Transfusion Reactions in Emergency Medicine

Updated: Dec 24, 2020
Author: Ross A Wanner, MD; Chief Editor: Barry E Brenner, MD, PhD, FACEP 

Overview

Practice Essentials

Patients with acute blood loss or symptomatic anemia frequently require blood replacement therapy in the emergency department (ED). Although blood replacement therapy is generally safe, it should be understood that certain risks accompany the transfusion of blood and plasma products. Reactions range from self-limited febrile reactions to life-threatening intravascular hemolysis. Therefore, patients should be informed of the risks and consent for transfusion, when appropriate. Similarly, emergency physicians must be familiar with and able to manage these adverse transfusion reactions.

Pathophysiology

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.[1]  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.[2]  

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.[3] 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.[4]

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) 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.[5, 6]

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.[7] 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.

Epidemiology

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.[8]  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[9, 10, 11] ):

  • 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
 

Presentation

History

In acute hemolytic transfusion reactions (AHTR), symptoms usually occur before the unit is transfused completely. The classic triad is fever, flank pain, and gross hematuria, but these reactions are also associated with the following:

  • Chills
  • Back pain
  • Petechial rash
  • Flushing
  • Nausea

Extravascular hemolytic reactions are associated with fever and chills. Onset is often several hours after the transfusion and sometimes may be observed several days later.

Transfusion-related acute lung injury (TRALI) signs and symptoms start suddenly, while the blood products are being transfused or shortly thereafter. Dyspnea is the primary presenting symptom, but fevers, chills, and chest pain are also common, with clinical signs of pulmonary edema and hypoxemia.

Transfusion-associated circulatory overload (TACO) symptoms start within 6 to 12 hours of transfusion and most often consist of respiratory distress and orthopnea.

Anaphylactic reactions are characterized by rapid (within seconds to minutes) development of the following:

  • Chills
  • Abdominal cramps
  • Dyspnea
  • Vomiting
  • Diarrhea
  • Urticaria

Graft-versus-host disease (GVHD) almost universally presents as fever within the first week following transfusion, although it may be delayed up to several weeks. Other symptoms include the following:

  • Diffuse rash
  • Nausea
  • Vomiting
  • Diarrhea
  • Anorexia

Febrile nonhemolytic reactions (FNHR) do not occur as rapidly as acute hemolytic reactions. They develop between 1 and 6 hours after transfusions and are associated with the nonspecific symptoms of fever, chills, and malaise. Some patients may complain of dyspnea. These nonspecific symptoms also occur with other, more dangerous transfusion reactions, so FHNR should be a diagnosis of exclusion.

Physical

AHTR may present as any combination of the following clinical features:

  • Tachycardia
  • Tachypnea
  • Hypotension
  • Oozing from the intravenous (IV) access site, diffuse bleeding indicative of disseminated intravascular coagulation (DIC)
  • Hemoglobinuria, oliguria
  • Shock

TRALI nearly always presents as hypoxemia and pulmonary infiltrates on chest x-ray, but the following clinical features may also be evident:

  • Tachycardia
  • Fever
  • Hypotension

TACO, unlike many other transfusion reactions, will present as fluid overload findings, including the following:

  • Hypertension
  • Edema
  • Jugular venous distension
  • Rales

Anaphylactic reactions are associated with the following classic findings:

  • Tachycardia
  • Flushing
  • Urticaria
  • Wheezing
  • Laryngeal edema
  • Hypotension

GVHD often presents as follows:

  • Fever
  • Diffuse maculopapular rash
  • Hypotension
  • Hepatitis

Causes

Donor blood is routinely screened for hepatitis B, hepatitis C, HIV-1, HIV-2, human T-lymphotropic virus 1 (HTLV-1), HTLV-2, syphilis, West Nile virus, and Zika Virus. Bacterial contamination is the most common transfusion-related infection, especially in platelets, which are stored at room temperature and without a preservative.

