Blood Journal
Leading the way in experimental and clinical research in hematology

Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease

  1. Grace Chen1,
  2. Dachuan Zhang1,
  3. Tobias A. Fuchs2,
  4. Deepa Manwani3,
  5. Denisa D. Wagner2,4, and
  6. Paul S. Frenette1
  1. 1Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY;
  2. 2Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, and Department of Pediatrics, Harvard Medical School, Boston, MA;
  3. 3Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY; and
  4. 4Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA

Key Points

  • NETs are present and pathogenic in sickle cell disease.

  • Plasma heme and proinflammatory cytokines collaborate to activate release of NETs.


Sickle cell disease (SCD) is characterized by recurring episodes of vascular occlusion in which neutrophil activation plays a major role. The disease is associated with chronic hemolysis with elevated cell-free hemoglobin and heme. The ensuing depletion of heme scavenger proteins leads to nonspecific heme uptake and heme-catalyzed generation of reactive oxygen species. Here, we have identified a novel role for heme in the induction of neutrophil extracellular trap (NET) formation in SCD. NETs are decondensed chromatin decorated by granular enzymes and are released by activated neutrophils. In humanized SCD mice, we have detected NETs in the lungs and soluble NET components in plasma. The presence of NETs was associated with hypothermia and death of these mice, which could be prevented and delayed, respectively, by dismantling NETs with DNase I treatment. We have identified heme as the plasma factor that stimulates neutrophils to release NETs in vitro and in vivo. Increasing or decreasing plasma heme concentrations can induce or prevent, respectively, in vivo NET formation, indicating that heme plays a crucial role in stimulating NET release in SCD. Our results thus suggest that NETs significantly contribute to SCD pathogenesis and can serve as a therapeutic target for treating SCD.

  • Submitted October 1, 2013.
  • Accepted February 27, 2014.
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