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Acute Hemolytic Transfusion Reactions

Acute hemolytic transfusion reactions (AHTRs) occur in 1:76 000 RBC transfusions (Eder and Chambers, 2007). Fatal AHTRs occur in 1:1 800 000 transfusions (Vamvakas and Blajchman, 2009). Typically AHTRs are hemolytic reactions that occur within 24 h of transfusion and lead to intravascular (rarely extravascular) hemolysis secondary to ABO incompatibility, but may result from other blood group incompatibilities. In contrast, DHTRs typically result in extravascular hemolysis.

Intravascular hemolysis is caused by RBC antigen interaction with preformed antibodies. Most often these are ABO (IgM) antibodies; however, sufficient concentrations of preformed IgG can also play a role. Other blood group incompatibilities can result in AHTR, such as antibodies to Kidd or Duffy blood group system antigens. Finally, incompatible plasma may be transfused to a patient and result in an AHTR. Most frequently, this occurs secondary to ABO incompatible platelet transfusion. The degree of hemolysis depends on the amount and strength (titer) of the ABO antibody.

After the initial antigen–antibody interaction, complement activation occurs, leading to formation of the membrane attack complex and eventual destruction of the RBC with the release of its components into the blood stream. Initially, hemoglobin is bound by haptoglobin and metabolized. When haptoglobin stores are exhausted, the hemoglobin and other constituents, such as RBC stroma, may travel to the kidney, leading to tissue damage due to toxicity. In addition, the RBC constituents can activate the coagulation cascade and lead to systemic vasoconstriction and shock (Bellone and Hillyer, 2013).

AHTRs are characterized by fever, back or flank pain, chest pain, hypotension, shock, and ‘impending sense of doom’ in the patient. These findings often occur soon after the start of the transfusion. The transfusion should be stopped immediately; treatment includes vigorous hydration, furosemide (to maintain urine output), as well as support of blood pressure, disseminated intravascular coagulation, and other clinical sequelae (Ludens et al., 1968).

A transfusion reaction workup should be initiated quickly to identify the cause of the reaction. Blood bank testing may reveal hemolysis, incompatibility between the donor and recipient, and positive DAT. Other laboratory analysis that may be helpful includes testing of bilirubin and LDH levels, and urinalysis (to identify free hemoglobin in the urine).

Human error is the most common cause of AHTRs due to ABO incompatibility. The error could be made in many places: during the initial blood draw, issuing of the blood product, and transfusing product to the wrong patient. When an AHTR occurs, a root cause analysis is imperative (and mandated by The Joint Commission) to initiate corrective action and prevent such occurrences in the future (Bellone and Hillyer, 2013). Efforts to further decrease the human error component include computerized matching of patient armband barcodes to blood product barcodes. Prevention mandates elimination of the possibility of human error. In contrast, due to low platelet inventories and short shelf-life of platelets, ABO incompatible platelet transfusions occur not uncommonly. AHTRs secondary to platelet transfusions are mitigated by transfusing low titer platelets or ABO compatible platelets.

Side Effects

Acute hemolytic transfusion reactions are usually caused by ABO incompatibility. This potentially fatal complication occurs in about 1 in 30,000 transfusions. As little as 20 to 30 mL of incompatible RBCs can cause agitation, nausea and vomiting, dyspnea, fever, flushing, hypotension, tachycardia, and hemoglobinuria. Two major complications of intravascular hemolysis include renal failure from acute tubular necrosis and disseminated intravascular coagulation (DIC).

