Platelet proteoglycans packing it in

Hundreds of proteins have been identified in platelet α-granules, yet little is known about how these proteins are packaged during granule formation. Woulfe and colleagues demonstrate that a proteoglycan termed serglycin participates in the sorting of proteins into α-granules.

Serglycin is a proteoglycan found in hematopoietic and endothelial cells. It contains a long Ser-Gly repeat (hence the name serglycin) in its central region to which glycosaminoglycans attach. Chondroitin sulfate is the primary glycosaminoglycan in platelet-derived serglycin. Studies of serglycin-null (SG^−/−) mice demonstrate impairment of granule formation in mast cells, cytotoxic T cells, and neutrophils. Specifically, soluble proteins with basically charged regions that would normally interact with the strongly anionic glycosaminoglycans within serglycin are not retained in leukocyte granules of SG^−/− mice.

Woulfe and colleagues used SG^−/− mice to evaluate the role of proteoglycans in platelet function. They showed that deletion of serglycin resulted in loss of all detectable platelet proteoglycans, indicating that serglycin is the dominant proteoglycan in platelets. They also showed that platelets from SG^−/− mice demonstrated several morphologic features consistent with a granule defect. Wright-Giemsa staining revealed that SG^−/− platelets had a pale, agranular appearance, similar to Gray platelets. These platelets also contained scroll-like membranous inclusions, as has previously been observed in platelets from patients with Medich syndrome and from Wistar Furth rats.¹  Consistent with these observations, the investigators found that platelet α-granules from SG^−/− mice were depleted of PF4, β-thromboglobulin, and platelet-derived growth factor. In contrast, PF4 mRNA was normal in these mice. These observations indicated a granule packaging disorder.

Platelets from SG^−/− mice also demonstrated several functional defects. Platelet aggregation in response to low doses of thrombin and collagen was impaired, as was release of serotonin and ADP from dense granules. Thrombus formation in the carotid artery FeCl₃-induced thrombus formation model was also defective. But why would loss of select α-granule proteins lead to these functional defects?

One explanation is that these α-granule proteins are required for normal aggregation, secretion, and thrombus formation. Both plasma and serum PF4 was markedly reduced in these mice. Like SG^−/− mice, PF4-null mice demonstrate decreased aggregation to low concentrations of agonist and a defect in thrombus formation.²  An alternative explanation is that dense-granule formation is impaired in SG^−/− mice. Serotonin and ADP release were significantly decreased in SG^−/− mice. Furthermore, aggregation was normal in response to exogenous ADP. ADP release is critical to normal platelet aggregation and thrombus formation. Thus, a defect in dense-granule storage or release may be responsible for platelet function defects observed in SG^−/− mice.

Much remains to be learned regarding how serglycin deficiency affects platelet function. Which platelet proteins are retained in α-granules by serglycin? Might serglycin function in recently described α-granule heterogeneity?^3,4  Does serglycin function in the formation of dense granules? Do defects in serglycin contribute to any variant of human platelet-storage disease? The observations described in this study, however, present a first indication of the essential role that this proteoglycan plays in platelet granule formation.