Current advances in 2024: A critical review of selected topics by the Association for the Advancement of Blood and Biotherapies (AABB) Clinical Transfusion Medicine Committee.
The Association for the Advancement of Blood and Biotherapies (AABB) Clinical Transfusion Medicine Committee (CTMC) is a multidisciplinary committee with broad expertise in transfusion medicine (TM) that provides evidence-based guidance on safe and effective transfusion practices. The CTMC provides an annual review of critical developments in TM for the AABB Board of Directors (BOD). This includes a written synopsis of these advancements, which has been published as a manuscript in Transfusion since 2018. A summary of key papers published in 2023 is provided below. CTMC members identified publications from calendar year 2023 with perceived important developments in TM. We attempted to consider all relevant English language publications, but this was not a systematic review with an exhaustive formal search. Evidence certainty was not formally evaluated. Two-to-three CTMC members summarized key publications that fell within their area of expertise. Additional citations may have been included for background or to provide context. These summaries were then reviewed and edited by two separate CTMC members. The first and senior authors then compiled, edited, and assembled the summaries into the final manuscript. The MINT multicenter randomized controlled trial (RCT) compared a liberal transfusion threshold (<10 g/dL) to a restrictive one (<7–8 g/dL) in 3504 patients with acute MI.1 The mean hemoglobin (Hb) was 1.3–1.6 g/dL lower in the restrictive group, which received an average of 1.8 fewer RBC units. The primary outcome of death or recurrent MI at 30 days showed a nonsignificant trend favoring the liberal arm (risk ratio 1.15; 95% confidence interval [CI], 0.99–1.34; p = .07). Potentially hampering interpretation of the results, discontinuation of the protocol occurred in 13.7% of the patients in the liberal arm versus only 2.6% in the restrictive arm. Furthermore, the REALITY trial involving 668 patients with MI demonstrated non-inferiority between a threshold of <8 g/dL versus <10 g/dL, with a trend toward favoring the restrictive group.2 Individual patient factors are important in the decision to transfuse in the setting of MI. Updated AABB RBC transfusion guidelines recommend an Hb threshold of <7 g/dL in hemodynamically stable hospitalized adults, hospitalized adults with hematologic and oncologic disorders, and critically ill children without hemoglobinopathies, cyanotic cardiac defects, or severe hypoxemia. The panel remarked that a threshold of <7.5 g/dL for cardiac surgery or <8 g/dL for orthopedic surgery may be considered based on published trial designs. Conditional recommendations for relatively liberal thresholds in certain congenital cardiac disease states were also included. The panel reviewed 45 RCTs with 20,599 participants; critically, the MINT trial1 was not published when the panel made its recommendations. A double-blind RCT (n = 8719) found no difference in survival between recipients of RBCs from male versus female donors (HR 0.97 [0.91–1.06]).3 The CRYOSTAT-2 RCT evaluated adding three cryoprecipitate pools (6 g fibrinogen equivalent within 90 min) to the institutional major hemorrhage protocol in 1604 trauma patients.4 There was no difference in 28-day mortality (26.1% for standard care vs. 25.3% for standard care + cryoprecipitate), safety outcomes, or transfusion requirements. These findings do not support empiric use of cryoprecipitate in this setting, and do not apply to patients with documented hypofibrinogenemia. The multicenter single-blind RCT, PACER, compared catheter-related bleeding in patients with severe thrombocytopenia (platelet count 10–50 × 109/L) receiving either no platelet transfusion or one platelet transfusion prior to ultrasound-guided CVC placement.5 Grade 2–4 catheter-related bleeding occurred in 4.8% (9/188) in the transfusion group versus in 11.9% (22/185) in the no-transfusion group (relative risk 2.45; 90%CI 1.27–4.70). Subgroup analyses suggest the possibility of subgroup effects. For example, grade 2–4 bleeding may have been more likely in subclavian than in internal jugular CVC placements, perhaps because the latter site is more compressible to limit bleeding. A 2023 FDA guidance updated donor eligibility questionnaires to gender-neutral individual risk-based questions to reduce the risk of transfusion transmitted HIV, replacing questions about men-who-have-sex-with-men (MSM) and women who have sex with MSM.6, 7 The guidance also included deferral criteria for individuals taking medications to treat or prevent HIV infection (ART, PrEP, and PEP). To date, the United Kingdom, Canada, and the United States have not reported safety concerns associated with these changes.8-10 A cluster of polymicrobial contaminated apheresis platelet components resulted in seven cases of TT-sepsis, including three fatalities in the United States from 2018–2022.11 The products underwent bacterial risk control strategies outlined in the 2020 FDA guidance and there was no evidence of a failure in pathogen reduction processes