A circular model of cold-evoked vaso-occlusive pain crisis in SCD. These data are consistent with a feedback loop pain model whereby the outputs of the model, for example, C5a, are used as inputs to drive more inflammation, vaso-occlusion, and pain. In this model, cold exposure induces pain, vasoconstriction, and hypoxia,^30,42 likely leading to hemoglobin S (HbS) deoxygenation/polymerization, and microvascular stasis (vaso-occlusion). Static venules can subsequently reopen producing I/R pathophysiology leading to complement activation, including the cleavage of C5 and the generation of the potent anaphylatoxin C5a. Cleavage of C5 can be blocked by anti-C5 mAb. In the absence of anti-C5 mAb, the C5a produced can bind to C5aR and promote vascular inflammation and pain. The binding of C5a to C5aR and its subsequent proinflammatory signaling can be blocked by anti-C5aR mAb. In the absence of anti-C5aR mAb, vascular inflammation promotes the expression of adhesion molecules leading to more vaso-occlusion, which can be blocked by anti-adhesion therapies such as anti–P-selectin. Inflammatory pain mediators can sensitize nociceptors in tissues leading to pain.