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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.

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., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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: 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.)

Background and Objectives: The aim of this study was to assess potentially relevant clinical characteristics which influence the decision to transfuse red cells in critically ill patients with low haemoglobin concentrations (6.0-10.0 g/dl)., Materials and Methods: This was a retrospective observational cohort study of patients admitted between November 2004 and May 2016 at the intensive care unit (ICU) of the Leiden University Medical Center, Netherlands. Haemoglobin measurements, clinical variables and the subsequent transfusion decision were extracted from the electronic health records. Clinical variables were grouped by organ system. We first examined the association of each of the clinical variables with the decision to transfuse during the following 6 h after a haemoglobin measurement using generalized estimating equations. We then compared the predictive abilities of single variables within an organ system and the predictive ability of an organ system's combined variables using the change in Akaike information criterion (AIC)., Results: A total of 83 394 haemoglobin measurements of 10 947 ICU admissions were included. Haemoglobin concentration was the most predictive for red cell transfusion. After the haemoglobin concentration, the combined variables for General Health, followed by the organ systems Cardiovascular and Pulmonary, were most predictive for red cell transfusion. Within these organ systems, the APACHE II score, referring department, APACHE admission diagnosis subgroup, troponin concentration, lactate concentration, respiratory rate, PaO 2 /FiO 2 and ventilation mode had the highest predictive ability., Conclusion: Haemoglobin concentration is the dominant predictor for red cell transfusion. Other clinical characteristics are also predictive, though to a lesser extent., (© 2019 International Society of Blood Transfusion.)

Increasingly restrictive red blood cell transfusion strategies have led to growing numbers of patients being discharged from hospital with moderate anaemia, and doubts about the effects of this trend on the outcomes of patients with anaemia are growing. One advantage of doubts is that they lead to variation in practice, which, in theory, allows the study of routinely collected data on the effects of an intervention (transfusion) on patient-relevant outcomes. To do this in a reliable way, we need solid data on outcomes and on all the potentially relevant clinical characteristics that are associated with both the decision to transfuse and the outcomes. Currently, such data are not available. As part of routine practice, clinicians should be encouraged to document the arguments for their treatment decisions and the intended outcomes. This will allow learning from daily practice in the field of transfusion medicine and in other health care disciplines.

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.

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.)

Red blood cell (RBC) alloimmunization is a major complication of transfusion therapy in sickle cell disease (SCD). Identification of high-risk patients is hampered by lack of studies that take the cumulative transfusion exposure into account. In this retrospective cohort study among previously non-transfused SCD patients in the Netherlands, we aimed to elucidate the association between the cumulative transfusion exposure, first alloimmunization and independent risk factors. A total of 245 patients received 11 952 RBC units. Alloimmunization occurred in 43 patients (18%), half of them formed their first alloantibody before the 8th unit. In patients with exposure to non-extended matched transfusions (ABO and RhD) the cumulative alloimmunization risk increased up to 35% after 60 transfused units. This was significantly higher compared to a general transfused population (HR 6.6, CI 4.2-10.6). Receiving the first transfusion after the age of 5 was an independent risk factor for alloimmunization (HR 2.3, CI 1.0-5.1). Incidental, episodic transfusions in comparison to chronic scheme transfusions (HR 2.3, CI 0.9-6.0), and exposure to non-extended matched units in comparison to extended matching (HR 2.0, CI 0.9-4.6) seemed to confer a higher alloimmunization risk. The majority of first alloantibodies are formed after minor transfusion exposure, substantiating suggestions of a responder phenotype in SCD and stressing the need for risk factor identification. In this study, older age at first transfusion, episodic transfusions and non-extended matched transfusions appeared to be risk factors for alloimmunization. Am. J. Hematol. 91:763-769, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Matching donor red blood cells based on recipient antigens prevents alloimmunisation. Knowledge about the immunogenicity of red-blood-cell antigens can help optimise risk-adapted matching strategies. We set out to assess the immunogenicity of red-blood-cell antigens., Methods: In an incident new-user cohort of previously non-transfused, non-alloimmunised white patients receiving non-extended matched red-blood-cell transfusions in six Dutch hospitals between 2006 and 2013, we determined the cumulative number of mismatched red-blood-cell units per patient. We used multiple imputation to address missing antigen data. Using Kaplan-Meier analysis, we estimated cumulative alloimmunisation incidences per mismatched antigen dose as a measure of immunogenicity., Findings: Of 54 347 patients assessed, 21 512 were included in our study. Alloantibodies occurred in 474 (2·2%) of all transfused patients, with cumulative alloimmunisation incidences increasing up to 7·7% (95% CI 4·9-11·2) after 40 units received. The antigens C, c, E, K, and Jk(a) were responsible for 78% of all alloimmunisations in our cohort. K, E, and C(w) were the most immunogenic antigens (cumulative immunisation incidences after 2 mismatched units of 2·3% [95% CI 1·0-4·8] for K, 1·5% [0·6-3·0] for E, and 1·2% [0·0-10·8] for C(w)). These antigens were 8·7 times (for K), 5·4 times (for E), and 4·6 times (for C(w)) as immunogenic as Fy(a). The next most immunogenic antigens were, in order, e (1·9 times as immunogenic as Fy(a)), Jk(a) (1·9 times), and c (1·6 times)., Interpretation: Red-blood-cell antigens vary in their potency to evoke a humoral immune response. Our findings highlight that donor-recipient red-blood-cell matching strategies will be most efficient when primarily focusing on prevention of C, c, E, K, and Jk(a) alloimmunisation. Matching for Fy(a) is of lower clinical relevance. Variations of antigen frequencies determined by ethnic background prevent extrapolating these conclusions to non-white populations., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Increasing evidence on the limited usefulness and the adverse consequences of erythrocyte transfusion has led to a large drop in the number of blood transfusions over the last 20 years. The results of randomised studies suggest that in most haemodynamically stable patients with acute anaemia an Hb transfusion threshold of 4.4 mmol/l for blood transfusion has the same outcomes as a higher transfusion threshold. The effect of blood transfusion in patients with anaemia is not only dependent on their Hb level, but also on other clinical factors that play a role in the balance between oxygen supply and its consumption. The Dutch '4-5-6' rule for indication for blood transfusion takes a number of important clinical factors into account, however, results of recent research suggest that the strict application of this rule will lead to unnecessary transfusions. New research in this area is focused on the quantification of the effect of blood transfusion in various combinations of relevant patient characteristics.

