Plasma proteomic profile associated with platelet dysfunction after trauma

Abstract

Background Coagulopathic bleeding is a major cause of mortality after trauma, and platelet dysfunction contributes to this problem. The causes of platelet dysfunction are relatively unknown, but a great deal can be learned from the plasma environment about the possible pathways involved. Objective Describe the changes in plasma proteomic profile associated with platelet dysfunction after trauma. Methods Citrated blood was collected from severely injured trauma patients at the time of their arrival to the Emergency Department. Samples were collected from 110 patients, and a subset of twenty‐four patients was identified by a preserved (n = 12) or severely impaired (n = 12) platelet aggregation response to five different agonists. Untargeted proteomics was performed by nanoflow liquid chromatography tandem mass spectrometry. Protein abundance levels for each patient were normalized to total protein concentration to control for hemodilution by crystalloid fluid infusion prior to blood draw. Results Patients with platelet dysfunction were more severely injured but otherwise demographically similar to those with retained platelet function. Of 232 proteins detected, twelve were significantly different between groups. These proteins fall into several broad categories related to platelet function, including microvascular obstruction with platelet activation, immune activation, and protease activation. Conclusions This observational study provides a description of the change in proteomic profile associated with platelet dysfunction after trauma and identifies twelve proteins with the most profound changes. The pathways involving these proteins are salient targets for immediate investigation to better understand platelet dysfunction after trauma and identify targets for intervention.

Platelet dysfunction after trauma: From mechanisms to targeted treatment

“…In line with this, high HMGB1 levels are associated with thrombosis and adverse outcomes 94,98,100 . Another DAMP activating TLR4 and RAGE that has recently gained interest with regards to trauma‐induced platelet dysfunction is S100A8/A9 96,101–103 . S100A8/A9 is a heterodimeric, intracellular protein, especially abundant in neutrophils, where it comprises almost half of the cytoplasm proteins.…”

“…94,98,100 Another DAMP activating TLR4 and RAGE that has recently gained interest with regards to trauma-induced platelet dysfunction is S100A8/A9. 96,[101][102][103] S100A8/A9 is a heterodimeric, intracellular protein, especially abundant in neutrophils, where it comprises almost half of the cytoplasm proteins. Platelets may have some capacity for de novo synthesis of S100A8/A9, but it is unknown if they are the main source after trauma.…”

“…Histones can activate platelets and facilitate platelet‐dependent thrombin generation 95 . Histones can induce platelet dysfunction after trauma 96 . Particularly, histone H4 has been shown to induce platelet ballooning and contribute to the formation of platelet EVs 7 .…”

“…95 Histones can induce platelet dysfunction after trauma. 96 Particularly, histone H4 has been shown to induce platelet ballooning and contribute to the formation of platelet EVs. 7 Histones have also been linked to the development of thrombosis and organ dysfunction after traumatic injury.…”

Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma

“…Finally, we did not normalize total protein concentration to control for hemodilution. This method has been utilized in similar proteomic studies and may provide distinct information [ 159 ].…”