A pivotal advancement in CV genomics has been the implementation of PRS, which synthesize the risk contributions of numerous common genetic variants. Modern-generation PRSs for CAD have been rigorously validated; these scores can identify individuals with a 3-fold increase in lifetime risk, often independent of traditional risk factors or familial history. ^, Beyond risk estimation, PRSs provide mechanistic insights into biological pathways. For instance, pathway-specific PRSs-clustering variants by functional ontology-have elucidated the distinct roles of lipid metabolism (e.g., LDL, Lp(a)) and pro-inflammatory signaling in driving CAD. Consequently, genomic risk profiles allow for the differentiation of CAD subtypes, carrying profound implications for stratified CV medicine. Integration of clinical and genetic datasets significantly enhances the discrimination of CAD phenotypes. Analysis of a large UK Biobank cohort demonstrated that models conflating clinical variables (e.g., lipid profiles, high-sensitivity C-reactive protein) with PRSs could superiorly differentiate subtypes-such as hypercholesterolemic vs. normocholesterolemic disease, ST-elevation vs. non-ST-elevation MI, and occlusive vs. non-occlusive CAD-compared to single-domain models. This phenotypic stratification facilitates the prediction of disease trajectories and the implementation of tailored clinical interventions.

While genomics characterizes inherited susceptibility, proteomics offers a dynamic assessment of circulating proteins mediating pathological processes. Recent proteome-wide Mendelian randomization (MR) studies have identified 41 circulating proteins with a causal association with CAD risk, 17 of which were substantiated by colocalization analyses. Specifically, proteins such as PCSK9, Tissue Inhibitors of Metalloproteinases (TIMP) 3, vimentin (VIM), and transgelin-2 (TAGLN2) have emerged as putative mediators linking obesity and lifestyle factors to CAD, highlighting them as potential novel therapeutic targets.

At the metabolomic level, lipidomics serves as a high-resolution tool for dissecting CAD pathophysiology. A recent multi-omics analysis identified lysophosphatidylcholine acyltransferase 1 (LPCAT1) as a central hub linking genetic polymorphisms with specific lipid species and clinical status. Furthermore, plasma phospholipids have demonstrated utility as biomarkers of disease progression. Leveraging these markers, machine learning-assisted trans-omics models have achieved an area under the curve (AUC) of 0.917, with LPCAT1 identified as a primary predictive feature. Incorporating such lipid metabolite profiles may refine risk stratification and elucidate novel metabolic axes for intervention.

The efficacy of multi-omics integration has been substantiated through summary-data-based MR combined with colocalization and single-cell RNA sequencing. This integrative approach prioritized key genes in CAD pathogenesis, strongly implicating TAGLN2, APOB, and Glucose-dependent Insulinotropic Polypeptid (GIP) through coordinated alterations in DNA methylation, gene expression, and protein abundance. Such findings underscore that synthesizing genomic (e.g., expression and methylation quantitative trait loci), transcriptomic, and proteomic data can reveal causal mechanisms obscured in single-layer analyses, potentially providing new substrates for “pharmacological revascularization” and primary prevention.

These complex datasets are optimally synthesized through AI. In the context of atherosclerotic CV disease (ASCVD), AI functions as an integrative translational bridge for multi-omic data. Machine learning algorithms are indispensable for navigating the high dimensionality, heterogeneity, and non-linear interactions characteristic of the omics layers. By conflating molecular data with clinical and imaging variables, AI enables molecular phenotyping, identifies disease endotypes, and prioritizes therapeutic targets. Additionally, AI optimizes biomarker selection, enhances radiomic analysis, and facilitates computational modeling of treatment responses, fundamentally underpinning the development of precision medicine.

Concurrently with refinements in mechanical revascularization, CV research has increasingly shifted toward targeting the molecular and biological substrates driving atherosclerotic disease ( Figure 2 ).