for implicated units that used this strategy.12, 13 Whole-genome sequencing demonstrated that environmental isolates from the platelet collection set manufacturing facility were the most probable source of polymicrobial contamination.11 In 2023, a practical guide and narrative review of 45 studies compiled metrics and data sources available from hospital information systems pertinent to PBM program performance.14 A retrospective study of a national German PBM network with over 1.2 million surgical patients demonstrated non-inferiority (i.e., safety of PBM) for a composite endpoint of in-hospital mortality and selected postoperative complications in the setting of reduced RBC utilization when compared to a comparable pre-PBM cohort.15 This PBM program included: preoperative anemia optimization, blood-sparing techniques, and standardization of blood transfusions. PBM was associated with reduced RBC transfusions, findings that align with other recent large-scale assessments of multimodal PBM efforts.16, 17 The STRATUS trial showed no difference in RBC transfusion between small-volume (~2–3 mL) and standard-volume (~4–6 mL) blood draw tubes in critically ill adults in the ICU for ≥48 h (n = 21,201; RR, 0.91 [95%CI, 0.79–1.05]).18 A prespecified secondary analysis including over 6000 additional patients (n = 27,411) showed a significant reduction in RBC transfusion (RR, 0.88 [95%CI, 0.77–1.00]). The use of small-volume tubes did not increase rates of insufficient volumes for laboratory testing, which were rare. In the HiFIT trial, 443 patients with preoperative Hb levels 9.5–13.0 g/dL were randomized to receive one of four conditions: double placebo, ferric derisomaltose (20 mg/kg IV) and placebo, TXA (1 g bolus IV followed by 1 g IV infusion over 8 h and 3 g topically during surgery) and placebo, or both drugs.19 RBC transfusion rates were twofold with double placebo versus both drugs (30% vs. 15%, RR 0.51, [98.3%CI 0.27–0.97]). Severe postoperative anemia (Hb <8 g/dL) was more common with double placebo. Adverse event rates were similar among all groups. In the PATCH-Trauma trial, 1310 patients with major trauma were randomized to receive TXA 1 g prehospital IV bolus followed by 1 g infusion over 8 h versus placebo.20 Favorable functional outcomes were comparable at 6 months based on the Glasgow Outcome Scale Extended [53.7% TXA vs. 53.5% placebo (risk ratio, 1.00; 95%CI 0.90–1.12)]. Similar to previous studies,21 early survival at 24 h and 28 days after injury was improved with TXA (HR 0.69; 95%CI 0.51–0.94 and 0.79; 95%CI 0.63–0.99, respectively). Other secondary outcomes were similar. The PROCOAG trial randomized patients with trauma to 1 mL/kg of 4F-PCC versus placebo in addition to ratio-based RBC and plasma transfusions.22 There was no difference in 24-h transfusion amounts (absolute difference 0.2 units; 95%CI −2.99–3.33). Thromboembolic events were more frequent in the 4F-PCC group (RR 1.48, 95%CI 1.04–2.10), despite the control group receiving more TXA and fibrinogen concentrate. A post hoc analysis showed increased thromboembolic risk in patients with elevated prothrombin time ratio (PTr) who received 4F-PCC versus placebo. This study does not support empiric use of 4F-PCC in trauma. TXA may reduce bleeding-related mortality in patients with postpartum hemorrhage after vaginal or cesarean delivery.23 A multicenter RCT randomized patients undergoing cesarean delivery to receive prophylactic TXA versus placebo after umbilical cord clamping.24 There was no significant difference in the composite outcome of maternal death or blood transfusion (3.6% TXA vs. 4.3% placebo, RR 0.89; 95%CI 0.74–1.07), but there was a small reduction in need for interventions for bleeding complications with TXA. Overall, the results are similar to previous RCTs that found modest benefits related to some blood loss outcomes in favor of TXA.25, 26 A meta-analysis of five studies with 294 patients with transfusion-dependent β-thalassemia found the mean interval between transfusions was higher in patients receiving hydroxyurea versus placebo (mean deviation {MD}: 10.07, 95%CI: 2.16–17.99).27 Hb was higher with hydroxyurea versus placebo (MD: 1.71, 95%CI: 0.84–2.57). Patients receiving hydroxyurea also had lower ferritin (MD: −299.65, 95%CI: −518.35, −80.96). Hydroxyurea may reduce RBC transfusions and need for iron chelation therapy. The BEST Collaborative compiled 11 years of data from eight institutions on SRUS during 284 pregnancies.28 There were no cases of HDFN in 124 pregnancies with SRUS in isolation (44% of overall SRUS population). Of 41 pregnancies with concurrent ABO incompatibility and SRUS, there were four cases (10%) of mild HDFN. Mild to severe HDFN occurred in a minority of SRUS with a concurrent identifiable alloantibody (19/98, 19%). SRUS preceded identifiable alloantibodies in 30% (63/212) of patients with follow-up testing; in five cases, SRUS preceded clinically significant alloantibodies associated with HDFN (3%, 5/188). Antibody titer proficiency test results from the College of American Pathologists (CAP) between 2014 and 2018 showed intra- and interlaboratory variation even when controlling for differences in