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Intravascular hemolysis and the pathophysiology of sickle cell disease
Gregory J. Kato, … , Martin H. Steinberg, Mark T. Gladwin
Gregory J. Kato, … , Martin H. Steinberg, Mark T. Gladwin
Published March 1, 2017
Citation Information: J Clin Invest. 2017;127(3):750-760. https://doi.org/10.1172/JCI89741.
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Review

Intravascular hemolysis and the pathophysiology of sickle cell disease

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Abstract

Hemolysis is a fundamental feature of sickle cell anemia that contributes to its pathophysiology and phenotypic variability. Decompartmentalized hemoglobin, arginase 1, asymmetric dimethylarginine, and adenine nucleotides are all products of hemolysis that promote vasomotor dysfunction, proliferative vasculopathy, and a multitude of clinical complications of pulmonary and systemic vasculopathy, including pulmonary hypertension, leg ulcers, priapism, chronic kidney disease, and large-artery ischemic stroke. Nitric oxide (NO) is inactivated by cell-free hemoglobin in a dioxygenation reaction that also oxidizes hemoglobin to methemoglobin, a non–oxygen-binding form of hemoglobin that readily loses heme. Circulating hemoglobin and heme represent erythrocytic danger-associated molecular pattern (eDAMP) molecules, which activate the innate immune system and endothelium to an inflammatory, proadhesive state that promotes sickle vaso-occlusion and acute lung injury in murine models of sickle cell disease. Intravascular hemolysis can impair NO bioavailability and cause oxidative stress, altering redox balance and amplifying physiological processes that govern blood flow, hemostasis, inflammation, and angiogenesis. These pathological responses promote regional vasoconstriction and subsequent blood vessel remodeling. Thus, intravascular hemolysis represents an intrinsic mechanism for human vascular disease that manifests clinical complications in sickle cell disease and other chronic hereditary or acquired hemolytic anemias.

Authors

Gregory J. Kato, Martin H. Steinberg, Mark T. Gladwin

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Figure 1

Tricuspid regurgitant velocity on echocardiogram is a physiological biomarker that predicts survival and functional outcomes.

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Tricuspid regurgitant velocity on echocardiogram is a physiological biom...
Tricuspid regurgitant velocity (TRV) that is less than two SD below the population mean is in the normal range (<2.5 m/s), is associated with normal calculated pulmonary artery systolic pressures (PASP, <25 mmHg), and generally corresponds to a mean pulmonary artery pressure (MPAP, <20 mmHg), good long-term survival, and good exercise tolerance, as indicated by a higher 6-minute walk distance (>400 m). Conversely, highly elevated TRV that is more than 3 SD above the mean (≥3 m/s) is strongly associated with poor exercise tolerance with lower 6-minute walk distance (<400 m), pulmonary artery systolic pressure greater than 40 mmHg, mean pulmonary artery pressure greater than 25 mmHg on right heart catheterization, and significantly poorer long-term survival. Intermediate TRV level (2.5–2.9 m/s) is associated with intermediate risk of exercise intolerance and mortality. Figure is adapted with permission from the Journal of the American Medical Association (39) and the American Journal of Respiratory and Critical Care Medicine (74).

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