Current and emerging pharmacological targets for systemic modification of coronary artery disease. Panel A shows the main biological drivers of atherosclerotic plaque progression, including lipid metabolism, inflammation, metabolic dysregulation, and genetic susceptibility. Panel B summarizes novel and emerging therapeutic targets acting on these pathways: the metabolic-inflammatory axis (GLP-1 receptor agonists and dual GIP/GLP-1 agonists), the lipid axis (PCSK9 inhibitors and RNA-based therapies), and therapies targeting genetic and residual risk. Abbreviations: GLP-1, glucagon-like peptide-1; GIP, glucose-dependent insulinotropic polypeptide; PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C, low-density lipoprotein cholesterol; siRNA, small interfering RNA.

In this paradigm, GLP-1 receptor agonists (GLP-1RAs) have emerged as potent disease-modifying therapies, facilitating CV risk reduction through systemic metabolic and inflammatory modulation. Originally developed for glycemic control via insulinotropic and glucagonostatic effects, GLP-1RAs improve blood pressure, body weight, and glycemic control, as reflected by HbA1c levels. However, the consistent CV benefit observed in clinical trials transcends these individual parameters. ^, Preclinical evidence suggests these agents promote a stable plaque phenotype by exerting anti-inflammatory and anti-atherogenic effects on endothelial cells, monocytes, and vascular smooth muscle cells expressing the GLP-1 receptor. ^,,

Clinical evidence from the LEADER (liraglutide), SUSTAIN-6 (semaglutide), and REWIND (dulaglutide) trials confirmed significant reductions in MACE in patients with type 2 diabetes. ^,, Notably, the SELECT trial demonstrated that semaglutide also reduces MACE in non-diabetic patients with established ASCVD, underscoring that its benefits are mediated by broader cardiometabolic and inflammatory pathways. Together, these data indicate that the CV benefits of GLP-1RAs are not mediated by glucose-lowering alone but likely reflect broader effects on cardiometabolic and inflammatory pathways relevant to atherosclerotic disease. ^,, Furthermore, the dual GIP/GLP-1 receptor agonist tirzepatide has shown non-inferiority to dulaglutide for MACE while achieving superior reductions in weight and adiposity in the SURPASS-CVOT trial.

Diffuse CAD poses a major management challenge because its long lesion length (>20 mm) often leads to poorer outcomes with mechanical revascularization. Stent length independently predicts target vessel failure, restenosis, and MACE, with ultra-long stents (≥40 mm) performing worse than focal interventions. ^, Physiologic assessments frequently show persistent flow abnormalities even after angiographically successful PCI. ^, In this setting, intensified lipid-lowering therapy as part of optimal medical therapy (OMT) is central to management. Evidence, including studies by Van Beek et al., suggests OMT can be comparable to CABG or stenting in selected diffuse disease, as it targets the underlying diffuse plaque burden that focal stenting cannot fully address. Indeed, parallel advancements in lipid biology have revolutionized secondary prevention. PCSK9i achieve profound LDL-cholesterol (LDL-C) reduction by preventing LDL-receptor degradation. The FOURIER (evolocumab) and ODYSSEY OUTCOMES (alirocumab) trials confirmed robust MACE reductions. ^, Beyond LDL-C lowering, PCSK-9 inhibition is associated with increased plaque stability and attenuated vascular inflammation. Meanwhile, gene-silencing via twice-yearly inclisiran (siRNA) provides sustained LDL-C reductions of >50%, with definitive CV outcomes pending from the ORION-4 and TIMI-65 trials.

Despite intensive LDL-C lowering, residual risk persists, frequently driven by Lp(a)- a highly heritable, pro-atherothrombotic, and pro-inflammatory lipoprotein refractory to conventional therapies. The advent of RNA-based therapies targeting the Lp(a) gene represents a critical milestone in precision prevention, with ongoing Phase 3 trials evaluating their impact on MI and stroke.

