Anti-D immunization after D positive platelet transfusions in D negative recipients: A systematic review and meta-analysis.

BACKGROUND: Anti-D can be formed after D-incompatible platelet transfusions due to contaminating D+ red blood cells. These antibodies are of particular importance in women of childbearing potential, because anti-D is most often involved in severe cases of hemolytic disease of the fetus and newborn. This systematic review determined the frequency of anti-D after D+ platelet transfusions and risk factors for D alloimmunization. STUDY DESIGN AND METHODS: Relevant literature was searched using PubMed, Embase and Web of Science until December 2022. Overall anti-D frequency and risk factors were estimated using a random effects meta-analysis. RESULTS: In 22 studies, a total of 3028 D- patients received a mean of six D+ platelet transfusions. After a mean follow-up of seven months 106 of 2808 eligible patients formed anti-D. The pooled anti-D frequency was 3.3% (95% CI 2.0-5.0%; I2 71%). After including only patients with an undoubtable follow-up of at least 4 weeks, 29 of 1497 patients formed anti-D with a pooled primary anti-D rate of 1.9% (95% CI 0.9-3.2%, I2 44%). Women and patients receiving whole blood derived platelets had two and five times higher anti-D rates compared with men and patients receiving apheresis derived platelets, respectively. DISCUSSION: Anti-D immunization is low after D incompatible platelet transfusions and dependent on recipients' sex and platelet source. We propose anti-D prophylaxis in girls and women, capable of becoming pregnant in the future, that received D+ platelets, regardless of platelet source, to reduce the risk of anti-D induced hemolytic disease of the fetus and newborn.

The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study.

In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C-reactive protein) and bleeding (WHO grading) in 88 patients with 116 on-protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05-1·46, P-value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C-reactive protein (CRP) (95% CI 1·04-1·60, P-value 0·02) after correction for morning platelet count. The 24 h post-transfusion corrected count increment (CCI24 ) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI24. We report two inexpensive and easy-to-apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients.

Platelets from donors with consistently low HLA-B8, -B12, or -B35 expression do not undergo antibody-mediated internalization.

Patients refractory to platelet transfusions because of alloimmunization require HLA-matched platelets, which is only possible if a large HLA-typed donor pool is available. However, even then, patients with broad immunization or rare haplotypes may not have suitable donors. In these patients, transfusions with platelets showing low HLA class I expression may be an alternative to fully HLA-matched transfusions. In this study, we quantified the proportion of donors with consistently low HLA-B8, -B12, and -B35 expression on platelets using human monoclonal antibodies specific for these antigens. Furthermore, as model for in vivo clearance, antibody-mediated internalization of these platelets by macrophages was investigated. The expression of HLA-B8, -B12, or -B35 on platelets was extremely variable between individuals (coefficients of variation, 41.4% to 73.6%). For HLA-B8, but not for HLA-B12 or -B35, this variation was in part explained by zygosity. The variation was most pronounced in, but not exclusive to, platelets. Expression within one donor was consistent over time. Remarkably, 32% of 113 HLA-B8, 34% of 98 HLA-B12, and 9% of 66 HLA-B35 donors showed platelet antigen expression that was not or only minimally above background. Antibody-mediated internalization of platelets by macrophages correlated with antibody opsonization and antigen expression and was absent in platelets with low or minimal HLA expression. In conclusion, our findings indicate that a substantial proportion of donors have platelets with consistently low expression of specific HLA class I antigens. These platelets may be used to treat refractory patients with antibodies directed against these particular antigens, despite HLA mismatches.

Hemostatic efficacy of pathogen-inactivated vs untreated platelets: a randomized controlled trial.

