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Summary: Red blood cell autoimmunity and alloimmunity are potentially linked. Quantification of this association can tailor extensively matched red blood cell transfusions in patients with autoimmunity. Using an incident new‐user cohort comprising 47 285 previously non‐transfused, non‐alloimmunised patients, we compared transfusion‐induced red blood cell alloimmunisation incidences in direct antiglobulin test (DAT)‐positive and control patients. Additionally, we performed case–control analyses to handle potential confounding by clinical immunomodulators. Among (IgG and/or C3d) DAT‐positive patients (N = 380), cumulative red blood cell alloimmunisation incidences after 10 units transfused reached 4.5% (95% confidence interval [CI] 2.5–8.2) versus 4.2% (CI 3.9–4.5, p = 0.88) in controls. In case–control analyses, alloimmunisation relative risks among DAT‐positive patients increased to 1.7 (CI 1.1–2.8). Additional adjustments for pre‐DAT transfusion exposure or the extent of Rh/K mismatching did not impact results. In conclusion, while patients with DAT positivity show an intrinsically increased alloimmune red blood cell response, their absolute risk is comparable to control patients due to counteracting co‐existing immunosuppressive conditions. Consequently, isolated DAT positivity in patients lacking overt haemolysis or complicated alloantibody testing does not seem to warrant extended matching strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Considering this finding, preventing transfusion-induced RBC alloimmunisation by antigen matching should be similarly pursued for immunocompetent young and elderly patients. Transfusion-induced red blood cell alloimmunisation is unhampered in elderly patients With advancing age, adaptive immune responses undergo significant deteriorating changes resulting in a gradual decline of protective responses to infections and long-term immune memory vaccination responses.1-4 Considering the pathophysiology of red blood cell (RBC) alloimmunisation shares several aspects with vaccination responses, primary transfusion-induced RBC alloimmunisation may similarly deteriorate with advancing age. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Summary: Maternal alloantibodies directed against fetal red blood cell (RBC) antigens may cause potentially life‐threatening haemolytic disease of the fetus and newborn (HDFN). Dutch transfusion guidelines therefore prescribe preventive cEK matching for all (pre‐)fertile females. To quantify the impact of cEK matching, we compared overall and antigen‐specific cumulative RBC alloimmunisation incidences in females and males aged <45 years. Among a multicentre cohort comprised of patients who received their first and subsequent RBC unit between 2005 and 2019, first‐formed RBC alloantibodies were detected in 47 of 2998 (1·6%) females and 49 of 2507 (2·0%) males. Comparing females and males, overall alloimmunisation incidences were comparable (3·1% [95% confidence interval (CI) 2·1–4·4] versus 3·5% (95% CI 2·4–4·9, P = 0·853) after 10 units transfused). However, cEK alloimmunisation incidences were significantly lower among females (0·6% (95% CI 0·3–1.5) versus 2·2% (95% CI 1·5–3·4, P = 0·001) after 10 units transfused). Yet, despite cEK‐matching guidelines being in effect, 6·5%, 3·6% and 0·2% of all RBC units remained mismatched for c, E or K antigens respectively. Most of these mismatches were almost always due to emergency settings. Even though cEK alloimmunisation was not prevented completely, implementation of cEK matching resulted in an alloantigen‐exposure risk reduction of up to 98%. [ABSTRACT FROM AUTHOR]

Haematopoietic stem-cell transplantation (HSCT) is performed mainly in patients diagnosed with malignancies or some severe congenital diseases. Significant reduction of red blood cell transfusion requirements by changing from a double-unit to a single-unit transfusion policy in patients receiving intensive chemotherapy or stem cell transplantation. Patients with PRCA can become RBC transfusion dependent for a long period, suffering an important long-term iron overload, alloimmunization and transfusion reactions [15]. [Extracted from the article]

