Transfusion Reactions

Adeola Sadik

Jarone Lee

I. TRANSFUSION REACTIONS

All types of transfusions carry the risk of causing subacute, acute, and delayed adverse events. Prompt recognition of a transfusion-related event may be difficult and even overlooked secondary to the patient’s underlying illness. In order to accurately diagnose a transfusion reaction, a detailed assessment of the patient’s vital signs prior to, during, and after transfusion must be examined in conjunction with any accompanying signs and symptoms (Table 28.1).

A. Epidemiology

According to the United States Food and Drug Administration (USFDA), from 2009 to 2013, transfusion-related acute lung injury (TRALI) caused the majority of transfusion-related deaths (38%), followed by transfusion-associated circulatory overload (TACO) (24%), and then acute hemolytic transfusion reactions (AHTRs) (total 22%: non-ABO and ABO incompatibilities at 15% and 7%, respectively). Transfusion-related infections accounted for 10% of transfusion-related fatalities, and anaphylaxis accounted for 5% of deaths. Other causes, such as transfusion-associated graft-versus-host disease (TA-GVHD) and hypotension, accounted for approximately 1% of transfusion-related deaths.

B. Noninfectious and Nonhemolytic Transfusion Reactions

1. Transfusion-related acute lung injury

TRALI is defined as new-onset acute lung injury within 4 to 6 hours of blood product transfusion. Patients usually present with acute hypoxemia, a PaO₂/FIO₂ ratio of less 300 mm Hg, and evidence of bilateral patchy infiltrates on chest radiography (without evidence of left atrial hypertension or other signs of left heart failure). TRALI is the most common cause of transfusion-related death, as documented by the USFDA. Case fatality estimates range from 5% to 25%. TRALI occurs when recipient neutrophils, located and sequestered within the lung, are activated by substances within donor blood products. These transfused substances can include anti-human neutrophil antibodies (HNAs), anti-human leukocyte antibodies (HLAs), and other mediators (cytokines and biologically active lipids and proteins) that bind to and cause the aggregation of the recipient’s neutrophils in the pulmonary vasculature. The activated neutrophils release inflammatory mediators that increase the permeability of the pulmonary vasculature, causing pulmonary edema and lung injury.

Several known risk factors that increase the risk for TRALI include having undergone cardiac surgery, patients with hematologic malignancies (with whom treatment is being initiated), mechanical ventilation with high peak airway pressures, a history of smoking, chronic alcohol abuse, and high serum interleukin-8 levels. Signs and symptoms include dyspnea, an oxygen saturation of less than

90%, cyanosis, hypotension, fever, chills, hypoxia, and a pulmonary artery pressure of less than 18 mm Hg.

TABLE 28.1 Types of Transfusion-related Reactions

Reaction	Signs and Symptoms	Treatment
Allergic reaction	Hives, pruritus, wheezing, erythema	Stop or slow rate of transfusion for 15-30 min Give antihistamines Monitor: hives (if only symptom), likely to resolve in less than 30 min and may resume transfusion If isolated allergic reaction, unlikely to recur in future; no evidence for premedication Give washed cells if repeated reactions
Anaphylaxis	Acute flushing, hypertension followed by hypotension, tachycardia, edema, bronchospasm, and shock, typically within minutes of initiating the transfusion	ACLS, fluid resuscitation, initiation of vasopressors, if necessary Epinephrine 0.3 mL of 1:1,000 solution SQ and methylprednisolone Prevent by limiting future transfusions to IgA-deficient blood (ultrawashed or deglycerolized RBCs)
TRALI	Acute hypoxemia and noncardiogenic pulmonary edema May have fever and hypotension Some definitions: TRALI must occur within 6 h of last transfusion	Resuscitation, supplemental oxygen, mechanical ventilation, and vasopressor support
TACO	Signs/symptoms are similar to that seen with TRALI, expect hypertension and volume overload	Diuretics Decrease subsequent transfusion rates and volumes, if possible
AHTR	Fever, chills, burning at IV site, flank pain, chest tightness, tachycardia, hypotension, hemoglobinuria, acute kidney injury, disseminated intravascular coagulation	Intravenous fluid resuscitation Diuretics May require vasopressors
FNHTR	Fever (with a greater than 1 Celsius (C) change from pretransfusion temperature), chills, flushing, tachycardia Similar to AHTR, with less severe symptoms	Treat symptoms with antipyretic Monitor post-transfusion platelet count
DHTR	Asymptomatic hematocrit decrease, flu-like illness, jaundice, unconjugated bilirubinemia	Treatment rarely necessary MUST identify the responsible antibody as a reference for future transfusions
Transfusion-associated GVHD	Fever, erythematous maculopapular rash, diarrhea, hepatomegaly, transaminitis, pancytopenia	Majority of cases (>90%) are fatal, no proven treatment Prevent by using irradiated products from related donors
Iron overload	Cirrhosis, endocrine failure, heart failure	Chelation, decreases the amount of transfusions
Hyperkalemia	ECG changes, hyperkalemic cardiac arrest Occurrence decreases with fresh blood and/or washed RBCs	Treat the hyperkalemia
Hypocalcemia	From citrate toxicity	Treat if symptomatic
Hypothermia	Temperature below 35°C (95°F)	Treat by warming blood

