A monthly roundup of key articles in other journals

Liberal or restrictive transfusion strategy in aneurysmal subarachnoid hemorrhage English SW, Delaney A, Fergusson DA, et al., N Engl J Med.; epub ahead of print. In patients with aneurysmal subarachnoid hemorrhage and anemia, a liberal transfusion strategy is not associated with a lower risk of unfavorable neurologic outcomes. Anemia is common in patients with subarachnoid hemorrhage and may exacerbate the adverse neurological outcomes of aneurysmal rupture, but evidence for the optimal red blood cell (RBC) transfusion approach in this population is limited. The Subarachnoid Hemorrhage Red Cell Transfusion Strategies and Outcome (SAHARA) trial was conducted across 23 centers. Critically ill adult patients within 10 days of their first aneurysmal subarachnoid hemorrhage and with hemoglobin (Hb) ≤10 g/dL were randomized to a liberal or restrictive transfusion strategy (transfusion when Hb ≤10 g/dL, n = 364; or 8 g/dL, n = 361, respectively). The primary outcome was an unfavorable neurologic functional outcome at 12 months (a score of ≥4 on the modified Rankin scale). Pretransfusion Hb was 9.6 g/dL in the liberal group and 7.6 g/dL in the restrictive group, and RBC transfusions were performed for 99.7% of the liberal strategy group, compared with only 34.9% of the restrictive group. The primary outcome was observed in 122 (33.5%) patients in the liberal strategy group and 136 (37.7%) in the restrictive group (risk ratio, 0.88; 95% confidence interval [CI], 0.72 to 1.09; p = .22). Functional independence scores, five level EuroQoL score (EQ-5D-5L), and visual analogue scale scores were also similar. Mortality rates were 27.2% and 27.1% in the liberal and restrictive strategy groups, respectively (risk ratio, 0.99; 95% CI, 0.77 to 1.28). Safety outcomes were comparable between groups, including rates of acute transfusion reactions and adverse events. ♦ ♦ ♦ Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): A prospective, multicentre, open-label, randomised, phase 3a trial Chowdary P, Angchaisuksiri P, Apte S, et al., Lancet Haematol. 2024; 11(12): e891-e904. Daily subcutaneous concizumab prophylaxis is associated with a reduction in bleeding rate in patients with hemophilia A and hemophilia B without inhibitors. Bleeding prophylaxis for patients with hemophilia A and B is commonly treated with intravenous factor replacement therapy, incurring a high treatment burden. Concizumab is a novel monoclonal antibody targeting anti-tissue factor pathway inhibitor, thus restoring thrombin generation and decreasing bleeding episodes. The explorer7 study demonstrated efficacy in patients with hemophilia A and B with inhibitors, and in the explorer8 trial concizumab prophylaxis was evaluated in patients without inhibitors. This phase 3, prospective, multicenter, open-label trial randomized male patients (12+ years old) with severe hemophilia A or moderate hemophilia B without inhibitors to either continue on-demand clotting factor concentrate or to receive concizumab prophylaxis. The trial was paused due to nonfatal thromboembolic events in two patients from explorer8 and one from explorer7, prior to restarting with an adjusted dosing regimen of a 1 mg/kg loading dose followed by daily doses of 0.2 mg/kg, with the option of decreasing to 0.15 mg/kg or increasing to 0.25 mg/kg, based on plasma concentrations after 4 weeks. The primary outcome was the number of treated spontaneous, traumatic bleeding episodes at the confirmatory analysis cutoff date. Two additional groups of patients who were not randomly assigned were included in the safety analyses. In this study, concizumab prophylaxis was superior to on-demand clotting factor concentrates in both hemophilia A and hemophilia B. The primary outcome, mean annualized bleeding rate ratio, was 0.14 (95% CI 0.07–0.29; p < .0001) for hemophilia A and 0.21 (0.10–0.45; p < .0001) for hemophilia B. Adverse events were largely mild or moderate with the most frequently reported being SARS-CoV-2 infection, increased D-dimers, and upper respiratory tract infections. One fatal adverse event deemed possibly related to treatment occurred in the concizumab group (intra-abdominal hemorrhage), and six patients had events that led to treatment discontinuation. No thromboembolic events were reported after the pause. Anti-concizumab antibodies were identified in 12 patients with hemophilia A (14%) and six with hemophilia B (9%) but demonstrated no effect on bleeding, adverse events, or pharmacokinetics. Concizumab decreased levels of free tissue factor pathway inhibitor within 24 h of first dose, resulting in increasing peak thrombin concentrations. While concizumab showed superiority to no prophylaxis in hemophilia A and B patients without inhibitors, non-inferiority to prior standard-of-care prophylaxis was not tested in this trial. ♦ ♦ ♦. Ferroptosis regulates hemolysis in stored murine and human red blood cells D'Alessandro A, Keele GR, Hay A, et al. Blood. 