- We systematically monitor the efficacy of platelet transfusions by a post-transfusion platelet count at 20 h after transfusion. The efficacy of platelet transfusions is not routinely measured by a post-platelet transfusion increment (PPI), however if there are any concerns regarding the daily platelet counts (e.g. persisting low counts after prior transfusion such that the patient is requiring very frequent transfusions), we would perform platelet increment testing at 30-60 min post-transfusion. We advise monitoring of post-transfusion platelet counts (15-60 min post) in "high-use alert cases" (three consecutive days with >=1 platelet transfusion per day), or in the evaluation of immune-selected single donor apheresis platelets (to assess the in vivo efficacy of products which had been selected to circumvent the last known array of HLA- and/or HPA-specific antibodies). We systematically monitor the efficacy of platelet transfusions in patients undergoing HSCT by a post-transfusion platelet count about an hour after finishing the transfusion. At our institution, if a patient is independent of RBC transfusion for 90 days and no incompatible isohemagglutinins against the new RBC phenotype are detected in two consecutive blood samples, then the patient's native blood type is switched to the donor type for future transfusion. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Background: In neonates, hypoglycemia is an emergency condition requiring urgent treatment. Therefore, rapid and reliable blood glucose measurements are necessary. However, this step has been proven difficult because of both analytical and preanalytical variables. In our children's hospital, we incidentally observed cases of hypoglycemia that were not in line with the clinical picture of the infants. Remarkably, most of these infants had a high hematocrit. Methods: Glucose concentrations were determined in blood samples from healthy participants that were collected in Li-heparin capillary and pediatric tubes. The effect of hematocrit on glucose consumption over time was studied by artificially increasing sample hematocrits. To study the effect of sample cooling, glucose concentrations were followed over time in samples stored at room temperature and on ice. Results: In all samples, glucose concentrations declined with time. This effect was most dramatic [up to 18 mg/dL (1 mmol/L) in the first 30 min] in samples with high hematocrits and collected in capillary tubes. Cooling of samples clearly reduced glucose consumption; however, this was not evident in the first 30 min. Conclusions: Overestimation of hypoglycemia in infants must be considered if samples are not centrifuged or are not analyzed immediately after sampling. The extent of overestimation is more pronounced in samples with a high hematocrit, collected in capillary tubes. Cooling of samples does not prevent glucose consumption in vitro during the first 30 min. These results emphasize that, for glucose analysis, prompt handling of samples of newborns with a high hematocrit is necessary. [ABSTRACT FROM AUTHOR]

Blood contains a mixture of extracellular vesicles from different cell types, primarily platelets, endothelial cells, leucocytes and erythrocytes. Erythrocytes are themost abundant cell type in blood and could, especially in certain pathologies, represent an important source of vesicles. Since erythrocytes contain the haemoglobin components iron and haem, which are potentially toxic, it is important to investigate the contribution of vesicle-associated haemoglobin to total cell-free haemoglobin levels. To our knowledge, this is the first time that cell-free plasma haemoglobin has been differentiated into vesicle-associated and molecular species. We investigated the contribution of vesicle-associated haemoglobin in residual patient material that was routinely analysed for total cell-free plasma haemoglobin. All patient samples included in the study were haemolytic with total cell-free haemoglobin concentration ranging from 80 to 2500 mg/l. In the majority of the samples, total cell-free haemoglobin concentration was between 100 and 200 mg/l. No haemoglobin could be detected in the vesicle fraction, indicating that the contribution of vesicle-associated haemoglobin to total cell free-haemoglobin levels in plasma is negligible. It is important to investigate whether erythrocyte vesicles are not formed in blood or that their production is not increased during pathologies associated with haemolysis or that the clearance rate of the vesicles surpasses the formation rate. [ABSTRACT FROM AUTHOR]

Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20–50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS. [ABSTRACT FROM PUBLISHER]

The article discusses a study which evaluated the effect of the gaming app Prik! on experienced pain and distress during venipuncture/fingerprick by comparing it to the use of a noninformative gaming app and no app. Topics include venipunctures and finger pricks are a major source of pain and distress in pediatric healthcare, main outcome of the study, and conclusion on playing a serious gaming app such as Prik! before blood sampling.