Pathogen inactivation of platelet concentrates reduces the risk for blood-borne infections. However, its effect on platelet function and hemostatic efficacy of transfusion is unclear. We conducted a randomized noninferiority trial comparing the efficacy of pathogen-inactivated platelets using riboflavin and UV B illumination technology (intervention) compared with standard plasma-stored platelets (control) for the prevention of bleeding in patients with hematologic malignancies and thrombocytopenia. The primary outcome parameter was the proportion of transfusion-treatment periods in which the patient had grade 2 or higher bleeding, as defined by World Health Organization criteria. Between November 2010 and April 2016, 469 unique patients were randomized to 567 transfusion-treatment periods (283 in the control arm, 284 in the intervention arm). There was a 3% absolute difference in grade 2 or higher bleeding in the intention-to-treat analysis: 51% of the transfusion-treatment periods in the control arm and 54% in the intervention arm (95% confidence interval [CI], -6 to 11; P = .012 for noninferiority). However, in the per-protocol analysis, the difference in grade 2 or higher bleeding was 8%: 44% in the control arm and 52% in the intervention arm (95% CI -2 to 18; P = .19 for noninferiority). Transfusion increment parameters were ∼50% lower in the intervention arm. There was no difference in the proportion of patients developing HLA class I alloantibodies. In conclusion, the noninferiority criterion for pathogen-inactivated platelets was met in the intention-to-treat analysis. This finding was not demonstrated in the per-protocol analysis. This trial was registered at The Netherlands National Trial Registry as #NTR2106 and at www.clinicaltrials.gov as #NCT02783313.

Prevalence of red-blood-cell and non-red-blood-cell-targeted autoantibodies in alloimmunized postpartum women.

BACKGROUND AND OBJECTIVES: Alloantibodies against red-blood-cell (RBC) antigens often coincide with alloantibodies against leucocytes and platelets and sometimes with autoantibodies towards various antigens. Chimerism may be one of the factors responsible for the combination of allo- and autoantibodies. Women with alloantibodies against RBC antigens causing haemolytic disease of the fetus and neonate may need to receive intrauterine transfusions. These transfusions increase not only maternal antibody formation but also fetomaternal bleeding and may enhance fetal chimerism. We determined the prevalence of and risk factors for autoantibodies against some common clinical target antigens, in alloimmunized women after IUT. MATERIALS AND METHODS: We tested for autoantibodies against RBC, anti-thyroid peroxidase, anti-extractable nuclear antigens, anti-cyclic citrullinated proteins and anti-tissue transglutaminase. Women with and without autoantibodies were compared for age; number of RBC alloantibodies, pregnancies and IUTs, and other factors that may play a role in immunization. RESULTS: Non-RBC-targeted autoantibodies were present in 40 of 258 tested women (15·5%, with 90% anti-TPO specificity), comparable to the prevalence reported in healthy Dutch women of these ages. Surprisingly, compared with women who had a single RBC alloantibody, a significantly higher proportion of women with multiple RBC alloantibodies had autoantibodies (5·3% and 18·4%, respectively; odds ratio 4·06, 95% CI: 1·20-13·7). Other characteristics of women with and without autoantibodies were not different. CONCLUSION: Multiple RBC alloantibodies after extensive allogeneic exposure during pregnancy and presumed increased fetomaternal chimerism are not associated with (selected) autoantibodies. Lack of allo-RBC multi-responsiveness seems associated with decreased auto(-TPO) antibody formation.

Medical student education in transfusion medicine, part II: Moving forward to building up a "Know How" education program in transfusion medicine for under-graduate medical students.

There is a general trend in changing paradigm in teaching medicine; the emerging concept relies on a competence-based approach. Transfusion is either a discipline or a subsidiary of others depending on the countries and systems; this variability can be explained because transfusion is a medical care that is transdisciplinary. As a collective of professionals in both transfusion medicine practice and education, authors aim to propose a revision of the way education in transfusion medicine is delivered in this era of the 'global competency approach'. They advocate in favor of a Know How on 5 key issues: Diagnosing the patient condition in line with the Patient Blood Management principles; Facing acute blood loss; Addressing compatibility and avoiding immunization; Seeking for maximized benefits and dampening complications; and Inlaying competence within global health care issues, also comprising od economy. The methods used would be those developed for medical education at large, such as assessment tools. The global objective is to deliver the necessary competence to manage patients by an intern/resident. At the end of the curriculum, students should be able to self-evaluate the following items: 1) Do I know why my patient is anemic, thrombocytopenic, bleeding….? 2) Do I know the best approach to treat anemia, thrombocytopenia, bleeding (including the "no treatment" option)? 3) Do I know whether a transfusion approach is appropriate for my patients? 4) Do I know how to evaluate and anticipate benefits from blood transfusion and to avoid side-effects in the patient? 5) Do I know how to avoid unnecessary use of the products?

