Pathophysiologic Mechanisms, Prevention and Treatment of Antibody Independent Transfusion Related Acute Lung Injury
Bibliographic record
Abstract
A key component of the ability to resuscitate or revive badly injured or ill patients involves transfusion of blood products. Though blood products offer incredible capacity to benefit patients in need, they are not without risk. Though infrequent, in 1 in 5000 transfusions, one of the most lethal (mortality ≈ 10%) and thus serious adverse events associated with receiving a blood transfusion is transfusion related acute lung injury (TRALI). TRALI causes chest infiltrates and hypoxia in part due to lung endothelial cell barrier disruption. Mechanistically, TRALI involves pathogenic antibodies or biological response modifiers (such as sphingolipids) from donor blood which damage transfusion recipients’ lungs. Antibody-mediated TRALI rates have fallen since interventions to reduce the amounts of antibodies in donated blood have been initiated. Antibody-independent-TRALI is hard to identify, let alone eliminate. To gain insights into antibody-independent-TRALI we elected to study platelet mediated TRALI. Platelets, especially those stored for extended periods prior to transfusion represent the highest risk cellular blood products for causing TRALI. We hypothesize that aged platelets are especially injurious due to key distinctions: 1) they contain more of the acid sphingomyelinase (ASM) derived sphingolipid ceramide (known to cause lung injury) and 2) have increased production of extracellular vesicles (EVs; small sub-cellular particles released from platelets during storage which we propose to mediate TRALI). TRALI’s low clinical incidence means studying this condition prospectively at the bedside is very challenging. As a result, we developed a novel murine platelet antibody-independent-TRALI model of TRALI as well as an in vitro human pulmonary microvascular endothelial cell injury model. Within these models we show that aged (stored 5-7 days), not fresh (stored 1 day) platelets or platelet EVs are able to mediate TRALI through an ASM/ceramide dependent mechanism. Present treatment of TRALI involves supportive care with oxygen and positive pressure ventilation. Our study offers pathophysiologic insights which may translate into novel therapies, for example inhibition of ASM during platelet storage or supplementation of the barrier-protective sphingolipid sphingosine-1-phosphate (S1P) within aged platelets may prove effective strategies to prevent or even treat antibody-independent-TRALI.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".