TY - JOUR
T1 - Pulmonary hypertension in sickle cell disease
T2 - Relevance to children
AU - Kato, Gregory J.
AU - Onyekwere, Onyinye C.
AU - Gladwin, Mark T.
N1 - Funding Information:
G.J.K. and M.T.G. are supported by intramural funding from the National Heart, Lung and Blood Institute and the Clinical Center of the National Institutes of Health. M.T.G. also receives research support through a cooperative research and development agreement with INO Therapeutics. O.C.O. receives support from Novartis Pharmaceuticals and INO Therapeutics. We thank Stephen C. Nelson, Farzana D. Pashankar, and Margaret T. Lee for sharing unpublished data.
PY - 2007/3
Y1 - 2007/3
N2 - Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.
AB - Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.
KW - Arginase
KW - Nitric oxide
KW - Pulmonary hypertension
KW - Sickle cell
KW - Thalassemia
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U2 - 10.1080/08880010601185892
DO - 10.1080/08880010601185892
M3 - Review article
C2 - 17454785
AN - SCOPUS:34247470728
SN - 0888-0018
VL - 24
SP - 159
EP - 170
JO - Pediatric Hematology and Oncology
JF - Pediatric Hematology and Oncology
IS - 3
ER -