AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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 components. Accordingly, emergency physicians must be familiar with and be able to manage adverse transfusion reactions, ranging from self-limited febrile responses to life-threatening intravascular hemolysis.

Pathophysiology

Hemolytic transfusion reactions

Hemolytic transfusion reactions are the result of antibodies in the recipient's plasma directed against antigens on the donor's erythrocytes. This results in rapid intravascular hemolysis of the donor red blood cells. ABO incompatibility due to clerical error is the most frequent cause. This results in hemoglobinemia, hemoglobinuria, disseminated intravascular coagulation (DIC), renal failure, and complement-mediated cardiovascular collapse.

The recipient's antibodies to Rh or non-ABO antigens cause extravascular hemolytic reactions. These patients usually have been exposed to the antigen through previous pregnancies, transplantation, or transfusions. Antibody titers often are too low to be detected through routine antibody screening, but production of antibodies becomes amplified with reexposure. These antibodies do not activate complement; therefore, no intravascular hemolysis occurs. Instead, the RBCs are tagged for removal by splenic macrophages.

Nonhemolytic febrile reactions

Nonhemolytic febrile reactions are thought to stem from the formation of cytokines during the storage of the blood. These reactions seldom proceed to hypotension or respiratory distress.

Anaphylactic reactions

Anaphylactic reactions most often are observed in those patients with a hereditary immunoglobulin A (IgA) deficiency. Some of these patients have developed complement-binding anti-IgA antibodies that cause anaphylaxis when exposed to donor IgA.

Proteins in the donor plasma can cause minor allergic reactions. This is an anaphylactoid reaction and is observed more frequently with components containing large amounts of plasma, such as whole blood, pooled platelets, and fresh frozen plasma.

Acquired diseases

Infectious diseases also may be transmitted through transfusion.

Graft-versus-host disease

Graft-versus-host (GVH) disease 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. In situations when the donor is immunocompromised or when the donor is homozygous and the recipient is heterozygous for an HLA haplotype, these normal defense mechanisms may fail, resulting in GVH disease.

Transfusion-related acute lung injury

Transfusion-related acute lung injury may be caused by transfusing any plasma-containing blood product. It is caused by the interaction between the recipient's leukocytes and preexisting donor antileukocyte antibodies. This results in complement activation and increased pulmonary vascular permeability. In addition, mediators of inflammation that form while the blood is in storage are also felt to be contributory.

Massive transfusion complications

Massive transfusion is defined as the replacement of more than one-half of the blood volume within a 24-hour period or the replacement of 10 units of blood over the course of a few hours. Complications of massive transfusion include the following:

• Coagulopathy is caused by a dilutional effect on the host's clotting factors and platelets, as well as the lack of platelets and clotting factors in packed red blood cells.
• Volume overload
• Hypothermia
• Hyperkalemia may be caused by lysis of stored red cells and is increased in irradiated red blood cells.
• Metabolic alkalosis and hypokalemia may be caused by the transfusion of a large amount of citrated cells.
• Hypocalcemia due to citrate toxicity may occur in those with hepatic failure, congestive heart failure (CHF), or other low-output states. It is increasingly uncommon with the use of component therapy.

Frequency

United States

• Hemolytic transfusion reactions occur in 1 per 40,000 transfused units of packed RBCs.
• Nonhemolytic febrile reactions and minor allergic reactions are the most common transfusion reactions, each occurring in 3-4% of all transfusions.
• Nonhemolytic febrile reactions and extravascular hemolysis are observed more commonly in patients who have developed antibodies from prior transfusions.
• Anaphylactic reactions occur in 1 per 20,000 transfused units.
• Due to improved preventative measures, the incidence of GVH disease is less than 0.15%
• Transfusion-related acute lung injury complicates 0.1-0.2% of all transfusions.
• Risk of transfusion-related hepatitis B is 1 per 50,000 units transfused. Risk for hepatitis C is 1 per 3000-4000 units transfused.
• Risk of transfusion-related HIV infection is 1 per 150,000 units transfused.

Mortality/Morbidity

Hemolytic transfusion reactions result in death in 1 per 100,000 units transfused.

• Transfusion-related hepatitis C causes chronic hepatitis and occurs in 50% of infected recipients.
• Cirrhosis develops in 10% of those with hepatitis.
• Transfusion-associated GVH disease is associated with an 80-90% mortality rate.
• The mortality rate of transfusion-related acute lung injury is 5%.

