Pathogenesis and therapeutic targets in hemolysis-associated pulmonary hypertension and vasculopathy. Intravascular hemolysis releases hemoglobin into plasma which reacts with and destroys endothelial derived nitric oxide (NO). Arginase is also released from the red cell into plasma during hemolysis and degrades arginine, further reducing NO formation from arginine. Xanthine oxidase bound to endothelium produces superoxide which also inhibits NO. Reduced NO bioavailability promotes vasoconstriction, activation of adhesion molecules (VCAM), activation of endothelin-1, a potent vasoconstrictor, and activation of platelets and thrombosis (tissue factor). Splenectomy is associated with pulmonary hypertension and may increase thrombotic risk as well as intravascular hemolysis. A number of therapies that target these pathways are shown on the outside of the blood vessel.

Abbreviations: Hb, hemoglobin; PDE5, phosphodiesterase 5; VCAM-1, vascular cell adhesion molecule-1.

Figure reproduced with permission from Lin et al.⁶³