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Platelet inhibition by low-dose aspirin is not influenced by body mass or weight

Heffron, Sean P; Windheim, Joseph; Barrett, Tessa J; Voora, Deepak; Berger, Jeffrey S
Aspirin's clinical efficacy may be influenced by body weight and mass. Although inadequate platelet inhibition by aspirin is suggested as responsible, evidence for this in non-diabetic patients is sparse. We investigated the influence of body weight and mass on aspirin's inhibition of platelet aggregation in healthy adults without diabetes. Cohort one (NYU, n = 84) had light transmission aggregometry (LTA) of platelet-rich plasma to submaximal adenosine diphosphate (ADP) and arachidonic acid (AA) before and following 1 week of daily 81 mg non-enteric coated aspirin. Subjects in the validation cohort (Duke, n = 66) were randomized to 81 mg or 325 mg non-enteric coated aspirin for 4 weeks, immediately followed by 4 weeks of the other dose, with LTA to submaximal collagen, ADP, and AA before and after each dosage period. Body mass index (BMI) range was 18.0-57.5 kg/m2 and 25% were obese. Inhibition of platelet aggregation was similar irrespective of BMI, body weight and aspirin dose. There was no correlation between platelet aggregation before or after aspirin with BMI or body weight. Our data demonstrate that aspirin produces potent inhibition of direct and indirect COX1-mediated platelet aggregation in healthy adults without diabetes regardless of body weight or mass - suggesting that other mechanisms explain lower preventive efficacy of low-dose aspirin with increasing body weight/mass.
PMID: 35768902
ISSN: 1369-1635
CID: 5281232

A Randomized Open Label Clinical Trial of Lipid-Lowering Therapy in Psoriasis to Reduce Vascular Endothelial Inflammation

Garshick, Michael S; Drenkova, Kamelia; Barrett, Tessa J; Schlamp, Florencia; Fisher, Edward A; Katz, Stuart; Jelic, Sanja; Neimann, Andrea L; Scher, Jose U; Krueger, James; Berger, Jeffrey S
PMID: 34808233
ISSN: 1523-1747
CID: 5063372

Platelets contribute to disease severity in COVID-19

Barrett, Tessa J; Bilaloglu, Seda; Cornwell, Macintosh; Burgess, Hannah M; Virginio, Vitor W; Drenkova, Kamelia; Ibrahim, Homam; Yuriditsky, Eugene; Aphinyanaphongs, Yin; Lifshitz, Mark; Xia Liang, Feng; Alejo, Julie; Smith, Grace; Pittaluga, Stefania; Rapkiewicz, Amy V; Wang, Jun; Iancu-Rubin, Camelia; Mohr, Ian; Ruggles, Kelly; Stapleford, Kenneth A; Hochman, Judith; Berger, Jeffrey S
OBJECTIVE:Heightened inflammation, dysregulated immunity, and thrombotic events are characteristic of hospitalized COVID-19 patients. Given that platelets are key regulators of thrombosis, inflammation, and immunity they represent prime candidates as mediators of COVID-19-associated pathogenesis. The objective of this study was to understand the contribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the platelet phenotype via phenotypic (activation, aggregation) and transcriptomic characterization. APPROACH AND RESULTS/UNASSIGNED:In a cohort of 3915 hospitalized COVID-19 patients, we analyzed blood platelet indices collected at hospital admission. Following adjustment for demographics, clinical risk factors, medication, and biomarkers of inflammation and thrombosis, we find platelet count, size, and immaturity are associated with increased critical illness and all-cause mortality. Bone marrow, lung tissue, and blood from COVID-19 patients revealed the presence of SARS-CoV-2 virions in megakaryocytes and platelets. Characterization of COVID-19 platelets found them to be hyperreactive (increased aggregation, and expression of P-selectin and CD40) and to have a distinct transcriptomic profile characteristic of prothrombotic large and immature platelets. In vitro mechanistic studies highlight that the interaction of SARS-CoV-2 with megakaryocytes alters the platelet transcriptome, and its effects are distinct from the coronavirus responsible for the common cold (CoV-OC43). CONCLUSIONS:Platelet count, size, and maturity associate with increased critical illness and all-cause mortality among hospitalized COVID-19 patients. Profiling tissues and blood from COVID-19 patients revealed that SARS-CoV-2 virions enter megakaryocytes and platelets and associate with alterations to the platelet transcriptome and activation profile.
PMID: 34538015
ISSN: 1538-7836
CID: 5018172

Effect of antiplatelet therapy on monocyte-platelet aggregates [Meeting Abstract]

