Abstract
ObjectiveTo determine differences in TNF-α, IL-1β, IL-10, sICAM-1 concentrations, leg hypoxia and whole blood viscosity (WBV) at shear rates of 46 sec-1 and 230 sec-1 in persons with homozygous S sickle cell disease (SCD) with and without chronic leg ulceration and in AA genotype controls.Design & Methods: fifty-five age-matched participants were recruited into the study: 31 SS subjects without leg ulcers (SSn), 24 SS subjects with leg ulcers (SSu) and 18 AA controls. Haematological indices were measured using an AC.Tron Coulter Counter. Quantification of inflammatory, anti-inflammatory and adhesion molecules was performed by ELISA. Measurement of whole blood viscosity was done using a Wells Brookfield cone-plate viscometer. Quantification of microvascular tissue oxygenation was done by Visible Lightguide spectrophotometry.ResultsTNF-α and whole blood viscosity at 46 sec-1 and 230 sec-1 (1.75, 2.02 vs. 0.83, 1.26, p<0.05) were significantly greater in sickle cell disease subjects than in controls. There were no differences in plasma concentration of sICAM-1, IL-1β and IL-10 between SCD subjects and controls. IL-1β (median, IQR: 0.96, 1.7 vs. 0, 0.87; p<0.01) and sICAM-1 (226.5, 156.48 vs. 107.63, 121.5, p<0.005) were significantly greater in SSu group compared with SSn. However there were no differences in TNF-α (2, 3.98 vs. 0, 2.66) and IL-10 (13.34, 5.95 vs. 11.92, 2.99) concentrations between SSu and SSn. WBV in the SSu group at 46 sec-1 and at 230 Sec 1 were 1.9 (95%CI; 1.2, 3.1) and 2.3 (1.2, 4.4) times greater than in the SSn group. There were no differences in the degree of tissue hypoxia as determined by lightguide spectrophotometry.ConclusionInflammatory, adhesion markers and WBV may be associated with leg ulceration in sickle cell disease by way of inflammation-mediated vasoocclusion/vasoconstriction. Impaired skin oxygenation does not appear to be associated with chronic ulcers in these subjects with sickle cell disease.
Highlights
Chronic leg ulceration is the most common cutaneous manifestation of homozygous sickle cell disease (SCD) [1], predominantly affecting the medial and lateral malleoli, and to a lesser extent, the anterior shin or dorsum of the foot [2]
Shiu et al demonstrated an increase in both membrane bound and soluble sICAM-1 expression upon perfusion of endothelial cells with sickle erythrocytes [13], where there was a greater concentration of inflammatory mediators suggesting a mechanistic link between vascular inflammation and adhesion
These data support the hypothesis that abnormal rheology, inflammation and endothelial dysfunction may be associated with chronic leg ulceration in sickle cell disease
Summary
Chronic leg ulceration is the most common cutaneous manifestation of homozygous sickle cell disease (SCD) [1], predominantly affecting the medial and lateral malleoli, and to a lesser extent, the anterior shin or dorsum of the foot [2]. Infection-mediated endothelial activation by way of NFk-β nuclear translocation is important in the inflammatory response through the synthesis and secretion of proinflammatory cytokines [14,15], a correlate of clinical severity in SCD [16,17]. Whether these inflammatory markers are associated with leg ulceration in sickle cell disease is unclear. In the present study the haematocrit-viscosity ratio (HVR), a measure of the effectiveness of erythrocytes in transporting oxygen [26,27,28,29], was used to assess blood flow conditions in the sickle cell disease subjects with ulcers and SCD controls. We propose that abnormal rheology, inflammation and endothelial dysfunction have important roles in the pathogenesis of chronic leg ulceration in homozygous sickle cell disease
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