma compartment transitions from FFP to S/D plasma was -52% (95% confidence interval [CI], -60% to -45%; p < 0.001). PLT count strengthened the effect, leading to an additional change in CLT 50% of -8% (95% CI, -14% to -2%; p = 0.012) as PLT count increased from 10 × 10 9 to 150 × 10 9 /L. MA and R-time were not associated with fraction of S/D plasma in whole blood. α2-Antiplasmin and TXA restored clot lysis time in S/D plasma whole blood., Conclusion: Whole blood with S/D plasma has shorter clot lysis times in vitro compared to whole blood with FFP. α2-Antiplasmin and TXA restore clot lysis time of S/D plasma whole blood to that of FFP whole blood. Clinicians should be aware of the decreased clot lysis time associated with S/D plasma transfusion., (© 2017 AABB.)

Background: Extension of storage time of platelet (PLT) concentrates may result in an increased risk of bacteremia, directly via transfusion of contaminated products or indirectly via transfusion-related immunomodulation. We aimed to quantify the association of storage time of PLT concentrates and all-cause bacteremia in hematologic patients., Study Design and Methods: We established a cohort of hematologic patients who received a PLT transfusion between 2005 and 2015. Cases were defined as patients with a bacteremia the day after transfusion and matched to as many controls as possible. A conditional logistic regression was performed, stratified by storage medium., Results: Among 3514 patients receiving 36,032 PLT concentrates stored in plasma, 613 cases of bacteremia were found. The relative risk of all-cause bacteremia the day after transfusion was 0.80 (95% confidence interval [CI], 0.58-1.12) for PLT concentrates stored 3 to 4 days and 0.67 (95% CI, 0.49-0.92) for at least 5 days, compared to no more than 2 days. Among 1527 patients receiving 11,822 PLT concentrates stored in PLT additive solution, 182 cases of bacteremia were found. The relative risk of all-cause bacteremia was 1.14 (95% CI, 0.70-1.84) for PLT concentrates stored for 3 to 4 days and 1.19 (95% CI, 0.70-2.01) for at least 5 days, compared to not more than 2 days., Conclusion: Storage time of PLT concentrates was not associated with increased occurrence of all-cause bacteremia the day after transfusion. If anything, fewer cases of bacteremia occurred with increasing storage time of PLT concentrates in plasma. These bacteremias are not directly caused by transfusion of a contaminated product and the underlying mechanism warrants further research., (© 2017 AABB.)

Background: We estimated rates for common plasma-associated transfusion reactions and compared reported rates for various plasma types., Study Design and Methods: We performed a systematic review and meta-analysis of peer-reviewed articles that reported plasma transfusion reaction rates. Random-effects pooled rates were calculated and compared between plasma types. Meta-regression was used to compare various plasma types with regard to their reported plasma transfusion reaction rates., Results: Forty-eight studies reported transfusion reaction rates for fresh-frozen plasma (FFP; mixed-sex and male-only), amotosalen INTERCEPT FFP, methylene blue-treated FFP, and solvent/detergent-treated pooled plasma. Random-effects pooled average rates for FFP were: allergic reactions, 92/10 5 units transfused (95% confidence interval [CI], 46-184/10 5 units transfused); febrile nonhemolytic transfusion reactions (FNHTRs), 12/10 5 units transfused (95% CI, 7-22/10 5 units transfused); transfusion-associated circulatory overload (TACO), 6/10 5 units transfused (95% CI, 1-30/10 5 units transfused); transfusion-related acute lung injury (TRALI), 1.8/10 5 units transfused (95% CI, 1.2-2.7/10 5 units transfused); and anaphylactic reactions, 0.8/10 5 units transfused (95% CI, 0-45.7/10 5 units transfused). Risk differences between plasma types were not significant for allergic reactions, TACO, or anaphylactic reactions. Methylene blue-treated FFP led to fewer FNHTRs than FFP (risk difference = -15.3 FNHTRs/10 5 units transfused; 95% CI, -24.7 to -7.1 reactions/10 5 units transfused); and male-only FFP led to fewer cases of TRALI than mixed-sex FFP (risk difference = -0.74 TRALI/10 5 units transfused; 95% CI, -2.42 to -0.42 injuries/10 5 units transfused)., Conclusion: Meta-regression demonstrates that the rate of FNHTRs is lower for methylene blue-treated compared with FFP, and the rate of TRALI is lower for male-only than for mixed-sex FFP; whereas no significant differences are observed between plasma types for allergic reactions, TACO, or anaphylactic reactions. Reported transfusion reaction rates suffer from high heterogeneity., (© 2017 AABB.)