Background: Usually, laboratory diagnostics of hereditary hemoglobin disorders is fairly straightforward. Sometimes, however, correct diagnosis can be difficult. In this study, we describe a family with multiple mutations and sequence variations in the α- and β-globin gene clusters. Methods: Hemocytometry results were obtained using an automated cell counter. Hemoglobin variant analysis was performed by cation-exchange HPLC. PCR and DNA sequence analyses were used to identify mutations in the globin genes. Results: The proposita was referred to our laboratory for hematological evaluation [hemoglobin 145 g/L (119-155 g/L) mean corpuscular volume 72 fl (80-97 fl), mean corpuscular hemoglobin 26 pg (28-36 pg), erythrocytes 5.6 x 1012/L (3.7-5.0 1012/L)]. Characterization and quantification of hemoglobin variants showed 11.3% HbA1, 4.4% HbA2, 58.9% HbC and 23.0% HbF. Subsequent analysis revealed, in addition to a heterozygous HbC mutation, the presence of a β-thalassemia causing mutation (-90C > T), a heterozygous α-thalassemia (-α-3.7/αα) and three different γ-globin sequence variations. Additional molecular analysis was performed in all family members. Conclusions: In the family presented in this study, 10 different mutations were found in the globin genes. Molecular analysis was necessary to clarify hemoglobin variant analysis, in particular the low amount of HbA1 in the proposita. Knowledge of the molecular background facilitates in the understanding of the hematological parameters and proper counseling of the patient. [ABSTRACT FROM AUTHOR]

Objectives: To identify indications for exchange transfusions, assess the use and waste of exchange transfusion products (ie, reconstituted whole blood exchange transfusions), and determine nationwide distribution and prevalence of these transfusions in the Netherlands., Study Design: All 9 neonatal intensive care units and 15 non-neonatal intensive care unit hospitals participated in this retrospective, observational, cohort study. We retrieved data on the indications for and use of all exchange transfusion products ordered by participating centers over an 11-year period., Results: A total of 574 patients for whom 1265 products were ordered were included for analyses. Severe ABO (32.6%) and non-ABO (25.2%) immune hemolysis and subsequent hyperbilirubinemia were the most frequent indications. Rare indications were severe leukocytosis in Bordetella pertussis (2.1%) and severe anemia (1.5%). Approximately one-half of all ordered products remained unused. In 278 of 574 neonates (48.4%), ≥1 products were not used, of which 229 (82.7%) were due to the resolving of severe hyperbilirubinemia with further intensification of phototherapy. The overall prevalence of neonates who received an exchange transfusion was 14.6:100 000 liveborn neonates., Conclusions: A considerable proportion of products remained unused, and annually a limited number of patients are treated with an exchange transfusion in the Netherlands, highlighting the rarity of the procedure in the Netherlands., Competing Interests: Declaration of Competing Interest This study is researcher initiated and not externally funded. No funds, grants, or other support were received. D.P.d.W. received funding from Momenta Pharmaceuticals, Inc., which was acquired by Johnson & Johnson, and is an investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of HDFN. E.J.T.V. is the principal investigator for a phase 2 trial (NCT03842189) and a phase 3 trial (NCT05912517) of a new drug for the treatment of HDFN, which is sponsored by Janssen Pharmaceuticals. E.L. is a sub-investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of HDFN, which is sponsored by Janssen Pharmaceuticals. All other authors reported to have no conflict of interest or financial disclosures., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Transfusion of red blood cells (RBCs) from female donors has been associated with increased risk of mortality. This study aims to investigate the associations between donor-recipient sex and posttransfusion mortality and morbidity in critically ill patients who received RBC transfusions from either male-only donors or from female-only donors (unisex-transfusion cases). Survival analysis was used to compare 4 groups: female-to-female, female-to-male, male-to-female, and male-to-male transfusion. Multivariate logistic model was used to evaluate the association between donor sex and intensive care unit (ICU) mortality. Associations between transfusion and acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), and nosocomial infections were assessed. Of the 6992 patients included in the original cohort study, 403 patients received unisex-transfusion. Survival analysis and the logistic model showed that transfusion of female RBCs to male patients was associated with an increased ICU mortality compared with transfusion of female RBCs to female patients (odds ratio, 2.43; 95% confidence interval, 1.02-5.77; P < .05). There was a trend toward increased ARDS in patients receiving RBC from female donors compared with those receiving blood from males (P = .06), whereas AKI was higher in donor-recipient sex-matched transfusion groups compared with sex-mismatched groups (P = .05). This was an exploratory study with potential uncontrolled confounders that limits broad generalization of the findings. Results warrant further studies investigating biological mechanisms underlying the association between donor sex with adverse outcomes as well as studies on the benefit of matching of blood between donor and recipient., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other 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.)

