Faculty Bibliography

Platelets, classically defined by their hemostatic function, are increasingly recognized as immune effectors that shape chronic inflammation and vascular pathology in immune-mediated inflammatory diseases. In conditions such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, immune activation skews platelet adhesion, secretion, and procoagulant activity, while persistent interferon signaling and immune complex engagement (via receptors such as FcγRIIA) amplify thromboinflammation. Platelets orchestrate leukocyte recruitment and endothelial activation through P-selectin/PSGL-1 (P-selectin glycoprotein ligand-1) interactions, CD40 ligand, interleukin-1β, and the release of extracellular vesicles carrying cytokines and RNAs. Platelet involvement manifests differently across immune-mediated inflammatory diseases. In systemic lupus erythematosus, they promote type I interferon priming, neutrophil extracellular trap formation, and endothelial dysfunction. In rheumatoid arthritis, they generate abundant synovial microparticles and systemic vascular changes. In psoriasis, they accumulate within skin lesions, enhance platelet-leukocyte aggregation and activate proatherogenic endothelial responses. These pathways promote, independent of traditional cardiovascular risk factors, atherothrombosis including myocardial infarction, stroke, and venous thromboembolism. Limited translational data suggest that hydroxychloroquine may attenuate platelet activation and improve endothelial function. P2Y₁₂ inhibition may blunt interferon-linked platelet RNA signatures and leukocyte-platelet interactions. However, some therapies targeting inflammation, such as Janus kinase inhibitors, may promote thrombosis, the mechanisms of which are not fully known. Advances in multiomics, single-cell and spatial profiling, and in vivo models are delineating targets for intervention and enabling biomarker-driven risk stratification. Collectively, platelets function as central translators between autoimmunity and atherothrombosis. Defining and modulating platelet-immune crosstalk holds the potential to reduce cardiovascular risk in rheumatologic populations.

BACKGROUND/UNASSIGNED:Psoriasis is a chronic immune-mediated inflammatory disease associated with heightened cardiovascular risk. Platelets are increasingly implicated in this link through their capacity to amplify vascular inflammation and interact with leukocytes. Circulating leukocyte-platelet aggregates are elevated in psoriasis, although the biological significance of these aggregates remains incompletely understood. We investigated whether increased leukocyte-platelet aggregates is associated with alterations in the platelet transcriptomic profile in psoriasis. METHODS/UNASSIGNED:Leukocyte-platelet aggregate levels were compared between psoriasis patients (n = 42) and healthy controls (n = 29). Psoriasis patients were stratified by the cohort median lymphocyte-platelet aggregate (LyPA) or neutrophil-platelet aggregate (NPA) levels into high vs low aggregate groups. Platelet RNA sequencing was then performed to define transcriptomic differences in high-vs low-aggregate psoriasis. RESULTS/UNASSIGNED:= 0.04) compared with healthy controls (mean age 42; 55% male; 69% Caucasian). Platelet RNA sequencing revealed that psoriasis patients with high LyPA or high NPA had downregulation of platelet inflammatory pathways, including interferon, tumor necrosis factor (TNF), IL-8, and IL-6 signaling. CONCLUSION/UNASSIGNED:These findings identify inflammatory platelet transcriptomic alterations associated with elevated lymphocyte-platelet and neutrophil-platelet aggregates in psoriasis and motivate further work to define the functional consequences of leukocyte-platelet aggregates in psoriasis.

Platelets are recognized as mediators of cancer progression, extending beyond hemostasis to influence tumor growth, metastatic dissemination, immune evasion, and thrombotic complications. Tumors remodel platelets through thrombocytosis and tumor cell-induced platelet aggregation, and locally through tumor-microenvironment cues that reprogram platelet function. These changes enable platelets to shield tumor cells, support epithelial-mesenchymal transition, promote angiogenesis and vascular remodeling, and establish immunosuppressive niches promoting metastasis. Platelets also drive both venous and arterial cancer-associated thrombosis via procoagulant platelet states, platelet-derived extracellular vesicles, and crosstalk with endothelium and innate immune pathways. Platelet RNA signatures and emerging proteomic/multi-omic profiling show promise for cancer detection, classification, and treatment monitoring. Preclinical and translational studies suggest that antiplatelet strategies (e.g., aspirin, P2Y12 inhibition) can modulate metastatic and thromboinflammatory pathways, motivating platelet-targeted interventions that mitigate bleeding risk. This review synthesizes platelet-tumor crosstalk linking tumor progression with cancer-associated thrombosis and vascular events and highlights emerging platelet-based biomarker and therapeutic opportunities.