Exposure to non-inherited maternal antigens by breastfeeding affects antibody responsiveness.

The observation, by Ray Owen and colleagues in 1954, that D-negative women were less likely to form anti-D antibodies against their D-positive fetus if their mother possessed the D-antigen, was not found in all later studies. We hypothesized that breastfeeding, received by the mother, may affect her immunity against non-inherited maternal red blood cell antigens. We studied a cohort of 125 grandmother-mother-child combinations, from a follow-up study of mothers after intrauterine transfusion of the fetus for alloimmune hemolytic disease. For mismatched red blood cell antigens the mother was exposed to, whether or not antibodies were formed, we determined whether her mother, the grandmother, carried these antigens. The duration for which the mothers were breastfed was estimated by way of a questionnaire. Using multivariate logistic regression analyses, the interaction term (non-inherited maternal antigen exposure by categorized breastfeeding period) showed that a longer breastfeeding period was associated with decreased alloimmunization against non-inherited maternal antigens (adjusted odds ratio 0.66; 95% confidence interval 0.48-0.93). Sensitivity analysis with dichotomized (shorter versus longer) breastfeeding periods showed that this lower risk was reached after two months (aOR 0.22; 95% CI 0.07-0.71) and longer duration of breastfeeding did not seem to provide additional protection. These data suggest that oral neonatal exposure to non-inherited maternal red blood cell antigens through breastfeeding for at least two months diminishes the risk of alloimmunization against these antigens when encountered later in life.

The role of pathogen-reduced platelet transfusions on HLA alloimmunization in hemato-oncological patients.

BACKGROUND: Platelet transfusions can induce alloimmunization against HLA antigens. The use of pathogen-reduced platelet concentrates (PCs) was suggested to reduce HLA alloimmunization and concomitant transfusion refractoriness. METHODS: This study investigated HLA alloimmunization in available samples from 448 hemato-oncological patients who were randomized for the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) trial to receive either untreated or pathogen-reduced PCs (Mirasol, Terumo BCT Inc.). Anti-HLA Class I and II antibodies were determined before the first platelet transfusion and weekly thereafter using multiplex assay with standard cutoffs to detect low- as well as high-level antibodies. RESULTS: When using the lower cutoff, in patients who were antibody negative at enrollment, 5.4% (n = 12) developed anti-HLA Class I antibodies after receiving untreated PCs, while this was significantly higher in patients receiving pathogen-reduced PCs, 12.8% (n = 29; p = 0.009, intention-to-treat [ITT] analysis). A similar but nonsignificant trend was observed in the per-protocol (PP) analysis (5.4% vs. 10.1%; p = 0.15). HLA class II antibody formation was similar between both types of PCs in the ITT analysis, while the PP analysis showed a trend toward lower immunization after receiving pathogen-reduced PCs. Multivariate analysis identified receiving pathogen-reduced platelets as an independent risk factor for HLA Class I alloimmunization (ITT: odds ratio [95% confidence interval] = 3.02 [1.42-6.51], PP: odds ratio [95% confidence interval] = 2.77 [1.00-5.40]), without affecting HLA Class II alloimmunization. When using the high cutoff value, the difference in HLA Class I alloimmunization between study arms remained significant in the ITT analysis and again was not significant in the PP analysis. CONCLUSION: Our data clearly indicate that Mirasol pathogen inactivation does not prevent HLA Class I or II alloimmunization after platelet transfusions.

Frequency and characterization of RHD variants in serologically D- Surinamese pregnant women and D- newborns.

