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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3458-3467.
Prepublished online as a Blood First Edition Paper on December 19, 2007; DOI 10.1182/blood-2007-07-104703.
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Submitted July 31, 2007
Accepted December 14, 2007
Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice
Donna S. Woulfe, Joanne Klimas Lilliendahl, Shelley August, Lubica Rauova, M. Anna Kowalska, Magnus Abrink, Gunnar Pejler, James G. White, and Barbara P Schick*
Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, United States
Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA, United States
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
Department of Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
Pathology Department, University of Minnesota, Minneapolis, MN, United States
* Corresponding author; email: barbara.schick{at}jefferson.edu.
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  -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 -granule proteins Platelet Factor 4,  -thromboglobulin, and platelet-derived growth factor were profoundly reduced in SG-/- platelets. Exposure of P-selectin and IIb after thrombin treatment were 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 -granule proteins and reduced secretion of dense granule contents critical for platelet activation.
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