INTRODUCTION

Although sickle cell disease (SCD) is characterized by a marked heterogeneity in clinical and hematologic severity [1,2], bone and joint problems are the most common manifestations. Pain, caused by vaso-occlusive crises (VOC), may occur as often as every week or as rarely as once a year. Many patients also suffer from the long-term consequences of VOC, such as avascular necrosis of the femoral heads or collapsed vertebral bodies, leading to a chronic state of pain in addition to the more acute painful crises.

Bone and joint complications in SCD are discussed here [3]. Other manifestations of the disease are discussed separately. (See "Overview of the clinical manifestations of sickle cell disease".)

PATHOGENESIS

The interaction between sickle red cells and the vascular endothelium appears to be of great importance in the pathogenesis of crises, including the role of hemoglobin S polymerization and subsequent red cell distortion, interaction of sickle cells with adhesion proteins of the vascular endothelium, as well as the ensuing inflammatory response, which further increases cellular adhesiveness [4-8]. (See "Vasoocclusion in sickle cell disease".)

Sickle erythrocytes can upregulate gene expression of the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in vascular endothelial cells in vitro, and certain drugs (eg, sulfasalazine) have been evaluated with regard to their effect on adhesion [9,10]. Heme and heme oxygenase, the heme-degrading enzyme, also are potent inducers of inflammation and endothelial cell adhesion [11], as is exposure of phosphatidylserine on the surface of the red cell [12].

Increased adhesion and subsequent inflammatory response decrease blood flow, leading to further sickling in an increasingly hypoxic and acidic environment, manifested by the typical pain associated with vaso-occlusive crises. Repeated episodes of decreased blood flow can lead to impaired nourishment of critical structures (eg, femoral head or vertebral bodies), leading to bony lesions with loss of trabeculae (eg, avascular necrosis, vertebral collapse).