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.)

Background: Red blood cells (RBCs) undergo changes during storage. Various studies have suggested a higher risk of adverse and often multifactorial clinical outcomes associated with older-stored RBCs. Our aim therefore was to examine if storage of transfused RBCs is also associated with the risk of RBC-specific alloantibody formation., Study Design and Methods: A two-center retrospective case-referent study was performed where case patients and control subjects were sampled from all consecutive patients who had received their first and subsequent RBC transfusions in one of the two centers only. Cases were defined as patients who developed a first RBC alloantibody. Control subjects were patients without detectable RBC alloantibodies, who were matched to the case patients regarding number of RBC transfusions. Binary logistic regression analysis was used to examine the association between storage time of RBCS and the occurrence of alloimmunization., Results: A total of 144 cases and 286 controls were selected for our study, who had received a total 5478 RBC units. Comparing patients receiving units stored shorter than a certain number of days versus older units (with various storage periods up to 4 weeks) did not reveal an association or a trend between alloimmunization risk and storage time categories., Conclusion: Our findings suggest that storage times of transfused RBCs between 1 and 4 weeks do not affect the risk of alloimmunization., (© 2013 American Association of Blood Banks.)

Background: Although quantitative evidence is lacking, it is generally believed that the majority of cases of transfusion-related acute lung injury (TRALI) are caused by female blood donors. We aimed to examine the relation between female donors and the occurrence of TRALI., Study Design and Methods: We performed an international, multicenter case-referent study. TRALI patients who were diagnosed clinically, independent of serology or donor sex, and had received transfusions either only from male donors or only from female donors (unisex cases) were selected. The observed sex distribution among the donors of these TRALI patients was compared to the expected sex distribution, based on the relevant donor populations., Results: Eighty-three clinical TRALI cases were included; 67 cases received only red blood cells (RBCs), 13 only plasma-rich products, and three both. Among RBC recipients the relative risk (RR) of TRALI after a transfusion from a female donor was 1.2 (95% confidence interval [CI], 0.69-2.1) and among plasma-rich product recipients the RR was 19 (95% CI, 1.9-191). The p value for the difference between RBCs and plasma was 0.023., Conclusion: Our data support the notion that plasma from female donors is associated with an increased risk of TRALI, while RBCs from female donors are not., (© 2010 American Association of Blood Banks.)