Sex

Nonhemolytic febrile reactions and extravascular hemolytic reactions are more common in parous females.

Age

Children have a greater risk of developing transfusion-related HIV than adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• In hemolytic transfusion reactions, symptoms usually occur after a small amount of blood has been transfused and almost always before the unit is transfused completely. These reactions are associated with the following:
• • Fever
  • Chills
  • Flushing
  • Nausea
  • Burning at the intravenous (IV) line site
  • Chest tightness
  • Restlessness
  • Apprehension
  • Joint pain
  • Back pain
• Nonhemolytic febrile reactions do not occur as rapidly as acute hemolytic reactions. They occur between 1 and 6 hours of 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 a hemolytic transfusion reaction.
• In anaphylactic reaction, symptoms usually occur with less than 10 mL of blood transfused and only rarely occur more insidiously. These reactions are associated with rapid development of the following:
• • Chills
  • Abdominal cramps
  • Dyspnea
  • Vomiting
  • Diarrhea
• Minor allergic reactions are associated with urticaria.
• Extravascular hemolytic reactions are associated with fever and chills. Symptoms often occur after several hours and sometimes may be observed several days after transfusion.
• Symptoms of transfusion-related acute lung injury start suddenly while the blood products are being transfused or shortly thereafter. Dyspnea is the primary presenting symptom.
• GVH disease often presents within the first week following transfusion, although it may be delayed up to several weeks following transfusion. Symptoms include the following:
• • Fever
  • Abdominal pain
  • Nausea
  • Vomiting
  • Diarrhea, often copious
  • Anorexia
• Hypocalcemia from multiple transfusions may present with circumoral tingling and tremors of the skeletal muscles.

Physical

• Hemolytic transfusion reactions are associated with the following signs, which usually occur after a small amount of blood has been transfused and almost always before the unit is transfused completely:
• • Tachycardia
  • Tachypnea
  • In severe cases, hypotension, oozing from the IV site, diffuse bleeding, hemoglobinuria, and shock
  • Oliguria may be seen in renal failure.
• In unconscious or obtunded patients, the diagnosis of hemolysis is suggested by development of the following:
• • Hypotension
  • Dark urine
  • Oozing from an IV or other puncture sites
• Nonhemolytic febrile reactions are associated with a fever.
• Anaphylactic reactions are associated with the following:
• • Anaphylactic reactions are associated with the following:
  • Tachycardia
  • Flushing
  • Urticaria
  • In more severe cases, wheezing, laryngeal edema, and hypotension
• Minor allergic reactions are associated with urticaria.
• Extravascular hemolytic reactions are associated with fever.
• • Only rarely are signs of shock and renal failure noted.
  • Clinical signs may occur several days later.
• Patients with transfusion-related acute lung injury will present with the following signs:
• • Fever
  • Tachycardia
  • Tachypnea
  • Rales
• GVH disease often presents with the following signs:
• • Erythematous, maculopapular rash, which may progress to toxic epidermal necrolysis
  • Right upper quadrant tenderness
  • Hepatomegaly

