Updates to Association for the Advancement of Blood and Biotherapies Standards for blood banks and transfusion services, 34th edition

The Association for the Advancement of Blood and Biotherapies (AABB) was formed in 1947 to encourage support and standardization of transfusion practice among the many independent blood centers in the United States. In 1959, AABB published the first edition of the Standards for Blood Banks to promote safety for blood donors, protocols for blood collectors, and guidelines for hospitals transfusing blood. Since then, the AABB mission of vein-to-vein safety has led to an expansion, with eight sets of Standards covering topics ranging from patient blood management to biotherapies and a Spanish language version of the Fundamental Standards for Blood Collection and Transfusion (Table 1). The Standards continue to evolve in response to changes in technology, emerging infectious diseases, new federal regulations, and feedback from AABB members. AABB and TRANSFUSION are launching a new ongoing series highlighting important recent changes to the Standards and explaining why the changes were made. The first in this series will focus on changes that appeared in the 34th edition of the Standards for Blood Banks and Transfusion Services, which became effective April 1, 2024. Prior to the early 1970s, all platelet units were stored refrigerated. However, a 1969 paper by Murphy demonstrated that room temperature storage (RTS) prolonged in vivo survival.1 Since cancer patients with chronic thrombocytopenia need platelet transfusions to prevent bleeding episodes, prolonged in vivo survival confers an advantage. As these patients receive the majority of platelet transfusions in the United States, room temperature storage became the norm. The main disadvantage of cold-stored platelets (CSP) is that they are rapidly cleared from the recipient's circulation. Clearance of CSP mainly occurs in the liver. In platelets refrigerated for a short period (e.g., 2 h), irreversible clustering of von Willebrand factor receptors leads to platelet clearance by 𝛽2 integrin receptors on hepatic macrophages (Kupffer cells).2 In contrast, platelets refrigerated for a longer period are mainly cleared due to exposed platelet-surface galactose residues binding to the Ashwell–Morell receptor on hepatocytes themselves.3 However, CSP may provide other advantages to patients. In patients with acute hemorrhage, the goal is to stop the bleeding right away; keeping the platelet count up over several days is not a priority. Cold storage causes platelets to transform into a partially activated state, which is associated with improved hemostatic function in many, although not all, in vitro assays.4-6 This enhanced activity, coupled with a reduced risk of bacterial growth and the potential for prolonged storage in the transfusion service laboratory, has led to a resurgence of interest in using CSP for patients with active bleeding. In 2015 the Mayo Clinic requested a variance for 5-day cold storage of platelets; however, the FDA approved only 3 days of cold storage. A change to AABB Standards followed soon thereafter but the limited storage period and large number of units with visible aggregates led to a high (80.9%) discard rate and the end of their use by 2017.7 Nonetheless, laboratory and clinical studies continued. A study by Getz et al. showed that storage of apheresis CSP in platelet additive solution could reduce the number of aggregates and thereby reduce wastage,8 and a pilot clinical trial in Norway found no significant differences in safety and efficacy in complex cardiac surgery patients when CSP (stored up to 14 days) were compared to RTS, both stored in platelet additive solution.9 These data were reviewed at an FDA Blood Products Advisory Committee (BPAC) meeting in 2019.10 The BPAC noted that there were no data to support the use of CSP for the prevention of bleeding and suggested that more data were needed to support indications for CSP when RTS units were available as an alternative. As a result, a clinical trial in cardiac surgery patients was launched (CHIlled Platelet Study "CHIPS") and is ongoing. In addition, in response to a strained platelet supply, the FDA issued a Guidance for Industry11 that allows for the use of CSP for actively bleeding patients when RTS platelets are not available. The guidance allows CSP to be stored for up to 14 days without agitation and requires no bacterial testing. The FDA further clarified this guidance during an AABB-hosted "Ask the FDA" webinar in which they made clear that "Transfusion Service may wish to establish standard operating procedures to maintain a dual inventory and use CSP for actively bleeding patients in circumstances where conventional platelets are not available, or their use is not practical."12 This guidance led the AABB to expand the standards focused on RTS platelet manufacture, transport, and storage so that they include information on CSPs as well. This resulted in six new standards (Table 2). The number of Apheresis Platelets Cold Stored components included in the overall monthly quality control testing plan shall represent the proportion of Apheresis Platelets Cold Stored in the total platelet inventory.† †FDA Guidance for Industry: Alternative Procedures for the Manufacture of Cold-Stored Platelets Intended for the Treatment of Active Bleeding when Conventional Platelets Are Not Available or Their Use Is Not Practical (June 2023). Cryoprecipitate, officially known as Cryoprecipitated Antihemophilic Factor (Cryo AHF or cryo), was initially developed as a treatment for patients with hemophilia A. The therapeutic value of cryo was first recognized by French physician Emile Rémigy in 1955.13 As Remigny's work remained unpublished, the 1959 paper by Judith Pool is generally accepted as the first description of the cold-insoluble fraction of plasma that was enriched for factor VIII, or AHF.14 Dr. Pool recognized that Cryo AHF could be easily manufactured from bags of carefully thawed plasma.14, 15 The Circular for Information for the Use of Human Blood and Blood Components,16 which is recognized by FDA as an acceptable extension of container labels, states that "Cryoprecipitated AHF is prepared by thawing whole-blood derived of apheresis fresh frozen plasma (FFP)…and recovering the precipitate. Each unit of Cryo AHF should contain ≥ 80 International Units of Factor VIII and ≥150 mg of fibrinogen." Researchers analyzed factor levels in FFP and plasma frozen within 24 h (PF24) and found that PF24 contains sufficient factor levels to satisfy these requirements.17-19 As demand for cryo increased, the American Red Cross conducted a feasibility study of Cryo AHF manufactured from whole-blood-derived PF24 as an alternative source material to FFP. Their findings confirmed that cryo derived from PF24 met all FDA and AABB quality control requirements. Soon after, the FDA approved ARC's Biologics License Application supplement request for an alternative procedure under 21 CFR 640.120 for the manufacturing of Cryo AHF single units and pools from PF24.20 As the manufacture of Cryo AHF from PF24 offers logistical advantages to blood manufacturers, this alternative cryo source has been widely adopted. In 2023, AABB updated the Circular of Information to include new language required by the FDA for the manufacture of cryo from PF24.21 It is important to note that an approved variance is still necessary under certain circumstances, but if Cryo AHF is prepared from PF24 using a blood collection set that is FDA-approved for this use then a variance is not necessary. The 34th edition of the AABB Standards for Blood Banks and Transfusion Services has several changes reflecting the use of PF24 as a source for cryo, as shown in Table 3. The AABB Standards continue to evolve in response to changes within the blood industry. This series will continue to highlight the important changes made in the different AABB Standards. The stringent and detailed standards ensure the greatest level of safety for blood collections, testing, and transfusions. No funding was provided for this work. The authors are employed by the Association for the Advancement of Blood and Biotherapies. There is no additional conflict of interest.