Mechanisms behind adhesive erythrocytes in sickle-cell disease

Erythrocytes containing primarily hemoglobin S (SS RBCs) are abnormally adherent to a number of ligands, including normal constituents of the extracellular matrix as well as those present on the surfaces of other blood cells and endothelial cells. However, SS RBCs are not really very different from normal (AA) RBCs, except that they are younger. In general, they express the same range of adhesion receptors, and the levels of expression of these receptors, although increased in some cases, are not sufficient to explain the difference between the adhesivity of SS and AA RBCs. However, SS RBCs have activated adhesion receptors, and the signaling pathways responsible for this activation are also upregulated in SS RBCs. In addition, SS RBCs convey different extracellular signals, which are also likely to affect their adhesion to other blood cells and endothelial cells. Together, SS RBCs induce cell–cell interactions mediated by the B‐CAM/LU, ICAM4 (LW), CD44 (In), CD47, α4β1 integrin, and CD36 adhesion molecules on SS RBCs with target ligands on leukocytes and endothelial cells. Other, as yet unidentified cell surface moieties on SS RBCs are probably also responsible for SS RBC interactions with P‐selectin. Interestingly, at least some of these RBC adhesion receptors may also mediate adhesion and adverse physiologic events in the setting of transfusion of stored normal RBCs. Therefore, understanding the mechanisms behind SS RBC adhesion may offer opportunities for improving both therapy of sickle‐cell disease as well as transfusion practices.