BACKGROUND: Numerous RHD variant genes affect the expression of D on the red blood cell surface. In Suriname, 4.3% of pregnant women were D-, ranging from virtually zero to 7% among ethnic groups. Characterization of RHD variants, which are associated with a variable potential to induce anti-D, is of practical clinical importance especially in case of limited access to preventive measures. Here we report on the occurrence of RHD variant genes in Surinamese serologically D- pregnant women and their D- newborns from different ethnic groups. STUDY DESIGN AND METHODS: The RheSuN study is a cross-sectional cohort study in D- pregnant women and their newborns, who visited hospitals in Paramaribo, Suriname, during routine pregnancy care. The presence of RHD variants was investigated using quantitative polymerase chain reaction targeting RHD Exons 5 and 7 and RH-multiplex ligation-dependent probe amplification. RESULTS: Seven RHD variant genes were detected in 35 of 84 women and four RHD variant genes in 15 of 36 newborns. The RHD*03 N.01 and RHD*08 N.01 variants represented 87% of a total of 62 variant genes. Variants were comparably frequent among ethnicities. In four cases genotyping would have changed anti-D prophylaxis policy: one woman with a RHD*01EL.01 variant, not associated with anti-D formation and three D- newborns with RHD*09.01 and RHD*09.03.01 variants, potentially capable of inducing anti-D. CONCLUSION: RHD variants at risk for anti-D are common among serologic D- individuals from African descent in Suriname. While genotyping D- women has limited added value, it may be considered in newborns from D- women.

Medical student education in transfusion medicine: Proposal from the "European and Mediterranean initiative in transfusion medicine".

A large body of observations indicate that there is an inconsistent knowledge of Transfusion Medicine among health care professionals as well as inconsistent knowledge in all aspects of the transfusion process, from blood donation to transfusion on the ward. It is obvious to consider that appropriate education in Transfusion Medicine should be achieved in the education of specialists who will prescribe transfusion on a regular basis (hematologists, critical care specialists, anaethesiologists and others.) However,we also believe that education in Transfusion Medicine should also be delivered to almost all other medical specialists who may prescribe blood components. The variability in education of undergraduates in medical schools is universal most likely due to an absence of a predefined common platform. This paper, therefore, focuses on education at the undergraduate level and advocates coverage of the essential physiology and pathophysiology of blood as applied to blood transfusion as well as the medical and societal aspects of issues related to blood donation. It proposes incremental levels of training in Transfusion Medicine, with what is being therefore referred to as 'A', 'B', 'C' etc. curricula in ascending order of complexity; for example, 'A' and 'B' levels would involve medical, midwifery and nursing students, covering a broad base of the subject: they will be detailed in the present essay; ongoing further curricula will focus on physicians and other professionals working within the area or with responsibility for different aspects of the transfusion chain. It is intended that these courses include aspects of donor care, patient care and the appropriate use, safety and effectiveness of blood products. Next, it is advocated that curricula are addressed not only for high-income countries but also for middle- and low-income ones.

Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.

BACKGROUND: Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use. METHODS: We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed. FINDINGS: Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2·05, 95% CI 1·18-3·56; p=0·0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay. INTERPRETATION: Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice. FUNDING: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health.

The increase of the global donor inventory is of limited benefit to patients of non-Northwestern European descent.

Between 2001 and 2012, the number of unrelated donors registered worldwide increased from 7 to 21 million, and the number of public cord blood units increased to over 500,000. We addressed the question of whether this expansion resulted in higher percentages of patients reaching transplantation. Unrelated donor searches were evaluated for 3,124 eligible patients in the Netherlands in two cohorts (2001-2006, n=995; 2007-2012, n=2129), comparing results for patients of Northwestern European and non-Northwestern European origin. Endpoints were 'donor found' and 'transplantation reached'. The substantial growth of the donor inventory over the period studied did not increase the median number of potential unrelated donors (n=7) for non-Northwestern European patients, but almost doubled the number for Northwestern European patients from 42 to 71. Before and after 2007, an unrelated donor or cord blood was identified for 91% and 95%, respectively, of Northwestern European patients and for 65% and 82% of non-Northwestern European patients (P<0.0001). Non-Northwestern European patients more often needed a cord blood transplant. The degree of HLA matching was significantly lower for non-Northwestern European patients (P<0.0006). The time needed to identify a donor decreased for both populations. The percentage of Northwestern European patients reaching transplantation increased from 77% to 83% and for non-Northwestern European patients from 57% to 72% (P=0.0003). The increase of the global inventory resulted in more transplants for patients lacking a family donor, although the quality and quantity of (potential) haematopoietic cell grafts for patients of a non-Northwestern European descent remained inferior, indicating the need for adaptation of recruitment.

