Belcher and colleagues (Belcher et al., 2014), pointed out that many local factors influence the different vascular beds e.g., EC heterogeneity, hemolysis, local cytokine milieux, HPX and Hp levels, HO activity, infections and oxygen gradients plus local or global changes in hemolytic rates, infection and hypoxia to trigger vaso-occlusive crisis. The gene discussed is HMOX1; the disease is infection.