Protein-protein interaction disruption as a next-generation antithrombotic strategy

Thrombosis is built, not merely catalyzed. Across arterial and venous disease, thrombus formation depends on a succession of protein-protein interactions (PPIs) that coordinate platelet capture and activation, thromboinflammatory amplification, and assembly of membrane-bound coagulation complexes. Although active-site inhibitors and receptor antagonists have transformed antithrombotic therapy, clinical benefit is often constrained by bleeding because many targets are indispensable for everyday hemostasis when inhibited systemically. This review advances a "thrombus assembly" framework that reframes drug discovery around disrupting interfaces that organize pathologic clot growth in a context-dependent manner shaped by shear, surfaces, local cofactors, and transient complex formation. We highlight translational proof that interface blockade works in humans, focusing on VWF A1-GPIbα inhibition and GPVI-directed strategies as exemplars of lesion- and shear-dependent antiplatelet therapy. We then survey platelet adhesion and activation PPIs (VWF-GPIb, collagen-GPVI, and αIIbβ3-ligand interactions), thromboinflammatory interfaces (including P-selectin-PSGL-1 and CLEC-2-podoplanin), and opportunities to target coagulation complex assembly and thrombin exosites without directly inhibiting catalytic active sites. A modality-focused section links interface class to therapeutic format-antibodies/nanobodies, aptamers with antidotes, peptides and macrocycles, and small-molecule PPI inhibitors-and summarizes trade-offs in reversibility, half-life, manufacturability, and immunogenicity. Finally, we discuss assays that preserve interface biology (whole-blood flow systems, microfluidics, thrombin generation, and clot mechanics) and propose clinical positioning and trial endpoints for context-gated mechanisms. By targeting the contacts that assemble and stabilize thrombi, PPI disruption offers a pragmatic route toward more selective, potentially bleeding-sparing antithrombotic therapy and a roadmap for next-generation pipeline development.