title: Pulmonary hypertension and nitric oxide depletion in sickle cell disease.
abstract: During the past decade a large body of experimental and clinical studies has focused on the hypothesis that nitric oxide (NO) depletion by plasma hemoglobin in the microcirculation plays a central role in the pathogenesis of many manifestations of sickle cell disease (SCD), particularly pulmonary hypertension. We have carefully examined those studies and believe that the conclusions drawn from them are not adequately supported by the data. We agree that NO depletion may well play a role in the pathophysiology of other hemolytic states such as paroxysmal nocturnal hemoglobinuria, in which plasma hemoglobin concentrations are often at least an order of magnitude greater than in SCD. Accordingly, we conclude that clinical trials in SCD designed to increase the bioavailability of NO or association studies in which SCD clinical manifestations are related to plasma hemoglobin via its surrogates should be viewed with caution.
authors.affiliation: Division of Hematology, Department of Medicine, Harvard Medical School, Boston, MA, USA. hfbunn@rics.bwh.harvard.edu
authors.forename: H Franklin
authors.initials: HF
authors.lastname: Bunn
authors.forename: David G
authors.initials: DG
authors.lastname: Nathan
authors.forename: George J
authors.initials: GJ
authors.lastname: Dover
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Orah S
authors.initials: OS
authors.lastname: Platt
authors.forename: Wendell F
authors.initials: WF
authors.lastname: Rosse
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D002648:Child; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D004730:Endothelium, Vascular / Q000503:physiopathology; D005189:False Positive Reactions; D005260:Female; D006454:Hemoglobins / Q000032:analysis / Q000737:chemistry; D006457:Hemoglobinuria, Paroxysmal / Q000150:complications; D006461:Hemolysis; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology* / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007871:Leg Ulcer / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008833:Microcirculation; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D009569:Nitric Oxide / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency* / Q000502:physiology / Q000627:therapeutic use; D011317:Priapism / Q000209:etiology / Q000503:physiopathology; D013923:Thromboembolism / Q000209:etiology / Q000503:physiopathology; D014262:Tricuspid Valve Insufficiency / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology
chemical_list: D006454:Hemoglobins; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D006918:Hydroxyurea