These therapeutic milestones address the complex, multidimensional architecture of ASCVD, which integrates dysregulated lipid metabolism, chronic inflammation, and oxidative stress across genomic, transcriptomic, and proteomic layers. In this context, emerging CRISPR-Cas9 gene-editing technologies represent a conceptual evolution of pharmacological revascularization. By durably modulating causal drivers through the correction of pathogenic variants or the regulation of atherogenic protein expression, these programmable interventions offer a pathway to long-term, mechanism-based CV risk modification. ^,

A fundamental challenge in contemporary CAD research remains the translation of high-dimensional molecular insights into actionable clinical strategies. While omics technologies (genomics, proteomics, lipidomics) have profoundly advanced our understanding of atherogenesis, their clinical integration is still nascent. However, the convergence of omics, advanced imaging, and AI is poised to facilitate the transition from discovery to bedside implementation.

A pivotal advancement involves integrating omics-derived risk profiles with high-resolution coronary imaging. Moving beyond luminal assessment, this approach identifies “vulnerable” plaques with adverse biological traits that predispose to rupture. PRS, combined with targeted proteomic profiling, can predict the presence of high-risk plaque features on coronary computed tomography angiography (CCTA), such as positive remodeling, low-attenuation necrotic cores, and complex microarchitecture. Recent data underscore a paradigm shift toward individualized treatment recommendations based on AI-facilitated plaque characterization.

AI serves as a primary catalyst in this framework. Deep-learning algorithms enable standardized, automated interpretation of imaging data, facilitating the synthesis of large-scale molecular datasets. AI applications in CCTA and optical coherence tomography (OCT) demonstrate diagnostic accuracy comparable to expert clinicians in quantifying stenosis and plaque burden. For instance, the CathAI pipeline has shown high performance in identifying significant angiographic stenoses in real-world cohorts. Beyond conventional diagnostics, AI extracts latent biological information from images, bridging the gap between imaging phenotypes and molecular pathology.

Intracoronary imaging can substantially benefit from these advances. While AI-driven OCT analysis shows promise in segmenting plaques and characterizing tissue components, clinical adoption is currently limited by methodological heterogeneity. Conceptually transformative research has demonstrated the potential for deep learning to generate “virtual histology” from OCT images, allowing non-invasive inference of plaque microarchitecture and composition. If rigorously validated, these techniques could revolutionize the assessment of plaque biology in vivo.

The integration of omics-informed risk with imaging necessitates a re-evaluation of therapeutic timing. In primary prevention, PRS can identify individuals with high lifetime genetic risk who may benefit from aggressive intervention-such as high-intensity statins or PCSK9 inhibitors-before clinical disease manifests. Refining risk with lipidomic and proteomic markers (e.g., PCSK9, TAGLN2, or LPCAT1-linked enzymes) enhances stratification beyond traditional clinical factors.

In patients with established atherosclerosis, multi-omics profiling permits the definition of distinct molecular phenotypes, such as inflammation-dominant, lipoprotein-driven, or matrix-remodeling-driven disease. These endotypes may predict differential responses to therapy; for example, patients with proteomic signatures of extracellular matrix dysregulation (e.g., elevated TIMP3 or vimentin) might preferentially benefit from emerging anti-fibrotic or matrix-modulating agents.

Targeted therapeutics represent the logical culmination of this model. Omics can refine anti-inflammatory strategies by identifying dominant pathways [e.g., IL-1β, IL-6, NLR family pyrin domain containing 3 (NLRP3)] for specific inhibition. Similarly, lipid therapies can address specific species or metabolic nodes identified by lipidomics. Furthermore, functional genomics and CRISPR/Cas9-based editing allow for the interrogation of causal CAD genes, offering the long-term prospect of permanent genomic risk modification.

Managing this complexity requires adaptive clinical trials and AI-driven treatment algorithms. Machine learning frameworks trained on deeply phenotyped cohorts can optimize treatment intensity and duration. Such decision support systems could eventually assist “Heart Teams” in integrating clinical, omics, and imaging data to choose between mechanical revascularization and advanced “pharmacological revascularization.”