Causes

• Transfusion-related infectious diseases caused by the presence of microorganisms in the donated blood include the following:
• • Hepatitis B
  • Hepatitis C
  • HIV-1
  • HIV-2
  • Cytomegalovirus (CMV)
  • West Nile virus
• Other diseases rarely reported to result from transfusion include the following:
• • Syphilis
  • Lyme disease
  • Malaria
  • Toxoplasmosis
  • Chagas disease
  • Jakob-Creutzfeldt disease
  • Filariasis
  • Babesiosis
• Donor blood is routinely screened for hepatitis B, hepatitis C, HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, and West Nile virus. Some, but not all donors, are screened for cytomegalovirus (CMV). Despite screening, some risk of transmission still occurs, since the donor may have been in the window where he or she is infectious but has not yet developed a detectable immunologic response at the time of donation.
• Transmission of HIV has occurred with the transfusion of only one unit, although greater risk exists with transfusion of multiple units.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Allergic reaction
Fever
Hemolysis
Sepsis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• When a hemolytic transfusion reaction is suspected, send the donor blood back to the blood bank to determine whether the correct unit of blood was administered to the intended recipient. In addition, the blood bank should perform a repeat type, crossmatch, antibody screen, and direct and indirect Coombs tests. Other considerations with a hemolytic transfusion reaction include the following:
• • Free serum hemoglobin appears as a pink color of the serum in a clotted centrifuged specimen. This may be observed with as little as 5-10 mL of hemolyzed blood.
  • Serum bilirubin level peaks in 3-6 hours as the free hemoglobin is metabolized.
  • Haptoglobin binds to hemoglobin and the serum hemoglobin level falls, reaching its nadir in 1-2 days.
  • Examine urine for hemoglobinuria.
• A repeat hemoglobin and hematocrit (H/H) fails to show the expected rise in hematocrit in patients developing intravascular or extravascular hemolysis.
• In acute transfusion-related acute lung injury, leukopenia and eosinophilia may be present.
• In GVH disease, the CBC will demonstrate pancytopenia and elevated liver enzymes levels. Electrolyte disturbances related to the diarrhea may be present.
• For the patient undergoing a massive transfusion, serially measure the following parameters:
• • Platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be checked after the transfusion of every 5 units of packed red cells and whenever signs or symptoms suggest a coagulopathy.
  • Potassium level
  • pH
  • Ionized calcium level should be measured in patients developing signs, symptoms, or ECG manifestations of hypocalcemia.
• It is recommended that in the massively transfused patient, plasma and platelets be administered in response to the results of platelet count and coagulation function.
• • Plasma and platelets should never be given solely in response to the number of units of packed cells transfused.

Imaging Studies

• In transfusion-related acute lung disease, the chest radiograph is consistent with noncardiogenic pulmonary edema. The cardiac silhouette is not enlarged. Bilateral infiltrates are in an alveolar pattern.

Other Tests

• The electrocardiogram may demonstrate prolongation of the QT interval in the massively transfused patient who develops hypocalcemia.

Procedures

• Endotracheal intubation may be required if respiratory insufficiency complicates a severe hemolytic or anaphylactic reaction.
• Hypoxemia severe enough to require endotracheal intubation occurs in 70-75% of patients with transfusion-related acute lung injury.
• Place a Foley catheter in all patients with an intravascular hemolytic reaction to ensure continuous measurement of urinary output.
• A careful assessment will often aid in differentiating transfusion-associated volume overload from transfusion-related acute lung injury. In some cases, however, making the correct diagnosis may be very difficult. In these cases, Swan-Ganz catheterization may provide useful information.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

All patients receiving blood products should be placed on continuous cardiac monitoring and pulse oximetry.

• Hemolytic transfusion reaction
• • Stop transfusion as soon as a reaction is suspected.
  • Replace the donor blood with normal saline.
  • Examine the blood to determine if the patient was the intended recipient and then send the unit back to the blood bank.
  • Furosemide may be administered to increase renal blood flow.
  • Low-dose dopamine may be considered to improve renal blood flow.
  • Make efforts to maintain urine output at 30-100 mL/h.
• Extravascular hemolytic reactions do not require any specific treatment. However, if clinically ruling out intravascular hemolysis is difficult, follow the same treatment.
• Nonhemolytic transfusion reaction
• • Aggressive treatment of simple febrile reactions is not necessary. However, because the nonspecific symptoms are similar to those of a hemolytic transfusion reaction, differentiating this entity from a hemolytic reaction is necessary.
  • The transfusion should be terminated.
  • Evaluate the patient for evidence of hemolysis.
  • The patient's fever can be treated with acetaminophen.
• Anaphylactic reaction
• • Stop the transfusion immediately.
  • Support the airway and circulation as necessary.
  • Administer epinephrine, diphenhydramine, and corticosteroids.
  • Maintain intravascular volume.
• Minor allergic reaction
• • Administer antihistamines.
  • Although the necessity of stopping the transfusion is unclear, in more severe cases and in uncertain cases, the transfusion should be stopped.
• Transfusion-related acute lung injury
• • Monitor oxygen saturation.
  • Provide supplemental oxygen to maintain oxygen saturation greater than 92%.
  • Hypoxemia severe enough to require endotracheal intubation and positive-pressure ventilation occurs in 70-75% of patients.
  • No evidence supports the routine use of corticosteroids.
  • The blood bank should be notified.
• GVH disease
• • No effective therapies currently exist.
  • Emphasis needs to be placed on prevention.
• Massive transfusion
• • To decrease the risk of hypothermia in patients receiving massive transfusion, administer the blood through a blood warmer. Do not place blood in a microwave oven to warm, as this causes hemolysis.
  • Do not administer platelets and fresh frozen plasma routinely or by using a formula based on the number of units of packed cells transfused. Only administer with evidence of abnormal bleeding associated with thrombocytopenia or an elevated PT or aPTT.
  • Treat symptomatic hypocalcemia with calcium chloride or calcium gluconate.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In hemolytic transfusion reactions, pharmacologic treatment is aimed at increasing renal blood flow and preserving urinary output. In anaphylaxis, the goals of therapy are to maintain hemodynamic stability and reverse the underlying process.