Plasma transfusion is indicated for replenishment of coagulative proteins to stop or prevent bleeding. In 2014, the Netherlands switched from using ~300mL fresh frozen plasma (FFP) units to using 200mL Omniplasma, a solvent/detergent treated pooled plasma (SD plasma), units. We evaluated the effect of the introduction of SD plasma on clinical plasma use, associated bleeding, and transfusion reaction incidences. Using diagnostic data from six Dutch hospitals, national blood bank data, and national hemovigilance data for 2011 to 2017, we compared the plasma/red blood cell (RBC) units ratio (f) and the mean number of plasma and RBC units transfused for FFP (~300mL) and SD plasma (200mL) for various patient groups, and calculated odds ratios comparing their associated transfusion reaction risks. Analyzing 13,910 transfusion episodes, the difference (Δf = f SD - f FFP ) in mean plasma/RBC ratio (f) was negligible (Δf entire&#95;cohort = 0.01 [95% confidence interval (CI): -0.02 - 0.05]; P =0.48). SD plasma was associated with fewer RBC units transfused per episode in gynecological (difference of mean number of units -1.66 [95% CI: -2.72, -0.61]) and aneurysm (-0.97 [-1.59, -0.35]) patients. SD plasma was further associated with fewer anaphylactic reactions than FFP (odds ratio 0.37 [0.18, 0.77; P <0.01]) while the differences for most transfusion reactions were not statistically significant. SD plasma units, despite being one third smaller in volume than FFP units, are not associated with a higher plasma/RBC ratio. SD plasma is associated with fewer anaphylactic reactions than FFP plasma/RBC units ratio., (Copyright© 2020 Ferrata Storti Foundation.)

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: The dramatic impact of hemosiderosis on survival in chronically transfused patients with hereditary anemia is well known. We evaluated whether patients receiving multiple red blood cell (RBC) transfusions are adequately screened for hemosiderosis., Methods: We retrospectively assessed hemosiderosis screening and prevalence in adult patients that received over twenty RBC units in the University Medical Centre Utrecht from 2010 till 2015. Hemosiderosis was defined as ferritin ≥1000 μg/L. Adequate screening for chronically transfused patients was defined as any ferritin determined up to 3 months before or any moment after the last transfusion, while for patients that received all transfusions within 3 months (bulk transfusion), ferritin had to be determined after at least twenty transfusions., Results: Of 471 patients, only 38.6% was adequately screened and hemosiderosis prevalence was 46.7%. Hemosiderosis prevalence was 47% in the chronic transfusion group and 12% in the bulk transfusion group. In patients transfused because of hematological malignancy or cardiothoracic surgery, respectively, 74% and 31% were adequately screened and hemosiderosis prevalence was 53% and 13%, respectively., Conclusion: Hemosiderosis screening in our routine practice is suboptimal. Hemosiderosis is not an exclusive complication of multiple transfusions in the hematology ward. We recommend screening for hemosiderosis in all patients receiving multiple transfusions., (© 2017 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

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.)