D antibodies in pregnant women in multiethnic Suriname: the observational RheSuN study.

BACKGROUND: Maternal antibodies against the D antigen are the most common cause of severe hemolytic disease of the fetus and newborn (HDFN). In high-income countries, the risk of D immunization has been reduced by routine antenatal and postpartum administration of RhIG from 13% to less than 0.5%. In less-resourced countries, such as Suriname, red blood cell (RBC) antibody screening during pregnancy and prophylactic RhIG administration are not routine. Accurate data on D immunization risk is not available. In the RheSuN (Rhesus Surinamese Neonates) study, the prevalence and the hemolytic potential of maternal D antibodies were investigated. STUDY DESIGN AND METHODS: A multicenter cross-sectional study in four major hospitals in Paramaribo, Suriname, covering 90% of approximately 10,000 births yearly in Suriname. Included were D- pregnant women of various ethnicities seeking routine prenatal care and/or their newborns. RESULTS: D antibodies were detected in 19 of 214 D- pregnancies (8.9%; 95% confidence interval, 5.1%-12.7%), in 2.0% of primigravid and 11.7% of multigravid women. The direct antiglobulin test was positive in 11 of 13 tested D+ newborns. Determination of D antibody titers and antibody-dependent cell mediated cytotoxicity (ADCC) assay revealed three newborns at high risk for HDFN (ADCC > 50%). CONCLUSION: D immunization risk in Suriname women is comparable to the pre-anti-D prophylaxis era in high-income countries. Recommended is free-of-charge routine RBC antibody screening and prophylactic RhIG administration for women at risk for D antibody formation as part of standard of ante- and postnatal care.

Prevalence of positive direct antiglobulin test and clinical outcomes in Surinamese newborns from D-negative women.

BACKGROUND: In low-resource countries, screening for D antibodies to detect pregnancies at risk for hemolytic disease of the newborn is not routine practice. Retrospective data showed that 5.5% of Surinamese newborns of D-negative women had a positive direct antiglobulin test (DAT), indicating the presence of maternal antibodies against fetal antigens. Here, the frequency and clinical relevance of DAT positivity is evaluated. STUDY DESIGN AND METHODS: Between April 2015 and June 2016, an observational, multicenter cohort study was undertaken among Surinamese newborns born to D-negative women. In newborns, the DAT was performed, and clinical outcomes between DAT-negative and DAT-positive newborns were compared. RESULTS: Of the 232 evaluable newborns, 19 (8.2%) had a positive DAT, of which 11 of 15 antibody-tested newborns had D antibodies. DAT-positive newborns had lower hemoglobin levels (p = 0.02) and a trend toward higher bilirubin concentrations (p = 0.09) in the first days of life compared with DAT-negative newborns. DAT-positive newborns were admitted more frequently (p = 0.02), needed phototherapy treatment almost four times as often as DAT-negative newborns (26% vs. 7%; p = 0.008), and therapy took 2 days longer (p = 0.01). Exchange transfusions were performed in two newborns with D antibodies, both complicated with sepsis. The hospital stay was 2.5 days longer for DAT-positive newborns (p = 0.007). Overall, the prevalence of hemolytic disease of the newborn requiring treatment was 2.2% among the whole cohort of newborns. CONCLUSION: We found a high prevalence of DAT positivity with substantial need for hyperbilirubinemia treatment in newborns in Suriname. These results stress the necessity for better management procedures in D-negative women.

Does a Platelet Transfusion Independently Affect Bleeding and Adverse Outcomes in Cardiac Surgery?

