Platelet‐derived extracellular vesicles released after trauma promote hemostasis and contribute to DVT in mice

Abstract

Background Traumatic injury can lead to dysregulation of the normal clotting system, resulting in hemorrhagic and thrombotic complications. Platelet activation is robust following traumatic injury and one process of platelet activation is to release of extracellular vesicles (PEV) that carry heterogenous cargo loads and surface ligands. Objectives We sought to investigate and characterize the release and function of PEVs generated following traumatic injury. Methods PEV content and quantity in circulation following trauma in humans and mice was measured using flow cytometry, size exclusion chromatography, and nanoparticle tracking analysis. PEVs were isolated from circulation and the effects on thrombin generation, bleeding time, hemorrhage control, and thrombus formation were determined. Finally, the effect of hydroxychloroquine (HCQ) on PEV release and thrombosis were examined. Results Human and murine trauma results in a significant release of PEVs into circulation compared with healthy controls. These PEVs result in abundant thrombin generation, increased platelet aggregation, decreased bleeding times, and decreased hemorrhage in uncontrolled bleeding. Conversely, PEVs contributed to enhanced venous thrombus formation and were recruited to the developing thrombus site. Interestingly, HCQ treatment resulted in decreased platelet aggregation, decreased PEV release, and reduced deep vein thrombosis burden in mice. Conclusions These data demonstrate that trauma results in significant release of PEVs which are both pro‐hemostatic and pro‐thrombotic. The effects of PEVs can be mitigated by treatment with HCQ, suggesting the potential use as a form of deep vein thrombosis prophylaxis.

Trauma-induced coagulopathy

“…A recent study suggested that myosin can bind factors Xa and Va, thereby increasing their ability to create prothrombinase and generate thrombin 87 . In both preclinical models and patient studies, tissue injury results in the production of extracellular vesicles from multiple cellular sources, which are strongly prothrombotic and may result in coagulation factor depletion after injury 88,89 .…”

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

“…57 Platelet-derived microparticles (PMPs) have shown possible therapeutic benefit in promoting hemostasis. These microparticles of platelet cell membrane are procoagulant, 58,59 and their levels in circulation increase after injury. 60 In one study, patients with only modest increases in the PMP level had a higher incidence of coagulopathy and higher blood transfusion requirement, 61 though another large study found no clear association.…”

“…However, it is also important to note that the techniques for isolating and measuring PMPs can vary widely, which could also explain these varied results. PMPs do seem to hold some importance in TIC, as two studies have shown the efficacy of exogenous PMP delivery in decreasing hemorrhage in mouse hemorrhage models, 59,63 suggesting that a deeper understanding is needed. Alternatively, treatments in TBI aimed at clearing brain-derived microparticles that activate platelets and preventing diffuse microthrombus formation have also shown promise by decreasing the incidence of coagulopathy in preclinical models.…”

Insights into the Procoagulant Profile of Patients with Systemic Lupus Erythematosus without Antiphospholipid Antibodies

“…Most of the patients with SLE from our cohort were treated with hydroxychloroquine, a substance known to have inhibitory effects on platelets [ 22 ]. Nevertheless, we and other authors [ 23 ] have observed that platelets from patients with SLE are basally activated.…”