Kevin Jenkins MD MBA MHSA Vanderbilt University Medical Center 121014 Overview What is TRALI Clinical presentation Prognosis Differential Diagnosis Standard therapy Traditionally accepted mechanism direct antibody mediated ID: 1040455
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1. Non-Antibody Mediated TRALIKevin Jenkins, MD, MBA, MHSAVanderbilt University Medical Center12/10/14
2. OverviewWhat is TRALIClinical presentationPrognosisDifferential DiagnosisStandard therapyTraditionally accepted mechanism (direct antibody mediated)Alternative mechanisms (indirect antibody and antibody independent mechanism)
3. What is TRALITRALI - transfusion related acute lung injuryAcute lung injury occurring within 6 hours of completion of transfusion of blood componentNo pre-existing acute lung injuryNo other associated risk factors for acute lung injuryAcute lung injuryNew onsetHypoxemia SpO2 <90% or PaO2/FiO2 <300 mm Hg on room airBilateral infiltrates on chest X-ray
4. PresentationRapid onset of dyspnea and tachypneaMay be associated fever, cyanosis, and hypotensionClinical exam reveals respiratory distress and pulmonary cracklesCXR shows evidence of bilateral pulmonary edema with bilateral patchy infiltratesthis may rapidly progress to complete "white out" indistinguishable from Acute Respiratory Distress Syndrome (ARDS)
5. PrognosisLung injury is generally transientPO2 levels returning to pretransfusion levels within 48 -96 hoursCXR returning to normal within 96 hoursSignificant 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 mechanismsEstimated 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 Diagnosistransfusion-associated circulatory overload (TACO)cardiogenic edemaallergic and anaphylactic transfusion reactionsbacteremia/sepsis due to transfusion of bacterially contaminated blood products
7. Differential DiagnosisTRALI 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 DiagnosisAllergic and anaphylactic transfusion reactions may be distinguished by: laryngeal edema or bronchospasm with wheezing normal CXRTransfusion 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 TherapyPrimarily supportiveMild cases may respond to supplemental oxygen therapySevere forms may require mechanical ventilation and ICU supportAs with ARDS there is no role for diuretics or corticosteroids.
10. Direct Antibody Mediated MechanismInfusion 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 MechanismPriming events such as infection, cytokine administration, recent surgery, or massive transfusion causes activation of the pulmonary endotheliumleads 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 MediatorsDuring leukocyte reduced RBC (LR-RBC) storage non-polar lipids accumulateStudies have demonstrated that these isolated lipids can activate neutrophilsNeutrophil activation was shown to occur using the isolated lipids from LR-RBC storage day 42 but not from storage day 1These lipids have been identified as arachidonic acid and 5, 12, 15-hydroxyeicosatetraenoic acid (HETE)
16. Lipid Mediators
17. Lipid MediatorsAre these lipids a significant factor in TRALI?
18. Lipid MediatorsOne 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 MediatorsIs there a difference in the priming ability of arachidonic acid versus 5-HETE?
20. Lipid MediatorsThe 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 EvidenceLipoxins demonstrate anti-inflammatory actionThey are enzymatically derived from arachidonic acid and 15-HETE is an important precursorLipoxins are formed by a combination of 12-lipoxygenase from platelets and LTA4 from neutrophils which is converted to LXA4 and LXAB
22. Additional EvidenceEpi-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 EvidenceAspirin has known efficacy in the indirect TRALI model There is evidence that aspirin diverts metabolism of arachidonic acid from eicosanoids to 15-epi-LXA4This supports the findings in other studies where reduction of 5-HETE mitigated TRALI
24. Therapeutic PossibilitiesThis proposed mechanism of non-antibody mediated TRALI provides possible therapeutic points of intervention such as previously described with aspirinSpecial filtration of RBC's and mitigation of TRALI by inhibition of lipid metabolism and accumulationAdditional research in this area is being performed
25. SummaryTRALI is inconsistently recognized making the true incidence difficult to defineThere are at least two proposed mechanisms for TRALI which may or may not act symbiotically or in mutual exclusionLipids accumulate in stored RBC's and have been shown to cause TRALI in animal modelsThe mechanism of lipid induced TRALI provides possible therapeutic opportunities
26. Referenceshttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636009/ http://www.bloodjournal.org/content/117/5/1463?sso-checked=true http://onlinelibrary.wiley.com.proxy.library.vanderbilt.edu/doi/10.1111/anae.12891/full http://www.bloodjournal.org.proxy.library.vanderbilt.edu/content/123/22/3488.long?sso-checked=true http://www.pubfacts.com/detail/21615744/Identification-of-lipids-that-accumulate-during-the-routine-storage-of-prestorage-leukoreduced-red-bhttp://www.transfusionmedicine.ca/articles/transfusion-related-acute-lung-injury-trali