TRIDENT Case Card: Sickle Cell Disease HbS polymerisation as a boundary-driven coherence failure in erythrocyte function

Sickle cell disease (SCD) is a monogenic disorder caused by a single point mutation in the β-globin gene (Glu6Val) that enables deoxygenated haemoglobin S (HbS) to polymerise under hypoxic conditions. Polymer formation drives erythrocyte stiffening, vaso-occlusive crisis, haemolysis, and progressive organ damage. The molecular mechanism linking mutation to polymer fibre assembly is structurally resolved. This case card applies the TRIDENT diagnostic framework (Bulk Lock, Boundary Flow, Constraint Field, Coherence Dependency) to evaluate mechanistic closure in SCD. Gates 1-3 pass robustly, supported by crystallographic structure, natural hereditary persistence of fetal haemoglobin (HPFH), hydroxyurea randomised trials, and Phase III gene therapy outcomes (Casgevy, Lyfgenia). Dilution of intracellular HbS via fetal haemoglobin (HbF) reactivation substantially suppresses polymerisation and reduces vaso-occlusive events. Gate 4 remains partially open. Outstanding uncertainties include long-term durability of gene therapy expression and the degree to which haemolysis-driven nitric oxide depletion and vasculopathy operate independently of polymerisation control. The mechanism underlying adverse signals observed with voxelotor remains under investigation. Contribution: methodological demonstration of TRIDENT applied to a high-resolution monogenic disease model. No new experimental data are presented. Part of the SHRF corpus. Keywords sickle cell disease haemoglobin S HbS polymerisation fetal haemoglobin gene therapy CRISPR vaso-occlusive crisis nitric oxide depletion haemolysis phase transition biology boundary scalar TRIDENT diagnostic framework SHRF