Patients with sickle cell disease have an abnormal hemoglobin that polymerizes under physiologic conditions, leading to the formation of distorted and rigid red blood cells. This in turn causes hemolysis and obstruction of blood flow in the microcirculation, with resultant tissue ischemia and necrosis. Pain and organ injury are the sequelae.
The organs damaged by the abnormal erythrocytes vary according to patient age, the specific sickle cell genotype, other gene polymorphisms, and environmental phenomena. Organ damage can be acute or chronic, symptomatic or clinically silent, and episodic or progressive. The most common organ-related complications that characterize sickle cell disease as a severe clinical entity include vaso-occlusive or pain crisis, acute chest syndrome, stroke, and priapism. Because of the clinical heterogeneity of sickle cell disease, there has been a great deal of interest in predicting at the earliest possible age which patients will be most severely affected. If such high risk patients could be identified, early intervention might be prescribed to avert organ injury. In 2000, Miller and colleagues reported for the Cooperative Study of Sickle Cell Disease that several clinical and laboratory markers during the first two years of life predict a severe clinical course (characterized by early death or recurrent pain crisis or chest syndrome) during the ensuing 10 years [1
]. However, a similar study of the Dallas Newborn Cohort reported by Quinn and colleagues in 2008 refuted this finding [2
]. Thus, at present, there are no reliably validated measures in the young child which can predict long term outcomes.
Although the acute events described above cause much morbidity during childhood as well as in adults, the toll of chronic sickling and vascular injury as well as ongoing hemolysis also promotes insidious, silent, clinically inapparent, but progressive organ damage. Such injury involves the lungs, heart, brain, kidneys, bones, and other organs. The damage may not become manifest until early or mid-adulthood, often after a seemingly benign clinical course during the childhood years. Some, if not much of this organ dysfunction, results primarily from the chronic anemia or perhaps more specifically from intravascular hemolysis. Specific complications include pulmonary hypertension, osteonecrosis, chronic renal disease, and cognitive dysfunction. Attention is currently being given by investigators and clinicians to this progressive organ damage, for it is a major cause of morbidity and premature death in adult patients with sickle cell disease. Many such patients seem to do well during childhood, but are vulnerable to developing irreversible organ damage due to chronic hemolytic anemia and/or vascular occlusion in young adulthood. These patients are now increasingly considered candidates for the same disease-modifying interventions as those children and adults with more clinically apparent recurrent vaso-occlusive events.
At this time, the major treatments which can truly prevent or lesson the burden of recurrent pain and organ damage are hydroxyurea, chronic blood transfusions, and hematopoietic stem cell transplantation (HSCT). The real question is which of these three approaches (as well as novel interventions yet to be developed or perfected) is most appropriate for an individual patient. An equally important question is when such intervention should be initiated to derive optimal benefit. Since each of the three primary treatment modalities has substantial adverse effects, the careful assessment of the risk-benefit ratio is crucial. Some clinical trials are ongoing, and many others need to be designed and performed to generate conclusive answers to this vexing question.