Abstract 3574: A Unique Model and Mechanisms of Hemolysis-Associated Pulmonary Hypertension
Pulmonary hypertension is a common complication of intravascular hemolysis and is suspected to be a strong mortality determinant of hemolytic disorders. However, the pathophysiologic mechanisms leading to hemolytic anemia-associated pulmonary hypertension remains unclear. Intermedilysin (ILY) is a cytolytic pore-forming toxin secreted by Streptococcus intermedius that lyses only human cells due to its unique receptor specificity for human CD59 (hCD59). We recently generated a novel intravascular hemolysis mouse model in which ILY exclusively lyses erythrocytes transgenically expressing hCD59 (ThCD59RBC mice) (Nature Medicine, 2008, 14: 98 –103). Using this model, we investigated the pathogenesis of hemolytic anemia-associated pulmonary hypertension. In ThCD59RBC mice, but not wild type mice, intravenous injection of ILY with a 1.5-fold lethal dose induced rapid intravascular hemolysis with acute death (less than 1 minute) that was preceded by a sharp increase in the pulmonary pressure (10.40 ± 0. 89 mmHg increase, n = 5) with 0.65 ± 0.36 mmHg/second rate of rise of systolic pulmonary artery pressure as measured by right-heart catheterization. We also observed decreased NO levels indirectly measured by plasma nitrate + nitrite concentration [10.01 ± 2.47μM in ThCD59RBC (n=3) vs 22.16 ± 2.20 μM in WT (n=3); P<0.001] and increased plasma P-selectin levels [445.65 ± 54.85 ng/ml in ThCD59RBC (n=4) vs 186.95 ± 18.64 ng/ml in WT (n=4); P<0.001]. These results suggest that the lethality of acute intravascular hemolysis may result from a sudden increase in pulmonary pressure likely a consequence of the reduced bioavailability of NO and resulting pulmonary vasoconstriction and platelet activation.
This research has received full or partial funding support from the American Heart Association, AHA National Center.