According to the International Society for Infectious Diseases, on nucleic acid amplification testing (NAAT), rates of transmission per transfused unit of the following viruses are:

  • Hepatitis B: 1 per 843,000-1,200,000
  • Hepatitis C: 1 per 1,100,000
  • HIV-1 and HIV-2: 1 per 1,500,000
  • Cytomegalovirus (CMV) in susceptible patients: 1-3 per 100

Many other diseases are rarely reported to be transmitted via transfusion, including (but not limited to) the following:

  • West Nile virus infection
  • Syphilis
  • Lyme disease
  • Malaria
  • Toxoplasmosis
  • Chagas disease
  • Creutzfeldt-Jakob disease
  • Filariasis
  • Babesiosis

According to the World Health Organization, Severe Acute Respiratory Syndrome coronavirus–2 (SARS-CoV-2) has not been reported to be transmitted through blood or blood components. In a small study, blood components collected from donors in the pre-symptomatic phase of COVID-19 did not transmit the infection.[12]

 

DDx

 

Workup

Laboratory Studies

For acute hemolytic transfusion reactions (AHTR), the following studies are indicated:

  • Complete blood cell count (CBC)
  • Metabolic panel
  • Liver function tests, including total and direct bilirubin
  • Haptoglobin
  • Reticulocytes
  • Lactate dehydrogenase (LDH)
  • Coombs test
  • Electrocardiogram (ECG)

Although transfusion-related acute lung injury (TRALI) is a clinical diagnosis, the following are adjuncts that can support the diagnosis:

  • Full vitals, including pulse oximetry
  • Arterial or venous blood gas
  • Chest x-ray
  • ECG

Transfusion-associated circulatory overload (TACO) is also a clinical diagnosis, but the following are adjuncts that can support the diagnosis:

  • Full signs, including blood pressure and heart rate
  • Chest x-ray
  • Evidence of fluid overload on physical exam
  • Acute respiratory distress

Anaphylaxis is a clinical diagnosis with involvement of two or more of the following systems after exposure:

  • Skin/mucosa,
  • Cardiovascular
  • Respiratory
  • Gastrointestinal

For graft-versus-host disease (GVHD), the following studies are indicated:

  • CBC (to assess for cytopenias)
  • Complete metabolic panel
  • Liver function tests
  • Coagulation studies
  • Stool studies in setting of profuse diarrhea
 

Treatment

Emergency Department Care

Every patient receiving blood products should be placed on cardiac monitoring and continuous pulse oximetry. If a reaction is suspected, stop the transfusion and discontinue any plans for future transfusions. If applicable, alerting the blood bank of the reaction as immediately as possible will prevent incorrect transfusion of blood products into another patient, if products were accidentally exchanged.

Treatment of transfusion reactions is specific to the type of reaction, as outlined below.

Acute Hemolytic Transfusion Reactions (AHTR)

Treatment of AHTR is largely supportive and renal-protective resuscitation is imperative. Aiming for urine output of 100 mL/hour or more with intravenous (IV) fluids and adjunctive diuretics (eg, furosemide) will help protect intrinsic renal function. Serial measurement of hemoglobin, hematocrit, and lactate dehydrogense (LDH) will help characterize the degree of hemolysis and drive management until the hemolysis has ended.

Transfusion-related Acute Lung Injury (TRALI) 

TRALIis treated similar to ARDS patients, even if the patient has not progressed to this degree of pulmonary insult. After stopping the infusion, oxygenation is the primary concern and measures should be taken to improve arterial oxygen levels with lung-protective strategies. Low flow nasal cannula, high flow nasal cannula, non-invasive positive-pressure ventilation (NIPPV) (CPAP, specifically), and ultimately endotracheal intubation with mechanical ventilation at lung-protective tidal volumes (6-8mL/kg of ideal body weight) is the general progression of measures taken. There is no current evidence that steroids improve outcomes (13).