BACKGROUND: Conflicting results have been reported concerning the effect of platelet transfusion on several outcomes. The aim of this study was to assess the independent effect of a single early intraoperative platelet transfusion on bleeding and adverse outcomes in cardiac surgery patients. METHODS: For this observational study, 23,860 cardiac surgery patients were analyzed. Patients who received one early (shortly after cardiopulmonary bypass while still in the operating room) platelet transfusion, and no other transfusions, were defined as the intervention group. By matching the intervention group 1:3 to patients who received no early transfusion with most comparable propensity scores, the reference group was identified. RESULTS: The intervention group comprised 169 patients and the reference group 507. No difference between the groups was observed concerning reinterventions, thromboembolic complications, infections, organ failure, and mortality. However, patients in the intervention group experienced less blood loss and required vasoactive medication 139 of 169 (82%) versus 370 of 507 (74%; odds ratio, 1.65; 95% CI, 1.05 to 2.58), prolonged mechanical ventilation 92 of 169 (54%) versus 226 of 507 (45%; odds ratio, 1.47; 94% CI, 1.03 to 2.11), prolonged intensive care 95 of 169 (56%) versus 240 of 507 (46%; odds ratio, 1.49; 95% CI, 1.04 to 2.12), erythrocytes 75 of 169 (44%) versus 145 of 507 (34%; odds ratio, 1.55; 95% CI, 1.08 to 2.23), plasma 29 of 169 (17%) versus 23 of 507 (7.3%; odds ratio, 2.63; 95% CI, 1.50-4.63), and platelets 72 of 169 (43%) versus 25 of 507 (4.3%; odds ratio, 16.4; 95% CI, 9.3-28.9) more often compared to the reference group. CONCLUSIONS: In this retrospective analysis, cardiac surgery patients receiving platelet transfusion in the operating room experienced less blood loss and more often required vasoactive medication, prolonged ventilation, prolonged intensive care, and blood products postoperatively. However, early platelet transfusion was not associated with reinterventions, thromboembolic complications, infections, organ failure, or mortality.

Predictors for successful PBSC collection on the fourth day of G-CSF-induced mobilization in allogeneic stem cell donors.

Peripheral blood stem cells (PBSCs) used for allogeneic transplantation are collected by apheresis after pre-treatment of donors with G-CSF. Using modern apheresis devices stem cells can be collected more efficiently. It was studied whether collection on the 4th instead of the 5th day after initiation of G-CSF treatment might be feasible. Stem cell yields that could have been collected on day 4 were calculated in two cohorts treated with 10 µg/kg G-CSF once daily (n = 106, cohort I) or 5 µg/kg twice daily schedule (n = 85, cohort II). Harvests were predicted using the median collection efficiency (CE) of the apheresis machine and regarded successful when > 5.0 x106 CD34+/ kg recipient body weight. Successful harvests at day 4 could have been obtained in only 22.6% and 41.2% of donors in cohort I and II respectively, while the expected successful collections on day 5 were 55.7% and 76.5%. Individual donor factors that correlated with a successful harvest on day 4 were weight, BMI, age, ratio donor/recipient weight and total G-CSF dose in cohort I, whereas ratio donor/recipient weight was the only significant predictor in cohort II. Donor weight, BMI and total G-CSF dose correlated positively with CD34+ values in the blood on day 4 in all donors. However, donor characteristics were not able to be used as strong predictors in daily practice. In conclusion, PBSC collection on day 4 will not result in a successful harvest in most stem cell donors, however using a twice daily G-CSF scheme increases the yield.

The European Hematology Association Roadmap for European Hematology Research: a consensus document.

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap.The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders.The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

Incidence of alloantibody formation after ABO-D or extended matched red blood cell transfusions: a randomized trial (MATCH study).

BACKGROUND: Most incidentally transfused patients receive only ABO-D-compatible transfusions and antibodies are formed in up to 8%. The effect of extended (c, C, E, K, Fy(a) , Jk(a) , and S antigens) matched (EM) and ABO-D-matched red blood cell (RBC) transfusions on the incidence of new clinically relevant RBC antibody formation after a first elective transfusion event in surgical patients was studied. STUDY DESIGN AND METHODS: A multicenter randomized trial was performed in nontransfused patients who were scheduled to experience a single elective transfusion event of maximal 4 RBC units. The primary outcome was the incidence of newly formed warm reacting clinically relevant RBC alloantibodies measured in three follow-up (FU) samples taken at 7 to 10 days, 4 to 6 weeks, and 4 to 6 months posttransfusion. RESULTS: A total of 853 patients were randomized, and of these, 333 patients were transfused with a total of 1035 RBC units. At least one FU sample was available from 97% of transfused patients. In intention-to-treat analysis, new antibodies were detected in 10 of 155 ABO-D and seven of 178 EM patients, respectively. Per-protocol analysis including 190 patients showed a nonsignificant absolute risk difference (ARD) of 5.3% (95% confidence interval [CI], -1.4% to 12%) in alloimmunization between study arms. In a post hoc analysis of 138 patients who received RBCs but no platelet (PLT) transfusions the ARD increased to significance, 8.0% (95% CI, 0.4-16.0). CONCLUSION: Extended matching for selected antigens reduced the alloimmunization risk by 64% in surgical patients. Extended matching seems successful only if the patient did not receive accompanying nonmatched PLT transfusions.