Background: Monoclonal antibodies (MoAbs) are increasingly integrated in the standard of care. The notion that therapeutic MoAbs can interfere with clinical laboratory tests is an emerging concern that requires immediate recognition and the development of appropriate solutions. Here, we describe that treatment of multiple myeloma patients with daratumumab, a novel anti-CD38 MoAb, resulted in false-positive indirect antiglobulin tests (IATs) for all patients for 2 to 6 months after infusion. This precluded the correct identification of irregular blood group antibodies for patients requiring blood transfusion., Study Design and Methods: The IAT was performed using three- and 11-donor-cell panels. Interference of daratumumab and three other anti-CD38 MoAbs was studied using fresh-frozen plasma spiked with different MoAb concentrations. Additionally it was tested whether two potentially neutralizing agents, anti-idiotype antibody and recombinant soluble CD38 (sCD38) extracellular domain, were able to inhibit the interference., Results: The CD38 MoAbs caused agglutination in the IAT in a dose-dependent manner. Addition of an excess of anti-idiotype antibodies or sCD38 protein to the test abrogated CD38 MoAb interference and successfully restored irregular antibody screening and identification., Discussion: CD38 MoAb therapy causes false-positive results in the IAT. The reliability of the test could be restored by adding a neutralizing agent against the CD38 MoAb to the patient's plasma. This study emphasizes that during drug development, targeted therapeutics should be investigated for potential interference with laboratory tests. Clinical laboratories should be informed when patients receive MoAb treatments and matched laboratory tests to prevent interference should be employed., (© 2015 AABB.)

Background: Patients receiving red blood cell (RBC) transfusions are at risk of developing alloantibodies against donor RBC antigens. The risk of alloimmunization is dependent on the number of units administered and patient's genetic predisposition, but has also been suggested to be modulated by a patient's clinical profile. Our aim was to examine whether immunosuppressants suppress the development of clinically relevant RBC antibodies., Study Design and Methods: A two-center case-referent study was performed where case patients and control patients were sampled from all consecutive patients (17,750 patients) who had received their first and subsequent RBC transfusions in a 5-year period in the study centers. Cases were all patients with a first detected RBC alloantibody preceded by negative antibody screens. Control patients were two-to-one matched to the case patients on the number of RBC transfusions. Logistic regression analysis was used to examine the association between immunosuppressant exposure and the subsequent occurrence of RBC alloimmunization., Results: A total of 156 case patients and 312 control patients in the study received a median of six transfusions (interquartile range, 3-11). Among the total study population, 207 patients received immunosuppressive therapy, with 142 patients receiving only corticosteroids, four receiving only other immunosuppressants, and 61 receiving both. The incidence of alloimmunization among patients using immunosuppressants was lower than among other patients receiving RBCs (adjusted relative rate, 0.55; 95% confidence interval, 0.34-0.91)., Conclusion: Our findings support a considerably lower risk of alloimmunization with the use of immunosuppressive medications., (© 2014 AABB.)

Background: Exposure to allogenic red blood cells (RBCs) may lead to formation of antibodies against nonself-antigens in transfused patients. While alloimmunization rates are known to increase with the number of transfusions, the transfusion course in patients can vary from receiving multiple units during a single transfusion event or getting them dispersed over a long(er) period. In this study we compared the immunization risk between different transfusion intensities., Study Design and Methods: An incident new-user cohort study was conducted among consecutive transfused patients at two university medical centers. All patients who received their first RBC transfusion within the study period from January 2005 to December 2011 were eligible. Intensive transfusions were defined as at least 5, at least 10, and at least 20 RBC units within 48 hours. Alloimmunization hazard ratios (HRs), comparing patients receiving intensive transfusions to patients never receiving intensive transfusions, were estimated., Results: The study cohort was composed of 5812 patients who had received a median of 7 (interquartile range, 4-12) units. RBC alloantibodies were formed by 156 patients. The adjusted Cox regression HRs for alloimmunization, with number of units as the time covariate and adjusted for patient age, sex, and follow-up time after first transfusion, ranged from 0.8 to 1.2 (95% confidence interval, 0.4-2.6)., Conclusion: The occurrence of RBC alloimmunization in patients receiving intensive transfusions did not differ significantly from patients receiving nonintensive transfusions., (© 2013 American Association of Blood Banks.)

