Transfusion reactions--how to diagnose, manage, and avoid them (Proceedings)

Since the early 1980s, the use of blood products in the treatment of critically ill companion animals and in supporting dogs and cats undergoing surgery and minimally-invasive diagnostic and therapeutic procedures has increased tremendously.  Blood components are, however, prepared from donor animals and consequently represent a limited resource.  This is despite the establishment of several commercial animal blood banks.  Moreover, blood components are biologic products that possess the inherent ability to cause transfusion reactions.  Fortunately, recent advances in modern blood banking techniques and transfusion medicine have markedly decreased the risks associated with transfusion therapy in companion animals.  Animal blood banks, veterinary clinicians, nurses and technicians play an essential role in ensuring the safety and efficacy of transfusion therapy, especially the recognition of transfusion reactions. 

Guidelines for the selection of healthy blood donors, the preparation and storage of the blood products, blood compatibility testing, and the monitoring of transfusions have been established, and are constantly being modified and improved as our understanding of transfusion medicine evolves. This presentation will discuss the various transfusion reactions that may be observed in companion animals, as illustrated by case examples, and will provide insights into how to recognize, manage and preferably avoid such reactions.

There are many different causes of transfusion reactions, although acute hemolytic transfusion reactions resulting from blood type incompatibilities and the transmission of infectious agents are feared the most (Table 1).  Transfusion reactions can be divided into two categories; 1. Infectious-disease complications and 2. Non-infectious serious hazards of transfusion (NISHOTs).  Any blood component has the potential to induce a transfusion reaction, but red cell products, which invariably contain other cellular components, are most likely to do so. 

There are over a dozen canine blood group systems and there persists controversy regarding the presence of clinically important naturally-occurring alloantibodies in dogs.  Acute hemolytic transfusion reactions in dogs, however, have only been documented in previously transfused patients. In these cases, the reactions were demonstrated to be associated with either DEA 1.1 incompatibilities, incompatibilities involving the common red cell antigens DEA 4 and dal, or incompatibilities involving several as yet undefined red cell surface antigens.  Sensitization becomes evident ≥4 days following a blood product transfusion. Pregnancy does not sensitize bitches, and bitches that have previously whelped can safely be used as blood donors without additional compatibility testing.  We recommend DEA 1.1 typing of any donor and recipient and crossmatching patients following transfusions. We match DEA 1.1 positive and negative donors albeit DEA 1.1 positive patients could safely get DEA 1.1 negative blood.  Simple typing cartridges and cards are available for in-clinic typing.

All donor and recipient cats should be blood typed for the A and B antigen and only receive matched transfusions. The rare type cat should be confirmed in a reference laboratory; if AB blood is not available type A packed red cells should be used. In cats older than three months, strong naturally-occurring anti-A alloantibodies exist in type B cats, and weak naturally-occurring anti-B alloantibodies exist in type A cats.  These alloantibodies can be responsible for serious acute hemolytic transfusion reactions.  In cats, however, there appear to be other clinically important blood types, such as the mik-antigen. Currently, these are best detected by crossmatching or extended typing by reference laboratories. 

Whilst many hemolytic transfusion reactions are the result of red cell alloimmune interactions, there are also other non-immunologic hemolytic transfusion reactions.  Outdated or damaged (frozen, contaminated) red cell products may be hemolyzed and should never be administered.  Interestingly, unlike humans, dogs and cats do not typically experience hemoglobin-induced nephropathies from intravascular hemolysis.  In humans, transfusion–related acute lung injury (TRALI) is currently considered the most common cause of transfusion-related mortality.  In humans TRALI has been associated with the administration of plasma products that test positive for HLA and other leukocyte antibodies, which it is suggested might arise during pregnancy.  The occurrence of TRALI in companion animals has been proposed, but remains unproven.  Fortunately, many transfusion reactions are self-limiting, but some can be life-threatening particularly in severely compromised patients.

Most blood transfusion reactions occur acutely, that is during or within hours of the blood product administration.  Delayed transfusion reactions may also be observed over days to weeks, as a result of the development of new alloantibodies or the transmission of infectious agents.   In some cases, it can be difficult to determine whether apparent reactions or complications are a result of the patient's primary disease process, the various therapeutic measures being instituted, or a genuine transfusion reaction.  In cases of a suspected transfusion reaction, any remaining blood product and fresh patient blood should be evaluated for compatibility and bacterial contamination (Gram stain, microbial culture, 16S rRNA PCR), as well as stored for any future analyses that may be indicated, and a transfusion reaction incident report compiled attempting to elucidate the underlying cause of the reaction. 