2024; epub ahead of print. Steap3 ferrireductase is implicated in lipid peroxidation, hemolysis, and RBC quality during storage. The genetic basis for the observed heterogeneity in post-transfusion recovery (PTR) is poorly understood. Jackson Labs recently developed an outbred mouse (J:DO) by crossing eight highly divergent strains. D'Alessandro et al. leveraged this new line to explore the genetic underpinnings of post-transfusion RBC performance. Cells from 350 J:DO mice were stored for 7 days before being used in PTR, metabolomic, and lipidomic studies. Genetic quantitative trait loci (QTL) analyses identified an association of PTR with the gene Steap3, which encodes an enzyme involved in transferrin-dependent iron uptake during erythropoiesis. Over 400 metabolomic associations with PTR were mapped, including hotspots proximal to Steap3; oxylipins; eicosanoid- and octadecadienoic-hydroxypeptides; and very long chain poly- and highly unsaturated fatty acids, together suggesting that lower storage-induced oxidation protects against decreases in PTR. The full dataset has been integrated into an interactive online portal (https://churchilllab.jax.org/qtlviewer/Zimring/RBC). Abrogating Steap3 (via Steap3 knockout or Steap3 hypomorph) increased lipid peroxidation and decreased PTR. Interestingly, gain-of-function mice also exhibited decreased PTR and increased oxylipin levels following RBC storage. The findings in mice were confirmed in humans using RBCs from donors in the Recipient Epidemiology and Donor Evaluation Study. Variants in Steap3, networks of genes associated with oxylipin levels, and RBC iron levels were significantly correlated with end-of-storage hemolysis. Many of the polymorphisms were more prevalent in donors of African heritage and were associated with lower Hb increments following single-unit transfusion. The authors conclude that RBC storage induces a ferroptosis-like response, wherein lipid peroxide accumulation drives iron buildup and cell death, and while mild variants in Steap3 may not impact blood count parameters and exclude a donor from the pool, they may nonetheless impact storage quality. ♦ ♦ ♦ Genetic engineering of transfusable platelets with mRNA-lipid nanoparticles is compatible with blood banking practices Strong C, Leung J, Kang E, et al. Blood. 2024; 144(21): 2223–2236. Lipid nanoparticles carrying mRNA can be used to drive exogenous protein expression in platelets stored under clinically relevant conditions. The therapeutic use of platelets has been hampered by their anucleate nature, constraining their capacity to undergo genetic modification. Nonetheless, preliminary studies have shown that platelets stored in crystalloid solution can be induced to express exogenous protein via lipid nanoparticles (LNPs) bearing an mRNA cargo. The capacity of platelets to be transfected under clinically relevant storage conditions remains to be determined. Here, Strong et al. evaluated a LNP transfection platform on platelets stored in plasma with or without platelet additive solution (PAS). The researchers began by optimizing major lipid components of the LNPs. Using a luciferase reporter, they identified an LNP formulation comprised of NTX-001, phosphatidylcholine-containing structural phospholipids and 1-palmitoyl-2-oleoyl (PO) tail groups, and a 0.5% DMG-PEG2000 lipid species as producing the greatest exogenous expression in platelets stored in both plasma and 70% PAS. Transfection under these conditions was scalable, showing robust efficacy in solutions with platelet concentrations corresponding to physiological (250 × 106/ml) and supraphysiological (800 × 106/ml) levels. Furthermore, while platelets can be highly responsive to stressors including phospholipids, the LNPs did not cause substantial platelet activation, and transfected platelets retained their capacity to be stimulated by agonists. Transfected cells also showed a normal coagulation response (clot formation, light transmission aggregometry, and ROTEM) and morphology. Lastly, the researchers demonstrated that platelets transfected with LNPs withstood storage at room temperature or at 4°C. In sum, the plasma-optimized LNPs can be used to transfect platelets stored in clinically relevant conditions without negatively impacting in vitro physiology. The findings may lay the foundation for the development of platelet-based cell therapies. ♦ ♦ ♦ Red cell specifications for blood group matching in patients with haemoglobinopathies: An updated systematic review and clinical practice guideline from the International Collaboration for Transfusion Medicine Guidelines Wolf J, Blais-Normandin I, Bathla A, et al. Br J Haematol. 2025; 206(1): 94–108. While extended antigen-matching is recommended for patients with sickle cell disease and thalassemia without inhibitors, there is a need for additional research into the impact of inhibitors and the costs, benefits, and feasibility of this approach. Patients requiring regular RBC transfusion are at increased risk of developing alloantibodies. Extended matching is believed to mitigate this risk; however, this has not been definitively established for all patient populations and can delay transfusion, complicating inventory management. In 2018, the International Collaboration for Transfusion Medicine Guidelines (ICTMG) published a systematic review and guidelines recommending extended matching, but a subsequent paper issued by the British Society of Haematology raised concern over the strength of the evidence for recommendations to provide extended matching in patients with existing RBC alloantibodies. To address the discrepancy and incorporate emerging research, the ICTMG commissioned an updated review of the evidence for RBC matching in patients with sickle cell disease (SCD) or thalassemia. The panel did not reach recommendations for whether more extensive matching should be used for patients with SCD or thalassemia who have one or more alloantibodies. Importantly, the risk of bias was deemed to be critical for one study, serious in one, and moderate for the remaining four. As a result, the certainty of evidence was deemed to be very low, emphasizing critical research priorities to support transfusion protocols in these patient populations with significant transfusion exposure.