Profile of endothelial and leukocyte activation in fabry patients

Abstract

Fabry disease is an X‐linked recessive disorder resulting in the deposition of globotriaosylceramide in numerous cell types including vascular endothelial cells. Because this disease is associated with vascular injury and a high recurrence rate of thrombotic events, measurements of factors regulating endothelium and leukocyte interaction may provide insight into the mechanisms leading to a prothrombotic state. Twenty‐five patients with Fabry disease and 25 control subjects participated in the study. Plasma from all 25 Fabry patients and 15 of the 25 controls were studied for multiple endothelial factors. Leukocyte integrins were measured by flow cytometry in 21 Fabry patients and 10 controls. The concentrations of soluble intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, P‐selectin, and plasminogen activator inhibitor were significantly higher and thrombomodulin was significantly lower in Fabry patients. Expression of the integrin CD11b on monocytes was also significantly higher in the Fabry patients. This study reveals measurable evidence for endothelium and leukocyte activation that is consistent with a prothrombotic state in Fabry patients compared with controls. Further investigations of these findings may help to understand the mechanism of stroke in Fabry disease and provide indicators (or markers) of efficacy of future therapeutic intervention. Ann Neurol 2000;47:229–233

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

“…Lyso-GL-3 concentration was significantly reduced from baseline at each successive Clinical assessment, and individual patient values of plasma lyso-GL-3 concentration fluctuated less than did those of plasma and urine GL-3 concentrations (data not shown). Although during the past decade attention has largely focused on the pathogenic role of GL-3 in FD (DeGraba et al 2000;Park et al 2011;Shen et al 2008), the importance of lyso-GL-3 in the FD process has become evident. For example, exposure of smooth muscle cells in vitro to lyso-GL-3 at concentrations similar to those seen in patients with FD (e.g., in the patients treated for 12 months with agalsidase alfa or beta at 0.2 mg/kg [van Breemen et al 2011]) stimulates proliferation of the smooth muscle cells (Aerts et al 2008), a finding consistent with the increased intima-media thickness observed in patients with FD (Barbey et al 2006).…”

Biomarkers of Fabry Disease Nephropathy

“…More systemic biomarkers, including vascular ones, indicated that inflammation or growth factors should be evaluated (40,41).…”

Fabry Disease: Treatment and diagnosis

“…Dr. Schiffmann's group has focused its studies on vascular disorder of Fabry disease, and has demonstrated the presence of abnormalities in blood flow, vessel wall, and blood components (56). In terms of alterations of blood components, they have detected an inflammation-activated state in endothelium and leukocytes in Fabry disease (57,58).…”

“…The gene NAIP (Neuronal apoptosis inhibitory protein) associated with inflammation was found to be upregulated in Fabry children (63). Exposure of endothelial cells to Gb3 resulted in increased intracellular production of reactive oxygen species (57).…”