title: Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease.
abstract: Pulmonary hypertension is prevalent in adult patients with sickle cell disease and is strongly associated with early mortality and markers of hemolysis, in particular, serum lactate dehydrogenase (LDH). Intravascular hemolysis leads to impaired bioavailability of nitric oxide (NO), mediated by NO scavenging by plasma oxyhemoglobin and by arginine degradation by plasma arginase. We hypothesized that serum LDH may represent a convenient biomarker of intravascular hemolysis and NO bioavailability, characterizing a clinical subphenotype of hemolysis-associated vasculopathy. In a cohort of 213 patients with sickle cell disease, we found statistically significant associations of steady-state LDH with low levels of hemoglobin and haptoglobin and high levels of reticulocytes, bilirubin, plasma hemoglobin, aspartate aminotransferase, arginase, and soluble adhesion molecules. LDH isoenzyme fractionation confirmed predominance of LD1 and LD2, the principal isoforms within erythrocytes. In a subgroup, LDH levels closely correlated with plasma cell-free hemoglobin, accelerated NO consumption by plasma, and impaired vasodilatory responses to an NO donor. Remarkably, this simple biomarker was associated with a clinical subphenotype of pulmonary hypertension, leg ulceration, priapism, and risk of death in patients with sickle cell disease. We propose that LDH elevation identifies patients with a syndrome of hemolysis-associated NO resistance, endothelial dysfunction, and end-organ vasculopathy.
authors.affiliation: Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Dr, MSC 1476, Bldg 10CRC, Rm 5-5140, Bethesda, MD 20892, USA. gkato@mail.nih.gov
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.forename: Vicki
authors.initials: V
authors.lastname: McGowan
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Jane A
authors.initials: JA
authors.lastname: Little
authors.forename: James
authors.initials: J
authors.lastname: Taylor
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Morris
authors.forename: James S
authors.initials: JS
authors.lastname: Nichols
authors.forename: Xunde
authors.initials: X
authors.lastname: Wang
authors.forename: Mirjana
authors.initials: M
authors.lastname: Poljakovic
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications*; D015415:Biomarkers / Q000097:blood; D004796:Clinical Enzyme Tests; D003643:Death; D005260:Female; D006461:Hemolysis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis; D007770:L-Lactate Dehydrogenase / Q000097:blood*; D007871:Leg Ulcer / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D011317:Priapism / Q000175:diagnosis; D014652:Vascular Diseases / Q000175:diagnosis
chemical_list: D015415:Biomarkers; D007770:L-Lactate Dehydrogenase