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J Trauma Acute Care Surg. 2019 Feb 13. doi: 10.1097/TA.0000000000002230. [Epub ahead of print]

Regulation of Endothelial Cell Permeability by Platelet-Derived Extracellular Vesicles.

Author information

1
Department of Laboratory Medicine, University of California, San Francisco, CA.
2
Blood Systems Research Institute, San Francisco, CA.
3
Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX.
4
Department of Surgery, University of California San Francisco, San Francisco, CA.
5
Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.
6
Department of Surgery, Oregon Health Science & University (OHSU), Portland, OR.

Abstract

BACKGROUND:

Platelet (Plt) derived-extracellular vesicles (Plt-EVs) have hemostatic properties similar to Plts. In addition to hemostasis, Plts also function to stabilize the vasculature and maintain endothelial cell (EC) barrier integrity. We hypothesized that Plt-EVs would inhibit vascular endothelial cell permeability, similar to fresh Plts. To investigate this hypothesis we utilized in vitro and in vivo models of vascular endothelial compromise and bleeding.

METHODS:

In vitro: Plt-EVs were isolated by ultracentrifugation and characterized for Plt markers and particle size distribution. Effects of Plts and Plt-EVs on endothelial barrier function was assessed by trans - endothelial electrical resistance (TEER) measurements and histological analysis of endothelial junction proteins. Hemostatic potential of Plt-EVs and Plts were assessed by multiple electrode Plt aggregometry. In vivo: The effects of Plts and Plt-EVs on vascular permeability and bleeding were assessed in NOD-SCID mice by an established Miles Assay of vascular permeability and a tail snip bleeding assay.

RESULTS:

In vitro: Plt-EVs displayed exosomal size distribution and expressed Plt specific surface markers. Plts and Plt-EVs decreased EC permeability and restored EC junctions after thrombin challenge. Multiplate aggregometry revealed that Plt-EVs enhanced Thrombin Receptor Activating Peptide (TRAP) mediated aggregation of whole blood, whereas Plts enhanced TRAP, Arachidonic Acid (ASPI), Collagen, and Adenosine Diphosphate (ADP) mediated aggregation. In vivo: Plt-EVs are equivalent to Plts in attenuating VEGF-A induced vascular permeability and uncontrolled blood loss in a tail snip hemorrhage model.

CONCLUSION:

Our study is the first to report that Plt-EVs might provide a feasible product for transfusion in trauma patients to attenuate bleeding, inhibit vascular permeability and mitigate the endotheliopathy of trauma (EOT).

STUDY TYPE:

Original Article LEVEL OF EVIDENCE: This is a pre-clinical study so it does not confirm to the level of evidence table for all clinical studies and case reports.

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