Apolipoprotein A-I, elevated in trauma patients, inhibits platelet activation and decreases clot strength

Abstract

Apolipoprotein A-I (ApoA-I) is elevated in the plasma of a subgroup of trauma patients with systemic hyperfibrinolysis. We hypothesize that apoA-I inhibits platelet activation and clot formation. The effects of apoA-I on human platelet activation and clot formation were assessed by whole blood thrombelastography (TEG), platelet aggregometry, P-selectin surface expression, microfluidic adhesion, and Akt phosphorylation. Mouse models of carotid artery thrombosis and pulmonary embolism were used to assess the effects of apoA-I in vivo. The ApoA-1 receptor was investigated with transgenic mice knockouts (KO) for the scavenger receptor class B member 1 (SR-BI). Compared to controls, exogenous human apoA-I inhibited arachidonic acid and collagen-mediated human and mouse platelet aggregation, decreased P-selectin surface expression and Akt activation, resulting in diminished clot strength and increased clot lysis by TEG. ApoA-I also decreased platelet aggregate size formed on a collagen surface under flow. In vivo, apoA-I delayed vessel occlusion in an arterial thrombosis model and conferred a survival advantage in a pulmonary embolism model. SR-BI KO mice significantly reduced apoA-I inhibition of platelet aggregation versus wild-type platelets. Exogenous human apoA-I inhibits platelet activation, decreases clot strength and stability, and protects mice from arterial and venous thrombosis via the SR-BI receptor.

Keywords:

• Hyperfibrinolysis
• microfluidics
• platelet inhibition
• SR-B1 receptor
• thrombelastography

Acknowledgements

WLJ, CRR, and BRB performed all experiments. WLJ and CRR wrote the initial drafts of the manuscript and BRB performed the bulk of writing as well as planning and helping to design the experiments. EEM provided data analyses and clinical correlation with injured patients. KCH performed experiments and identified apoA-I. JC and MK performed experiments and analyzed the TEG data. KBN assisted with experiments and reviewed/edited the manuscript. CCS synthesized and provided data from trauma patient samples, contributed to overall conceptualization of the project, and reviewed/edited the manuscript. AB contributed to overall conceptualization of the project and reviewed/edited the manuscript. JDP provided equipment, supplies, and reagents, as well as contributing to overall conceptualization of the project, experiment planning, and reviewing/editing the manuscript. All authors have reviewed, and approved, the manuscript for submission.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Branchford: HRSA/MCHB H30MC24049Jones, Ramos, Coleman: NIGMS, NIH: T32-GM008315.Moore, Silliman, Hansen, Banerjee: NIGMS, NIH: grants P50 GM49222 and 1RM1GM131968, NHLBI R01 HL120728,R01 HL139825,UM1 HL120877, NIH: UM1 HL120877 and Department of Defense: W81XWH-12-2-08.Di Paola: HRSA/MCHB H30MC24049, University of Colorado School of Medicine Postle Endowed Chair in Cancer and Blood Disorders, and NHLBI, NIH: R01 HL120728, R01 HL1398; Maternal and Child Health Bureau.