Haemato-oncological patients receive many red blood cell (RBC) transfusions, however evidence-based guidelines are lacking. Our aim is to quantify the effect of restrictive and liberal RBC transfusion strategies on clinical outcomes and blood use in haemato-oncological patients. A literature search, last updated on 11 August 2016, was performed in PubMed, EMBASE (Excerpta Medica Database), Web of Science, Cochrane, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Academic Search Premier without restrictions on language and year of publication. Randomized controlled trials and observational studies that compared different RBC transfusion strategies in haemato-oncological patients were eligible for inclusion. Risk of bias assessment according to the Cochrane collaboration's tool and Newcastle-Ottawa scale was performed. After removing duplicates, 1142 publications were identified. Eventually, 15 studies were included, reporting on 2636 patients. The pooled relative risk for mortality was 0·68 [95% confidence interval (CI) 0·46-1·01] in favour of the restrictive strategy. The mean RBC use was reduced with 1·40 units (95% CI 0·70-2·09) per transfused patient per therapy cycle in the restrictive strategy group. There were no differences in safety outcomes. All currently available evidence suggests that restrictive strategies do not have a negative impact regarding clinical outcomes in haemato-oncological patients, while it reduces RBC use and associated costs., (© 2017 John Wiley & Sons Ltd.)

Background: Prolonged storage improves availability of platelet products but could also influence safety and efficacy. This systematic review and meta-analyses summarize and quantify the evidence of the effect of storage time of transfused platelets on clinical outcomes., Methods: A systematic search in seven databases was performed up to February 2016. All studies reporting storage time of platelet products and clinical outcomes were included. To quantify heterogeneity, I² was calculated, and to assess publication bias, funnel plots were constructed., Results: Twenty-three studies reported safety outcomes and fifteen efficacy outcomes. The relative risk of a transfusion reaction after old platelets compared to fresh platelets was 1·53 (95% confidence interval (CI): 1·04-2·25) (12 studies). This was 2·05 (CI:1·47-2·85) before and 1·05 (CI: 0·60-1·84) after implementation of universal leucoreduction. The relative risk of bleeding was 1·13 (CI: 0·97-1·32) for old platelets compared to fresh (five studies). The transfusion interval was 0·25 days (CI: 0·13; 0·38) shorter after transfusion of old platelets (four studies). Three studies reported use of platelet products: two for haematological patients and one for trauma patients. Selecting only studies in haematological patients, the difference was 4·51 units (CI: 1·92; 7·11)., Conclusion: Old platelets increase the risk of transfusion reactions in the setting of non-leucoreduction, shorten platelet transfusion intervals, thereby increase the numbers of platelet transfusions in haematological patients, and may increase the risk of bleeding., (© 2017 International Society of Blood Transfusion.)

Background/objectives: Negative experiences (NEs) have been shown to result in an increased stress response, as indicated by blood pressure, at the subsequent donation. This response might be influenced by how the donor rates the donation in terms of importance and pleasantness [affective attitude (AA)/cognitive attitude (CA)] or by anxiety about donating blood. We investigated the effect of AA/CA/anxiety on the impact of NEs on pre-donation blood pressure (pd-BP) in the subsequent donation., Materials/methods: pd-BP at visit 3 was compared between donors with and without a history of NEs during or after their first two visits (visit 1: medical check, visit 2: first donation). The effect of AA/CA/anxiety (measured 1 month prior to visit 1 on a 7-point scale) on visit 3 pd-BP was explored using linear regression and interaction analyses. Analyses were stratified for gender, age and pd-BP at visit 1, which were taken into account as confounders., Results: In 1106 first-time blood donors (70% female), 632 donors (57% of total) indicated an NE at their first donation. Mean scores for AA/CA/anxiety were 5·2/6·5/2·2 (men without NE), 4·8/6·3/3·0 (men with NE), 5·2/6·6/2·6 (women without NE) and 4·8/6·6/3·2 (women with NE). No significant associations were found for NE and pd-BP at visit 3 after adjusting for confounding. Of 48 interaction effects, four were significant, but effects were small and inconsistent., Conclusion: In donors who had had negative experiences during their first donation, anxiety and attitude to donation did not influence their pre-donation blood pressure at their subsequent visit., (© 2016 British Blood Transfusion Society.)