Drug Category: Diuretics

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.

Drug Category: Vasopressors

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.

Drug Category: Antihistamines

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

Drug Category: Corticosteroids

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Continue IV fluids to maintain urine output.
• Monitor urine output.
• Continuous cardiac and blood pressure monitoring for early detection of any hemodynamic instability
• Transfusion-related acute lung injury
• • Intubated patients usually improve quickly with supportive care.
  • Once patients recover from transfusion-related acute lung injury, they can safely receive blood products as needed.

Deterrence/Prevention

• All healthcare personnel should be familiar with the hospital's policy of checks and cross-checks to ensure that donor blood being transfused is administered to the intended patient. This best prevents hemolytic reactions.
• Administer leukocyte-poor packed RBCs in patients who have had 2 previous febrile nonhemolytic reactions and in patients who frequently receive blood products.
• If the patient has history of previous anaphylactic reactions to transfused blood, transfuse blood from IgA-deficient donors, or if this is not available, frozen deglycerolized packed RBCs.
• Administer CMV-negative blood in patients who are immunocompromised.
• To reduce the risk of GVH disease, irradiated blood should be given to immunocompromised patients, those receiving bone marrow transplants, and those receiving blood products from a blood relative donor.
• Nonhemolytic febrile reactions recur in 15-20% of patients receiving future transfusions.

Complications

• Intravascular hemolysis may result in the following:
• • Acute renal failure
  • DIC
  • Cardiovascular collapse
  • Death

Patient Education

• Patients and family members of patients having 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to carefully examine and compare patient's name and identification numbers to label on unit of blood to ensure administration to the intended recipient.
• Failure to diagnose acute intravascular hemolysis in patients who are obtunded, unconscious, or anesthetized
• Failure to suspect acute intravascular hemolysis if patient develops hypotension, dark urine, or oozing from IV or other puncture sites
• Failure to obtain informed consent, when possible, from the patient or their family or power of attorney
• Failure to inform patient of risk of transmission of infectious diseases
• Monitor coagulation parameters, potassium, and ionized calcium in patients receiving massive transfusion.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Stainsby D, MacLennan S, Thomas D, Isaac J, Hamilton PJ. Guidelines on the management of massive blood loss. Br J Haematol. Dec 2006;135(5):634-41. [Medline].
• Cherry T, Steciuk M, Reddy VV, Marques MB. Transfusion-related acute lung injury: past, present, and future. Am J Clin Pathol. Feb 2008;129(2):287-97. [Medline].
• Dellinger EP, Anaya DA. Infectious and immunologic consequences of blood transfusion. Crit Care. 2004;8 Suppl 2:S18-23. [Medline].
• Dodd RY, Leiby DA. Emerging infectious threats to the blood supply. Annu Rev Med. 2004;55:191-207. [Medline].
• Fiebig EW, Busch MP. Emerging infections in transfusion medicine. Clin Lab Med. Sep 2004;24(3):797-823, viii. [Medline].
• Goodnough LT. Risks of blood transfusion. Anesthesiol Clin North America. Jun 2005;23(2):241-52, v. [Medline].
• Looney MR, Gropper MA, Matthay MA. Transfusion-related acute lung injury: a review. Chest. Jul 2004;126(1):249-58. [Medline].
• Spahn DR, Rossaint R. Coagulopathy and blood component transfusion in trauma. Br J Anaesth. Aug 2005;95(2):130-9. [Medline].
• Stainsby D, Russell J, Cohen H, Lilleyman J. Reducing adverse events in blood transfusion. Br J Haematol. Oct 2005;131(1):8-12. [Medline].
• Williams AE, Thomson RA, Schreiber GB, et al. Estimates of infectious disease risk factors in US blood donors. Retrovirus Epidemiology Donor Study. JAMA. Mar 26 1997;277(12):967-72. [Medline].

Article Last Updated: Jul 2, 2008