1. Non-Antibody Mediated TRALI
Kevin Jenkins, MD, MBA, MHSA
Vanderbilt University Medical Center
12/10/14

2. Overview What is TRALI Clinical presentation Prognosis
Differential Diagnosis
Standard therapy
Traditionally accepted mechanism (direct antibody mediated)
Alternative mechanisms (indirect antibody and antibody independent mechanism)

3. What is TRALI TRALI - transfusion related acute lung injury
Acute lung injury occurring within 6 hours of completion of transfusion of blood component
No pre-existing acute lung injury
No other associated risk factors for acute lung injury
Acute lung injury
New onset
Hypoxemia SpO2 <90% or PaO2/FiO2 <300 mm Hg on room air
Bilateral infiltrates on chest X-ray

4. Presentation Rapid onset of dyspnea and tachypnea
May be associated fever, cyanosis, and hypotension
Clinical exam reveals respiratory distress and pulmonary crackles
CXR shows evidence of bilateral pulmonary edema with bilateral patchy infiltrates
this may rapidly progress to complete "white out" indistinguishable from Acute Respiratory Distress Syndrome (ARDS)

5. Prognosis Lung injury is generally transient
PO2 levels returning to pretransfusion levels within hours
CXR returning to normal within 96 hours
Significant mortality rate, often approximated at 5 to 10%
Incidence has not been well established due to difficulty in defining the syndrome and to variable reporting mechanisms
Estimated the overall frequency between 1/1,120 and 1/57,810 units transfused. However, there is wide discrepancy in the literature with the reported frequency is as low as 1/557,000 RBC units and as high as 1/432 platelet units

6. Differential Diagnosis
transfusion-associated circulatory overload (TACO)
cardiogenic edema
allergic and anaphylactic transfusion reactions
bacteremia/sepsis due to transfusion of bacterially contaminated blood products

7. Differential Diagnosis
TRALI may be distinguished from TACO and cardiogenic pulmonary edema by the absence of signs of circulatory overload such as:
normal central venous pressure (CVP)
normal pulmonary capillary wedge pressure (PCWP)
clinical response to diuretics suggests TACO rather than TRALI

8. Differential Diagnosis
Allergic and anaphylactic transfusion reactions may be distinguished by:
laryngeal edema or bronchospasm with wheezing
normal CXR
Transfusion transmitted bacteremia my present with fever, hypotension, and culminate in severe sepsis with associated acute lung injury which may be difficult to distinguish from TRALI

9. Standard Therapy Primarily supportive
Mild cases may respond to supplemental oxygen therapy
Severe forms may require mechanical ventilation and ICU support
As with ARDS there is no role for diuretics or corticosteroids.

10. Direct Antibody Mediated Mechanism
Infusion of donor anti-HLA (human leukocyte antigens) or anti- HNA (human neutrophil antigens) antibodies directly cause complement activation, resulting in the influx of neutrophils into the lung, followed by neutrophil activation and release of cytotoxic agents, with subsequent endothelial damage and capillary leak.
Donor derived antibodies to HLA class I antigens and neutrophils have been demonstrated in up to 89% of TRALI cases examined in the literature.

11. Direct Antibody Mediated Mechanism

12. Indirect and Antibody Independent Mechanism
Priming events such as infection, cytokine administration, recent surgery, or massive transfusion causes activation of the pulmonary endothelium
leads to the sequestration of primed neutrophils to the activated pulmonary endothelium.
Infusion of donor derived anti-HLA or anti-HNA antibodies against antigens on the neutrophil surface and/or biological response modifiers (e.g., lipids) activate the neutrophils, causing neutrophil-mediated endothelial damage

13. Indirect and Antibody Independent Mechanism

14. Neutrophil Activation

15. Lipid Mediators
During leukocyte reduced RBC (LR-RBC) storage non-polar lipids accumulate
Studies have demonstrated that these isolated lipids can activate neutrophils
Neutrophil activation was shown to occur using the isolated lipids from LR-RBC storage day 42 but not from storage day 1
These lipids have been identified as arachidonic acid and 5, 12, 15- hydroxyeicosatetraenoic acid (HETE)

16. Lipid Mediators

17. Lipid Mediators
Are these lipids a significant factor in TRALI?

18. Lipid Mediators
One study compared standard leukoreduction of RBC units to special filtration which duplicated standard leukoreduction but also showed decreased accumulation of priming activity of the supernatant by lipids
With special filtration at storage day 42 there was a 50% reduction in 5-HETE with no change in the arachidonic acid level when compared to standard LR-RBC's at day 42
It was speculated that the filtration reduced enzymes necessary for conversion from arachidonic acid to 5-HETE

19. Lipid Mediators
Is there a difference in the priming ability of arachidonic acid versus 5-HETE?

20. Lipid Mediators
The day 42 supernatant with reduced 5-HETE and the day 42 supernatant from standard LR-RBC's were used in a TRALI animal model
The 5-HETE reduced supernatant mitigated TRALI in the animal model compared to the supernatant from standard LR-RBC's
These studies suggest that accumulation of lipids, especially 5-HETE, in stored RBC's may play an important role in antibody independent TRALI

21. Additional Evidence Lipoxins demonstrate anti-inflammatory action
They are enzymatically derived from arachidonic acid and 15-HETE is an important precursor
Lipoxins are formed by a combination of 12-lipoxygenase from platelets and LTA4 from neutrophils which is converted to LXA4 and LXAB

22. Additional Evidence
Epi-lipoxins are derived from arachidonic acid by non-enzymatic peroxidation
15-epi-lipoxin A4 is induced by aspirin and can mimic many of the anti-inflammatory action of native lipoxins

23. Additional Evidence
Aspirin has known efficacy in the indirect TRALI model
There is evidence that aspirin diverts metabolism of arachidonic acid from eicosanoids to 15-epi-LXA4
This supports the findings in other studies where reduction of 5-HETE mitigated TRALI

24. Therapeutic Possibilities
This proposed mechanism of non-antibody mediated TRALI provides possible therapeutic points of intervention such as previously described with aspirin
Special filtration of RBC's and mitigation of TRALI by inhibition of lipid metabolism and accumulation
Additional research in this area is being performed

25. Summary
TRALI is inconsistently recognized making the true incidence difficult to define
There are at least two proposed mechanisms for TRALI which may or may not act symbiotically or in mutual exclusion
Lipids accumulate in stored RBC's and have been shown to cause TRALI in animal models
The mechanism of lipid induced TRALI provides possible therapeutic opportunities

26. References http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636009/
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