Rolling, C C; Myndzar, K; El, Bannoudi H; Schwartz, T; Barrett, T J; Berger, J S
Background : In addition to their role in thrombosis and hemostasis, platelets are key mediators of inflammation and altered immunity. Circulating monocyte-platelet aggregates (MPA) represent the crossroads between thrombosis and inflammation and may represent a therapeutic target. While antiplatelet therapy (APT) reduces platelet activity and thrombosis, its effect on MPA is uncertain. Aims : To analyze the effect of APT on MPA in vitro. Methods : The effect of different platelet-activating agonists (thromboxane analog U-46619, ADP, PAR4, collagen, and epinephrine) on MPA formation in whole blood (WB) was measured via flow cytometry. Agonist-stimulated WB was incubated in the presence of inhibitors against P-selectin, PSGL-1, PAR1 (ML161), P2Y12 (AZD1283), GPIIb/IIIa (eptifibatide), acetyl salicylic acid (ASA), and dipyridamole and assessed for MPA formation. RNA-Seq data sets of monocytes incubated with healthy platelet releasates (PR) were used to identify platelet-induced upregulation of monocyte transcripts and were validated by RT-qPCR in monocyte-PR co-incubation assays in the presence of APT. Results : Circulating MPA are increased in prothrombotic and inflammatory diseases including the most recent COVID-19. Monocytes aggregated to platelets have more CD40 and tissue factor expression than monocytes not aggregated to platelets ( P < 0.05 for each comparison). As expected, targeting P-selectin (85.4% reduction) and PSGL-1 (88.2% reduction) had the greatest attenuation of MPA. Among platelet inhibitors, P2Y12 inhibition was most effective in lowering MPA formation (30.7% reduction) (figure 1). Flow cytometry analysis of MPA. Incubation of monocytes with platelet releasate induced upregulation of inflammatory mRNA transcripts suppressor of cytokine signaling 3 ( SOCS3 ) and o ncostatin m ( OSM ). Following pretreatment of platelets with APT, both GPIIb/IIIa and P2Y12 inhibition was associated with lower expression of SOCS3 and OSM (figure 2) . SOCS3 and OSM in monocytes incubated with APT-treated PR. Conclusions : Circulating MPA represent a crossroad of platelet and monocyte activation. We show that APT is associated with both reduced MPA formation and platelet-induced monocyte activation
EMBASE:636407806
ISSN: 2475-0379
CID: 5044652

History of cancer is associated with increased platelet activity and atherothrombosis in patients with peripheral arterydisease [Meeting Abstract]

Cofer, L; Barrett, T; Xia, Y; Luttrell-Williams, E; Myndzar, K; Wong, K -K; Wise, D; Berger, J
Background : Cancer and peripheral artery disease (PAD) share common risk factors and are frequently coprevalent. Platelets are culprits in the pathogenesis of PAD and mediators of arterial cardiovascular events. The association between platelet activity and cardiovascular events in patients with versus without cancer is uncertain. Aims : To investigate if cancer history is associated with platelet activity and incident cardiovascular events in a cohort of patients with PAD. Methods : 289 patients with PAD undergoing lower extremity revascularization enrolled in the Platelet Activity and Cardiovascular Events (PACE) study were followed longitudinally for a median of 18 months. Prior to revascularization, patients had platelet activity measured via light transmission aggregometry in response to ADP, collagen, epinephrine, and serotonin. The primary clinical outcome was myocardial infarction (MI). Other endpoints were MI/stroke and major adverse cardiovascular event (MACE; MI/stroke/death). Results : 64 patients (22.1%) reported a cancer history, 10 (15.6%) with metastatic and 10 (15.6%) with active cancer. Patients with (versus without) cancer history were older, less often Hispanic, and less frequently current smokers ( P < 0.05 for each). There was no difference in prevalent diabetes, coronary artery disease, hypertension, or antiplatelet therapy between groups. Platelet aggregation in response to submaximal ADP (0.4 muM, 1.0 muM), collagen (0.2 mug/ml, 1.0 ug/ml), and serotonin (10 muM) was higher in patients with versus without cancer history. Consistently, patients with cancer history experienced more incident MI (18.8% vs. 7.6%, P = 0.02), MI/stroke (25.0% vs. 9.3%, P = 0.002), and MACE (35.9% vs. 22.2%, P = 0.04). After adjustment for age, sex, race/ethnicity, smoking, diabetes, prior stroke, CAD, revascularization procedure, and antiplatelet therapy, patients with cancer history were at higher hazard for MI, MI/stroke, and MACE (Figure). The association between cancer and thrombotic events was most apparent in patients with metastatic and active cancer (Figure). Conclusions : In patients with PAD, cancer history was associated with increased platelet aggregation and risk for arterial thrombotic events
EMBASE:636405232
ISSN: 2475-0379
CID: 5044682