BACKGROUNDPlatelets are increasingly recognized as active participants in immune signaling and systemic inflammation. Upon activation, platelets form monocyte platelet aggregates (MPA) representing the crossroads of thrombosis and inflammation. We hypothesized that platelet transcriptomics could capture this thromboinflammatory axis and identify individuals at elevated cardiovascular risk.METHODS: MPA levels, defined as CD14+CD61+ cells, were measured using flow cytometry at 2 time points, 4 weeks apart, in healthy individualsPlatelets were isolated and sequenced. Individuals were categorized as MPAhi or MPAlo based on consistently high or low MPA levels across time points.RESULTSAmong 149 participants (median age 52 years, 57% female, 50% non-White), MPAhi individuals exhibited increased expression of platelet activation markers P-selectin (P < 0.001), PAC-1 (P = 0.021), and CD40L (P < 0.001) and enriched immune signaling pathways. Informed by MPA levels and derived from the platelet transcriptome, we developed a 42-gene thromboinflammation platelet signature (TIPS), which correlated with MPA levels in multiple cohorts and was reproducible over time. TIPS was elevated in patients with COVID-19 (P = 0.0002) and myocardial infarction (Padj = 0.008), and as in predicted future cardiovascular events in patients who underwent lower extremity revascularization after a median follow-up of 18 months (adjusted for age, sex, race, and ethnicity [adjHR] 1.55, P = 0.006). Notably, TIPS was modifiable by ticagrelor (P = 0.002) but not aspirin.CONCLUSIONThese findings establish MPA as a biomarker of thromboinflammation and introduce TIPS, a platelet RNA signature, that captures thromboinflammation and provides a promising tool for cardiovascular risk stratification and a potential therapeutic target.TRIAL REGISTRATIONNCT04369664FUNDINGNIH R35HL144993, NIH R01HL139909, and AHA 16SFRN2873002 to JSB, DFG Walter-Benjamin-Programme 537070747 to AB.

Coronary endothelial dysfunction plays a key role in the pathogenesis of acute coronary syndromes. During myocardial infarction (MI), activated platelets release prothrombotic and proinflammatory factors, contributing to vascular injury and dysfunction. To investigate platelet-mediated endothelial dysfunction, endothelial cells (ECs) were treated with platelet-released factors from patients with MI and non-MI controls undergoing coronary angiography. RNA sequencing revealed that MI platelets induced EC mitochondrial dysfunction, confirmed by reduced mitochondrial membrane potential and disrupted mitochondrial networks. Integrating platelet transcriptomic data, we identified the C-C motif chemokine ligand 3 (CCL3) as significantly up-regulated in MI platelets and a key mediator of EC mitochondrial dysfunction. Blocking its receptor, CCR5, attenuated CCL3 effects. In an independent cohort of 261 patients with established cardiovascular disease, higher circulating CCL3 levels were associated with incident major adverse cardiovascular events. Together, these findings establish a mechanistic link between platelet activation and coronary endothelial dysfunction in MI.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an increased risk of vascular dysfunction and cardiovascular disease. We validate our previously developed Systemic Lupus Erythematosus Activity Platelet-Gene Expression Signature (SLAP-GES) score and investigate its relationship with platelet activity and vascular health. SLAP-GES was associated with the SLE Disease Activity Index (Padj < 0.001) and consistent over time (r = 0.76; P = 9 × 10^-5). Moreover, SLAP-GES was associated increased platelet aggregation in response to submaximal epinephrine (P = 0.084), leukocyte platelet aggregates (P = 0.014), and neutrophil platelet aggregates (P = 0.043). SLAP-GES was also associated with impaired glycocalyx (P = 0.011) and brachial artery flow-mediated dilation (P = 0.045). Altogether, SLAP-GES is associated with SLE disease activity, platelet activity, and impaired vascular health.

Insulin resistance impairs benefits of lipid-lowering treatment as evidenced by higher cardiovascular risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid-lowering. In mice with obesity and insulin resistance, we induced advanced plaques, then implemented lipid-lowering to promote atherosclerotic plaque inflammation-resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid-lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, scRNA seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased pro-inflammatory signaling pathways in circulating non-classical monocytes after lipid-lowering. These findings highlight that platelets hinder inflammation-resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation-resolution.