Reflex vasoconstriction to thermal stimuli in healthy individuals and patients with SCD. (A) Cutaneous vessel and flowing red blood cells at baseline in a healthy individual. (B) Normal reflex vasoconstriction to thermal stimuli applied to the skin and flowing red blood cells in a healthy individual. The x-axis at the bottom of the figure indicates red blood cell velocity. The release of norepinephrine (NE) and neuropeptide Y (NPY) causes vasoconstriction. The vertical dashed lines crossing panels A and B are arbitrary time points to show the impact of vasoconstriction on the red blood cell transit time. (C) Reflex vasoconstriction to thermal stimuli is faster and stronger in patients with SCD compared with healthy volunteers. Additional factors, such as inflammation, nitric oxide (NO) bioavailability, and endothelin-1 (ET-1) levels could modulate the level of this vasoconstrictive response. (D) The repetition of thermal stimuli results in progressive and increasing vasoconstriction in SCD patients whereas blood flow of healthy volunteers partially recovers. Vasoconstriction prolongs the transit time of red blood cells and increases the risk of vaso-occlusion. Blue arrows indicate thermal stimuli.