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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: Anemia in myelodysplastic syndromes (MDS) is associated with poorer health‐related quality of life (HRQoL) and physical function, and is frequently treated with transfusions. The current common practice of transfusing multiple red blood cells (RBC) units every 2–4 weeks may result in peaks/troughs in hemoglobin (Hb) level, yet maintaining a stable Hb may better improve HRQoL. We describe a study protocol aiming to investigate the feasibility of weekly low‐dose RBC transfusion in MDS patients, including assessing HRQoL and physical function outcomes. Study Design and Methods: In this n‐of‐1 pilot study, patients receive two treatment arms, with randomly allocated treatment sequence: arm A (patient's usual transfusion schedule) and arm B (weekly transfusion, individualized per patient). To facilitate timely delivery of weekly transfusion, extended‐matched RBCs are provided, with transfusion based upon the previous week's Hb/pre‐transfusion testing results to eliminate delays of awaiting contemporaneous cross‐matching. Primary outcome is the feasibility of delivering weekly transfusion. Secondary outcomes include HRQoL, functional activity measurements, RBC usage, and alloimmunization rates. A qualitative substudy explores patient and staff experiences. Results: The trial is open in Australia, Netherlands, and UK. The first patient was recruited in 2020. Inter‐country differences in providing RBCs are observed, including patient genotyping versus serological phenotyping to select compatible units. Discussion: This pilot trial evaluates a novel personalized transfusion approach of weekly matched RBC transfusion and challenges the dogma of current routine pre‐transfusion matching practice. Findings on study feasibility, HRQoL, and physical functional outcomes and the qualitative substudy will inform the design of a larger definitive trial powered for clinical outcomes. [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]

Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder, mediated by auto-antibodies, and has a variable clinical course ranging from fully compensated low grade hemolysis to severe life-threatening cases. The rarity, heterogeneity and incomplete understanding of severe AIHA complicate the recognition and management of severe cases. In this review, we describe how severe AIHA can be defined and what is currently known of the severity and outcome of AIHA. There are no validated predictors for severe clinical course, but certain risk factors for poor outcomes (hospitalisation, transfusion need and mortality) can aid in recognizing severe cases. Some serological subtypes of AIHA (warm AIHA with complement positive DAT, mixed, atypical) are associated with lower hemoglobin levels, higher transfusion need and mortality. Currently, there is no evidence-based therapeutic approach for severe AIHA. We provide a general approach for the management of severe AIHA patients, incorporating monitoring, supportive measures and therapeutic options based on expert opinion. In cases where steroids fail, there is a lack of rapidly effective therapeutic options. In this era, numerous novel therapies are emerging for AIHA, including novel complement inhibitors, such as sutimlimab. Their potential in severe AIHA is discussed. Future research efforts are needed to gain a clearer picture of severe AIHA and develop prediction models for severe disease course. It is crucial to incorporate not only clinical characteristics but also biomarkers that are associated with pathophysiological differences and severity, to enhance the accuracy of prediction models and facilitate the selection of the optimal therapeutic approach. Future clinical trials should prioritize the inclusion of severe AIHA patients, particularly in the quest for rapidly acting novel agents. [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]

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]