Ideally, a transfusion monitoring record should be completed during any transfusion, which includes recording specific unit and donor identification, pre- and post-transfusion hematocrit, and serially obtained parameters such as temperature, heart rate, respiratory rate, pulse pressure and demeanor, thus facilitating the early recognition of transfusion reactions.  Immediate cessation of the transfusion and supportive care are the only therapeutic measures for an acute transfusion reaction.  Antihistamines and glucocorticoids are often administered to dogs and cats when an acute transfusion reaction is suspected, but there is insufficient evidence to support their efficacy.  Limiting the risk of transfusion reactions, through the application of appropriate blood banking procedures and transfusion techniques, is therefore essential.

Most blood type incompatibilities and their associated transfusion reactions can now be readily avoided by DEA 1.1 or AB typing all canine or feline patients and donors. Crossmatching or extended typing is indicated under certain circumstances, particularly in patients receiving multiple transfusions (>4 days after the first transfusion).   As a result of the development of alloantibodies against blood types other than the ones routinely typed for, previously transfused animals must be crossmatched, even when transfused with blood from the same donor.  In-clinic blood-typing and cross-matching assays are now readily available and simple to perform. Confirmation of these test results and extended typing are also now widely available through reference laboratories.  The practice of testing patient and donor compatibility by administering one to a few milliliters of the donor's blood to the patient cannot be advocated as the transfusion of as little as 1 ml of incompatible blood to a patient has the potential to elicit a fatal transfusion reaction. 

Febrile reactions are the most commonly observed complications, but are generally mild and transient unless related to hemolysis or sepsis.  Febrile non-hemolytic transfusion reactions are likely induced by leukocyte and cytokines.  The utilization of leukocyte-depleted blood products, particularly when accomplished prior to storage, can reduce some of the hypersensitivity / allergenic and febrile reactions, but this filtration process adds considerable expenses.

Infectious disease transmission is now effectively limited by using only healthy donors and screening each donor routinely by antigen (PCR, blood smear) and serologic testing (titers).  Specific guidelines for infectious disease screening of blood donors were presented in the 2005 ACVIM consensus statement, but emerging infectious diseases and newer technologies have resulted in changing those guidelines.  To that end, comprehensive commercial blood donor infectious disease screening panels which are mostly PCR-based have recently been introduced that offer improved sensitivity and specificity.  Depending on the geographic location more or less extensive screening programs are warranted.  Some blood banks are now screening every blood unit as done in human medicine.

It is evident that careful blood donor selection, stringent infectious disease screening of donors, blood compatibility testing of all patients and donors, appropriate selection of the type of volume of blood product to be administered, and exceptional blood component processing and storage procedures, are essential measures in ensuring safe and efficacious transfusion medicine in our companion animals.  Whilst the administration of blood products will never be completely without risk, remarkable progress has been made over the last two decades and promising new approaches are on the horizon.

Table 1. Transfusion Reactions in Companion Animals

Non-infectious Complications Infectious Complications Immune-mediated hemolytic reactions: DEA 1.1, 4, dal, other incompatibilities; AB, mik, other incompatibilities Bacteremia and sepsis: Blood product or catheter related Non-immune red cell hemolysis: Freezing during storage, outdated blood; bacterial contamination Infectious disease transmission: Dogs-Babesia spp., Leishmania spp., Ehrlichia spp., Brucella canis, Anaplasma spp., Rickettsia rickettsii, Mycoplasma spp., Heptazoon spp., Dirofilaria immitis, Trypanosoma cruzi, Bartonella spp.; Cats-FeLV, FIV, FCoV, Mycoplasma spp., Bartonella spp., Cytozoon felis, Ehrlichia spp., Anaplasma phagocytophilum, Toxoplasma spp. Febrile non-hemolytic reactions (FNHTR, >1 C): Most common, self-limiting; hypothermia rare   Allergic reactions: Urticaria; anaphylaxis   Nausea and vomiting: Related to feeding during transfusion   Post-transfusion purpura   Transfusion-associated acute lung injury   Transfusion-associated circulatory overload: Cardiac & normovolemic patients   Metabolic disturbances: Hypocalcemia; hyperammonemia   Thromboemboli   Air embolism  

Acknowledgements

The author would like to thank the many transfusion fellows and blood bank nurses at the University of Pennsylvania for their contributions. Part of the author's studies were supported by NIH 02512 and supplies were provided by various companies related to blood banking and transfusion medicine.

Selected veterinary references

Alter HJ, Klein HG: The hazards of blood transfusion in historical perspective. Blood 11: 2617-2625, 2008.

Auer L, Bell K: The AB blood group system of cats. Anim Blood Groups Biochem Genet 12:  287-297, 1981.

