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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2279-2285. Prepublished online as a Blood First Edition Paper on November 15, 2005; DOI 10.1182/blood-2005-06-2373. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: 2005-06-2373v1 107/6/2279    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kato, G. J. Articles by Gladwin, M. T. Search for Related Content PubMed PubMed Citation Articles by Kato, G. J. Articles by Gladwin, M. T. Related Collections Hemostasis, Thrombosis, and Vascular Biology Red Cells Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease Gregory J. Kato, Vicki McGowan, Roberto F. Machado, Jane A. Little, James Taylor, VI, Claudia R. Morris, James S. Nichols, Xunde Wang, Mirjana Poljakovic, Sidney M. Morris, Jr, and Mark T. Gladwin From the Vascular Medicine Branch, National Heart, Lung and Blood Institute, and Department of Critical Care Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; Department of Emergency Medicine, Children's Hospital and Research Center at Oakland, CA; and Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA. 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. 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