The use of blood transfusions in veterinary practice has increased dramatically in recent years. Providing safe and effective transfusion therapy is essential. There are many definitions for the term transfusion reaction (TR), but the following is simple and clear: “any adverse event following a blood transfusion, attributed to the transfusion.” The risk of a TR is present whenever a blood product is administered. These adverse effects can occur despite appropriate prescreening of donors, blood collection techniques, and pre-transfusion compatibility testing. Transfusion reactions can be categorized into acute or delayed immunologic and non-immunologic reactions. Immunologic reactions occur secondary to components within the blood product, including red blood cells (RBC), white blood cells (WBC), platelets (PLT), and plasma proteins.^1,15

Non-infectious aetiologies far exceed infectious causes due to the high level of adherence to donor prescreening standards as recently outlined in the American College of Veterinary Internal Medicine consensus statement on canine and feline blood donor screening for infectious diseases.²³ The non-infectious aetiologies can be subdivided into those that cause acute reaction (febrile non-haemolytic reactions [FNHR], transfusion associated circulatory overload [TACO], haemolysis of incompatible red blood cells/plasma, transfusion-related acute lung injury [TRALI], allergic reactions, sepsis, and metabolic and coagulation abnormalities) vs. those that are delayed (immune-mediated haemolysis, iron overload from long-term transfusions, and TRIM being most common). FNHR and TACO are the most common TR in dogs and cats.³ Acute haemolytic transfusion reactions is the most serious and life-threatening. FNHR and allergic complications are the most immediate reactions. Acute complications can occur during or within hours of the transfusion whereas the delayed reactions are typically noted days to months following transfusion.^1,12,13

The reported frequency of canine and feline TR varies depending on the product administered and the study performed with values from 1–26% reported in dogs and cats.^{1,3,10,12,14,15} This very wide range reflects the difficulty in determining whether a TR has occurred when performing a retrospective study and the lack of standardization in determining canine and feline TRs. Much of the veterinary literature in this area focuses more on the clinical findings that led to a diagnosis of a TR (vomiting, dyspnoea), rather than which type of TR was seen. The clinical signs seen are often non-specific to the underlying cause. This lecture aims to describe how to effectively manage transfusion reactions to ensure patient recovery.

Table 1. Classification of transfusion reactions^1,12

Febrile Non-Haemolytic Reactions (FNHR), Transfusion Acute Cardiocirculatory Overload (TACO), Transfusion-Related Acute Lung Injury (TRALI)

1. Febrile Non-Haemolytic Reactions (FNHR)

Definition: These reactions are defined as a temperature rise of 1°C or greater associated with the transfusion.¹ FNHR are one of the most common TR seen in human transfusion recipients. A large veterinary retrospective study noted fever in 9% of transfusion recipients.³

Cause: FNHR are caused by pro-inflammatory pyrogenic cytokines. These are either produced in the blood product during storage or by the recipient in response to infused antigen (generally leucocyte associated) due to prior sensitization.

Clinical signs: It is usually self-limiting and of little clinical significance. However, although not medically dangerous, it can cause patient discomfort.

Diagnosis: Fever can be the first sign of more serious complications such as sepsis, bacterial contamination of the blood unit, or an acute haemolytic transfusion reaction. Therefore, any rise in temperature requires immediate investigation. Diagnosis of a FNHR is a diagnosis of exclusion.

Treatment: Aims at slowing or temporarily stopping the transfusion. Active cooling is recommended when temperature >40°C and discontinue once <39.5°C to avoid hypothermia. Administration of a non-steroidal anti-inflammatory medication can be considered and is recommended for temperature over 41.5°C. Antipyretics (e.g., dipyrone), can also be used.

Prevention: There is evidence that leukodepletion decreases the likelihood of these reactions.¹⁷

2. Acute Haemolytic Transfusion Reaction (AHTR)

Definition: AHTR are caused by antibody-mediated destruction of RBC, either recipient mediated destruction of donor cells or antibodies in the donor product leading to recipient red cell destruction. The recipient is more at risk and AHTR are commonly associated with an incompatible donor. The recipient can have pre-formed circulating naturally occurring antibodies (cats^{2,5,9,11,16,21,24}) or acquired antibodies that react against the donor’s transfused RBC (mainly dogs^2,5,8,11).

Cause: Complement activation, release of inflammatory cytokines, histamines, bradykinin, and vasoactive amines occur resulting in a systemic inflammatory response in the recipient. This reaction is mostly IgG mediated in the dog and IgM mediated in the cat. Intravascular haemolysis of the red blood cells leads to haemoglobinuria, haemoglobinemia, acute renal failure, disseminated intravascular coagulation, circulatory collapse, vasoconstriction, and death.^4,6,7,18 The amount of RBC destruction determines the severity of the patient’s response.¹⁶ Depending on the antibody titre in the recipient these can be fatal. In dogs, it is generally thought that pre-formed antibodies against differing canine blood antigens are not present and so the risk of an AHTR on first transfusion administration is negligible.⁸

Diagnosis: Clinical signs and evidence of haemolysis.

