Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

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.

Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease

“…In the course of a number of studies in humans using peripheral perfusion as a biomarker to understand the triggers of VOC, we have shown that cold, 8 mental stress, 5 respiration, 7 and pain itself, 4,23 all factors mentioned by patients to precede VOC, cause significant peripheral vasoconstriction, and that each study participant, both SCD and controls, seems to have a characteristic baseline vasoconstriction pattern that was observed over several experimental visits 6 . We suspected that individuals with high inherent vasoconstriction would have more frequent VOC 2 .…”

“…While much of the literature in SCD has focused on nitric oxide (NO)‐mediated vascular dysfunction and cellular adhesion in the post‐capillary venules as key factors that may decrease microvascular flow and promote vaso‐occlusion, the role played by the sympathetic and parasympathetic nervous systems in causing vasoconstriction in the pre‐capillary arteriole, and decreasing microvascular flow has only recently been considered 3 . Our prior work has demonstrated that anticipatory pain, 4 experimental mental stress, 5 and cold exposure 6 all cause significant global vasoconstriction in SCD and non‐SCD controls and these responses vary significantly among all individuals 3 . Sighs (deep breaths) trigger peripheral vasoconstriction frequently in SCD but rarely in non‐SCD indivuals, 7 and cold face stimulation reduces the sensitivity of the baroreflex control of peripheral vascular resistance more in non‐transfused than transfused individuals with SCD or in controls 8 .…”

The Effect of Use of Individualized Pain Plans in Sickle Cell Patients Presenting to the Emergency Department

“…This has been associated with increased risk of vaso-occlusive crisis and acute chest syndrome because of concomitant vasoconstriction, making sickling in clinically relevant blood vessels more likely. 8 In the same vein, given the association between hypertension and risk for CKD, 9 the same mechanisms of increased disease severity could be at play for the findings of increased ED length of stay for patients with kidney disease. Patients with kidney disease have worse SCD, as evidenced by end-organ damage caused by inflammation from high levels of hemolysis.…”

Aura and mental stress are associated with reports of pain in sickle cell disease‐a pilot study using a mobile application

“…The underlying mechanisms that trigger VOC are still unknown, but recent research has suggested that autonomic dysfunction may play an important role. [1][2][3] We have been able to quantify blood flow and autonomic mediated vasoconstriction under different stimuli such as stress and cold. 1 Khaleel et al found that patients vasoconstricted in response to pain anticipation even before the actual pain stimuli.…”

“…[1][2][3] We have been able to quantify blood flow and autonomic mediated vasoconstriction under different stimuli such as stress and cold. 1 Khaleel et al found that patients vasoconstricted in response to pain anticipation even before the actual pain stimuli. 3 In fact, clinically, patients have observed subtle differences in their body with no evidence of pain in the pre-pain phase.…”