Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: pathophysiological implications

Abstract

To understand the role of sickle cell adherence to the vascular endothelium in the pathophysiology of sickle cell anemia (SS) vasoocclusion, we have carried out a microcirculatory study utilizing the ex vivo mesocecum vasculature of the rat. A single bolus of washed oxy-normal (AA) erythrocytes or oxy-SS cells (unseparated or density-defined SS cell classes) was infused. Hemodynamic monitoring and intravital microscopic observations of the microvascular flow revealed higher peripheral resistance for SS erythrocytes and adherence of these cells exclusively to the venular endothelium but rare or no adherence of AA cells. The extent of adhesion was inversely correlated with venular diameters (r = -0.812; P less than 0.00001). The adhesion of SS erythrocytes is density-class dependent: reticulocytes and young discocytes (SS1) greater than discocytes (SS2) greater than irreversible sickle cells and unsicklable dense discocytes (SS4). Selective secondary trapping of SS4 (dense cells) is found in postcapillary venules where deformable SS cells are preferentially adhered. We conclude that in the oxygenated condition, vasoocclusion can be induced by two events: (i) random precapillary obstruction by a small number of SS4 cells; (ii) increased adhesion of SS1 and SS2 cells in the immediate postcapillary venules. A combination of precapillary obstruction, adhesion in postcapillary venules, and secondary trapping of dense cells may induce local hypoxia, increased polymerization of hemoglobin S, and rigidity of SS erythrocytes, thereby extending obstruction to nearby vessels.