In 2018, an international committee of veterinary specialists convened in partnership with the Association of Veterinary Hematology and Transfusion Medicine (AVHTM) to develop consensus guidelines regarding transfusion reactions in veterinary patients (Davidow et al. 2021a, Davidow et al. 2021b, Odunayo et al. 2021). The aim was to produce veterinary definitions for specific transfusion reactions and provide evidence-based recommendations for prevention and treatment of transfusion reactions. The process allowed us to recognise where evidence was lacking and therefore where further investigations were required. These notes discuss some of those findings.

What is a Transfusion Reaction?

An acute transfusion reaction was defined as an adverse reaction to blood, blood components, or plasma derivatives within 24 hours of administration. A delayed transfusion reaction was defined similarly, but after 24 hours post administration. The guidelines noted that, although transfusion reactions have traditionally been split into immunological and non-immunological reactions, this is not necessarily very helpful clinically as often this distinction is unclear during initial patient assessment (and may not ever be fully understood if investigation into the event is not very thorough). Therefore, algorithms were produced based on changes in physical examination findings that may occur during or after the transfusion period which could allow recognition of the likely transfusion reaction occurring (if any). Hopefully, this approach should allow a simpler and consistent approach to recognition and treatment of reactions (Davidow et al. 2021a).

Leukoreduction—Yes or No?

Leukoreduction can be used both pre- or post-storage to remove white blood cells from blood products, but in the vast majority of cases, it is performed immediately post-donation and pre-storage. It is suggested to be advantageous in decreasing cytokine levels in blood products, preventing adverse recipient reactions to donor white cells and also in decreasing the likelihood of infectious disease transmission. The TRACS guidelines reported there was insufficient veterinary evidence to either recommend for or against the use of leukoreduction to decrease the likelihood of transfusion reactions. However, they argued that it should be considered given human evidence suggesting it decreases the rate of febrile non-haemolytic transfusion reactions (Davidow et al. 2021b). Since the publication of the AVHTM guidelines, Radulescu et al. (2021) reported a randomised controlled trial of 194 dogs which showed no difference in transfusion reaction rate between leukoreduced and non-leukoreduced blood product recipients. But Davidow et al. (2022) found that dogs receiving leukoreduced packed red blood cells were less likely to have a febrile non-hemolytic transfusion reaction than those receiving non-leukoreduced cells in a large retrospective trial. This suggests there may be a benefit to leukoreducing packed red blood cells, but that it requires a large number of cases to be treated for this benefit to become evident.

Storage Lesion—Is It an Issue?

The AVHTM guidelines describe 10 veterinary studies looking at the influence of age of red cell products on the likelihood of transfusion reaction. The evidence was deemed difficult to interpret due to lack of use of illness severity scores, small sample sizes in some studies, and inconsistency in transfusion reaction definitions. One clinical study found that administering older units was associated with decreased survival in dogs with a haemolytic cause of anaemia, leading to the suggestion that fresher units should be considered in these patients (Hann et al. 2014). Many changes occur in red cell-containing units as they age, including modifications in electrolytes, glucose, pH, cytokines, etc. The implications of these are generally not clear, but increased haemolysis of older units has been noted in several studies and this is consistent with human evidence. Experimental canine studies suggest that free haemoglobin is detrimental (Wang et al. 2014) and a clinical case series discusses adverse effects thought to be due to the transfusion of a haemolysed product (Patterson et al. 2011). To assess for haemolysis, samples should be taken directly from the bag rather than using a segment. Measurement can be made using a haemoglobin monitor, which many practices may not have, but they may have the ability to measure haemoglobin as part of a critical care/emergency profile on an ISTAT or similar. Testing for haemolysis should probably be considered in any red cell unit over 28 days of age. Further prospective studies in this area are needed to determine the clinical severity and relevance of storage lesion and its various components.

Typing or Not Typing?

In dogs, DEA 1 is considered the most clinically important blood group in dogs due to its strong antigenicity. Dogs are either DEA 1 negative or weakly, moderately, or strongly DEA 1 positive (Kessler et al. 2010, Acierno et al. 2014). Naturally occurring alloantibodies against DEA 1 antigen have not been described and no AHTR have been reported following a DEA 1 mismatched transfusion. However, there are laboratory and clinical reports of severe AHTR in previously immunized dogs who receive a further DEA 1 mismatched transfusion (Callan et al. 1995, Giger et al. 1995). Typing both recipient and donor for DEA 1 before a first transfusion prevents further immunization against DEA 1 antigen. DEA 1-negative dogs should only receive DEA 1-negative blood. DEA 1-positive recipients can receive either DEA 1 negative or positive blood. Because approximately half of the dogs are DEA 1 positive, the use of DEA 1-positive blood products for DEA 1-positive recipient, is encouraged to make better use of blood resources.

