Platelets are dispensable for antibody‐mediated transfusion‐related acute lung injury in the mouse

Abstract

Role of platelets in immunological transfusion‐related acute lung injury (TRALI) is debated. Immunological TRALI was tested in mice exhibiting severe thrombocytopenia or platelet dysfunction. Platelets are required to prevent lung hemorrhage but not edema formation and respiratory distress. Platelets are dispensable for the initiation and development of TRALI. Summary BackgroundTransfusion‐related acute lung injury (TRALI) is a serious transfusion‐related complication. Previous conflicting studies have indicated that platelets are either crucial or dispensable for TRALI. ObjectivesTo evaluate the role of platelets in major histocompatibility complex (MHC) I‐induced‐TRALI. MethodsAntibody‐mediated TRALI was experimentally induced in mice by lipopolysaccharide priming followed by the administration of an anti‐MHC I mAb. ResultsTRALI was tested in the context of severe thrombocytopenia provoked by the administration of diphtheria toxin (DT) in transgenic iDTR mice selectively expressing DT receptor in megakaryocytes. The pathologic responses occurring within the first 10 min following the injection of the anti‐MHC I mAb, i.e. the severity of lung edema and the drop in aortic blood oxygenation, were similar in severely thrombocytopenic DT‐iDTR and control mice. At later times, mortality was nevertheless increased in DT‐iDTR mice, owing to lung hemorrhages. When less severe thrombocytopenia was induced with an antiplatelet mAb, TRALI started and developed similarly as in control mice, but hemorrhages were absent. Furthermore, when platelet functions were defective because of administration of aspirin or clopidogrel, or because of glycoprotein (GP)IIbIIIa deficiency, TRALI still developed but no lung hemorrhages were observed. In contrast, when GPVI was immunodepleted, TRALI still occurred, but was occasionally accompanied by hemorrhages. ConclusionsPlatelets are dispensable for the initiation and development of MHC I‐induced TRALI. Although they do not protect against the disruption of the vascular endothelial cell barrier and the subsequent plasma leakage and edema formation, platelets are essential to prevent more serious damage resulting in hemorrhages in alveoli.

Platelet depletion limits the severity but does not prevent the occurrence of experimental transfusion‐related acute lung injury

“…Hechler et al show unequivocally that platelets are dispensable for TRALI induction, a result that is consistent with ours. However, P2Y12 receptor inhibition with clopidogrel seems to suggest a role for the receptor, although limited, in the physiopathology of TRALI.…”

“…Therefore, platelets are not critical in the pathophysiology of TRALI, as underlined by consistently altered physiological indicators. Other studies, based on the induction of severe thrombocytopenia in ad hoc genetically modified mice, reported significantly higher mortality rates following TRALI induction, most likely explained by the excessive hemorrhage rather than by the immune pathophysiology linked to TRALI …”

“…Some studies suggest that platelets play a significant role in the pathogenesis of TRALI, while other reports show they are dispensable . Nevertheless, inflammation remains a major risk factor for TRALI, the syndrome resulting from a surge of activity in inflammatory cells .…”

Measuring and interpreting platelet-leukocyte aggregates

“…However, even low platelet levels (approx. 6%–10% residual platelets) are sufficient to prevent haemorrhagic complications, indicating a low threshold platelet level to maintain basic haemostatic platelet function (122). In response to local and systemic triggers, however, platelets can also facilitate leukocyte recruitment towards sites of injury and thereby support inflammatory responses and defence mechanisms against invading pathogens.…”

The Role of Complement in Transfusion-Related Acute Lung Injury

“…Much more research is required to understand the specific nature of the pathogenic immune responses occurring in TRALI. The complexity in dissecting the pathophysiology of TRALI is further illustrated by controversies which have arisen, such as the involvement of recipient platelets [19,20]. One of the other controversies appears to be the involvement of the complement system in TRALI, which will be the focus of the current article.…”