What is Transfusion-Related Acute Lung Injury (TRALI) and how does it cause increased vascular permeability?

Transfusion-Related Acute Lung Injury (TRALI): Mechanism of Vascular Permeability

TRALI is a serious transfusion complication characterized by non-cardiogenic pulmonary edema occurring within 6 hours of transfusion, caused primarily by antibody-mediated neutrophil activation that damages pulmonary endothelium, leading to increased vascular permeability and fluid leakage into the lungs. 1

What is TRALI?

TRALI is defined as:

• Non-cardiogenic pulmonary edema occurring within 6 hours of blood transfusion
• One of the leading causes of transfusion-related morbidity and mortality
• Characterized by acute respiratory distress with hypoxemia and bilateral pulmonary infiltrates
• Occurs typically within 1-2 hours after transfusion 1, 2

TRALI is distinguished from Transfusion-Associated Circulatory Overload (TACO) by:

• Normal blood pressure or hypotension (vs. hypertension in TACO)
• Normal cardiac function (vs. evidence of cardiac strain in TACO)
• Normal or mildly elevated BNP/NT-proBNP levels (vs. significantly elevated in TACO) 1

Pathophysiology of Vascular Permeability in TRALI

TRALI follows a "two-hit" model that explains how vascular permeability increases:

First Hit: Patient-Related Factors

• Pre-existing inflammation in the patient (the "primed" state)
• This priming increases expression of adhesion molecules on pulmonary endothelium
• Neutrophils become sequestered in the pulmonary microvasculature
• Critically ill patients are at higher risk due to their inflammatory state 3, 4

Second Hit: Transfusion-Related Factors

• Primarily caused by:

  1. Antibody-mediated mechanism (immune-mediated TRALI):

     • HLA class I and II antibodies or Human Neutrophil Antibodies (HNA) in donor plasma
     • These antibodies react with recipient's white blood cells
     • About two-thirds of TRALI cases are immune-mediated 5

  2. Non-antibody mediated factors:

     • Biologically active substances in stored blood products
     • Lipids and other inflammatory mediators 4

The Vascular Permeability Cascade:

1. Antibodies bind to neutrophils and/or pulmonary endothelium
2. This binding triggers neutrophil activation and aggregation
3. Activated neutrophils release:
   • Reactive oxygen species
   • Proteolytic enzymes
   • Inflammatory cytokines
4. These substances damage the pulmonary endothelium
5. Endothelial damage leads to increased expression of TLR4 and ICAM-1 3
6. The damaged endothelium allows fluid to leak into the alveolar spaces
7. This creates an "amplification loop" where initial damage leads to more inflammation 3

Clinical Presentation and Diagnosis

Key clinical features include:

• Acute respiratory distress
• Hypoxemia
• Bilateral pulmonary infiltrates on chest imaging
• Fever may be present
• Normal blood pressure or hypotension
• No evidence of left atrial hypertension 1, 6

Diagnostic criteria require:

• Acute onset within 6 hours of transfusion
• PaO2/FiO2 ≤ 300 mmHg or SpO2 < 90% on room air
• Bilateral infiltrates on chest imaging
• No evidence of circulatory overload or other causes 2, 6

Management and Prevention

Management focuses on supportive care:

• Immediate cessation of transfusion
• Respiratory support (oxygen, mechanical ventilation if needed)
• Avoiding diuretics unless there is concurrent fluid overload
• Judicious fluid management
• Vasopressors for persistent hypotension 1

Prevention strategies include:

• Using male-only plasma when possible
• Screening donors with history of pregnancy for anti-HLA antibodies
• Deferring donors implicated in previous TRALI cases
• Implementing appropriate blood product utilization to avoid unnecessary transfusions 1, 5

Prognosis

• Most patients show clinical improvement within hours
• Complete resolution typically occurs within 96 hours
• TRALI remains one of the top three most common causes of transfusion-related deaths
• The incidence of TRALI is approximately 0.81 per 10,000 transfused blood components 7, 1

Key Pitfalls to Avoid

• Confusing TRALI with TACO (transfusion-associated circulatory overload)
• Failing to report suspected cases to the blood bank
• Administering diuretics inappropriately (may worsen TRALI)
• Overlooking the diagnosis in patients with other risk factors for acute lung injury