Patients receiving an ABO-incompatible hematopoietic stem cell transplantation (SCT) are at an increased risk for immune-mediated hematological complications including immediate and delayed hemolysis, late red blood cell engraftment, and pure red cell aplasia. Much research effort has been invested in the unraveling of the immunological mechanisms underyling these complications and approaches to prevent them. Only minimal attention has been paid to the fact that in some SCT patients, even after years, a persistent patient A- and/or B-antigen is detected in the clinical laboratory, despite 100% white cell donor chimerism. The impact for the patient can be substantial: fear that the transplantation was not successful, concern of relapse, and other anxieties influence the quality of life. Little is known about the possible causes of this phenomenon, making appropriate counseling and reassurance of patients by the clinician difficult. In this letter, we describe two cases and a short review on the putative causes of persistent blood group antigens after SCT.

Background: Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and α(v)-integrin. Phagocytosis via the phosphatidylserine-lactadherin-α(v)-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes., Design and Methods: Endothelial cell phagocytosis of red blood cells was further explored using a more (patho)physiological approach. Red blood cells were exposed to oxidative stress, induced by tert-butyl hydroperoxide. After opsonization with lactadherin, red blood cells were incubated with endothelial cells to study erythrophagocytosis and examine cytotoxicity., Results: Red blood cells exposed to oxidative stress show alterations such as phosphatidylserine exposure and loss of deformability. When incubated with endothelial cells, marked erythrophagocytosis occurred in the presence of lactadherin under both static and flow conditions. As a consequence, intracellular organization was disturbed and endothelial cells were seen to change shape ('rounding up'). Increased expression of apoptotic markers indicated that marked erythrophagocytosis has cytotoxic effects., Conclusions: Activated endothelial cells show significant phagocytosis of phosphatidylserine-exposing and rigid red blood cells under both static and flow conditions. This results in a certain degree of cytotoxicity. We postulate that activated endothelial cells play a role in red blood cell clearance in vivo. Significant erythrophagocytosis can induce endothelial cell loss, which may contribute to vasopathological effects as seen, for instance, in sickle cell disease.

Background: Hexokinase is one of the key enzymes of glycolysis and catalyzes the phosphorylation of glucose to glucose-6-phosphate. Red blood cell-specific hexokinase is transcribed from HK1 by use of an erythroid-specific promoter. The aim of this study was to investigate the molecular basis for hexokinase deficiency in a patient with chronic hemolysis., Design and Methods: Functional studies were performed using transient transfection of HK promoter constructs in human K562 erythroleukemia cells. The DNA-protein interaction at the promoter of hexokinase was studied using electrophoretic mobility shift assays with nuclear extracts from K562 cells. DNA analysis and reverse transcriptase polymerase chain reaction were performed according to standardized procedures., Results: On the paternal allele we identified two novel mutations in cis in the erythroid-specific promoter of HKI: -373A>C and -193A>G. Transfection of promoter reporter constructs showed that the -193A>G mutation reduced promoter activity to 8%. Hence, -193A>G is the first mutation reported to affect red blood cell-specific hexokinase specific transcription. By electrophoretic mobility shift assays we showed that in vitro binding of c-jun to an AP-1 binding site was disrupted by this mutation. Subsequent chromatin-immunoprecipitation assays demonstrated that c-jun binds this region of the promoter in vivo. On the maternal allele we identified a novel missense mutation in exon 3: c.278G>A, encoding an arginine to glutamine substitution at residue 93, affecting both hexokinase-1 and red cell specific-hexokinase. In addition, this missense mutation was shown to compromise normal pre-mRNA processing., Conclusions: We postulate that reduced erythroid transcription of HK1 together with aberrant splicing of both hexokinase-1 and red cell specific-hexokinase results in hexokinase deficiency and mild chronic hemolysis.