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 Machado, Jane A. Little, James Taylor VI, Claudia R. Morris, James S. Nichols, Xunde Wang, Mirjana Poljakovic, Sidney M. Morris, Mark T. Gladwin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2279-2285
Number of pages7
JournalBlood
Volume107
Issue number6
DOIs
StatePublished - Mar 15 2006
Externally publishedYes

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Priapism
Sickle Cell Anemia
Biomarkers
Hemolysis
L-Lactate Dehydrogenase
Pulmonary Hypertension
Leg
Nitric Oxide
Plasmas
Arginase
Hemoglobins
Biological Availability
Oxyhemoglobins
Haptoglobins
Nitric Oxide Donors
Reticulocytes
Scavenging
Fractionation
Aspartate Aminotransferases
Plasma Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. / Kato, Gregory J.; McGowan, Vicki; Machado, Roberto; Little, Jane A.; Taylor VI, James; Morris, Claudia R.; Nichols, James S.; Wang, Xunde; Poljakovic, Mirjana; Morris, Sidney M.; Gladwin, Mark T.

In: Blood, Vol. 107, No. 6, 15.03.2006, p. 2279-2285.

Research output: Contribution to journalArticle

Kato, GJ, McGowan, V, Machado, R, Little, JA, Taylor VI, J, Morris, CR, Nichols, JS, Wang, X, Poljakovic, M, Morris, SM & Gladwin, MT 2006, 'Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease', Blood, vol. 107, no. 6, pp. 2279-2285. https://doi.org/10.1182/blood-2005-06-2373
Kato, Gregory J. ; McGowan, Vicki ; Machado, Roberto ; Little, Jane A. ; Taylor VI, James ; Morris, Claudia R. ; Nichols, James S. ; Wang, Xunde ; Poljakovic, Mirjana ; Morris, Sidney M. ; Gladwin, Mark T. / Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. In: Blood. 2006 ; Vol. 107, No. 6. pp. 2279-2285.
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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.",
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AU - Taylor VI, James

AU - Morris, Claudia R.

AU - Nichols, James S.

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AU - Poljakovic, Mirjana

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AU - Gladwin, Mark T.

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