No abstract

The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure and pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser-Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (p < 0.01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso-reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (p = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso-occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady-state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.

Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.

No abstract