Clinical signs: They can include pyrexia, shaking, hypotension, wheezing, nausea, vomiting, pain, restlessness, salivation, incontinence, and shock.

Treatment: Is supportive with appropriate fluid therapy and pressors to maintain cardiovascular stability and renal perfusion (due to the risk of haemoglobinaemia induced acute kidney injury). Fluid resuscitation aims to maintain mean arterial blood pressure >70–80 mm Hg. Efficacy of glucocorticoids is unproved.

Prevention: For a first transfusion: blood typing (dogs and cats), cross-matching (cats). Further transfusion (>4 days after a previous transfusion): blood typing (dogs and cats), cross-matching (dogs and cats).¹

3. Allergic Reactions (Type I Hypersensitivity)

Definition: Allergic reactions result from a response to allergens in the donor blood, including RBC, platelets, granulocytes, and plasma proteins (often complement immunoglobulins). Allergic reactions are reported to occur in about 1% of canine and feline transfusions³ and are again common in humans.

Causes: Allergic reactions are caused by a type 1 (IgE mediated) hypersensitivity reaction to plasma proteins.²⁰

Clinical signs: Minor reactions are often cutaneous and include pruritus, urticarial lesions (hives), erythema, and angioedema. They can progress to involve more systemic responses. Clinical signs of these major reactions can include dyspnoea, stridor from laryngeal oedema, wheezing, tachycardia, nausea, vomiting, and diarrhoea. Gastrointestinal signs are often noted.

Diagnosis: Clinical signs

Treatment: For minor reactions treatment includes temporarily stopping the transfusion and administering an antihistamine. Anti-inflammatory steroids should be considered for more severe reactions with the transfusion discontinued during treatment. Epinephrine should be considered for patients with dyspnoea or those experiencing anaphylaxis.

Prevention: In human and veterinary hospitals, clinicians have used antihistamines as a pre-transfusion treatment to decrease the likelihood of allergic transfusion reaction. The veterinary study by Bruce et al. (2015) found an association between pre-transfusion administration of diphenhydramine and decreased allergic transfusion reactions.³

4. Transfusion-Associated Circulatory Overload (TACO)

Definition: TACO occurs when the transfusion volume or rate exceeds cardiovascular compensation.

Causes: Risk factors include compromised cardiovascular function, a volume overload state (concurrent renal failure, congestive heart failure), high volume fluid infusion, transfusion over a short period, old/young patients, and patients with severe, compensated chronic anaemia.^1,12

Clinical signs: Include tachypnoea, dyspnoea, dry cough, orthopnea, cyanosis, murmur or gallop rhythm, weight gain, serous nasal discharge, development of pulmonary oedema, or pleural effusion. Patients can have distended neck veins.

Diagnosis: Clinical signs. This syndrome clinically appears like TRALI but improves with diuresis. Treatment: is with diuretics (generally furosemide) and oxygen therapy.

Prevention: If the patient is at risk, treatment involves slowing the transfusion or discontinuing it if overloaded, dividing the transfusion into smaller aliquots, increasing the transfusion time, administration of diuretics, and oxygen support.¹

5. Transfusion-Related Acute Lung Injury (TRALI)

Definition: TRALI is characterized by its acute onset, severe hypoxaemia, bilateral infiltrates on chest radiographs, and no evidence of left atrial hypertension (absent findings of circulatory overload). TRALI is an uncommon condition in dogs. A prospective veterinary study found that 2/54 cases enrolled had acute onset hypoxaemia and bilateral radiographic infiltrates.²² Bruce et al. (2015) reported dyspnoea in 1% of their transfusions (TACO, TRALI, or other pathology).³ Frequency of TRALI is still unknown in dogs and cats.

Cause: TRALI is caused by activated neutrophils damaging pulmonary endothelial cells leading to an inflammatory alveolar infiltrate. It is recognized by bilateral radiographic pulmonary infiltrates and a PaO₂/FiO₂≤300 which is not caused by fluid overload or cardiac failure.²²

Clinical signs: Clinical signs associated with TRALI include severe dyspnoea, tachypnoea, hypoxaemia, fever, hypotension, cyanosis, diffuse crackles, decreased breath sounds, and tachycardia, with no evidence of circulatory overload. The onset of dyspnoea is usually during or within 6 hours of a transfusion.

Diagnosis: Clinical signs. It is similar to TACO in appearance but does not respond to diuretic therapy.

Treatment: Treatment is mainly supportive and involves discontinuing the transfusion, supplemental oxygen, intravenous fluids, and possibly mechanical ventilation.²²

Prevention: In humans, TRALI may relate to use of plasma from female donors with a history of previous pregnancy. Since canine donors with this history are uncommon, TRALI may not be a major transfusion concern in our recipients. Careful monitoring and slow rates of transfusion in patients with pulmonary disease.^1,22

6. Delayed Haemolytic Transfusion Reaction (DHTR)

Definition: A haemolytic reaction is classified as delayed if it occurs between 1- and 28-days post-transfusion.¹

Cause: It is caused by the formation of red blood cell antibodies shortly after transfusion and leads to red cell haemolysis. Antibody formation can also occur to platelets, granulocytes, and plasma proteins. Formation depends on the underlying illness, genetic predisposition, immune status, degree and duration of antigen exposure, degree of antigen disparity with the blood donor, and transfusion to an already sensitized patient. It generally leads to extravascular haemolysis. The question about recognized canine/feline RBC antigens causing delayed haemolytic TR is still pending.

