Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease
Open accessAbstract
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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SCD patients with higher hemolysis rates have lower steady-state hemoglobin and are more likely to develop vascular injury and organ dysfunction with age, including pulmonary hypertension, diastolic left heart disease, and renal dysfunction.
“Patients with higher rates of hemolysis have lower steady-state Hb levels and are more likely to develop vascular injury and organ dysfunction as they age, manifesting as pulmonary hypertension, diastolic left heart disease, and renal dysfunction (proteinuria, albuminuria, and chronic kidney dysfunction) (62, 64, 65, 70, 79).”
From Pathophysiology of Sickle Cell Disease (2019) · cites this paper as [65]
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Self-citation
- Authors
- Kato, G. J., McGowan, V., Machado, R. F., Little, J. A., Taylor, J., Morris, C. R., Nichols, J. S., Wang, X., Poljakovic, M., Morris, S. M., & Gladwin, M. T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Kato, Gregory J.
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-03-15
- Volume
- 107
- Issue
- 6
- Pages
- 2279-2285
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895723
- OpenAlex
- W2170995347
- Cited by
- 661
- References
- 71
- Citations by year
- 2026: 24 · 2025: 28 · 2024: 25 · 2023: 24 · 2022: 25 · 2021: 37 · 2020: 37 · 2019: 35 · 2018: 32 · 2017: 35 · 2016: 46 · 2015: 28 · 2014: 20 · 2013: 32 · 2012: 35
- FWCI
- 12.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (Z99 HL999999)
- National Heart, Lung, and Blood Institute (HL-04386-05, ZIAHL006012, K23HL004386)
- National Institute of General Medical Sciences (R01GM57384, R01GM057384)
- National Center for Research Resources (M01 RR 01271, M01RR001271)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- lactate dehydrogenase, sickle cell disease, hemolysis, nitric oxide resistance, pulmonary hypertension, priapism, leg ulcers, mortality, biomarkers, intravascular hemolysis, free hemoglobin, arginase, endothelial dysfunction, vasculopathy, haptoglobin, reticulocytes
- MeSH terms
- Adult, Anemia, Sickle Cell, Death, Clinical Enzyme Tests, Female, Hemolysis, Humans, Hypertension, Pulmonary, L-Lactate Dehydrogenase, Leg Ulcer, Male, Middle Aged, Priapism, Vascular Diseases, Biomarkers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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