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

Abstract

Key Points NETs are present and pathogenic in sickle cell disease. Plasma heme and proinflammatory cytokines collaborate to activate release of NETs.

Intravascular hemolysis and the pathophysiology of sickle cell disease

“…This was recently confirmed in a study of SCD patients correlating high plasma hemoglobin levels appreciated as an additional important mediator of inflammation and vascular injury (102,103). In sickle cell mice, free heme drives inflammation, vaso-occlusion, and coagulation that are blocked by the heme scavenger hemopexin (104)(105)(106)(107)(108)(109). In cultured cells, heme promotes secretion of high levels of placenta growth factor (110), which in turn induces release of the potent vasoconstrictor endothelin 1 (111), a common mediator of PH.…”

Elevated hypercoagulability markers in hemoglobin SC disease

“…The pathophysiological link between hemolysis and hemostatic activation is probably heme, a product of intravascular hemolysis, which is capable of inducing TF expression by endothelial cells and inducing neutrophil extracellular trap formation in sickle cell disease. 24,25 Similarly to observations in SCA, the hypercoagulability state encountered in HbSC disease seems to be associated with inflammation and hemolysis. 17,19,26 Thus, our results demonstrate similarities between the pathophysiological mechanisms involved in the activation of coagulation in HbSC disease and SCA.…”

Nouvelle Cuisine: Platelets Served with Inflammation

“…Furthermore, platelets were implicated in the clearance of bacterial infections: thrombin-stimulated platelets facilitated clearance of streptococci in infective endocarditis (18). In addition, activated platelets were shown to surround Staphylococcus aureus, thereby inhibiting their bacterial growth rate via secretion of the antimicrobial peptide b-defensin and the induction of neutrophil extracellular trap (NET) formation (13,19), a process that also was described to occur in other settings, including thrombosis, transfusion-related acute lung injury, storage of RBCs, and sickle cell disease (20)(21)(22)(23)(24)(25). Interestingly, platelets also were shown to be involved in the trapping of bacteria (methicillin-resistant S. aureus and Bacillus cereus) on the surface of Kupffer cells in the liver (5).…”