Febrile nonhemolytic transfusion reaction is relatively common (0.1%-1% of RBC transfusions). Other immunologic complications of transfusion include HLA alloimmunization, graft-versus-host disease, and immunosuppression triggered by donor leukocytes.⁹ The risk of these complications can be partially reduced by use of leukocyte adsorption (leukoreduction) filters at blood collection, and γ-irradiation after collection to prevent lymphocyte proliferation. The leukoreduction process presumably reduces virologic risks associated with leukocytes including cytomegalovirus, Epstein-Barr virus, and human T-cell leukemia virus I and II. Although transfusion-related variant Creutzfeldt-Jakob diseases (vCJD and bovine spongiform encephalopathy) are rare, there is a theoretical advantage in leukodepletion to prevent prion transmission.¹⁰

Acute Hemolytic Transfusion Reactions

Acute Hemolytic Transfusion Reaction

Acute hemolytic transfusion reaction (AHTR) is a potentially fatal transfusion reaction and can be either due to immune or nonimmune mechanisms. Immune mediated acute hemolytic transfusion reactions are typically due to infusion of red blood cells (RBCs) which are hemolyzed by the recipients anti-A, anti-B, or other antibodies. Acute hemolytic transfusion reaction may be precipitated by as little as 5 mL of incompatible RBCs. Transfusion with significant amount of incompatible plasma is another example of such mistransfusion. Rarely, acute immune mediated hemolytic transfusion reaction may be due to transfusion of incompatible plasma, usually from an apheresis platelet transfusion. Nonimmune mediated acute hemolytic reactions may be due to coadministration of RBCs with an incompatible crystalloid solution (e.g., 5% dextrose), incorrectly stored blood or use of malfunctioning or nonvalidated administration system [2,3].

Approximately 70% of such errors are preanalytical errors which occur outside the blood bank.

Investigation of suspected transfusion reaction

Serious or life-threatening acute reactions are very rare. Acute haemolytic transfusion reactions are most commonly a consequence of errors in taking or labelling the sample, collecting wrong blood from the blood bank, inadequate checking of the product at the bedside or laboratory errors. Symptoms, such as the patient having a feeling of impending doom, agitation, flushing or pain at the venepuncture site or in the abdomen, flank or chest can occur after transfusion of only a few drops of blood. Clinical signs include fever and hypotension; generalized oozing from wounds or puncture sites can occur and there may be haemoglobinaemia or haemoglobinuria. Life-threatening transfusion reactions can also occur with platelet and FFP transfusions, for example owing to bacterial contamination or transfusion-related acute lung injury.

Following a suspected transfusion reaction, urgent blood tests (full blood count, assessment of kidney and liver function), along with assessment of the urine for haemoglobinuria, should be undertaken. The donor units and giving set should be returned to the laboratory, along with a fresh blood sample. The blood sample and donor units along with the original ‘group and save’ sample are then tested retrospectively for compatibility. At this point, it is also important to confirm the blood group of any units transfused and send the giving set and donor packs for culturing. Blood cultures should be taken if the patient has a persistent fever, and a coagulation screen performed to exclude developing DIC if the reaction is severe.

Administration of blood and plasma

The person administering the blood should pay careful attention to the blood bag label before transfusion. The most common reason for an acute hemolytic transfusion reaction in human patients is clerical error—the wrong unit of blood is released from the blood bank or a unit of blood is given to a patient who was not intended to receive a transfusion.¹¹⁰ In veterinary medicine, it is crucial to confirm that the blood comes from the correct species of blood donor in addition to being typed and matched to the patient requiring a transfusion. The contents of the bag also should be examined for normal color and consistency. Bacterially contaminated blood often appears brown or purple because of deoxygenation, hemolysis, and formation of methemoglobin.^55,65

Blood and plasma can be administered using several routes. Most commonly, blood is given intravenously. The diameter of the catheter used for transfusion is important in determining the rate of blood flow because blood flows more slowly through a small catheter; however, small diameter catheters have not been associated with increased risk of hemolysis during transfusion.¹¹⁸

The intraosseous route can be used successfully for administration of blood and plasma.⁸⁸ In normal dogs, 93% to 98% of red blood cells administered through an intraosseous catheter are found in the peripheral circulation within 5 minutes.²⁴ This rapid and simple method is especially useful in animals with vascular collapse and in extremely young puppies and kittens. Special intraosseous catheters are available, but a spinal needle, bone marrow aspiration needle, over-the-needle catheter, or even an ordinary hypodermic needle can be used. Sites for the placement of the intraosseous catheter include the trochanteric fossa of the femur, the medial tibia, and the iliac crest. Blood flows very rapidly through an intraosseous catheter, and rate of administration should be monitored closely. Plasma can be administered intraperitoneally in emergency situations, but red blood cells are slowly and poorly absorbed when administered by this route, and it is not recommended for red blood cell transfusions.

