Sickle cell vaso-occlusion

The last century has seen a flourishing of intensive study into the origin of sickle cell disease and the pathophysiology underlymig vaso-occlusion. Sickle cell anemia was first described in a dental student from Grenada in 1910 by james Herrick [1], who hypothesized that his symptoms arose from the sickle-shaped erythrocytes in the blood. Two decades later, it was discovered that sickle-shaped erythrocytes were more prominently found in the relatively deoxygenated venous circulation and that these erythrocytes regained their normal shape after reoxygenation [2-4]. hi their landmark paper of 1949, Linus Paulig mid colleagues [5] verified the abnormal electrophoretic mobility of the mutated hemoglobin molecule in the erythrocytes of patients With sickle cell disease. The differentiating characteristic of sickle hemoglobin (HbS) was later discovered to be a single amino acid substitution on the beta-globin chain of HbS [6], which leads to the abnormal susceptibility of HbS to polymerization in the presence of decreased pH or oxygen tension. From these early observations, sickle cell vaso-occlusion appeared to result from the passive physical obstruction of small blood vessels with deoxygenated, rigid, sickle-shaped erythrocytes. However, it became increasingly recognized that HbS polymerization alone was not sufficient to produce vaso-occlusion. Conceptualization of sickle cell vaso-occlusion grew beyond the hemoglobin molecule when it was recognized that sickle erythrocytes had a striking propensity to adhere to cultured vascular endothelial cells [7,8]. hi addition, in vitro adhesiveness of sickle erythrocytes (SSRBCs) was shown to correlate with clinical disease severity [9]. The adherence of SSRBCs to die endothelium has since been well characterized in various in vitro and ex vivo models [10,11]. It is now recognized that SSRBCs actively participate in vaso-occlusion through multiple overlapping cell and matrix adhesion molecules. Both dense, sickle-shaped erythrocytes and immature reticulocytes may participate in adhesion to the vascular endothelium. Reticulocytes appear to be more adherent than mature erythrocytes to cultured endothelium in vitro [12-14]; however, it may be that older erythrocytes subjected to repetitive cycles of deoxygenation can regain or maintain their adhesiveness [15]. These findings led to a proposed model in which reticulocytes initiated vaso-occlusion by first adhering to the endothelium, then secondarily adhering to and trapping circulating dense SSRBGs. However, recent evidence from clinical observations and animal models suggests that vaso-occlusion most likely results from a complex inter-play of several processes, involving SSRBCs, endothelial cells, leukocytes, and platelets, along with coagulative factors and other plasma proteins. This article focuses on the contributions of the cellular elements and selected plasma proteins, which demonstrate the significant advances made in our current understanding of sickle cell vaso-occlusion.