Thus, while blood typing is mandatory prior to transfusion, typing alone is insufficient to prevent all AHTRs in cats. The presence of Mik antigen and potentially other unrecognized antigens remains a potential cause of severe transfusion reactions despite AB type-matching (Auer et Bell 1983, Giger et al. 1990, Weingart et al. 2004, Weinstein et al. 2007, McClosky et al. 2018). While there are no confirmed reports of non-immunologic AHTR in cats, this also remains a potential in feline type-matched transfusions.

Should We Be Crossmatching?

There is good evidence to support crossmatching prior to a transfusion more than 4 days after a first red cell transfusion. However, whether or not a crossmatch should be performed prior to the first red cell transfusion itself is less obvious. In human medicine, a crossmatch is generally performed prior to every transfusion, and so we could not use the human evidence base so readily as we did with other AVHTM PICO questions. There is, however, more veterinary research in this area (unusually, with a bias towards feline studies). The guidelines suggest that major crossmatching should be performed prior to first feline red cell transfusion alongside AB typing (Davidow et al. 2021). Prospective studies have not shown a benefit in crossmatching, but they may be underpowered, and the guidelines suggest the most compelling reason for crossmatching is the knowledge of cats with pre-formed antibodies against non-AB antigens, most commonly FEA1 which is thought to be the same antigen as the previously described Mik (Binvel et al. 2021).

In dogs, it could be hypothesized that even naturally occurring alloantibodies that are of less importance and strength in transfusion-naïve dogs could gain further clinical significance, if enhanced in their expression after multiple incompatible transfusions. The immunogenicity of blood types other than DEA 1, the presence of naturally occurring antibodies against them, the type of antibodies they generate, and their potential clinical relevance even after first-time transfusion, remains largely unknown (Goy-Thollot et al. 2017, Goulet et al. 2018, Guidetti et al. 2019). Major crossmatching may not be necessary for transfusion-naïve dogs. Crossmatching is strongly recommended in any dog that has been previously transfused more than 4 days prior, independent of initial DEA 1 typing and crossmatching results. The use of the same compatible donor dog will not assure compatibility for a second transfusion even if the original testing was compatible. Better standardization of pre- and post-transfusion immunohematology testing, including crossmatching, is needed to understand blood type-mediated immunologic reactions (Davidow et al. 2021b).

Should We Pre-treat Prior to Transfusion?

There is a large veterinary retrospective study that found a decreased rate of allergic transfusion reactions in dogs administered pre-transfusion diphenhydramine (Bruce et al. 2015). Despite this, the AVHTM guidelines did not support pre-transfusion treatment with an antihistamine due to large prospective human studies which suggested the practice was not helpful, as well as possible adverse effects and cumulative costs associated with administration (Davidow et al. 2021b). This advice was consistent even when a patient had had a previous allergic reaction as this was found not to increase the risk of a further allergic reaction. When considering the use of paracetamol as a premedicant, again this was not recommended. These guidelines were fairly clear compared to other PICO questions considered.

Overall, the AVHTM TRACS project allowed a gathering of large amounts of data to provide guidance on a variety of pertinent clinical questions. They showed many areas where veterinary, and human, medical literature is lacking, which should hopefully spur researchers on to examine these areas more closely.

References

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18.  McClosky ME, Cimino Brown D, Weinstein NM, et al. Prevalence of naturally occurring non-AB blood type incompatibilities in cats and influence of crossmatch on transfusion outcomes. J Vet Intern Med. 2018;32(6):1934–1942.

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22.  Wang D, Cortés-Puch I, Sun J, et al. Transfusion of older stored blood worsens outcomes in canines depending on the presence and severity of pneumonia. Transfusion. 2014;54:1712–1724.

23.  Weinstein NM, Blais M-C, Harris K, et al. A newly recognized blood group in domestic shorthair cats: the Mik red cell antigen. J Vet Intern Med. 2007;21(2):287–292.