Fig. 2.

The complex downstream events induced by VOC. Among the many downstream events are the following five pathways, all of which result in a positive-feedback into the VOC process to induce secondary VOC: (1). Increased hemolysis produces more free heme and overwhelms heme scavenging mechanisms, precipitating the development of neutrophil extracellular traps that promotes a local prothrombotic condition. (2). Local hypoxemia caused by vaso-occlusion induces sickling of erythrocytes in the vicinity. (3). Cytokine release due to VOC activates leukocytes and platelets and increases their recruitment to the site of local tissue damage. (4). Increased enterocyte damage due to VOC further increases the gut permeability and worsens the translocation of luminal bacteria/bacterial products into the systemic circulation. (5). Stress induced by painful VOC leads to increased production of epinephrine and glucocorticoid response. The former enhances the expression of adhesion molecules on the erythrocytes and the latter worsens the translocation of luminal bacteria/bacterial products into the systemic circulation