ABO mistransfusions are rare and potentially fatal events. Protocols are required by regulatory agencies to minimize this risk to patients, but how these are applied in the context of massive transfusion protocols (MTPs) is not specifically defined.
To evaluate the approaches used by transfusion services for switching from universally compatible to patient ABO type-specific blood components during massive hemorrhage.
We added 1 supplemental multiple-choice question to address the study objective to the 2019 College of American Pathologists proficiency test J-survey (J-A 2019). We also reviewed the available literature regarding this topic.
A total of 881 laboratories responded to the supplemental question. Approximately 80% (704 of 881) reported a policy for ABO-type switching during an MTP. Policies varied considerably between responding laboratories, but most (384 of 704, 55%) required 2 ABO types to match before switching from universal to recipient-specific blood components. Additional safety measures used in a minority of these protocols included reaction strength criteria (103 of 704, 15%), on-call medical director approval (41 0f 704, 5.8%), universal red cell unit number limits (12 of 704, 1.7%), or the presence of a mixed field (3 of 704, 0.4%).
This survey reveals that significant heterogeneity exists regarding the available approaches for ABO-type switching during an MTP. Specific expert guidance regarding this issue is very limited, and best practices have not yet been established or rigorously investigated.
In the United States, many hospitals have now adopted massive transfusion protocols (MTPs) to ensure that patients with life-threatening hemorrhage receive red cells and plasma in a safe, timely, evidence-based, and controlled manner.1,2 When the patient's blood type is unknown, it is established that red cells provided for such protocols are from universal donors, group O, and the plasma received is from either group AB or A donors. The patient who receives these products, however, may not be of those blood types.
Recent studies indicate that group O red cell use for non–group O recipients is increasing, putting a strain on blood inventories and providers.3 One large study3 revealed that nearly 9% of all group O red cell use and 24% of all group O Rh-negative red cell use were for non–group O recipients. Another study4 revealed that while 7% of donors are group O Rh(D)-negative, the proportion of group O Rh(D)-negative units transfused increased to nearly 11% in 2015.
Reasons for this increasing demand are varied and appear not solely related to changes in the frequency of MTPs.5,6 Smaller or rural hospitals are providing group O red cells to non–group O patients because they only stock, or stock a proportionally higher number of, group O red cells in their inventory.5,6 Larger hospitals provide more group O red cells to non–group O recipients to accommodate the complex needs of transfused neonates, stem cell or solid organ transplant recipients, and patients requiring antigen-negative blood, such as those with sickle cell disease. In addition, mid-sized and larger hospitals with active obstetric services may provide group O Rh(D)-negative red cells to women with discordant or weak D antigen typing in the absence of definitive molecular testing of the RHD gene. Lastly, larger hospitals may receive short-outdate group O red cells and often provide these group O red cells to non–group O patients to avoid wasting blood products.5,6
To account for these challenging inventory demands and to minimize the risk for group O red cell inventory shortages, the AABB recently published a bulletin recommending that all hospitals have protocols to quickly switch patients, including those during an MTP, to type-specific blood.6 How these standards are or should be applied to massive transfusions by hospital transfusion services is currently not clear. The current AABB Standards (Standards 5.14.5 and 8.2; 32nd edition)7 provide only general guidance regarding how transfusion services can switch these patients to type-specific blood components and monitor group O red cell use.
To elucidate current practices, we developed a single multiple-choice survey question to characterize the protocols currently used by transfusion services to switch blood types during MTPs. Further, we reviewed the available literature regarding the safety and risks associated with these protocols.
The College of American Pathologists (CAP) proficiency testing program offers samples for ABO typing, unexpected antibody detection, and compatibility testing to laboratories 3 times each year, and 5 specimens are provided with each proficiency test (J survey).
The CAP Transfusion, Apheresis, and Cellular Therapy Committee sought to determine what protocols were used by participating laboratories to allow for switching from group O red cells to patient type-specific red cells during or soon after MTPs. To this end, the CAP Committee added 1 multipart supplemental question to the 2019 J-survey, mailing A (J-A) proficiency test.8 The question was developed by 1 committee member (M.S.K.) and reviewed by other members for content and readability. The added question was as follows: “Based on your current blood bank protocol, when is red cell ABO-type switching allowed in a massive transfusion situation, where O red cell units are initially provided and no ABO type is already on file for a patient?” Respondents were allowed to select any combination of 8 possible answer choices that best described their current blood bank service protocol (Table 1). An “other” option was offered as a free-text option if respondents had additional details to share about their protocol. Participating laboratories were allowed to involve their medical director, as needed, to assist with this question.
