Atherothrombosis is a process mediated by dysregulated platelet activation that can cause life-threatening complications and is the leading cause of death by cardiovascular disease. Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein (oxLDL) particles, a process that induces an overt prothrombotic phenotype. The mechanisms by which CD36 promotes platelet activation and thrombosis remain incompletely defined. In this study, we identify a mechanism for CD36 to promote thrombosis by increasing activation of MAPK extracellular signal-regulated kinase 5 (ERK5), a protein kinase known to be exquisitely sensitive to redox stress, through a signaling pathway requiring Src kinases, NADPH oxidase, superoxide radical anion, and hydrogen peroxide. Pharmacologic inhibitors of ERK5 blunted platelet activation and aggregation in response to oxLDL and targeted genetic deletion of ERK5 in murine platelets prevented oxLDL-induced platelet deposition on immobilized collagen in response to arterial shear. Importantly, in vivo thrombosis experiments after bone marrow transplantation from platelet-specific ERK5 null mice into hyperlipidemic apolipoprotein E null mice showed decreased platelet accumulation and increased thrombosis times compared with mice transplanted with ERK5 expressing control bone marrows. These findings suggest that atherogenic conditions critically regulate platelet CD36 signaling by increasing superoxide radical anion and hydrogen peroxide through a mechanism that promotes activation of MAPK ERK5.

Dyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). However, the events downstream of platelet ERK5 are not clear. In this study, we report that oxidized low-density lipoprotein (oxLDL) promotes exposure of procoagulant phosphatidylserine (PSer) on platelet surfaces. Studies using pharmacologic inhibitors indicate that oxLDL-CD36 interaction–induced PSer exposure requires apoptotic caspases in addition to the downstream CD36-signaling molecules Src kinases, hydrogen peroxide, and ERK5. Caspases promote PSer exposure and, subsequently, recruitment of the prothrombinase complex, resulting in the generation of fibrin from the activation of thrombin. Caspase activity was observed when platelets were stimulated with oxLDL. This was prevented by inhibiting CD36 and ERK5. Furthermore, oxLDL potentiates convulxin/glycoprotein VI–mediated fibrin formation by platelets, which was prevented when CD36, ERK5, and caspases were inhibited. Using 2 in vivo arterial thrombosis models in apoE-null hyperlipidemic mice demonstrated enhanced arterial fibrin accumulation upon vessel injury. Importantly, absence of ERK5 in platelets or mice lacking CD36 displayed decreased fibrin accumulation in high-fat diet–fed conditions comparable to that seen in chow diet–fed animals. These findings suggest that platelet signaling through CD36 and ERK5 induces a procoagulant phenotype in the hyperlipidemic environment by enhancing caspase-mediated PSer exposure.

Background Youth violence is a major public health concern in the United States. Hospital-based Violence Intervention Programs (HVIPs) are integral in connecting youth sustaining interpersonal violence-related injuries to medical, mental health, and social services. At our pediatric emergency department, our baseline referral rate to the established HVIP was 32.5%. From November 2018–2019, we aimed to increase the percent of eligible patients referred to our HVIP from 32.5 to 70% for patients aged 7–18 years who present to our Level 1 emergency department/trauma center with a violent injury. Methods For this quality improvement project, we recorded key aspects of the referral process, such as patient eligibility, who placed referrals, and when referrals were placed in relation to the ED admission. Key stakeholders were interviewed to identify specific interventions. Our key interventions were: 1. Educating providers on eligibility requirements. 2. Encouraging nurses to enter consults at the time of admission. 3. Publishing information about program referrals in the weekly nursing newsletter. 4. Updating social workers on eligibility requirements for the HVIP. We used PDSA cycles to inform our project. Our primary outcome measure was the number of eligible patients referred to our HVIP and measures were analyzed using statistical process control charts. Results The HVIP-eligible population had the following demographics: 31.1% female and a mean age 14.3 ± 2.7, 82.6% assaults and 17.4% gunshot wounds. From 11/2018 to 11/2019, there were 78 referrals to the HVIP, out of 167 eligible patients. The referral rate improved from 32.5% pre-interventions to 61.1% post-interventions, showing an 88% increase. Conclusion(s) We noted an increase in referrals to our HVIP following our interventions that centered on educating, advertising, and encouraging. Future studies will focus on analyzing other aspects of the enrollment process, such as obtaining patient consent.

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