Genetic variation reduced hospitalizations in children with sickle cell disease

Lakshmanan Krishnamurti, MD

The results are important because they give another insight into why some patients with sickle cell disease are less likely to have acute chest syndrome, one of the major complications of the disease. Research in the past several years has generated new insights into the pathophysiology of sickle cell disease. We have known for a long time that vasocclusion secondary to polymerization of hemoglobin and distortion of the red cell shape is the central event in this disease. In the last few years, there has been a better understanding of the role played by hemolysis and plasma free hemoglobin on vascular homeostasis on the pathophysiology of sickle cell disease. This paper provides evidence of a relationship between the metabolism of plasma free hemoglobin and risk for acute chest syndrome. If proven by further studies that include plasma hemooxygenase levels in patients with or without the polymorphism, these data suggest a molecular basis for variability in risk for acute chest syndrome in patients with sickle cell disease. These mechanistic insights are important in developing prediction models for risk for complications in sickle cell disease and potentially in the development of novel, targeted therapies.

Gregory M. Vercellotti, MD

The findings of Bean and colleagues highlight the importance of the pro-inflammatory molecule heme in the pathogenesis of acute chest syndrome in sickle cell disease. Hemolysis and the release of hemoglobin and heme may be critical in vaso-occlusion and vasculopathy of sickle cell disease. Hemoglobin and heme removal by haptoglobin and hemopexin is compromised in sickle cell disease. Heme detoxification by HO-1 with the concomitant release of anti-inflammatory biliverdin/bilirubin and CO can prevent vascular stasis in murine models of sickle cell disease as shown by Belcher and colleagues (Belcher JD. J Clin Invest. 2006;116:808-816). These studies by Bean and colleagues support the concept that enhanced heme degradation by inducible HO-1 is associated with a decrease in acute chest syndrome in children with sickle cell disease. These observations may explain some of the phenotypic variability of the severity of sickle cell disease in patients. Unfortunately, only 4% of the children were homozygous for the protective short (GT)n genotype. However, the low prevalence of the protective genotype underscores the intriguing opportunity of HO-1 induction as a pharmacologic target in sickle cell disease.