Each respondent was assigned a unique identification number, and data analyses were performed in a blinded fashion. Given that the respondent could select multiple answer choices, the following a priori criteria were applied to each response: (1) When the forward and reverse type was selected to be observed on both 1 (answer choice 1) and 2 (choice 5) separate occasions, only answer choice 5 would be used in the analysis; (2) when the respondent selected more than 1 test strength option (answer choice 2, 3, 4), only the weakest reaction strength selected was used for the analysis; and (3) any described protocol option, including “other” was favored in the analysis over the selection of no class switching (answer choice 6) or no policy (answer choice 7).
Multivariate logistic regression models were used to test for practice differences regarding use of a policy and policy-specific practices, and these models were fit with 2 institutional characteristics. These characteristics included institution type (medical center, academic/university medical center, commercial reference laboratory, and non–hospital site/clinic) and institution size, based on reported overall laboratory test volume per year (categorized as <250 000; 250 000–2 million; >2 million). For the policy-specific practices models, only those institutions with a specific reported policy were included in the analysis. A P value <.05 was considered statistically significant. The survey results and analyses were generated with SAS 9.4 (SAS Institute, Cary, North Carolina).
A total of 3418 laboratories participated in the 2019 J-A survey, and most (85.9%; 2936 of 3418) were from the United States. Of those that participated, 881 of 3418 (26%) responded to the supplemental question (5.7%; 50 of 881 international). More than half of all responding institutions were from nonacademic medical centers (56%; 479 of 856; 25 did not provide demographic information), and about half performed between 250 000 and 2 million tests a year (50%; 431 of 857) (Table 2). Also, most of the responding sites served mainly adult populations, as only 23 of 881 respondents (3%) represented children's hospitals. The trauma service level of each responding site was not determined.
Most respondents (80%; 704 of 881) reported that they had a specific protocol to guide switching from universal to patient ABO type-specific blood components during MTPs (Table 3). Of these, more than half (54%; 384 of 704) reported a protocol in which 2 separate ABO types needed to be performed and needed to match each other before switching to type-specific blood. The reaction strength of the forward and reverse type results was a consideration for only a minority (15%; 103 of 704) of respondents' protocols, with a 2+ reaction strength being the most commonly reported minimum acceptable strength. Slightly more than 20% (151 of 704) of respondents required that only 1 ABO type match before class switching. In contrast, about 10% (73 of 704) of respondents reported that they would not ABO class switch at all and would provide only group O red cells for the duration of that patient's entire hospitalization. Lastly, a small number of respondents reported additional/other protocolized safety measures before switching to type-specific blood (other responses are available in Supplemental Table 1, see the supplemental digital content at https://meridian.allenpress.com/aplm in the December 2021 table of contents), including on-call medical director approval (5.8%; 41 of 704), universal red cell unit number limits (1.7%; 12 of 704), or the presence of a mixed field (0.4%; 3 of 704).
Logistic regression revealed that there was no significant difference between laboratories that did and did not have a policy based on test volume (P = .88), but there was a significant difference between institution types (P = .02). Only slightly more than half of the commercial reference laboratories (56.5%; 13 of 23) had a policy, compared with the other institution types, where the policy percentages ranged from 78% to 91% (hospital/medical center: 375 of 479, 78%; academic center: 278 of 333, 83.5%; non–hospital clinic: 19 of 21, 90.5%) (Table 2). For those institutions with a specific policy in place, there were no significant overall practice differences between institution types or test volume groups, except that respondents who specifically required 2 separate ABO types tended to be from institutions with more than 250 000 tests annually (P = .02). Lastly, there was no statistically significant practice differences between pediatric-focused and adult-focused hospital blood banks (P = .85).
In the context of an MTP, initially using uncrossmatched group O red cells provides the safest and most conservative transfusion option and remains the standard of care for these situations.1,2 However, group O red cells, especially group O Rh(D)-negative red cells, are relatively limited, and so the ability to switch a massively bleeding patient to their own blood type can help conserve resources. AABB Standards permit a transfusion service to provide ABO type-specific blood so long as a person's ABO type result can be confirmed by testing a second blood sample from the patient, by comparison to a historic result from the blood bank, or by using another form of electronic verification and retesting the same sample7 ; however, implementing these standards safely in the context of a massive transfusion event has not been rigorously evaluated.
To our knowledge, this supplemental question provided to a large number of transfusion service laboratories as part of a CAP proficiency J-survey represents the first attempt to address how laboratories are currently switching from universal blood components during an MTP to recipient type-specific blood components. While most responding laboratories, especially higher‐volume services (>250 000 annual tests), revealed that 2 matching ABO types are required, some only required 1 ABO type, and others integrated additional measures to potentially reduce the risk of providing incompatible transfusions or promoting red cell hemolysis, such as using ABO testing mixed-field reactions or reaction strength limits, universal red cell unit number limits, or medical director review and approval before class switching. Consequently, the survey revealed that most respondents do have a specific protocol, but a high degree of protocol variability currently exists, likely reflecting limited evidence regarding the safety of these protocols and expert guidance regarding best practice.
