Thrombomodulin protects against acute vascular and multiorgan injury in sickle cell disease.

Vaso-occlusive episodes (VOEs) in the setting of hyperhemolysis can rapidly evolve into multiorgan failure in sickle cell disease (SCD). Although the mechanisms for rapid progression to multiorgan failure are unclear, a systemic vasculopathy with thrombotic microangiopathy-type features has been described. Reduced thrombomodulin (TM) function is implicated in some thrombotic microangiopathy syndromes. We observed a greater decline in platelet count and hemoglobin concentration and an increase in vascular injury biomarkers within 24 hours of admission for a VOE in 12 patients with SCD with multiorgan failure versus 12 patients without multiorgan failure. We observed decreased TM expression on the lung and kidney vasculature of 3 additional patients with SCD with multiorgan failure compared with a control patient without SCD. Transgenic SCD mice challenged with cell-free hemoglobin had reduced TM function, increased vascular injury biomarkers, and reduced renal cortical blood flow. Infusion of recombinant TM 2 or 24 hours after the challenge restored cortical blood flow and mitigated increases in vascular injury, complement activation, and tubular injury biomarkers, and protected against acute kidney and lung injury. We demonstrated that impaired TM function may be involved in the systemic vasculopathy of SCD-related multiorgan failure, and infusion of recombinant TM may restore vascular function and protect against acute organ damage.