Platelets amplify endotheliopathy in COVID-19

Barrett, Tessa J; Cornwell, MacIntosh; Myndzar, Khrystyna; Rolling, Christina C; Xia, Yuhe; Drenkova, Kamelia; Biebuyck, Antoine; Fields, Alexander T; Tawil, Michael; Luttrell-Williams, Elliot; Yuriditsky, Eugene; Smith, Grace; Cotzia, Paolo; Neal, Matthew D; Kornblith, Lucy Z; Pittaluga, Stefania; Rapkiewicz, Amy V; Burgess, Hannah M; Mohr, Ian; Stapleford, Kenneth A; Voora, Deepak; Ruggles, Kelly; Hochman, Judith; Berger, Jeffrey S
[Figure: see text].
PMCID:8442885
PMID: 34516880
ISSN: 2375-2548
CID: 5012252

Chronic stress primes innate immune responses in mice and humans

Barrett, Tessa J; Corr, Emma M; van Solingen, Coen; Schlamp, Florencia; Brown, Emily J; Koelwyn, Graeme J; Lee, Angela H; Shanley, Lianne C; Spruill, Tanya M; Bozal, Fazli; de Jong, Annika; Newman, Alexandra A C; Drenkova, Kamelia; Silvestro, Michele; Ramkhelawon, Bhama; Reynolds, Harmony R; Hochman, Judith S; Nahrendorf, Matthias; Swirski, Filip K; Fisher, Edward A; Berger, Jeffrey S; Moore, Kathryn J
Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.
PMID: 34496250
ISSN: 2211-1247
CID: 5012012

Reshaping of the gastrointestinal microbiome alters atherosclerotic plaque inflammation resolution in mice

Garshick, Michael S; Nikain, Cyrus; Tawil, Michael; Pena, Stephanie; Barrett, Tessa J; Wu, Benjamin G; Gao, Zhan; Blaser, Martin J; Fisher, Edward A
Since alterations in the intestinal microbiota may induce systemic inflammation and polarization of macrophages to the M1 state, the microbiome role in atherosclerosis, an M1-driven disease, requires evaluation. We aimed to determine if antibiotic (Abx) induced alterations to the intestinal microbiota interferes with atherosclerotic plaque inflammation resolution after lipid-lowering in mice. Hyperlipidemic Apoe-/- mice were fed a western diet to develop aortic atherosclerosis with aortas then transplanted into normolipidemic wild-type (WT) mice to model clinically aggressive lipid management and promote atherosclerosis inflammation resolution. Gut microbial composition pre and post-transplant was altered via an enteral antibiotic or not. Post aortic transplant, after Abx treatment, while plaque size did not differ, compared to Apoe-/- mice, Abx- WT recipient mice had a 32% reduction in CD68-expressing cells (p = 0.02) vs. a non-significant 12% reduction in Abx+ WT mice. A trend toward an M1 plaque CD68-expresing cell phenotype was noted in Abx+ mice. By 16S rRNA sequence analysis, the Abx+ mice had reduced alpha diversity and increased Firmicutes/Bacteroidetes relative abundance ratio with a correlation between gut Firmicutes abundance and plaque CD68-expressing cell content (p < 0.05). These results indicate that in a murine atherosclerotic plaque inflammation resolution model, antibiotic-induced microbiome perturbation may blunt the effectiveness of lipid-lowering to reduce the content of plaque inflammatory CD68-expressing cells.
PMCID:8076321
PMID: 33903700
ISSN: 2045-2322
CID: 4889262

CCL20 in Psoriasis: A Potential Biomarker of Disease Severity, Inflammation, and Impaired Vascular Health

Elnabawi, Youssef A; Garshick, Michael S; Tawil, Michael; Barrett, Tessa J; Fisher, Edward A; Lo Sicco, Kristen; Neimann, Andrea L; Scher, Jose U; Krueger, James; Berger, Jeffrey S
BACKGROUND:Psoriasis is associated with increased cardiovascular risk that is not captured by traditional pro-inflammatory biomarkers. OBJECTIVE:To investigate the relationship between psoriasis area and severity index (PASI), circulating pro-inflammatory biomarkers, and vascular health in psoriasis. METHODS:In psoriasis and age, sex-matched controls, 273 proteins were analyzed utilizing the OLINK platform, while vascular endothelial inflammation and health was measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS:= 48.18, p<0.001) in predicting vascular endothelial inflammation. LIMITATIONS/CONCLUSIONS:Our study was observational and does not allow for causal inference in the relationship between CCL20 and cardiovascular risk. CONCLUSION/CONCLUSIONS:We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.
PMID: 33259876
ISSN: 1097-6787
CID: 4694102

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice

Voisin, Maud; Shrestha, Elina; Rollet, Claire; Nikain, Cyrus A; Josefs, Tatjana; Mahé, Mélanie; Barrett, Tessa J; Chang, Hye Rim; Ruoff, Rachel; Schneider, Jeffrey A; Garabedian, Michela L; Zoumadakis, Chris; Yun, Chi; Badwan, Bara; Brown, Emily J; Mar, Adam C; Schneider, Robert J; Goldberg, Ira J; Pineda-Torra, Inés; Fisher, Edward A; Garabedian, Michael J
Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.
PMID: 33772096
ISSN: 2399-3642
CID: 4823692