Intravascular hemolysis and the pathophysiology of sickle cell disease

J Clin Invest. 2017 Mar 1;127(3):750-760. doi: 10.1172/JCI89741. Epub 2017 Mar 1.

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.

Publication types

  • Review

MeSH terms

  • Anemia, Sickle Cell* / blood
  • Anemia, Sickle Cell* / physiopathology
  • Hemolysis*
  • Humans
  • Methemoglobin / metabolism*
  • Nitric Oxide / blood*
  • Vascular Diseases* / blood
  • Vascular Diseases* / physiopathology
  • Vasomotor System* / metabolism
  • Vasomotor System* / physiopathology

Substances

  • Nitric Oxide
  • Methemoglobin