Longitudinal monitoring-incorporating serial imaging and omics assessments-will be essential to track therapeutic response and residual risk. Large-scale biobanks and registries will provide the necessary evidence to refine these predictive models and ensure long-term efficacy. Collectively, the convergence of omics, AI, and imaging heralds a shift from mechanical to “molecular revascularization”-interventions tailored to an individual’s genetic predisposition, proteomic milieu, and plaque phenotype. Despite translational challenges, the potential impact on CV health is profound ( Figure 3 ).

Integrated approach- Look into the Future. Abbreviations: AI- Artificial Intelligence, CAD- Coronary Artery Disease, CCTA- Coronary Computed Tomography Angiography, IVUS- intravascular ultrasound; OCT- Optical Coherence Tomography.

The management of CAD is undergoing a paradigm shift from an anatomy-centric focus on mechanical revascularization toward a biologically targeted pharmacological model addressing the inflammatory substrate of atherosclerosis. While PCI and CABG remain pivotal for symptomatic relief and the management of high-risk anatomical scenarios, landmark trials-including COURAGE, ISCHEMIA, BARI 2D, and FAME 2-demonstrate that intensive medical therapy achieves comparable or superior long-term outcomes in stable CAD. ^,,

Atherosclerosis is increasingly recognized as a chronic, immune-mediated inflammatory pathology. Pro-inflammatory cytokines, specifically IL-1β, IL-6 and tumor necrosis factor-α (TNF-α), orchestrate endothelial dysfunction, leukocyte recruitment, and plaque destabilization. In acute coronary syndromes (ACS), this inflammatory response exhibits a distinct biphasic temporal profile. The early phase (0-4 days) is characterized by a surge in polymorphonuclear neutrophils, IL-1, and IL-6 driven by plaque rupture and myocardial necrosis, respectively, which exacerbates microvascular obstruction and reperfusion injury. Conversely, the late phase manifests as a “smoldering” low-grade inflammatory state perpetuated by NLRP3 inflammasome activation, driving adverse ventricular remodeling. This persistent residual inflammatory activity-manifesting as elevated high-sensitivity C-reactive protein (hsCRP) despite therapeutic LDL-C control-remains a primary determinant of recurrent ischemic events. ^,, Large-scale registry data confirm that elevated CRP during hospitalization is non-linearly associated with long-term mortality, while high post-STEMI IL-6 concentrations correlate with larger infarct size and more severe microvascular obstruction.

These biological insights have catalyzed the development of non-invasive imaging biomarkers to detect vascular inflammation in vivo. The perivascular fat attenuation index (FAI) has emerged as a robust marker of local inflammatory activity. Cytokine-driven crosstalk between the vessel wall and surrounding pericoronary adipose tissue (PCAT) induces adipocyte shrinkage and reduced lipid content, shifting CCTA attenuation values. This transformation allows PCAT to function as a sensitive reporter of endothelial injury and plaque vulnerability. Elevated FAI values correlate with non-calcified plaque burden and high-risk morphological features (e.g., positive remodeling), independently predicting cardiac mortality. Notably, FAI identifies inflamed, non-obstructive lesions that may benefit from the early intensification of anti-inflammatory or metabolic therapies. ^,,

The 2025 American College of Cardiology (ACC) Scientific Statement on “Inflammation and Cardiovascular Disease” establishes inflammation as a modifiable therapeutic target, recommending the integration of hsCRP into CV risk stratification. This paradigm shift toward “biological revascularization” emphasizes that stabilizing plaque biology and attenuating inflammation are integral to long-term cardioprotection, extending the benefits of mechanical intervention.

Given the distinct temporal and biological profiles of inflammation in acute versus chronic coronary settings, clinical evidence supporting anti-inflammatory strategies differs substantially across the revascularization continuum. Table 1 summarizes major randomized trials according to ACS and chronic coronary syndrome (CCS) populations.