Background: Foetal/neonatal allo-immune neutropenia (FNAIN) is a serious condition usually resulting from immunisation of the mother to paternally inherited neutrophil antigens of the foetus. Understanding the biology of female immunisation against neutrophils could help predict or prevent FNAIN., Objectives: To quantify differences in the prevalence of specific and pan-reactive granulocyte antibodies, between allo-exposed and never allo-exposed male and female blood donors., Methods/materials: We previously reported the prevalence of granulocyte antibodies in healthy male and female blood donors. Here, we compare specific vs. pan-reactive antibodies., Results: The prevalence of specific granulocyte antibodies was similar in male [1.0%; 95% confidence interval (CI): 0.70-1.4] and female nulliparous blood donors (0.87%; CI: 0.029-1.7) and doubled after pregnancies (1.8%; CI: 0.52-3.0). In contrast, pan-reactive antibodies were almost three times less common in male (0.81%; CI: 0.50-1.1) compared to female nulliparous blood donors (2.3%; CI: 0.91-3.8) and were half as high after pregnancies (1.1%; CI: 0.58-1.7)., Conclusion: We found unexpected differences between male and female blood donors. Determining the clinical relevance of the pan-reactive antibodies requires further research, but none of the tested blood donors experienced any symptoms of neutropenia., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Transfusion-transmitted bacterial infections (TTBIs) are among the most concerning risks of transfusion of platelet (PLT) concentrates. Storage medium influences bacterial growth dynamics and thereby the sensitivity of screening tests for bacterial contamination., Study Design and Methods: The aim of this study was to quantify the association of storage media with the incidence of TTBIs after transfusion of PLT concentrates. In the Netherlands, the choice of storage medium is determined solely by geographic location of the hospital. We compared types of storage medium of all reported cases of TTBIs after transfusion of a PLT concentrate with types of storage medium of all produced PLT concentrates in the Netherlands from 2003 to 2014., Results: Fourteen cases of TTBIs were reported, of which 57.1% received a PLT concentrate stored in PLT additive solution (PAS) and 42.9% a PLT concentrate stored in plasma. Of all produced PLT concentrates 22.3% were stored in PAS and 77.7% in plasma. The relative risk of TTBI after transfusion of a PAS-stored PLT concentrate was 4.63 (95% confidence interval [CI], 1.4-16.2) compared to transfusion of a plasma-stored PLT concentrate. The incidence of TTBIs was 22.2 per million (95% CI, 12.1-37.2 per million) transfused buffy coat PLT concentrates., Conclusion: Transfusion of PAS-stored PLT concentrates is associated with a fourfold increased incidence of TTBIs, compared to plasma-stored PLT concentrates., (© 2017 AABB.)

Red cell alloimmunization may induce severe hemolytic side effects. Identification of risk-modifying conditions will help tailor preventative strategies. This study aims to quantify the associations of hematologic malignancies and solid cancers with red cell alloimmunization in patients receiving red cell transfusions. We performed a nested multicenter case-control study in a source population of 24,063 patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Cases (n=505), defined as patients developing a first transfusion-induced red cell alloantibody, were each compared with 2 non-alloimmunized controls (n=1010) who received a similar number of red cell units. Using multivariate logistic regression analyses, we evaluated the association of various malignancies and treatment regimens with alloimmunization during a delineated 5-week risk period. The incidence of alloimmunization among patients with acute (myeloid or lymphoid) leukemia and mature (B- or T-cell) lymphoma was significantly reduced compared to patients without these malignancies: adjusted relative risks (RR) with 95% confidence interval (CI) 0.36 (range 0.19-0.68) and 0.30 (range 0.12-0.81). Associations were primarily explained by immunosuppressive treatments [RR for (any type of) chemotherapy combined with immunotherapy 0.27 (95%CI: 0.09-0.83)]. Alloimmunization risks were similarly diminished in allogeneic or autologous stem cell transplanted patients (RR 0.34, 95%CI: 0.16-0.74), at least during the six months post transplant. Alloimmunization risks of patients with other hematologic diseases or solid cancers, and their associated treatment regimens were similar to risks in the general transfused population. Our findings suggest that, in contrast to malignancies in general, hemato-oncological patients treated with dose-intensive regimens have strongly diminished risk of red cell alloimmunization., (Copyright© Ferrata Storti Foundation.)

Red cell alloantigen exposure can cause alloantibody-associated morbidity. Murine models have suggested that inflammation modulates red cell alloimmunisation. This study quantifies alloimmunisation risks during infectious episodes in humans. We performed a multicentre case-control study within a source population of patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Patients developing a first transfusion-induced red cell alloantibody (N = 505) were each compared with two similarly exposed, but non-alloimmunised controls (N = 1010) during a 5-week 'alloimmunisation risk period' using multivariate logistic regression analysis. Transfusions during 'severe' bacterial (tissue-invasive) infections were associated with increased risks of alloantibody development [adjusted relative risk (RR) 1·34, 95% confidence interval (95% CI) 0·97-1·85], especially when these infections were accompanied with long-standing fever (RR 3·06, 95% CI 1·57-5·96). Disseminated viral disorders demonstrated a trend towards increased risks (RR 2·41, 95% CI 0·89-6·53), in apparent contrast to a possible protection associated with Gram-negative bacteraemia (RR 0·58, 95% CI 0·13-1·14). 'Simple' bacterial infections, Gram-positive bacteraemia, fungal infections, maximum C-reactive protein values and leucocytosis were not associated with red cell alloimmunisation. These findings are consistent with murine models. Confirmatory research is needed before patients likely to develop alloantibodies may be identified based on their infectious conditions at time of transfusion., (© 2016 John Wiley & Sons Ltd.)