Protocols such as these are critical because providing the incorrect blood type, or the correct blood type at the wrong time to a patient, could lead to morbidity or mortality. Unlike other transfusion situations, MTP-associated hemolytic transfusion reactions can theoretically occur either from the transfusion of non–group O type-specific red cells in patients who have acquired high concentrations of passively received anti-A or anti-B from the MTP, or from the transfusion of non–group O type-specific red cells where the ABO interpretation was incorrect. Mistransfusion, including that associated with an MTP, is considered to be a sentinel event according to The Joint Commission, and thus requires formal reporting of the event with a root cause analysis and an action plan to reduce the risk of future errors.9,10 The estimated mortality from an ABO-incompatible transfusion ranges from 5.5% to 14%, corresponding to an overall mortality risk of 1:1.5 million to 1:2 million for individuals receiving red cell transfusions.11–13 Since 2014, there have been 13 (7% of all reported transfusion-associated fatalities) ABO-incompatibility–related FDA-documented deaths, and 1 transfusion fatality specifically associated with an MTP.14,15 The estimated incidence of an ABO-incompatible transfusion is much higher than reported fatalities, and generally ranges between 1:19 000 and 1:100 000, with some studies reporting rates as high as 1 in 3400.13,16,17 Considering that approximately two-thirds of mistransfused units could be ABO compatible owing to epidemiologic factors alone, and up to 50% of these transfusion errors can be asymptomatic, the actual risk of mistransfusion is likely underestimated.9,18
The actual risk of developing a clinically significant hemolytic reaction from receiving ABO-incompatible blood products during an MTP is not known. Simply, most studies regarding hemolysis and ABO-incompatible blood components involve recipients who are not massively bleeding. One review of incompatible platelet transfusions estimated the risk of hemolysis from incompatible plasma to be 1 in 9000, with anti-A from group O plasma–containing components (200–400 mL plasma) imparting the highest risk.19 Similar observations have not been made in studies involving massive transfusion. Williams et al20 recently found no evidence of hemolytic reactions when using group O, low-titer, whole blood for trauma resuscitation, which has potentially lower concentrations of incompatible anti-A, anti-B, and anti-A,B antibodies than group O plasma from platelet units. Dunbar and Yazer21 similarly found no increased risk of hemolysis when evaluating group B and AB trauma patients after receiving large volumes of emergency group A plasma.
There are at least 2 explanations why hemolytic events during MTPs are rare, and why incompatible blood products may be safe when used during an MTP. First, the early and active use of group O red blood cells during the MTP reduces the volume of the autologous red cells that could be susceptible to hemolysis from incompatible plasma. Second, 80% of recipients are secretors of soluble A or B substance that could neutralize the antibodies present in the transfused incompatible plasma-containing blood products.22 That said, studies on massively bleeding patients have not yet addressed whether and when type-specific blood components were eventually provided to these individuals, and so it remains unclear whether the use of type-specific products after the provision of multiple incompatible blood components increases the risk for hemolysis in these patients.
Avoiding mistransfusion and acute hemolysis also requires the accurate interpretation of ABO type results for a patient undergoing an MTP, but blood samples obtained from these patients present a unique interpretive challenge. During an MTP, the rapid transfusion of group O red cells and group AB or A donor plasma for a non–group O patient causes their forward and reverse type to increasingly reflect the mixture of the different transfused blood products and not the patient's original blood type. The forward type will increasingly demonstrate 2 populations of red cells (a mixed field) and, after a certain volume of group O red cells, testing will detect only the transfused group O cells. The reverse type, due to the anti-A and anti-B imparted from the plasma in group O red cell units, the antibodies from the likely ABO incompatible platelets, and the anti-B from any group A donor plasma transfused, will also confuse the issue and potentially create a situation where the reaction strengths of the patient's native antibodies weaken to 2+, 1+, or negative. Avoidance of these complexities to minimize the risk of test misinterpretation may explain why 15% of respondents report using either reaction strength or mixed-field determinations as a part of their protocol.