Background and Aims: Standard treatment for naïve hereditary hemochromatosis patients consists of phlebotomy or a personalized erythrocytapheresis. Erythrocytapheresis is more efficient, but infrequently used because of perceived costs and specialized equipment being needed. The main aim of our study was to develop a model that predicts the number of initial treatment procedures for both treatment methods. This information may help the clinician to select the optimal treatment modality for the individual patient. Methods: We analyzed retrospective data of 125 newly diagnosed patients (C282Y homozygous), treated either with phlebotomy (n = 54) or erythrocytapheresis (n = 71) until serum ferritin (SF) reached levels ≤100 μg/L. To estimate the required number of treatment procedures multiple linear regression analysis was used for each treatment method separately. Results: The linear regression model with the best predictive quality (R2 = 0.74 and 0.73 for erythrocytapheresis and phlebotomy respectively) included initial SF, initial hemoglobin (Hb) level, age, and BMI, where initial SF was independently related to the total number of treatment procedures for both treatment methods. The prediction error expressed in RMSPE and RMSDR was lower for erythrocytapheresis than for phlebotomy (3.8 and 4.1 vs 7.0 and 8.0 respectively), Conclusions: Although the prediction error of the developed model was relatively large, the model may help the clinician to choose the most optimal treatment method for an individual patient. Generally erythrocytapheresis halves the number of treatment procedures for all patients, where the largest reduction (between 55% and 64%) is reached in patients with an initial Hb level ≥ 9 mmol/L (14.5 g/dL). ClinicalTrials.gov number NCT00202436. [ABSTRACT FROM AUTHOR]

Objectives: There is scarce evidence about the effectiveness of anti‐bleeding measures in hematological outpatients experiencing persistent severe thrombocytopenia. We aim to describe clinical practice and clinicians' considerations on the administration of prophylactic platelet transfusions and tranexamic acid (TXA) to outpatients with acute leukemia, myelodysplastic syndrome (MDS), or aplastic anemia (AA) in the Netherlands. Methods: We conducted an online survey among members of the Dutch Society for Hematology. Results: The survey was filled out by 73 respondents. Prophylactic platelet transfusions are widely used in acute leukemia and MDS outpatients receiving disease‐modifying treatments (87%‐98% of respondents). TXA is predominantly prescribed in case of bleeding (tendency) (71%‐88% of respondents). Conditions potentially increasing bleeding risks highly variably influence clinicians' decision making on anti‐bleeding regimens, which includes a wide range in adhered platelet thresholds. Conclusion: Considering that both the contribution of prophylactic platelet transfusions as well as TXA to limiting bleeding is insufficiently evidence‐based, there is an urgent need for trials on optimal anti‐bleeding strategies in this outpatient population, which should encompass efficacy, logistic, financial, and quality‐of‐life aspects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

2008; 48 (1): 81 - 91. 6 Berger MD, Gerber B, Arn K, Senn O, Schanz U, Stussi G. 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. Safety and efficacy of a Hb-triggered single-unit red cell transfusion policy for haemato-oncological inpatients Regarding threshold non-adherences during the restrictive period, patients' measured Hb levels exceeded their individual Hb transfusion threshold by <=3 and <=8 g/l in 16-9% and 30-9% of all RBC transfusions (Fig 2B). This patient characteristic imbalance resulted in a higher proportion of patients under the restrictive protocol who did not receive RBC transfusions at the stricter Hb threshold of <73 g/l, potentially inducing an underestimation of the impact outcomes described below. [Extracted from the article]

Objectives: Secondary iron overload due to red blood cell transfusions (RBCT) is associated with increased morbidity and mortality. However, attention for secondary iron overload and its side effects in patients with hematological malignancies may need improvement. The aim of this study was to determine the number of transfused RBCT needed to reach a maximum bone marrow iron score (BMIS). Methods: Bone marrow iron score was independently assessed by two researchers on consecutive bone marrow samples of 35 acute myeloid leukemia (AML) patients. The slides were blinded to both researchers to prevent bias. A Kaplan‐Meier survival analysis was performed for estimation of the proportion of patients reaching a maximum BMIS. Results: In total, 141 bone marrow specimens from 35 patients were included. The median number of RBCT to reach a maximum was 20 units (range 6‐42, IQR 15‐26), after a mean of 1.64 chemotherapy courses (SD 0.99). Conclusions: In conclusion, the cumulative RBCT number is associated with BMIS. Due to the considerable variation in number of RBCT to reach a maximum BMIS, BMIS instead of only considering the cumulative RBCT number may be a valuable indicator of secondary iron overload in AML patients. BMIS could guide iron‐lowering therapy and/or transfusion strategies in an early stage. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (HctB), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE. J. Clin. Apheresis 29:133-138, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]