Platelet and myeloid cell phenotypes in a rat model of Fabry disease

Fabry disease results from a deficiency of the lysosomal enzyme alpha-Galactosidase-A (alpha-Gal A) and is estimated to occur in approximately 1:4100 live births. Characteristic of the disease is the accumulation of alpha-Gal-A substrates, primarily the glycosphingolipids (GSLs) globotriaosylceramide and glohotriaosylsphingosine. Thrombotic events are a significant concern for Fabry patients, with strokes contributing to a. significant decrease in overall lifespan. Currently, the mechanisms underlying the increased risk of thrombotic events experienced by Fabry patients are incompletely defined. Using a rat model of Fabry disease, we provide an improved understanding of the mechanisms linking GSL, accumulation to thrombotic risk. We found that alpha-Gal A-deficient rats accumulate myeloid-derived leukocytes at sites of GST, accumulation, including in the hone marrow and circulation, and that myeloid-derived leukocyte and megakaryocyte populations were prominent among cell types that accumulated GSLs. In the circulation, alpha-Gal A-deficient rats had increases in cytokine-producing cell types and a corresponding elevation of pro-inflammatory cytokines. Lastly, circulating platelets from alpha-Gal A-deficient rats accumulated a similar set of alpha-Galactosidase-A substrates as was observed in megakaryocytes in the bone marrow, and exhibited increased platelet binding to fibrinogen in microfluidic and flow cytometric assays.

Automated summary

Fabry disease is caused by a deficiency of the lysosomal enzyme alpha-Galactosidase-A, leading to the accumulation of alpha-Gal A substrates and increased risk of thrombotic events. Studies in a rat model found that alpha-Gal A-deficient rats accumulate myeloid-derived leukocytes and megakaryocytes, increased levels of pro-inflammatory cytokines, and platelets with elevated binding ability to fibrinogen.