The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model

Pulmonary arterial hypertension (PAH) is suspected to be a strong mortality deter- minant of hemolytic disorders. However, direct contribution of acute intravascular hemolysis to fatal PAH has not been investigated. The roles of nitric oxide (NO) insufficiency and platelet activation in hemolysis-associated fatal PAH have been suspected but not been experimen- tally studied. We recently generated a unique intravascular hemolysis mouse model in which the membrane toxin, in- termedilysin (ILY), exclusively lyses the Introduction erythrocytes of transgenically express- ing human CD59 mice (ThCD59RBC), thereby inducing ILY-dose–dependent massive hemolysis. Using this murine hemolysis model, we found that the acute increase in pulmonary arterial pressure leading to right ventricle failure caused sudden death. Reduced NO bioavailabil- ity and massive platelet activation/aggre- gation leading to the formation of mas- sive thrombosis specifically in the pulmonary microvasculature played the critical roles in pathogenesis of acute hemolysis-associated fatal PAH. Thera- peutic interventions enhancingNObioac- tivity or inhibiting platelet activation pre- vented sudden death or prolonged survival time via the suppression of the acute increase in pulmonary arterial pres- sure and improvement of right ventricle function. These findings further highlight the importance of the inhibition of platelet activation and the enhancement of NO bioavailability for the treatment and pre- vention of hemolysis-associated (fatal) PAH. (Blood. 2010;116(9):1613-1622)