Faculty Bibliography

Thrombotic risk in COVID-19 extends beyond acute illness, including in nonhospitalized individuals, suggesting that thrombo-inflammatory biology may persist during recovery. Longitudinal sampling with pre-infection baselines is needed to distinguish infection-associated signals from inter-individual variability and time-related drift in blood gene expression. To define coordinated, time-resolved whole-blood transcriptomic programs during SARS-CoV-2 convalescence using longitudinal within-person comparisons before and after infection, alongside COVID-19-naïve controls. Adults were sampled longitudinally with specimens collected before SARS-CoV-2 infection (T0) and at ~3 months (T1) and ~6 months (T2) post-infection; COVID-19-naïve controls were sampled across matched timepoints. COVID-19-naïve status was confirmed using a multiplex anti-nucleocapsid IgG assay spanning multiple variant antigens. Whole-blood RNA-seq (PAXgene) was analyzed with DESeq. 2 using models that incorporated time point and participant. To prioritize infection-linked changes, genes differentially expressed over time in controls were identified and excluded from comparisons between COVID-19 time points. Pathways were assessed by pre-ranked GSEA (MSigDB) and clustered with aPEAR. After excluding control-associated genes, COVID-19 convalescence remained associated with marked transcriptional remodeling (T1 vs. T0: 782 genes; T2 vs. T0: 655 genes; p < 0.05) and persistent pathway-level changes. Interferon-α and interferon-γ signatures were enriched at both T1 and T2, and a core set of interferon-associated genes remained elevated across convalescence. SARS-CoV-2 infection is followed by durable whole-blood immune-defense programs, including persistent interferon signaling, detectable up to 6 months post-infection. These sustained signatures support a model of prolonged post-infectious immune activation that may contribute to extended thromboinflammatory risk.

Platelets are central to hemostasis and thrombosis. Excessive platelet activation contributes to arterial thrombotic events, including myocardial infarction, ischemic stroke, and complications of peripheral artery disease, whereas excessive platelet inhibition increases bleeding risk. Antiplatelet therapy remains a cornerstone of secondary prevention in atherosclerotic and thrombotic cardiovascular diseases, yet current treatment paradigms do not fully account for biological heterogeneity in platelet function, including differences related to sex, age, hormonal status, and disease context. This state-of-the-art review examines current antiplatelet strategies, fundamental mechanisms of signal transduction, clinical indications, and limitations of preclinical and clinical studies, with a focus on sex-specific considerations and opportunities for personalized antiplatelet therapy. Aspirin and P2Y₁₂ receptor antagonists are widely used for secondary prevention. However, women have been underrepresented in many pivotal clinical trials, limiting the precision of sex-specific estimates of efficacy and bleeding risk. In parallel, commonly used preclinical models often fail to recapitulate the physiological conditions in which platelets interact with the vasculature, leukocytes, and soluble factors. Emerging therapeutic approaches seek to refine platelet inhibition by targeting pathways that reduce thrombotic risk while preserving hemostasis. Advancing antiplatelet therapy will require integration of mechanistic platelet biology with diverse clinical trial populations, standardized platelet phenotyping, and disease-specific approaches that account for how platelet function is altered across health and vascular disease.

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.