Transfusion-associated Circulatory Overload (TACO)

TACO is treated similarly to other syndromes of fluid overload. Hypoxemia from pulmonary edema can be improved with bilevel positive airway pressure (BPAP) in the short term, and diuretics such as furosemide can help with fluid management in the less immediate management. If the patient continues to decompensate, intubation with mechanical ventilation is often necessary.

Anaphylaxis

Anaphylaxisis treated in the usual manner. Intramuscular epinephrine 1:1,000 (1 mg/mL) concentration is given at 0.01 mg/kg every 2-5 minutes. In refractory cases, patients can be started on an epinephrine drip (0.1 mcg/kg/min) and resuscitated with IV fluids. Bronchodilators such as albuterol should be administered for patients with bronchospasm without evidence of upper airway swelling or angioedema. Antihistamines and steroids may be used as adjuncts, although evidence of their utility in the acute phase is limited. Endotracheal intubation with mechanical ventilation may be necessary if the condition continues to be refractory to medical treatment or the patient develops altered mental status or evidence of impending respiratory compromise.

 

Medication

Diuretics

Class Summary

These agents are used to increase renal blood flow and preserve urinary output in hemolytic transfusion reactions. They also may be used in transfusion-related volume overload.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system, which results in inhibition of sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Individualize dose to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after previous dose, until desired diuresis occurs.

Vasopressors

Class Summary

These agents are used to increase renal blood flow and preserve urinary output in hemolytic transfusion reactions. In severe allergic reactions, epinephrine is used for its inotropic properties and ability to maintain perfusion of vital organs.

Epinephrine (Adrenalin, Epinal, Epifrin)

DOC for treating anaphylaxis. Stimulates alpha-, beta1, and beta2-adrenergic receptors, which in turn results in bronchodilatation, increased peripheral vascular resistance, hypertension, increased chronotropic cardiac activity, and positive inotropic effects.

Antihistamines

Class Summary

Used to treat minor allergic reactions and anaphylaxis. Diphenhydramine may be used to pretreat patients with prior documentation of minor allergic reactions.

Diphenhydramine (Benadryl, Benylin, Bydramine)

Used for symptomatic relief of allergic symptoms caused by histamine released in response to allergens.

Cimetidine (Tagamet)

H2 antagonist that, when combined with H1 type, may be useful in treating itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis that do not respond to H1 antagonists alone. Use in addition to H1 antihistamines.

Corticosteroids

Class Summary

These agents have limited benefit in the initial acute treatment of rapidly deteriorating anaphylactic patient. However, they may benefit patients with persistent bronchospasm or hypotension. Onset of action is approximately 4-6 h following its administration.

Methylprednisolone (Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Useful in treatment of inflammatory and allergic reactions. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation.

 

Follow-up

Further Inpatient Care

Inpatient treatment is largely supportive. Any combination of the following may be necessary in the management of these patients:

  • Intravenous fluids to maintain appropriate urine output
  • Diuretics for fluid overload
  • Airway management with noninvasive positive pressure ventilation (NIPPV) or endotracheal intubation
  • Hemodynamic support with inotropes and vasopressors
  • Continuous cardiac monitoring
  • Short-term dialysis or continuous renal replacement therapy, in severe cases of acute kidney injury

Deterrence/Prevention

Acute hemolytic transfusion reactions (AHTR) can be prevented by appropriate cross-matching of blood products and ensuring processes to minimize clerical error, including correct patient transfusion and double-checking that the patient’s blood type matches that on the product to be transfused.

Transfusion-related acute lung injury (TRALI) reactions have no specific mitigation strategies, but more detailed donor selection and screening for HLA antibodies has substantially decreased the incidence of these reactions. New methods include filtration of reactive antibodies, antigens, and other products implicated in TRALI pathogenesis.

Transfusion-associated circulatory overload (TACO) has no definite prevention strategy, but it has been postulated that diuretics either before or with transfusion may help decrease symptoms.