methodology, highlighting the need to clarify the role of antibody titer thresholds for clinical decision-making.29 The anti-A and anti-D titers were >1 titer outside the expected range in 21.6% (865/4004) and 11% (1197/10852) of transfusion service laboratories, respectively. Patients with serologic weak D require RhIg during obstetrical care when RHD genotyping is unavailable to inform risk of anti-D alloimmunization.30 Eighty-one transfusion services that routinely support obstetrics completed a CAP educational exercise on maternal and fetal serologic weak D in conjunction with proficiency testing samples.31 After testing two samples from the same serologic weak D donor, 14% (11/80) of laboratories had discordant immediate spin (IS) reactions. In response to a case of a maternal serologic weak D sample, 16% of laboratories did not recommend RhIg; laboratories with positive IS reactions were less likely to recommend RhIg than those with negative IS reactions (68% vs. 89%, p = .04). Some (28%, 16/57) laboratories performed non-indicated antiglobulin testing on routine maternal samples with negative IS reactions, resulting in some incorrectly advising against RhIg when no genetic information was available on the weak/partial D subtype. Approximately 47% (34/73) mistakenly recommended the fetal rosette test to assess for fetomaternal hemorrhage with a serologic weak D infant. In addition to providing standardized terminology, the authors make the following recommendations for RhD-negative mothers: perform antiglobulin anti-D typing on newborn samples when initial RhD typing is negative; give RhIg when the newborn is weak D-reactive; use quantitative tests to assess for fetomaternal hemorrhage when the newborn is weak D-reactive. Higher Hb transfusion thresholds did not improve outcomes compared to lower thresholds in 1692 extremely low-weight infants in the TOP RCT.32 A secondary sub-analysis of 179 preterm infants evaluated cerebral and mesenteric tissue saturation (Csat and Msat, respectively) and fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) via near-infrared spectroscopy.33 Tissue oxygenation of the brain and mesenteric regions improved after transfusion despite no change in peripheral oxygenation. In 97 infants with available data, the mean pre-transfusion Csat ≤48.6% and total number of transfusions with a pre-transfusion Csat <50% were associated with adverse outcomes of neurodevelopmental impairment and death. Further investigation is needed to evaluate whether there is benefit to transfusion strategies using tissue oxygenation measurements compared with current guidelines using hemoglobin thresholds. In a single center prospective randomized, observational trial of anemia in infants <32 weeks gestational age, the impact of 15 mL/kg versus 20 mL/kg RBC transfusions on cerebral and intestinal oxygen saturation was investigated.34 After transfusion, cerebral and intestinal tissue oxygen saturation increased significantly, fractional tissue oxygen extraction decreased, and vital signs improved in both the 15 mL/kg (n = 73) and 20 mL/kg (n = 78) groups. Fewer transfusions (1.9 ± 0.3 vs. 2.6 ± 0.9, p < .01) and fewer hospitalization days (44.3 ± 8.2 vs. 47.6 ± 9.8, p < .05) were noted in the 20 mL/kg versus 15 mL/kg group. A follow-up study was conducted on the two-year mortality and neurodevelopmental outcomes of 660 preterm infants in the PlaNeT-2/MATISSE trial.35, 36 In the primary trial, infants were randomized to a platelet transfusion threshold of 50 × 109/L or 25 × 109/L. Follow-up data were available for 601 of 653 (92%) eligible participants at a corrected age of 2 years. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, versus 120 (39%) of 305 infants in lower threshold group (OR 1.54, 95%CI 1.09–2.17). Two subgroup analyses were reported from the Age of Blood in Children in Pediatric Intensive Care Unit (ABC-PICU) RCT conducted from 2014–2018. Preplanned secondary analysis of 178 children undergoing cardiac surgery with cardiopulmonary bypass found fresh (median 5 days vs. median 18 days) did not reduce the incidence of new or progressive multiorgan dysfunction syndrome (relative risk 1.12, 95%CI 0.81–1.54).37 A non-prespecified secondary analysis of noncardiac, hemodynamically stable patients examined the clinical and economic impact of restrictive transfusion practice.38 Among critically ill children (3 days to 16 years old), 49% (338/687) received "non-compliant" RBC transfusion with initial transfusion at Hb ≥7 g/dL. Children with "compliant" transfusion with initial transfusion at Hb <7 g/dL had more ICU-free days (mean difference, 1.73; 95%CI, 0.57–2.88), ventilator-free days (mean difference 1.56; 95%CI, 0.49–2.62), and lower ICU costs ($38,845 reduced cost per patient, 95% CI $65,048–$12,641). There was no difference in rate of new or progressive multiple organ system dysfunction (relative risk 0.86, 95%CI 0.61–1.22). The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee released the ninth edition of clinical guidelines on the use of therapeutic apheresis, introducing seven new category III indications.39 Therapeutic plasma exchange (TPE) remains a first-line treatment for TTP. Recently, the US