Auer L, Bell K: Transfusion reactions in cats due to AB blood group incompatibility. Res Vet Sci 35: 145-152, 1983.

Blais M-C, Berman L, Oakley DA, Giger U. Canine dal blood type: a red cell antigen lacking in some Dalmatians. J Vet Internal Med 21: 281-286, 2007.

Callan MB, Jones LT, Giger U. Hemolytic transfusion reactions in a dog with an alloantibody to a common antigen. J Vet Internal Med. 9: 277-279, 1995.

Gary AT, Richmond HL, Tasker S, Hackett TB, Lappin MR. Survival of Mycoplasma haemofelis and ‘Candidatus Mycoplasma haemominutum' in blood of cats used for transfusions. J Fel Med Surg 8: 321-326, 2006.

Giger U, Bucheler J: Transfusion of type-A and type-B blood to cats. J Am Vet Med Assoc 198: 411-418, 1991.

Giger U, K Stieger, H Palos. Comparison of various canine blood-typing methods. Am J Vet Res. 66: 1386-1392, 2005.

Giger U, Gelens CJ, Callan MB: An acute hemolytic transfusion reaction caused by dog erythrocyte antigen 1.1 incompatibility in a previously sensitized dog. J Am Vet Med Assoc. 206: 1358-1362, 2005.

Giger U: Blood-typing and crossmatching. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Saunders Elsevier Press; 260-265, 2009.

Hackett TB, Jensen WA, Lehman TL, et al: Prevalence of DNA of Mycoplasma haemofelis, 'Candidatus Mycoplasma haemominutum', Anaplasma phagocytophilum, and species of Bartonella, Neorickettsia, and Ehrlichia in cats used as blood donors in the United States. J Am Vet Med Assoc 229: 700-705, 2006.

Harrel KA, Kristensen AT: Canine transfusion reactions and their management. The Veterinary Clinics of North America Small Animal Practice: Canine and Feline Transfusion Medicine 25: 1333-1364, 1995.

Hohenhaus AE, Drusin LM, Garvey MS: Serratia marcescens contamination of feline whole blood in a hospital blood bank. J Am Vet Med Assoc 210: 794-798, 1997.

Hohenhaus AE. Importance of blood groups and blood group antibodies in companion animals. Transfus Med Rev. 18 (2): 117-126, 2004.

Kessler RJ, Rankin S, Young S, O'Shea K, Calabrese M, Guldin A, Lipson N, Oakley DA, Giger U: Pseudomonas fluorescens contamination of a feline packed red blood cell unit and studies of canine units. Vet Clin Pathol. 39: 29-38, 2010.

Kessler RJ, Reese J, Cheng D, Seth M, Hale AS, Giger U: DEA 1.1, 1.2, 3, 4, and 7, and Dal blood typing and crossmatching by gel column technique. Vet Clin Path. 39:306-16, 2010.

Klaser DA, Reine NJ, Hohenhaus AE: Red blood cell transfusions in cats: 126 cases (1999). J Am Vet Med Assoc 226: 920-923, 2005.

Melzer KJ, Wardrop KJ, Hale AS, et al: A hemolytic transfusion reaction due to DEA 4 alloantibodies in a dog. J Vet Internal Med 17: 931-933, 2003.

Owens SD, Oakley DA, Marryott K, Giger U: Transmission of visceral Leishmaniasis through blood transfusions from infected English Foxhounds to anemic dogs. J Am Vet Med Assoc 219: 1076-1083, 2001.

Patterson J, Rousseau A, Kessler RJ, Giger U: In Vitro lysis and acute transfusion reactions with hemolysis caused by inappropriate storage of canine red blood cell products. J Vet Intern Med, in press, 2011.

Stageman JR, Birkenheuer AH, Kruger JM, Breitschwerdt EB: Transfusion-associated Babesia gibsoni infection in a dog. J Am Vet Med Assoc 222: 959-963, 2003.

Seth M, Jackson KV, Giger U: Comparison of 5 blood typing methods for the feline AB blood group system. Am J Vet Res. 72:203-9, 2011.

Seth M, Jackson K,V, Winzelberg S, Giger U: Comparison of Gel Column, Card and Cartridge Techniques 1 for Dog Erythrocyte Antigen. Am J Vet Res, in press 2011.

Tocci LJ, Ewing PJ: Increasing patient safety in veterinary transfusion medicine: an overview of pretransfusion testing. J Vet Emerg Crit Care 19: 66-73, 2009.

Wardrop KJ, Reine N, Birkenheuer A, et al: Canine and feline blood donor screening for infectious disease. J Vet Intern Med 19: 135-142, 2005.