Chapter 17: Sickle Cell Trait

Overview

Sickle cell trait (SCT), defined as the heterozygous inheritance of sickle hemoglobin (HbS), is one of the most common hemoglobin mutations in the world. Prevalence estimates suggest that SCT is found in approximately 300 million individuals worldwide and nearly 3 million individuals in the United States. The rates of SCT are highest among populations living in sub-Saharan Africa and parts of the Mediterranean, the Middle East, and India, as well as among individuals whose ancestors come from these areas, such as people of African descent living in Europe or the Americas. Prevalence of SCT ranges from 7% to 9% in the African American population in the United States, and rates may exceed 25% in regions of malarial endemicity such as Nigeria and tribal India.¹ Evidence of the evolutionary advantage of SCT in conferring protection against severe malaria is profound and undisputed. Consistent studies have demonstrated a 90% risk reduction of severe and cerebral malaria among SCT carriers.¹

Basic Biological and Physiological Aspects of SCT

Blood Rheology

Blood rheologic properties are severely affected in the context of sickle cell disease (SCD) and play a key role in the pathophysiology of acute painful vaso-occlusive crises and chronic complications.^2-4 Blood is a shear-thinning fluid, which means that its viscosity decreases with increasing shear rates.⁵ For instance, blood viscosity is higher in veins than in arteries, arterioles, or capillaries. Blood viscosity is highly dependent on hematocrit, with viscosity being more affected by hematocrit at a low shear rate than at a high shear rate. However, the non-Newtonian property of the blood is mainly related to the red blood cell (RBC) rheologic properties (ie, RBC deformability and RBC aggregation). While a reduction in RBC deformability mainly affects blood viscosity at high shear rate, increased RBC aggregation is responsible for a rise in blood viscosity at low shear rate.⁵ Several studies have characterized the blood rheologic properties of SCT carriers. Although RBC deformability is severely decreased in patients with SCD,⁵ SCT carriers have a slight reduction in RBC deformability compared to non-SCT carriers.^6-9

More recently, 2 studies investigated the changes in RBC deformability^6-9 and RBC fragility¹⁰ during deoxygenation and after reoxygenation in SCT carriers. Using ektacytometry, Rab et al¹¹ described a slight but significant reduction in RBC deformability (~4%-5% compared to normoxic conditions) during the deoxygenation procedure, mainly at low oxygen pressure, which was due to HbS polymerization and sickling of few RBCs. Tarasev et al¹⁰ found that RBC fragility increased during hypoxic stress in SCT carriers, and recovery at reoxygenation was observed only in half of the cases. When compared to what happens in SCD, the magnitude of changes is very low in SCT carriers,^10,11 but these studies demonstrate that RBC deformability measured in normoxic or hypoxic conditions is not completely normal in SCT carriers compared ...