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

Systemic anticoagulation remains standard of care for arterial thrombosis but indiscriminately suppresses hemostasis, imposing substantial bleeding risk. This conceptual, computationally grounded framework introduces the Shear-Activated Nano-Inhibitor of Polyphosphate (SANIPP), a theoretical drug-delivery architecture designed to selectively neutralize platelet-derived polyphosphate (PolyP)-driven contact-pathway amplification of thrombin generation under pathological high wall shear stress (τ greater than 100 dyn/cm2), while sparing von Willebrand factor (vWF)-mediated platelet adhesion and physiological hemostasis. SANIPP is conceived as micron-scale aggregates of PolyP-binding nanoparticles that remain stable at physiological shear and dissociate cumulatively, via a fatigue-integrated shear-activation law, only within stenotic vessel segments. The framework couples a 24-state extension of the Hockin-Mann coagulation model with PolyP binding, factor VIIIa decay, vWF-dependent platelet activation, and anti-lytic fibrin kinetics; a mass-conserving description of aggregate dissociation and inhibitor transport; and three-dimensional CFD of pulsatile flow in a 60 percent stenosed carotid geometry supplying the wall-shear-stress field that drives activation. All parameters are calibrated against previously published empirical benchmarks, including lab-on-a-chip shear-disassembly thresholds and human-plasma thrombin generation assay (TGA) data, rather than new experimental measurements. Under these conditions, the reference implementation predicts a 67.6 percent reduction in peak thrombin generation at pathological shear (65.3 nM low shear versus 21.2 nM high shear), with a 4.9 percent change in peak fibrin generation, consistent with preserved hemostasis. A multi-layered uncertainty quantification, comprising local sensitivity, a Jansen-estimator total-order Sobol analysis with 60 base samples, and Monte Carlo propagation with 150 draws, run directly on this code shows the predicted selectivity is dominated by the shear-dependent tenase-attenuation coefficient and tenase catalytic rate, with Monte Carlo mean thrombin reduction of 64.6 percent (bootstrap 95 percent confidence interval of 62.6 to 66.5 percent; coefficient of variation approximately 18.7 percent). Falsifiability criteria, a risk assessment of critical assumptions, and a staged experimental roadmap from lab-on-a-chip validation to murine thrombosis models render the framework empirically testable. As a purely theoretical construct not yet synthesized or tested in any biological system, SANIPP is proposed as a conceptual paradigm, not a validated therapeutic, for spatially selective hemostasis modulation, with prospective relevance to acute coronary syndrome, ischemic stroke prevention, and in-stent thrombosis.