Anaphylaxis can be prevented by using IgA-depleted blood products or washed blood products to remove the reactive antigens. There is no evidence to support the routine use of antihistamines or glucocorticoids as pretreatment.

Graft-versus-host disease (GVHD) reactions can be prevented by transfusing blood products that have been irradiated or treated with reagents that disrupt the ability for lymphocytes to proliferate.

Febrile nonhemolytic reactions (FNHR) can be prevented by administering leukocyte-reduced blood products.

Patient Education

Patients and family members of patients who have any reaction to blood products must be educated about the reaction. They should be instructed to inform healthcare workers about this in order to prevent any future transfusion reactions. Patients should also be counseled on these risks and provide consent for transfusion when appropriate. For patient education information, see Blood Transfusion: What to Know If You Get One.

Acknowledgements

We thank the previous authors, Dr. S Gerald Sandler and Dr. Viviana V. Johnson, for their contributions and framework for the current updated article.

 

Questions & Answers

Overview

What is the range of blood transfusion reactions in the emergency department (ED)?

What is the pathophysiology of hemolytic transfusion reactions?

What is the pathophysiology of nonhemolytic febrile transfusion reactions?

What is the pathophysiology of anaphylactic transfusion reactions?

Can infections be transmitted through transfusion?

What is the pathophysiology of graft-versus-host (GVH) disease from transfusions?

What is the pathophysiology of transfusion-related acute lung injury?

What are the possible complications of massive transfusion?

What is the prevalence of adverse transfusion reactions?

What is the mortality and morbidity associated with adverse transfusion reactions?

What are the sexual predilections of adverse transfusion reactions?

Which age groups are at higher risk of developing transfusion-related HIV?

Presentation

Which clinical history findings are characteristic of nonhemolytic febrile transfusion reactions?

Which clinical history findings are characteristic of allergic and anaphylactic transfusion reactions?

Which clinical history findings are characteristic of extravascular hemolytic transfusion reactions?

Which clinical history findings are characteristic of transfusion-related acute lung injury?

Which clinical history findings are characteristic of transfusion-related GVH disease?

Which clinical history findings are characteristic of transfusion-related hypocalcemia?

Which clinical history findings are characteristic of hemolytic transfusion reactions?

Which physical findings are characteristic of nonhemolytic febrile transfusion reactions?

Which physical findings are characteristic of anaphylactic transfusion reactions?

Which physical findings are characteristic of extravascular hemolytic transfusion reactions?

Which physical findings are characteristic of transfusion-related acute lung injury?

Which physical findings are characteristic of transfusion-related GVH disease?

Which physical findings are characteristic of hemolytic transfusion reactions?

What causes transfusion-related infectious diseases?

DDX

What are the differential diagnoses for Transfusion Reactions in Emergency Medicine?

Workup

What is the role of lab tests in the workup of adverse transfusion reactions?

What is the role of radiography in the workup of adverse transfusion reactions?

What is the role of ECG in the workup of adverse transfusion reactions?

What is the role of catheters in the workup of adverse transfusion reactions?

What is the role of endotracheal intubation in the workup of adverse transfusion reactions?

Treatment

How are adverse transfusion reactions treated?

How are adverse reactions of massive transfusion treated?

Medications

What is the role of medications in the treatment of adverse transfusion reactions?

Which medications in the drug class Corticosteroids are used in the treatment of Transfusion Reactions in Emergency Medicine?

Which medications in the drug class Antihistamines are used in the treatment of Transfusion Reactions in Emergency Medicine?

Which medications in the drug class Vasopressors are used in the treatment of Transfusion Reactions in Emergency Medicine?

Which medications in the drug class Diuretics are used in the treatment of Transfusion Reactions in Emergency Medicine?

Follow-up

What is included in inpatient care for adverse transfusion reactions?

How are adverse transfusion reactions prevented?

What are the possible complications of adverse transfusion reactions?

What is included in patient education about adverse transfusion reactions?