Clinical signs: Clinical signs often seen are fever and jaundice. Patient haematocrit decreases.

Diagnosis: These reactions may not even be recognized in some cases.

Treatment: Do not need any specific treatment.

Prevention: Prevention involves administering DEA 1 negative blood to DEA 1 negative recipients and cross matching any patients which have had a previous transfusion. Crossmatch compatibility testing may not detect these antibodies if they are present in low volume. Patients should be observed for post-transfusion anaemia and reactions and monitored for decreasing benefit with subsequent transfusions. Unnecessary transfusions should be avoided and when transfusing, attempt to minimize blood group antigen incompatibility to prevent sensitizing patients to future transfusions.^1,12

7. Non-Immune-Mediated Haemolysis

This reaction usually results from a physical destruction of the cells in vitro. Temperature damage and cell destruction can occur from freezing or overheating through use of microwave ovens, hot water baths, or malfunctioning blood warmers. Mishandling during collection and processing and improper storage can lead to cell lysis. Additionally, mechanical damage from pressure bags or small-bore needles, or osmotic damage through concurrent drug or non-isotonic solution administration with the blood product can cause cell damage. To avoid this problem, hospital protocols should be developed and strictly enforced for collection, processing, storage, administration, and patient monitoring during transfusions.¹

8. Metabolic and Coagulation Abnormalities¹

Metabolic abnormalities often result from biochemical changes in the blood product during storage and also from constituents of the product’s preservative, anticoagulant, and additive solutions. Hyperkalaemia can occur from potassium accumulation during storage as part of the RBC storage lesion and hypo- or hyperglycaemia can be present as well.

Coagulopathies develop from dilution of the patient’s blood with platelet and coagulation factor-poor RBCs. This is often a result of massive transfusion, resulting in a complex coagulopathy characterized by hypothermia, shock, tissue anoxia and damage, and disseminated intravascular coagulation. Hypothermia can result from administration of chilled blood products rapidly and can impair platelet function and prolong the prothrombin time and activated partial thromboplastin time. Signs of hypothermia include chills, decreased body temperature, irregular heart rate from ventricular arrhythmias, and possibly cardiac arrest. Treatment includes warming the blood and the patient and possibly stopping or slowing the transfusion, depending on the severity of clinical signs.

9. Citrate toxicity¹

This is also a manifestation of massive transfusion of fresh frozen plasma, whole blood, or platelets. Citrate is a common additive in blood components and when these levels rise in the recipient, it binds ionized calcium causing clinical signs of hypocalcaemia. Hypocalcaemia can result in prolongation of the QT interval, decreased left ventricular function, hypotension, hypomagnesaemia, and cardiac arrhythmias. Clinical signs can include tetany, muscular cramps, hyperactive reflexes, seizure activity, laryngeal spasms, and respiratory arrest. Treatment involves slow infusion of the blood product, discontinuation if tetany occurs, and calcium supplementation.

References

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2.  Bovens C, Gruffydd-Jones T. Xenotransfusion with canine blood in the feline species: review of the literature. J Feline Med Surg. 2013;15:62–67.

3.  Bruce JA, Kriese-Anderson L, Bruce AM, Pittman JR. Effect of premedication and other factors on the occurrence of acute transfusion reactions in dogs. J Vet Emerg Crit Care. 2015;25(5):620–630. doi:10.1111/vec.12327.

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

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7.  Giger U, Gelens CJ, Callan MB, et al. An acute hemolytic transfusion reaction caused by dog erythrocyte antigen 1.1 incompatibility in a previously sensitized dog. J Am Vet Med Assoc. 1995;206:1358–1362.

8.  Goy-Thollot I, Giger U, Boisvineau C, Perrin R, Guidetti M, Chaprier B, et al. Pre- and post-transfusion alloimmunization in dogs characterized by 2 antiglobulin-enhanced cross-match tests. J Vet Intern Med. 2017;31(5):1420–1429. DOI:10.1111/jvim.14801.

9.  Goy-Thollot I, Nectoux A, Guidetti M, et al. Detection of naturally occurring alloantibody by an in-clinic antiglobulin-enhanced and standard crossmatch gel column test in non-transfused domestic shorthair cats. J Vet Intern Med. 2019;33(2):588–595.

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16.  McClosky ME, Brown DC, Weinstein NM, Chappini N, Taney MT, Marryott K, 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;32:1934–1942.

17.  McMichael MA, Smith SA, Galligan A, et al. Effect of leukoreduction on transfusion-induced inflammation in dogs. J Vet Intern Med. 2010;24:1131–1137.

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19.  Prittie JE. Controversies related to red blood cell transfusion in critically ill patients. J Vet Emerg Crit Care. 2010;20(2):167–176.

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