Safety and hematologic impact of high-dose N-acetylcysteine infusion in sickle cell disease

Sickle cell disease (SCD) is characterized by oxidative stress, erythrocyte dehydration, and endothelial activation, promoting vaso-occlusion through expression of adhesion molecules, including von Willebrand factor (VWF), and the presence of rigid erythrocytes. N-acetylcysteine (NAC), a thiol-containing reducing agent, can decrease VWF multimer size and oxidative stress, which may reduce vaso-occlusive complications in SCD. We report Part 1 of a two-part phase I/II pilot study (NCT01800526) examining the safety and tolerability of high-dose intravenous NAC and, as a primary outcome, its effects on plasma VWF parameters (multimer distribution, VWF antigen, ADAMTS13 activity), and, as secondary parameters, on systemic redox status (plasma and whole blood thiol species), and RBC function (dense cell fraction and erythrocyte hydration) in SCD at baseline. We enrolled five adults [four with SCD (HbSS or HbSβ 0 ) and one with sickle trait]. Each received two intravenous NAC infusions—150 mg/kg and 300 mg/kg—separated by four weeks. After mild adverse events (pruritus, headache, nausea, and vomiting) in the first two subjects during bolus dosing, the protocol was changed to continuous infusion; subsequent subjects had no adverse events. NAC reduced high-molecular-weight VWF multimers, reduced oxidized plasma thiol species, and produced rapid, sustained decreases in dense, dehydrated erythrocytes lasting up to 72 hours. VWF antigen levels and ADAMTS13 activity did not change significantly. Continuous intravenous NAC infusion is safe and well tolerated in adults with SCD and improves erythrocyte hydration and systemic redox balance, supporting further evaluation as an adjunctive therapy in SCD.