A blood transfusion administration set is required for administration of red blood cells or plasma to remove blood clots and debris, which form during storage and which could cause embolism. The filter typically used in veterinary medicine is 170 μm in size. For small-volume transfusions, an 18-μm filter attached to intravenous tubing is useful. An 18-μm filter does not work well for large-volume transfusions because it rapidly becomes obstructed with debris, and transfusion rate slows. The risk of an air embolism is increased when blood is collected into glass bottles. A blood administration set does not remove air from stored blood; accordingly, glass bottles are not recommended for collection and storage of blood.

The American Association of Blood Banks explicitly states that medications should not be added to blood or components.¹¹⁸ In addition, no fluid should be added to blood excep. 0.9% sodium chloride when it is necessary to decrease the viscosity of PRBCs. Fluids containing calcium such as lactated Ringer’s solution may overcome the anticoagulant properties of citrate, resulting in coagulation of the blood. Solutions such as 5% dextrose in water are hypotonic and may induce hemolysis.

The recommended rate of transfusion of red blood cells depends on the status of the recipient. In massive hemorrhage, the transfusion should be given as rapidly as possible. In a normovolemic, stable transfusion recipient, some clinicians recommend a rate of 0.25 mL/kg for the first 30 minutes, after which the rate is increased if no reaction is seen.¹¹² In patients with heart disease, a rate of 4 mL/kg/hr should not be exceeded.⁴⁵ Transfusion rates of 10 mL/kg/hr, 4 mL/kg/hr, and up to 60 mL/kg/hr were used to transfuse red blood cells to cats with normovolemia, cardiovascular dysfunction. and hypovolemic shock, respectively.¹²⁶ Plasma can be given more rapidly (4 to 6 mL/min).⁶⁷ Whatever the rate chosen, it should be rapid enough to complete the transfusion within 4 hours of initiation because of the risk of bacterial growth in blood maintained at room temperature for a prolonged period.

Control of blood product delivery rate can be accomplished by use of infusion pumps to deliver a preset volume over a specific period of time. The use of infusion pumps must be limited to devices approved for use with blood because some infusion pumps can result in hemolysis of red blood cells as a result of excessive pressure.¹⁰⁷

Because blood does not contain any antibacterial agents, it must be refrigerated until used to retard bacterial growth and maintain red blood cell viability. If the clinical status of the animal requires that the transfusion be given over a period greater than 4 hours, the blood can be split into smaller units with a transfer bag. One portion of the blood is transfused while the other is returned to the refrigerator until the first half of the transfusion is completed. In patients with cardiac disease at risk for volume overload, the risk can be further minimized by use of PRBCs, which require infusion of a lower volume than whole blood.

Warming of blood before transfusion has been recommended to prevent hypothermia in the transfusion recipient. Warming of blood probably is only necessary if a large volume of blood is to be given or if the recipient is a neonate. For adult animals receiving a single unit of blood, the blood can be administered directly from the refrigerator. Warming blood has the potential for excessive heating, causing red blood cell membrane damage and hemolysis or promoting bacterial growth if contamination is present. Blood warming devices that use dry heat, radio waves, microwaves, or electromagnetic energy are available, but cost often is prohibitive. Refrigerated human blood can be warmed quickly by admixing it with warm (45° C to 60° C) 0.9% saline in a ratio of 1:1 without damage to red blood cells.⁶¹ This method has not been tested for dogs or cats. Once blood is warmed to 37° C, it deteriorates rapidly and, if not used, should be discarded. Fresh frozen plasma must be thawed before transfusion. A method for thawing canine fresh frozen plasma in a microwave oven has been described, but the author has found this unsatisfactory because of uneven heating by household microwave ovens.⁶⁰ Plasma can be thawed at room temperature, and if the thawing time needs to be shortened, the plasma can be placed into a plastic bag and thawed in a 37° C water bath. The plastic bag is necessary to prevent contamination of the infusion ports in the water bath. If thawed and not used within 1 hour, it maybe refrozen with out loss of anticoagulant activity.¹³¹ Plasma should be used within 4 hours of thawing or discarded.

