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

Abstract

Fabry disease results from a deficiency of the lysosomal enzyme ⍺-Galactosidase-A (⍺-Gal A) and is estimated to occur in approximately 1:4100 live births. Characteristic of the disease is the accumulation of α-Gal-A substrates, primarily the glycosphingolipids (GSLs) globotriaosylceramide and globotriaosylsphingosine. 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 ⍺-Gal A-deficient rats accumulate myeloid-derived leukocytes at sites of GSL accumulation, including in the bone marrow and circulation, and that myeloid-derived leukocyte and megakaryocyte populations were prominent among cell types that accumulated GSLs. In the circulation, ⍺-Gal A-deficient rats had increases in cytokineproducing cell types and a corresponding elevation of pro-inflammatory cytokines.Lastly, circulating platelets from ⍺-Gal A-deficient rats accumulated a similar set of ⍺-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.

Platelets in Alcohol-Associated Liver Disease: Interaction With Neutrophils

“… 14 Platelet activation is characterized by distinct features, including shifts in platelet morphology, increased levels of platelet-specific products in plasma, and the expression of specific proteins on the platelet surface. 15 , 16 Understanding the intricacies of platelet biology and activation is not only essential for comprehending normal physiological processes, but also for investigating their involvement in pathologic conditions, such as ALD, as mentioned in the initial discussion and in more detail later.…”