Red blood cells are the most transfused product in the world and many patients depend on their accessibility.1 While modern additives have boosted their shelf life from 21 days to 42 days, hypothermic storage causes negative changes to the RBCs over time. This “storage lesion” results in numerous changes including a decrease in glucose, 2,3-diphosphoglycerate (DPG) and ATP in the unit, and an increase in potassium levels.2 There is also loss of red cell membrane integrity with reduced deformability and hemolysis, leading to less viable RBCs upon transfusion.3 One of the mechanisms leading to these changes is oxidative damage;, so Hemanext Inc. (Lexington, MA, United States) has developed a device for hypoxic processing and storage of RBCs. The device, Hemanext ONE®, is CE mark certified in Europe and has been granted marketing authorization by the FDA in the United States.
Hypoxic storage has been shown to result in improved energy and redox metabolism of RBCs as well as improved transfusion outcomes in animal models.4,5 Lower volumes of hypoxic RBCs are needed to resuscitate from hemorrhagic shock and demonstrate a lower incidence of organ injury.5 Autologous post-transfusion in vivo recovery values are also greater in hypoxically stored RBCs (90.2 % versus 87.3 %; p < 0.05 by one-tailed paired t-test).4
As the device is still new, a paper by Reikvam et al. is an interim analysis of a surveillance study looking at the safety of single administrations of hypoxic RBCs.6 The authors’ plan is to eventually enroll 10 patients with hematological malignancies and 10 patients with burns; but for this analysis, only the first five patients with malignancies have been studied. All patients received a one-time transfusion of two units of hypoxic RBCs that were stored at 1-6 C for up to 42 days. Vital signs were checked every 15 minutes during transfusion as well as 15 minutes post-transfusion. Adverse events (AEs) were monitored directly during transfusion. Post-transfusion, patients were given diaries to record their AEs and received phone check-ins at 24 hours and 7 days after. They returned to clinic for a final visit 28 days after transfusion or just prior to their next transfusion, whichever occurred first. Blood samples were collected 15 minutes to 4 hours pre-transfusion, 15-60 minutes post-transfusion, and at the end of the study period.
Of the five enrolled, the mean ± SD pre-transfusion hemoglobin level was 7.7 ± 0.5 g/dL, and patients were transfused with 478.0 ± 20.5 mL of hypoxic RBCs, aged 20.8 ± 12.3 days. Only one AE (rhinovirus infection) was reported two days post-treatment, and it was designated as unrelated to treatment. The hemoglobin level immediately post-transfusion was 9.0 ± 0.9 g/dL, an increase of 17%. Subsequent transfusion occurred 22.8 ± 6.4 days after the first transfusion with hemoglobin levels being 8.2 ± 1.7 g/dL.
The interim analysis showed that hypoxic RBCs were effective and safe with hemoglobin increasing by 17% and staying higher than pre-transfusion levels until subsequent transfusion. There were no relevant AEs in the 28 days post-transfusion and no changes in vital signs. The surveillance study is still ongoing, but the authors discussed plans for other trials in light of the increased yield of viable RBCs from hypoxic storage. This may reduce needs in transfusion-dependent patients, leading to lower doses and decreased risk of iron overload in those with hematologic malignancies. Similar studies are planned for patients with thalassemia in Italy and sickle cell disease in the United States.
While this study demonstrates the safety of hypoxic red blood cells and their efficacy in increasing recipient hemoglobin levels, it remains a very limited safety survey. There was no comparison to standard RBCs in terms of final hemoglobin levels or time until the next transfusion. Other studies will need to prove a sustained advantage over standard RBCs, especially as this product poses significant operational challenges for manufacturers and will require hospitals to manage an additional red cell product inventory, complicating logistics and storage in blood banks.
References
1. García-Roa M, Del Carmen Vicente-Ayuso M, Bobes AM, Pedraza AC, González-Fernández A, Martín MP, Sáez I, Seghatchian J, Gutiérrez L. Red blood cell storage time and transfusion: current practice, concerns and future perspectives. Blood Transfus. 2017 May;15(3):222-231. doi: 10.2450/2017.0345-16. PMID: 28518049; PMCID: PMC5448828.
2. Kim-Shapiro DB, Lee J, Gladwin MT. Storage lesion: role of red blood cell breakdown. Transfusion. 2011 Apr;51(4):844-51. doi: 10.1111/j.1537-2995.2011.03100.x. PMID: 21496045; PMCID: PMC3080238.
3. Yoshida T, Prudent M, D’Alessandro A. Red blood cell storage lesion: causes and potential clinical consequences. Blood Transfus. 2019 Jan;17(1):27-52. doi: 10.2450/2019.0217-18. PMID: 30653459; PMCID: PMC6343598.
4. DʼAlessandro A, Yoshida T, Nestheide S, Nemkov T, Stocker S, Stefanoni D, Mohmoud F, Rugg N, Dunham A, Cancelas JA. Hypoxic storage of red blood cells improves metabolism and post-transfusion recovery. Transfusion. 2020 Apr;60(4):786-798. doi: 10.1111/trf.15730. Epub 2020 Feb 27. PMID: 32104927; PMCID: PMC7899235.
5. Williams AT, Jani VP, Nemkov T, Lucas A, Yoshida T, Dunham A, D’Alessandro A, Cabrales P. Transfusion of Anaerobically or Conventionally Stored Blood After Hemorrhagic Shock. Shock. 2020 Mar;53(3):352-362. doi: 10.1097/SHK.0000000000001386. PMID: 31478989; PMCID: PMC7017949.
6. Reikvam H, Hetland G, Ezligini F, Dorsch K, Omert L, Dunham A, Almeland SK. Safety of hypoxic red blood cell administration in patients with transfusion-dependent hematological malignancies: An interim analysis. Transfus Apher Sci. 2023 Oct;62(5):103755.
