Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice

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Abstract
Serglycin (SG), the hematopoietic cell secretory granule proteoglycan, is crucial for storage of specific secretory proteins in mast cells, neutrophils, and cytotoxic T lymphocytes. We addressed the role of SG in platelets using SG−/− mice. Wild-type (WT) but not SG−/− platelets contained chondroitin sulfate proteoglycans. Electron microscopy revealed normal α-granule structure in SG−/− platelets. However, SG−/− platelets and megakaryocytes contained unusual scroll-like membranous inclusions, and SG−/− megakaryocytes showed extensive emperipolesis of neutrophils. SG−/− platelets had reduced ability to aggregate in response to low concentrations of collagen or PAR4 thrombin receptor agonist AYPGKF, and reduced fibrinogen binding after AYPGKF, but aggregated normally to ADP. 3H-serotonin and ATP secretion were greatly reduced in SG−/− platelets. The α-granule proteins platelet factor 4, β-thromboglobulin, and platelet-derived growth factor were profoundly reduced in SG−/− platelets. Exposure of P-selectin and αIIb after thrombin treatment was similar in WT and SG−/− platelets. SG−/− mice exhibited reduced carotid artery thrombus formation after exposure to FeCl3. This study demonstrates that SG is crucial for platelet function and thrombus formation. We propose that SG−/− platelet function deficiencies are related to inadequate packaging and secretion of selected α-granule proteins and reduced secretion of dense granule contents critical for platelet activation.