FDA approved recombinant ADAMTS13 for treatment of congenital TTP in adult and pediatric patients.40, 41 An RCT of recombinant ADAMTS13 without TPE in immune-mediated TTP is ongoing (NCT05714969).42 Fourteen patients with newly diagnosed multiple myeloma, not having achieved complete response, were given survivin (an apoptosis inhibitor) dendritic cell vaccine prior to hematopoietic stem cell collection and after autologous stem cell transplant.43 Eleven (85%) of 13 patients demonstrated either cellular or humoral immune response. Clinical response was improved in seven (54%) patients, and six remain event-free at a median follow-up of 4.2 years. This supports the pursuit of dendritic cell vaccine application in multiple myeloma treatment. Exagamglogene autotemcel (exa-cel) is the first FDA-approved treatment to utilize the novel genome editing technology, CRISPR/Cas9, signaling an innovative advancement in the field of gene therapy.44, 45 Both exa-cel and lovotibeglogene autotemcel (lovo-cel), a lentiviral vector gene modification of HbA are approved for the treatment of sickle cell disease in patients age 12 and older with recurrent vaso-occlusive crises.45 Exa-cel, which increases fetal hemoglobin production, is also FDA-approved for transfusion-dependent β-thalassemia.46 The FDA and the European Society for Blood and Marrow Transplantation (EMBT) and European Hematology Association (EHA) released statements on reports of T cell malignancies following BCMA or CD19-directed autologous CAR T cell immunotherapies resulting in an FDA boxed warning to these product labels.47-50 Multiple studies published in 2023 indicated inequity among editorial positions. Algorithmic tools were used to infer gender and examined 81,000 editors from more than 1000 journals and 15 disciplines over five decades and found only 14% female editors and 8% female editors-in-chief compared to 26% female scientists.51 Analysis of more than 1 million papers in over 500 different journals from six publishers found fewer non-White editors than expected.52 There was no change in the proportion of women on seven TM journal editorial boards despite addition of 54 new editorial positions between 2022 and 2019.53 Among nine TM journals with 398 editorial positions, only 31.2% positions were held by women. Inclusion of a DEI editorial position has been proposed as a means for improving DEI in academia, but only six (6%) of the top 100 high impact factor journals have implemented this position.54 Absolute neutrophil count (ANC) varies significantly based on Duffy status.55 In a cross-sectional study of 120 adults presenting for nonurgent care visits at a single primary care center, 66.7% (80/120) of those self-identified as Black or African American were found to be Duffy-null [Fy(a-b-)]. The median ANC among Duffy-null individuals was significantly lower than among Duffy non-null individuals. The authors note that ANC reference ranges that do not reflect Duffy-null individuals (the majority phenotype among Black individuals) can cause iatrogenic harm with unnecessary testing/referrals including bone marrow biopsy, discontinuation of medications, and exclusion form clinical trials.56, 57 The authors propose addressing the inequity by replacing the term "benign ethnic neutropenia" with "Duffy-null associated neutrophil count" and implementation of Duffy-null-specific ANC reference ranges with investigation of impact on clinical care such as chemotherapy administration. A retrospective cohort study of 46,200 children (<18 years) who required transfusion within 72 h of an index operation found minority children requiring postoperative transfusion had a higher odds of death than White children.58 White children had lower incidence of mortality (2.0%), compared to children of "Other" race (2.5%), Hispanic children (3.1%), and Black children (3.6%). Black children experienced greater odds of mortality following a postoperative transfusion compared to White children after adjustment for sex, age, comorbidities, case status, preoperative transfusion within 48 h, and year of operation (risk-adjusted odds ratio (aOR): 1.24; 95%CI, 1.03–1.51). Hispanic children were more likely to die following a postoperative transfusion than White children (aOR: 1.19; 95%CI, 1.02–1.39). Future studies should explore differences in management by race that may contribute to higher mortality in minority children. Jennifer Andrews was a Patient Blood Management (PBM) Advisory Board member for CSL Behring and received a speaker honorarium from Terumo BCT in 2023. Moritz Stolla received research funding from Cerus Corp and Terumo BCT. Nicole Zantek is on the Board of Directors for the American Society for Apheresis (ASFA), External Quality Assurance in Hemostasis and Thrombosis (EQATH), and the North American Specialized Coagulation Laboratory Association (NASCOLA) and spouse is an employee of Boston Scientific and has financial interest related to ENDO International. Ryan Metcalf reports being a scientific advisor for Werfen. The other authors have no conflicts of interest to disclose related to this manuscript submission to TRANSFUSION.
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