Transfusion recipients should be monitored during transfusion to allow early detection of a transfusion reaction. Rectal temperature, heart rate, and respiratory rate should be recorded every 10 minutes during the first 30 minutes and then every 30 minutes thereafter. The patient should be monitored for vomiting, diarrhea, urticaria, and hemoglobinuria or hemoglobinemia. Changes in vital signs or clinical status may indicate a transfusion reaction. Patients developing volume overload will become tachypneic or dyspneic, and tachycardic.

Massive transfusions (1 blood volume in 24 hours) have been reported in both dogs and cats.^16,62,97 Patients receiving massive transfusions of stored blood may develop specific abnormalities. Consequently, patients receiving massive transfusions should be monitored for changes in serum potassium, ionized calcium, and ionized magnesium concentrations, as well as hypothermia and coagulation abnormalities.^16,62,97

Exchange transfusion

Favorable results of exchange transfusion in a variety of diseases in adults, for example sickle cell disease, severe clotting disorders, hepatic failure, and acute hemolytic transfusion reactions, have been published [1]. Today, however, machine apheresis procedures are more effective and safer for patients requiring exchange of cellular elements or plasma. Exchange transfusion is the most effective therapeutic procedure in the treatment of hemolytic disease of the newborn. Bilirubin removal prevents damage to the central nervous system caused by hyperbilirubinemia. In addition, sensitized erythrocytes are replaced by normally surviving cells and anemia is corrected.

The risks of exchange transfusion are essentially the same as those described above for massive transfusions, and their magnitude depends on the health of the newborn infant and its gestational age and weight. The transfused blood should be as fresh as possible and should not have been stored for more than 4–5 days. It must be free from antigens that react with antibodies in the maternal plasma. Technical errors involving perforation of the umbilical vein, wrong placement of the cannula, or air embolism are fortunately only rare complications.

Severe Transfusion Reactions in Felines

A severe transfusion reaction in felines may present as tachypnea, collapse, tachycardia or bradycardia, hypotension, fever, or hypothermia and most likely is due to an acute hemolytic transfusion reaction. These are most commonly seen with type B cats (having strong anti-A antibodies) inadvertently getting type A blood. Epinephrine (0.01 mg/kg IV) or albuterol (albuterol inhaler attached to an Aerokat chamber and given as 2 actuations) should be given and the cat immediately provided with supplemental oxygen. The albuterol or epinephrine can be repeated if there is no improvement within 10 minutes. Because of the rapid, severe hemolysis that often accompanies these reactions, isotonic crystalloid fluids should be started immediately after the cat is stable, or sooner if necessary to aid resuscitation. In an acute hemolytic crisis, there is often no volume loss and fluid therapy should be used judiciously to prevent volume overload. Repeat baseline parameter monitoring should be done every 5 minutes until the cat is stable. In addition to checking the bag and recipient for hemolysis, a baseline chemistry panel and urinalysis should be assessed for renal function along with a CBC if there is not one from just before the transfusion (to assess for trends suggestive of sepsis). Renal function may decline because of hemolysis and should be monitored closely for several days.

Transfusion Reactions

Alloantigens vary in their potential to cause hemolytic transfusion reactions when mismatched blood is given. Many alloantigens are weak (do not induce antibodies of high titer) or induce antibodies that do not act at normal body temperature. Fortunately only a few alloantigens appear to be important in producing hemolytic disease in animals.

