Proposed model of heme-induced stasis. Intravascular hemolysis in SCD leads to release of heme from methemoglobin S. Heme release can be blocked by haptoglobin or the liberated heme can be bound and removed by hemopexin. When plasma levels of haptoglobin and hemopexin are depleted, heme can activate TLR4 signaling at the EC membrane independently of LPS, but in manner similar to LPS + LPS binding protein that is dependent on cofactors CD14 and MyD88.4 TLR4 signaling, which can be inhibited by TAK-242, leads to the activation of NF-κB phospho-p65 and the transcription of NF-κB–responsive genes in ECs including VCAM-1, P-selectin, E-selectin, interleukin-1, interleukin-6, interleukin-8, and tissue factor. TLR4 signaling also activates an acute stress sentinel pathway that involves PKC activation leading to the production of ROS by endothelial NOX and EC degranulation of WPB P-selectin and VWF to the cell surface. Rapid mobilization of P-selectin and VWF to the cell surface, triggers vaso-occlusion. Vaso-occlusion also requires the expression of NF-κB–responsive adhesion molecules VCAM-1, ICAM-1, and E-selectin that are chronically upregulated on the endothelium of transgenic sickle mice in steady state.7