The GPVI is a platelet-specific collagen receptor expressed exclusively on platelets and megakaryocytes. Activated by subendothelial collagen exposed during vascular injury, GPVI has emerged as a high-priority target for selective antithrombotic strategies designed to decouple pathological thrombosis from physiological hemostasis. ^, Within the coronary vasculature, GPVI signaling is mechanistically critical under high-shear conditions-characteristic of severe stenoses-where it stabilizes platelet aggregates and ensures thrombus persistence.

In the context of elective PCI, GPVI appears to modulate a broader thrombo-inflammatory axis. Evidence from a cohort of 334 patients suggests that post-procedural fluctuations in circulating chemokines [e.g., eotaxin, Monokine Induced by interferon-gamma (MIG), and Chemokine (C-C motif) ligand (CCL) 4] correlate with collagen-induced platelet activation and bleeding risk. These data indicate that GPVI-dependent pathways bridge thrombotic mechanisms with inflammatory signaling, potentially impacting procedural safety.

Two primary pharmacological strategies have been developed to target this axis:

Revacept: A soluble GPVI-Fc fusion protein that functions as a decoy receptor, binding to exposed collagen at the lesion site to prevent platelet recruitment. In the ISAR-PLASTER trial involving stable ischemic heart disease patients undergoing elective PCI, Revacept demonstrated a safety profile comparable to placebo, though it did not significantly reduce ischemic endpoints.

Glenzocimab (ACT017): A humanized antibody fragment (Fab) that directly inhibits the collagen-GPVI interaction. Translational studies indicate that glenzocimab attenuates plaque-induced platelet activation and exerts additive antithrombotic effects when combined with dual antiplatelet therapy (DAPT). Furthermore, the GREEN study in acute ischemic stroke has provided essential safety data for GPVI blockade during neurovascular reperfusion.

GPVI remains a biologically compelling target situated at the initiation phase of the thrombotic cascade. Future investigations will determine if GPVI-directed interventions can translate this mechanistic rationale into clinical reductions in thrombosis, microvascular obstruction, and thrombo-inflammatory injury. ^,

The platelet GPIb-IX-V receptor complex, specifically its GPIbα subunit, serves as the primary ligand for von Willebrand factor (vWF) and facilitates the initial stages of platelet adhesion under high-shear conditions. This hemodynamic environment is characteristic of arterial flow and is markedly intensified within critical stenosis or at sites of vascular denudation. High shear stress induces conformational unfolding of vWF, exposing the A1 domain and enabling high-affinity binding to GPIbα. This interaction initiates platelet tethering and rolling, subsequent intracellular signaling, and the activation of secondary pathways involving ADP, thromboxane A₂, and integrin αIIbβ₃. Operating upstream of platelet aggregation, the vWF-GPIb axis is mechanistically distinct from that of P2Y12 inhibition, primarily targeting shear-dependent platelet capture rather than longitudinal aggregate propagation. ^,

Experimental evidence suggests that vWF-GPIbα signaling is a predominant driver of arterial thrombosis in stenotic vessels. While targeting this pathway offers a rationale for attenuating pathological thrombosis, inhibition of the vWF-GPIb axis does not guarantee a superior safety profile; mucocutaneous bleeding remains a concern, and the therapeutic window likely depends on dosing, clinical context, and concomitant antithrombotic regimens. ^,

Translational research has explored CV settings where localized high shear facilitates vWF-mediated intracoronary thrombosis. The ARC1779 aptamer, which targets the vWF A1 domain, provided human proof-of-mechanism by inducing dose-dependent inhibition of vWF activity and platelet function. Similarly, caplacizumab, an anti-A1 nanobody, demonstrated antithrombotic efficacy in non-human primates with a therapeutic window favorable to conventional antiplatelet agents. Despite this biological rationale, these agents have not yet reached routine coronary application, though caplacizumab has established a standard of care in immune thrombotic thrombocytopenic purpura.

