Shear-Activated Nano-Inhibitor of Polyphosphate: A Conceptual Theoretical Framework for Selective Antithrombotic Therapy

This conceptual theoretical manuscript introduces the Shear-Activated Nano-Inhibitor of Polyphosphate (SANIPP), a novel framework for antithrombotic therapy that selectively neutralizes polyphosphate (PolyP)-driven coagulation amplification under pathological high shear stress, while preserving physiological hemostasis. SANIPP features microscale aggregates of inhibitor-loaded nanoparticles that dissociate exclusively in stenotic vessels (\(\tau > \SI{100}{\dyne\per\centi\metre\squared}\)). The framework relies on computational simulations calibrated to empirical data from peer-reviewed literature, including lab-on-a-chip (LOC) disassembly thresholds \cite{Korin2012} and thrombin generation assays (TGA) in human plasma \cite{Mailer2023,Smith2015}. An expanded mathematical model, integrating Hockin-Mann kinetics with PolyP dynamics, vWF-mediated platelet activation, fibrin polymerization with anti-lytic effects, mass-balanced aggregate dissociation, diffusion-limited tenase complex formation, and coupled computational fluid dynamics (CFD) via transport equations, demonstrates \( \approx 65\% \) thrombin reduction under high shear with $ < 5% $ impact on hemostatic endpoints. Comprehensive sensitivity analyses (local, global Sobol, Monte Carlo) and falsifiability criteria ensure rigor. Originality stems from the coupled spatial-kinetic modeling incorporating mechanical fatigue thresholds and dimensionless numbers for dissociation physics. This self-contained work positions SANIPP as a paradigm for targeted hemostasis modulation, with potential clinical applications in conditions like acute coronary syndrome and stroke prevention.