Model of SS RBC activation by plasma TSP and shear stress. We previously demonstrated that basal or resting SS RBCs (left) could adhere to immobilized TSP (representing subendothelial matrix- or cell-associated TSP in vivo) by an IAP-mediated adhesion to the “cell binding domain” of TSP (binding site 1) when soluble TSP levels are negligible, as in individuals who do not have SCD. In contrast, when plasma levels of TSP are elevated, as in SCD, we propose that IAP is largely occupied by plasma TSP and unable to participate directly in adhesion to immobilized TSP. However, IAP stimulation by plasma TSP in combination with physiological shear stress, via a G_i- and tyrosine kinase–dependent pathway, activates a distinct, yet unidentified, TSP receptor that preferentially recognizes immobilized matrix- or cell-associated TSP (binding site 2). We further propose that site 2 is relatively inaccessible in plasma TSP, thus explaining the marked IAP-mediated activation of SS RBCs by soluble TSP, instead of an inhibition of adhesion to immobilized TSP. Finally, we demonstrate that activation of a distinct TSP receptor more than compensates for a loss of direct IAP adhesion to immobilized TSP, therefore promoting overall SS RBC avidity for immobilized TSP.