Abstract
Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.
Highlights
Sickle cell disease (SCD) is a monogenic disorder in which a single amino acid substitution in the beta globin gene (A→T) gives rise to the formation of abnormal hemoglobin, i.e., hemoglobin S (HbS) that polymerizes upon deoxygenation [1,2,3]
It is clear that patients with SCD have a hyper-responsive autonomic nervous system
Abnormalities in heart rate variability have been observed in several studies of SCD subjects, though it is only recently that neural-mediated vasoconstriction and dysautonomia have been considered to possibly play a significant role in causing sickle vaso-occlusive crises (VOC) [19,35,53,54,59,67]
Summary
Sickle cell disease (SCD) is a monogenic disorder in which a single amino acid substitution in the beta globin gene (A→T) gives rise to the formation of abnormal hemoglobin, i.e., hemoglobin S (HbS) that polymerizes upon deoxygenation [1,2,3]. Genetic modifiers of disease such as co-inheritance of alpha thalassemia, beta globin haplotypes and elevated hemoglobin F are thought to act in concert with various mediators of hemolysis and inflammation to modulate disease severity [11,12]. These biological and cellular profiles still do not fully account for disease variability, which remains mostly unexplained.
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