Abnormal adhesion of red blood cells to the endothelium has been linked to the pathophysiology of several diseases associated with vascular disorders. Various biochemical changes, including phosphatidylserine exposure on the outer membrane of red blood cells as well as plasma protein levels, have been identified as being likely to play a key role, but the detailed interplay between plasma factors and cellular factors remains unknown. It has been proposed that the adhesionpromoting effect of plasma proteins originates from ligand interaction, but evidence substantiating this assumption is often missing. In this work, we identified an alternative pathway by demonstrating that nonadsorbing macromolecules can also have a marked impact on the adhesion efficiency of red blood cells with enhanced phosphatidylserine exposure to endothelial cells. It is concluded that this adhesion-promoting effect originates from macromolecular depletion interaction and thereby presents an alternative mechanism by which plasma proteins could regulate cell-cell interactions. These findings should thus be of potential value for a detailed understanding of the pathophysiology of diseases associated with vascular complications and might be applicable to a wide range of cellcell interactions in plasma or plasma-like media. The adhesion of red blood cells (RBC)2 to endothelial cells (EC) is usually insignificant. However, increased RBC adhesion to endothelial cells has been observed in various clinical states such as sickle cell disease, ␤-thalassemia, and diabetes mellitus, and the degree of RBC-EC adhesiveness has been linked to the vascular complications associated with these diseases (1-5). There is now general agreement that various cell surface alterations control the increased RBC adhesiveness in such disease states. For example, an enhanced phosphatidylserine (PS) exposure on the outer leaflet of the RBC membrane has been linked to abnormal RBC-EC adhesion in sickle cell disease, hereditary hydrocytosis, and chronic uremia (6 -8). Usually this anionic phospholipid is located exclusively on the inner leaflet of the RBC membrane but is translocated to the outer leaflet in hemoglobinopathies and oxidative stress states (9). The role of PS in adhesion has not been fully understood, but RBC with enhanced PS exposure have been identified to establish specific interactions with EC or the endothelial matrix via several receptors including thrombospondin, ␣ V ␤ 3 , CD36, and PS receptor (6, 10, 11).Moreover, several plasma factors have been identified to be involved in abnormal RBC adhesion to EC. For example, fibrinogen enhances the adhesion of pathological RBC to EC (12, 13), which is consistent with the observation that the onset of vaso-occlusive crisis in sickle cell disease is always accompanied by a temporally elevated level of this acute phase protein (12,14). However, the underlying mechanisms behind the increased adhesion efficiency in the presence of this acute phase protein remain obscure. It has been suggested that fibrinogen acts...

Adhesion of red blood cells (RBCs) to endothelial cells (ECs) is usually insignificant but an enhanced adhesion has been observed in various diseases associated with vascular complications. This abnormal adhesion under pathological conditions such as sickle cell disease has been correlated with increased levels of various plasma proteins but the detailed underlying mechanism(s) remains unclear. Usually it is assumed that the proadhesive effects of plasma proteins originate from ligand interactions cross-linking receptors on adjacent cells, but explicit results detailing binding sites or receptors for some proteins (e.g., fibrinogen) on either RBC or EC surfaces that would support this model are missing. In this study, the authors tested whether there is an alternative mechanism. Their results demonstrate that dextran 2 MDa promotes the adhesion of normal RBCs to thrombin-activated ECs and that this effect becomes more pronounced with increasing thrombin concentration or with prolonged thrombin incubation time. It is concluded that depletion interaction originating from nonadsorbing macromolecules (i.e., dextran) can modulate the adhesion of red blood cells to thrombin-activated EC. This study thereby suggests macromolecular depletion as an alternative mechanism for the adhesion-promoting effects of nonadsorbing plasma proteins. These findings should not only aid in getting a better understanding of diseases associated with vascular complications but should also have many potential applications in biomedical or biotechnological areas that require the control of cell-cell or cell surface interactions.