DEA 1.1 antibody-antigen interactions result in most of the acute hemolytic transfusion reactions in dogs,¹ but transfusion reactions have been reported against DEA 1.2,⁶⁵ DEA 4,¹⁰³ and an unclassified common antigen²³ on dog erythrocytes. A blood type termed Dal has been reported to be lacking in some Dalmatian dogs but is present in a high percentage of dogs other than Dalmatians. Dalmatians lacking the Dal antigen are likely at risk of delayed, and possibly acute hemolytic transfusion reactions if transfused with Dal antigen-positive blood.¹⁵⁰

Incompatibilities in the AB blood group of cats has been recognized to cause transfusion reactions.^55,56,76 The A and B alloantigens (blood types) result from the expression of two different alleles at the same gene locus, with A being dominant over B.¹ Cats rarely express both type A and type B antigens (type AB) on erythrocytes. The frequency of blood types varies with location and breed of cat. From 0.3% (Northeast) to 4.7% (West Coast) of domestic short- and long-hair cats in the United States are type B, but up to 50% of purebred cats of certain breeds in the United States are type B.¹ A blood group antigen termed Mik has been reported in domestic shorthair cats that is capable of inducing a hemolytic transfusion reaction when Mik-positive RBCs are transfused into a Mik-negative recipient cat that has naturally occurring anti-Mik alloantibodies in its plasma.¹⁵⁰

Aa and Qa are the most immunogenic alloantigens in horses and presumably the most likely to cause a hemolytic transfusion reaction.¹³³ A-negative pigs exhibit intravascular hemolysis when transfused with A-positive blood.¹¹⁰

For most blood groups in animals, antibody formation occurs only following prior exposure to different erythrocyte alloantigens via transfusion, pregnancy, or vaccination with products containing blood group antigens.⁷¹ Consequently adverse transfusion reactions to unmatched erythrocytes generally do not occur at the time of the first blood transfusion. However, the AB and Mik groups in cats and the A group in pigs are characterized by “naturally occurring” antibodies (i.e., antibodies that occur in plasma in the absence of prior exposure to blood from another individual).¹⁴⁰ In these cases, hemolytic transfusion reactions can occur at the time of the first blood transfusion. This is especially true in the case of B-positive cats, which have naturally occurring anti-A antibodies of high hemolytic titer. In contrast, cats with type A blood have weak anti-B antibodies in their blood. Type B blood transfusions given to type A cats do not result in severe intravascular hemolysis, but the transfusion is not efficacious because the transfused erythrocytes are phagocytized and removed within a few days.¹⁹

Platelets

Observational studies The role of ABO compatibility in platelet transfusion was recently reviewed [24^R]. When ABO-identical platelets are not available, then the physician is stuck choosing between an ABO major and minor mismatch. With a major mismatch, the risk is decreased efficacy of the transfusion. Whereas, a minor mismatch potentially risks an acute haemolytic transfusion reaction.

For 4 years, one institution made the policy of transfusing ABO identical whenever possible, regardless of inventory considerations [25^c]. When ABO-identical platelets were not available, minor mismatch units were chosen and washed prior to transfusion. The group looked at 4 years before and after this policy change. The incidence of febrile transfusion reactions decreased from 8 to 4.3 per 10,000 components. Likewise, the incidence of allergic transfusion reactions decreased from 7 to 5.4 per 10,000 components. There was also a progressive reduction in the number of red cell antibodies identified per screen with institution of the new policy. The authors mention a nonsignificant decrease in the number of HLA-matched platelets requested.

Respiratory Neutrophil extracellular traps (NET), are a novel type of cell death in which long filaments are released for microbial capture. A group used in vitro mouse TRALI models to demonstrate that NETs cause increased endothelial permeability, high prevalence of NETs in experimental models, inactivation of platelets reduced NET formation and treatment with either histone-blocking antibody or DNase1 was protective of lung injury in TRALI models [26^E]. These findings suggest new therapeutic approaches to TRALI prevention and management.

Haematologic There is a lot of interest in pathogen-reduced platelets for increased safety, yet there is concern for increased bleeding risk. A metanalysis integrated the five currently available studies, which demonstrated equivocal results (odds ratio (OR) = 1.24; 95% CI, 0.79–1.93) [27^M].

Infection risk A review and analysis of pathogen-inactivated blood products cited the concern of increased bleeding; however, most of the world has transfused these products for a number of years without bleeding complications [28^R]. Authors argue that years of safe use internationally, combined with the reduced-risk of bacterial contamination, are reasons to adopt the technology in the United States.