Transfusion Reactions in Emergency Medicine

Non–Life-Threatening Reactions

Non–life-threatening transfusion reactions comprise febrile nonhemolytic reactions (FNHR) and primary urticarial or hypotensive reactions.

Febrile nonhemolytic reactions

FNHR are the most common type of transfusion reaction and tend to be more common in children than in adults. ^[2]  FNHR are the result of cytokine release from leukocytes during blood product storage and therefore may be prevented by using leukoreduced blood products. Patients typically develop fever within 6 hours of transfusion. Although premedication with acetaminophen or diphenhydramine to prevent FNHR is sometimes tried, a systematic review and meta-analysis did not demonstrate a benefit to the practice. ^[3]  

Primary urticarial or hypotensive reactions

Transfusion of blood products may be associated with either urticaria or hypotension without other signs of clinical instability. The exact mechanisms behind these reactions have not been entirely elucidated. Note that to be considered a primary urticarial or hypotensive reaction, the urticaria or hypotension must occur in isolation; if they occur together, that points to the more life-threatening sequela of anaphylaxis. Therefore, these reactions should be diagnoses of exclusion. In contrast to FNHR, primary urticarial reactions can be prevented with antihistamine premedication, so prophylaxis is indicated in patients with a past history of a primary urticarial reaction. ^[4] Primary hypotensive reactions resolve with discontinuation of the transfusion. 

Life-Threatening Reactions

Potentially life-threatening transfusion reactions include the following:

• Anaphylactoid reactions
• Acute hemolytic transfusion reactions
• Transfusion-related acute lung injury
• Transfusion-associated circulatory overload
• Infection
• Graft-versus-host disease

Anaphylactoid reactions

Anaphylactic reactions most often are observed in recipients with a hereditary immunoglobulin A (IgA) deficiency. The reactions occur when the recipient has developed anti-IgA antibodies from previous exposure to donor IgA. These reactions develop more immediately, with the familiar sequelae of urticaria, angioedema, wheezing, and hypotension in severe cases.

Less severe anaphylactoid reactions can also occur when recipients have antibodies to various antigens in the donor blood products. These reactions develop most often with platelet transfusions, and are also more frequently observed with larger-volume transfusions. Anaphylactic and anaphylactoid reactions are treated by discontinuing the transfusion and providing symptomatic therapy.

Acute hemolytic transfusion reactions

Acute hemolytic transfusion reactions (AHTR) are most commonly the result of antibodies in the recipient's plasma that aredirected against antigens on the donor RBCs. ABO incompatibility due to clerical error is the most frequent cause. AHTR present as fever, chills, hypotension, hemoglobinemia, hemoglobinuria, disseminated intravascular coagulation (DIC), acute kidney injury, and complement-mediated cardiovascular collapse. Management is largely supportive and hinges on hydration and renal protective measures (urine output >100mL/h) in addition to serial hematocrit measurements until hemolysis has ended. ^[5]

Recipient antibodies to Rh or non-ABO antigens can also cause extravascular hemolysis in reticuloendothelial organs. These patients usually have been exposed to the antigen through previous pregnancies, transplantation, transfusions, or through cross-reactive antigen exposure. Antibody titers often are too low to be detected through routine antibody screening, but production of antibodies becomes amplified with re-exposure. These antibodies do not activate complement as strongly and are removed primarily by splenic macrophages.

Transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is the second leading cause of death related to blood transfusion. ^[6] It may be caused by transfusion of any plasma-containing blood product. Although not entirely understood, TRALI is currently believed to involve a “two hit” mechanism. The first hit is pre-transfusion inflammation for patient-specific reasons, which activates pulmonary endothelial cells to express adhesion molecules. The second is neutrophil activation upon receipt of the transfusion. Activated neutrophils interact with activated endothelium, resulting in further neutrophil recruitment, local inflammation, and a consequent increase in permeability within the pulmonary vasculature. ^{[7, 8]}

Signs and symptoms of TRALI typically develop within minutes of transfusion, but can occur within 6 hours afterward. Manifestations include fever, chills, respiratory distress, and chest pain, with clinical signs of pulmonary edema and hypoxemia. Chest x-ray shows pulmonary infiltrates. Treatment is largely supportive and involves discontinuing the transfusion, supplemental oxygenation, and, often, intubation with mechanical ventilation.