TRALI can be difficult to distinguish from other causes of acute hypoxemia with noncardiogenic pulmonary edema, such as TACO and acute respiratory distress syndrome. As such, it is often a diagnosis of exclusion. The laboratory workup often includes a complete blood count with differential (to show evidence of neutropenia) and labs to exclude AHTRs. The mainstay of treatment of TRALI is respiratory support with lung protective mechanical ventilation and vasopressor support. About 80% of patients recover within 48 to 96 hours of onset of symptoms. Prevention of TRALI is aimed at identifying donors with antineutrophil and anti-HLA antibodies (such as childbearing female donors) and limiting future blood donations.

2. Transfusion-associated circulatory overload

TACO occurs when the volume of a transfused blood component cannot be effectively managed by the recipient, thus leading to progressive respiratory failure, hypoxemia, and dyspnea, along with evidence of right or left heart failure within 2 to 6 hours of blood component transfusion. TACO was the second leading cause of transfusion-related death in the United States from 2009 to 2013, as reported to the USFDA. TACO occurs as a result of the rapid infusion or a large volume of blood product transfusion in the setting of underlying cardiac, renal, and chronic pulmonary disease. It can often present in a similar fashion to TRALI and other causes of acute lung injury, and often proves to be difficult to distinguish between the two diagnoses. Symptoms may include dyspnea, an oxygen saturation of 90% or less, cyanosis, nonproductive cough, orthopnea, hypertension,
tachycardia, left atrial hypertension, congestive heart failure, and evidence of myocardial ischemia with new-onset ST segment and T-wave changes on electrocardiography. Diagnosis involves monitoring for signs of volume overload and checking serum brain natriuretic peptide. Treatment frequently involves decreasing the infusion rate of subsequent transfusions and using diuretics with administration of blood products.

3. Allergic reactions and anaphylaxis

Post-transfusion allergic reactions are usually mild and are caused by IgE-mediated reactions to donor plasma proteins. These reactions are type 1 hypersensitivity reactions that lead to widespread mast cell activation and the systemic release of mediators of inflammation. They occur most often in patients who have received a prior blood component transfusion or in those who have been presensitized to an allergen within the donor blood product (typically serum proteins and medications). The allergic reaction can present with hives, erythema, pruritus, and wheezing. Treatment options involve slowing or stopping the transfusion, with concomitant administration of antihistamines or steroids. A subset of patients with IgA deficiency may have anti-IgA antibodies, which can react with the donor serum, and subsequently cause an anaphylactic reaction. Often, the IgA-deficient patient has not been sensitized to the responsible antigen by prior exposures. These patients typically have anti-IgA antibodies that develop naturally. Symptoms include dyspnea, bronchospasm, hypotension, sweating, flushing, nausea, vomiting, abdominal pain, chest pain, shock, and angioedema. Treatment is primarily supportive, focusing on the maintenance of hemodynamic stability and prevention of cardiovascular collapse with vasopressors, antihistamines, corticosteroids, respiratory support, and mechanical ventilation. IgA-deficient patients should be transfused with washed RBCs or blood products from IgA-deficient donors and with plasma-reduced platelets.

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