Beyond ligand-directed approaches, receptor-directed strategies have also advanced. Anfibatide, a GPIbα antagonist, was developed to inhibit vWF-dependent adhesion under high shear stress. In a Phase I trial, anfibatide exhibited a rapid, reversible antiplatelet effect and a clear dose-dependent pharmacodynamic signal. Notably, it did not significantly alter global coagulation parameters or induce excessive bleeding at tested doses, supporting the feasibility of direct GPIbα blockade.

The vWF-GPIb axis remains a credible target for managing shear-driven arterial thrombosis. Its ultimate integration into interventional cardiology will depend on clinical trials demonstrating a favorable safety profile and superior ischemic protection compared to existing standards. ^,,,,

Protease-activated receptors (PARs) are G-protein-coupled receptors activated by proteolytic cleavage that unmasks a tethered ligand. On human platelets, PAR-1 and PAR-4 are the principal receptors mediating thrombin-induced activation. PAR-1 is engaged at lower thrombin concentrations owing to higher apparent affinity, whereas PAR-4 predominates at higher thrombin levels and sustains signaling to preserve platelet aggregate stability during thrombus growth ^, Cardiovascular development initially targeted PAR-1 with vorapaxar as adjunct antiplatelet therapy.

In the TRACER study, conducted in patients with non-ST-elevation ACS, any ischemic benefit was modest while major bleeding, including intracranial hemorrhage, was increased, prompting early termination. In the TRA 2°P-TIMI 50 trial, performed for secondary prevention after prior MI, ischemic stroke, or peripheral arterial disease, vorapaxar reduced ischemic events on top of standard therapy but increased bleeding. These data indicate clinical efficacy in selected settings but delineate a narrow safety margin for thrombin-receptor blockade in coronary populations.

This has motivated strategies to modulate thrombin-PAR signaling with rapid reversibility or receptor selectivity.

Pepducins are lipidated, cell-penetrating peptides that disrupt GPCR-G-protein coupling from the cytoplasmic face. The PAR-1 pepducin PZ-128 produced rapid, reversible inhibition of PAR-1-mediated platelet responses in early proof-of-mechanism studies in subjects with CAD or high-risk profiles, a pharmacologic profile compatible with short peri-procedural use. In TRIP-PCI, a randomized phase-2 study, PZ-128 was well tolerated and induced rapid, reversible inhibition of PAR-1-mediated platelet function, with an exploratory signal toward reduced peri-procedural myocardial injury; however, the study was not powered for clinical ischemic endpoints.

Interest has also shifted to PAR-4 antagonism, given PAR-4’s role in sustained thrombin signaling during thrombus propagation. In first-in-human studies, the oral PAR-4 antagonist BMS-986120 reduced ex vivo platelet-rich thrombus formation under high shear and exerted minimal effects on standard coagulation assays. In stable CAD, a phase-2a translational study reported that BMS-986141 produced additive antithrombotic effects in thrombosis-chamber assays when combined with aspirin, ticagrelor, or both. Whether these pharmacodynamic effects translate into fewer ischemic events without unacceptable bleeding-particularly when added to DAPT-remains the central unresolved question. Overall, the thrombin-PAR axis remains a rational target for residual thrombotic risk, but clinical implementation is constrained by bleeding liability. Current approaches prioritize reversibility and selectivity-intracellular PAR-1 modulation (PZ-128) and PAR-4 antagonism-yet their definitive role will depend on outcome trials demonstrating net clinical benefit on top of contemporary standards of care. An overview of the main human clinical trials targeting GPVI, the vWF-GPIbα axis, and PAR signaling is provided in Table 2 .

Table 2

Human clinical trials targeting platelet GPVI, the vWF-GPIbα axis, and protease-activated receptors (PARs), stratified by clinical context.