Transfusion-associated circulatory overload

Transfusion-associated circulatory overload (TACO) is a form of iatrogenic pulmonary edema that most commonly occurs in patients receiving large-volume transfusions, or those with underlying cardiopulmonary disease. The amount of product has been shown to correlate directly with the degree of pulmonary edema and respiratory distress. Patients generally begin having symptoms within 6 hours of transfusion and treatment is largely supportive, with fluid restriction, oxygen supplementation, noninvasive positive-pressure ventilation, and intubation if severe. TACO is very rarely fatal. 

Infection

Transfusion products may have infectious contaminants, including bacteria, viruses, parasites, and prion diseases. According to the Centers for Disease Control and Prevention (CDC), bacterial contamination is most common, occurring in approximately 1 in 2000-3000 platelet transfusions, with Staphylococcus aureus being the most common.

Graft-versus-host disease

Graft-versus-host disease (GVHD) occurs when donor lymphocytes mount an immune response against the recipient's lymphoid tissue. Normally, the donor lymphocytes are recognized as being foreign and are destroyed. However, if the donor is immunocompromised or the donor is homozygous and the recipient is heterozygous for an HLA haplotype, these normal defense mechanisms may fail, resulting in GVHD. The true incidence is unknown. Patients almost universally present with fever within a week of transfusion. Other symptoms include diffuse rash, diarrhea, hepatitis, anorexia, nausea, and vomiting. ^[9] Treatment is supportive and prognosis is poor regardless of management.

Massive Transfusion Complications

Massive transfusion is traditionally defined as transfusion of 10 units of red blood cells (RBCs) within 24 hours. It has more recently also been defined as transfusion of 3 units of RBCs within 1 hour, or any 4 components over 30 minutes. Such rapid transfusions are fraught with complications with an array of severity, including the following:

• Coagulopathy
• Volume overload (as described above, in discussion of TACO)
• Hyperkalemia - May be caused by lysis of stored RBCs and is increased in transfusion of irradiated RBCs
• Hypothermia 
• Hypocalcemia and alkalosis 

Coagulopathy can result from various causes, including dilution, as packed RBCs are devoid of platelets and clotting factors necessary for hemostasis. It is prevented by running products through a warmer.

Hypocalcemia and alkalosis result from citrate additive and may occur in patients with liver failure, congestive heart failure (CHF), or other low-output states. It is increasingly uncommon with the use of component therapy. Calcium gluconate can be given intravenously for repletion.

Frequency of Transfusion Reactions

In the United States in 2017, adverse transfusion reactions requiring any diagnostic or therapeutic intervention were reported to the National Blood Collection and Utilization Survey in 45,165 (0.28%) of 16,029,000 transfused components. ^[10]  Numbers of specific reactions are as follows:

• Febrile, non-hemolytic transfusion reactions – 19,317
• Mild to moderate allergic reactions - 14,170
• Delayed serologic transfusion reactions – 2,981
• Transfusion-associated circulatory overload (TACO) – 1,877
• Hypotensive transfusion reactions – 1,462
• Transfusion-associated dyspnea – 1,036
• Delayed hemolytic transfusion reactions – 770
• Life-threatening reactions requiring major medical intervention - 758
• Post-transfusion purpura - 579
• Severe allergic reactions - 398
• Transfusion-related acute lung injury (TRALI) - 293
• Acute hemolytic transfusion reactions (AHTR), non–ABO related - 135
• Transfusion-transmitted bacterial infection - 37
• AHTR (ABO) - 33
• Transfusion-transmitted parasitic infection - 10
• Transfusion-transmitted viral infection - 6
• Transfusion-associated graft-versus-host disease - 0

Transfusion-Related Mortality

In combined fiscal years 2013-2017, the US Food and Drug Administration (FDA) reported a total of 185 transfusion-related fatalities. Of these deaths, TACO (59, 32%) was the leading cause of death, followed by TRALI (56, 30%), contamination (23, 12%), AHTR non-ABO (20, 11%), AHTR ABO (12, 7%), anaphylaxis (12, 6%), and hypotension (3, 2%). The estimated total risk of transfusion-related death in 2019 was approximately 2.3 per 1,000,000 transfused products ^{[11, 12, 13]} ):

• AHTR result in 1 death per 1,800,000 units transfused
• TRALI results in 1 death for every 5,000 cases
• Transfusion-related sepsis due to bacterial contamination occurs in 1 of every 75,000 platelet transfusions and 1 in every 500,000 RBC transfusions. There is approximately 1 death per 498,711 units of platelets transfused
• Transfusion-associated graft versus host disease has an estimated 80-90% mortality rate