Large volumes of blood are not required to observe these changes, as it has been estimated that only about 10 mL of incompatible plasma needs to be transfused into a child or smaller adult (50 kg) to have detectable passively received antibody.23 More units, however, may be needed to observe these effects during massive transfusion in adults, as recent studies have indicated that while receiving as few as 6 emergency units are sufficient to elicit an ABO-typing discrepancy, only 15% of patients who received more than 10 units of emergency blood have such a discrepancy on their first sample.24,25
Outside of the AABB Standards, additional guidance regarding the safe transition to type-specific blood components, despite the unique laboratory complexities, is quite limited. Hess et al26 suggest that each transfusion service should develop a policy that takes into account the number of group O red cells transfused.26 They further suggest that once 12 group O red cell units have been transfused, the detection of anti-A and anti-B should be considered before switching to a non–group O blood type, owing to the potential risk of hemolysis to the non–group O red cells.26 Harm and Dunbar27 suggest that as long as the patient's ABO type can be confirmed, the ABO type-switch can safely occur at any time, with the caveat that group O red cells should be continued in pediatric patients or in patients who have already received “large volumes” of group O red cells. Lastly, Dunbar et al28 do not offer advice beyond suggesting that ABO-type switching should be attempted. Of note, all authors26–28 suggest that samples for ABO determination should be sent to the blood bank as early as possible so that ABO-type switching could be initiated.
The most explicit recommendations to date come from a recently published case report documenting a death from ABO mistransfusion in an MTP patient.15 The authors of this report note that a 2 ABO check system, similar to that reported in about half of our respondents, was used at the time of the error and was followed appropriately, based on their protocol. The authors note, however, that both the first and second sample received by the blood bank came after many emergency units had been already transfused, and the results of the forward typing were weak, likely contributing to a misinterpretation of the ABO type results. As a consequence, they concluded that the AABB Standard was insufficient to prevent mistransfusion errors associated with an MTP. Consequently, they additionally suggested that (1) the initial sample for ABO typing be obtained as early as possible during the MTP, (2) group O red cells be used during the entire MTP, switching only after the resuscitation is completed, (3) the switch of emergency plasma to type-specific plasma occur during the MTP so long as the ABO type of the patient can be confirmed via early testing, and (4) the transfusion service attending review and approve red cell ABO-type switching after the MTP is completed, based on test results.
There are some limitations to this survey. First, this survey only asked 1 question of respondents, which may have resulted in errors in interpretation. Second, not all individuals who completed the proficiency test also completed our voluntary supplemental question. Reasons for this difference are unclear, but our respondents are representative of the overall J-A survey subscribers in terms of practice setting (institution type) and test volume. Third, while this question was reviewed by our committee of transfusion medicine experts for content and readability in a manner similar to our committee's previous work,29 it must be noted that no formal reliability and validity measures were used for this survey question. Lastly, our single survey question was not able to answer some potentially important protocol variations, such as whether a respondent could retest a single sample in order to allow for class switching. Future surveys could help clarify these and other such questions.
Despite these limitations, our survey is instructive, as the significant heterogeneity in responses, while not in itself novel, highlights the fact that the transfusion medicine community currently lacks a gold standard method for transitioning a patient to ABO type-specific components during an MTP. The relative impact of using reaction strength criteria, the presence of a mixed field, universal red cell unit number limits, or on-call medical director oversight on patient safety is unknown. However, some protocols reported by respondents could be improved, as the best protocols balance both safety and inventory management considerations. For example, laboratories that allow a transition to patient type-specific blood on the basis of only 1 ABO type result/sample (21% of laboratories with a defined policy) may minimize the use of universal blood components, but also may be at the greatest risk for misinterpreting test results. On the other hand, laboratories (10% of laboratories with a defined policy) that do not allow any switching to type-specific blood during an entire hospitalization after an MTP may entirely prevent the risk of mistransfusion, but they also will undoubtedly overuse limited universal blood components.
Our survey of 881 laboratories reveals that policy and practice regarding ABO-type switching during MTPs vary considerably. While it is well-known that mistransfusions can be fatal, known studies to date indicate that this is a relatively rare event during MTPs, suggesting that multiple different protocols could be effective. Studies have not yet been done to clearly define the safest way in which to quickly expedite the transition to type-specific blood for these patients, but the best protocols will both minimize the risk for mistransfusion and limit the unnecessary use of universal blood components. At the very least, all laboratories that provide blood for massively hemorrhaging patients should work to ensure that all necessary specimens for ABO and confirmatory typing are obtained as early as possible during the MTP, and have a distinct protocol that clearly defines when the patient can transition to type-specific blood.
Thank you to Roger Dodd, PhD, and Zbigniew Szczepiorkowski, MD, PhD, for their valuable comments on this manuscript.
Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the December 2021 table of contents.
DeSimone is a consultant for Instrumentation Laboratory. The other authors have no relevant financial interest in the products or companies described in this article.
All authors are current or past members of the College of American Pathologists Transfusion, Apheresis, and Cellular Therapy Committee. Souers and Thomas are employees of the College of American Pathologists.