A) Coronary outcomes trials (ACS, PCI context and secondary prevention)
Study	Target axis	Agent/ strategy	Receptor/pathway	Mechanism of action (MoA)	Study design	Population	Key efficacy/PD finding	Key safety finding
Tracer	PAR	Vorapaxar	PAR-1 (thrombin receptor)	Orthosteric PAR-1 antagonist (blocks thrombin-mediated platelet activation via PAR-1)	Randomized clinical outcomes trial (TRACER)	Patients with ACS	Tested for reduction of ischemic events in ACS (trial-level endpoints per paper)	Bleeding risk/concerns reported in outcomes trial (per paper)
TRA 2°P-TIMI 50	PAR	Vorapaxar	PAR-1 (thrombin receptor)	Orthosteric PAR-1 antagonist	Randomized clinical outcomes trial (TRA 2°P-TIMI 50)	Patients in secondary prevention of atherothrombotic disease	Tested for reduction of recurrent ischemic events in secondary prevention (per paper)	Bleeding risk/concerns reported in outcomes trial (per paper)
ISAR-PLASTER	GPVI	Revacept (soluble GPVI-Fc)	GPVI-collagen axis	Collagen-binding decoy that reduces GPVI-dependent platelet activation in a lesion-directed manner	Randomized, double-blind, placebo-controlled Phase 2 trial	Patients undergoing elective PCI	Did not reduce ischemic endpoints versus placebo	Safety profile comparable to placebo
TRIP-PCI	PAR	PZ-128 (pepducin)- TRIP-PCI	PAR-1 intracellular signaling	Cell-penetrating pepducin that modulates PAR-1-G protein coupling from the cytoplasmic side	Randomized trial; results posted on ClinicalTrials.gov (TRIP-PCI; NCT02561000)	Patients undergoing cath/PCI	Assessed periprocedural antiplatelet PD and exploratory clinical endpoints (per registry)	Bleeding safety evaluated (per registry)
Nash et al	PAR	BMS-986141	PAR-4	Selective PAR-4 antagonist	Early-phase clinical study (per paper)	Patients with coronary artery disease receiving antiplatelet therapies	Reduced thrombus formation/antithrombotic PD on background therapy (per paper)	Safety/tolerability assessed (per paper)
B) Neurovascular reperfusion (non-coronary).
Study	Target axis	Agent/strategy	Receptor/pathway	Mechanism of action (MoA)	Study design	Population	Key efficacy/PD finding	Key safety finding
GREEN	GPVI	Glenzocimab (ACT017)	GPVI-collagen axis	Humanized Fab fragment blocking GPVI-collagen interaction	Clinical reperfusion study (published ahead of print)	Acute ischemic stroke patients undergoing EVT	Evaluated in reperfusion setting (endpoint details per study report)	Provides clinical safety experience for GPVI blockade in reperfusion context
C) Healthy volunteer/first-in-human studies
Study	Target axis	Agent/strategy	Receptor/pathway	Mechanism of action (MoA)	Study design	Population	Key efficacy/PD finding	Key safety finding
Gilbert et al.	vWF-GPIbα	ARC1779 (aptamer)	vWF A1-GPIbα interaction	Binds vWF A1 domain and inhibits vWF-GPIbα binding	First-in-human evaluation	Healthy subjects	Dose-dependent inhibition of vWF activity and platelet function	PK/PD compatible with periprocedural use (bleeding details per study report)
Li et al.	vWF-GPIbα	Anfibatide	vWF-GPIbα interaction	GPIbα antagonist; inhibits vWF-dependent platelet adhesion under high shear	Phase I randomized clinical trial (+ in vitro assessment)	Healthy subjects	Rapid and reversible antiplatelet pharmacodynamic effect with clear dose-response	No excessive bleeding signal within tested doses; limited effects on global coagulation parameters
Gurbel et al.	PAR	PZ-128 (pepducin)	PAR-1 intracellular signaling	Cell-penetrating pepducin that modulates PAR-1-G protein.	Phase I, single ascending IV doses (clinical pharmacology)	Subjects with vascular disease or multiple CAD risk factors	Demonstrated pharmacodynamic platelet inhibition with dose-response (per paper)	Safety/tolerability evaluated in Phase I (per paper)

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