The HLA-DRB1*15 phenotype is associated with multiple red blood cell and HLA antibody responsiveness.

BACKGROUND: Once a patient has produced a red blood cell (RBC) antibody, there is an increased risk of additional antibody formation after subsequent RBC exposure. Recently, we observed that HLA-DRB1*15 was overrepresented in 379 multiple RBC antibody responders compared to controls or 562 patients with a single RBC antibody (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.3-2.3). In this study we evaluated whether the HLA-DRB1*15 represents a responder phenotype against HLA and/or RBC antigens. STUDY DESIGN AND METHODS: HLA-DRB1*15 frequencies in single and multiple antibody responders were compared between three groups of individuals: 1) those with HLA antibodies, 2) those with RBC antibodies, and 3) those with both RBC and HLA antibodies. RESULTS: A total of 3959 immunized patients (female-to-male ratio, 2.3) had been HLA-DRB1 typed. Among the 3275 individuals with HLA antibodies, the frequency of the DRB1*15 phenotype differed significantly from 19.7% in patients with a panel reactivity (PRA) of not more than 20% to 26.9% in patients with PRA of more than 80% (OR, 1.5; 95% CI, 1.2-1.9). This association between DRB1*15 and multiresponsiveness was mainly due to pregnancy-induced HLA immunization. In the 257 individuals with RBC and HLA antibodies, the frequency of DRB1*15 was 4.2 times (95% CI, 1.1-16) higher in those with multiple RBC antibodies and HLA-PRA of more than 50% compared to only single RBC responders with PRA of less than 20%. CONCLUSION: The HLA-DRB1*15 phenotype is associated with broad RBC and HLA immunization.

Intraoperative Anemia and Single Red Blood Cell Transfusion During Cardiac Surgery: An Assessment of Postoperative Outcome Including Patients Refusing Blood Transfusion.

OBJECTIVES: Increasing evidence suggests benefits from restrictive red blood cell transfusion (RBC) thresholds in major surgery and critically ill patients. However, these benefits are not obvious in cardiac surgery patients with intraoperative anemia. The authors examined the association between uncorrected hemoglobin (Hb) levels and selected postoperative outcomes as well as the effects of RBCs. DESIGN: Cohort study with prospectively collected data from a cardiac surgery registry. SETTING: A major cardiac surgical hospital within the Netherlands, which is also a referral center for Jehovah's Witnesses. PARTICIPANTS: Patients (23,860) undergoing cardiac surgery between 1997 and 2013. INTERVENTIONS: Comparisons were done in patients with intraoperative nadir Hb<8 g/dL and/or an Hb decrease ≥ 50%. Comparison (A) between Jehovah's Witnesses (Witnesses) and matched non-Jehovah's Witnesses (non-Witnesses) transfused with 1 unit of RBC, and comparison (B) between patients given 1 unit of RBC intraoperatively versus matched non-transfused patients. MEASUREMENTS AND MAIN RESULTS: Postoperative outcomes were myocardial infarction, renal replacement therapy, stroke, and death. With propensity matching, the authors optimized exchangeability of the compared groups. Adverse outcomes increased with a decreasing Hb both among Witnesses and among non-Witnesses. The incidence of postoperative complications did not differ between Witnesses and matched non-Witnesses who received RBC (adjusted odds ratio 1.44, 95% confidence interval 0.63-3.29). Similarly, postoperative complications did not differ between patients who received a red cell transfusion and matched patients who did not (adjusted odds ratio 0.94, confidence interval 0.72-1.23). CONCLUSION: Intraoperative anemia is associated with adverse outcomes after cardiac surgery, and a single RBC transfusion does not seem to influence these outcomes.