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Archives of cardiovascular diseases
Volume 102, n° S1
page 15 (mars 2009)
Doi : 10.1016/S1875-2136(09)72158-8
Themes et posters

A025 P38 MAPK inhibition prevents TACE-mediated receptor shedding and improves the hemostatic function of stored platelets
 

M. Canault 1, D. Duerschmied 1, I.-S. Patten 1, A. Brill 1, S.-M. Cifuni 1, W. Bergmeier 2, D.-D. Wagner 1
1 Immune Disease Institute, Boston, USA 
2 t. Jefferson University, Philadelphia, USA 

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Platelet transfusion is a lifesaving procedure widely used during surgery and chemotherapy. During storage platelets undergo several modifications that reduce their postransfusion survival and functionality. One important feature of this platelet storage lesion (PSL) is the shedding of surface glycoproteins such as GPIb⍺ and GPV. We have recently demonstaretd that metalloproteinase inhibitors prevent storage-induced shedding of adhesion receptors, resulting in markedly improved postransfusion recovery and hemostatic function of platelets in mice. We now demonstrate that TNF-alpha converting enzyme (TACE/ADAM17) mediates receptor shedding during platelet storage for 16 to 18hours at 37oC or 22oC. Using pharmacological inhibitors, we demonstrate that TACE/ADAM17-dependent shedding of GPIb⍺ and GPV from both mouse and human platelets during storage required p38 MAP kinase signaling. In contrast, protein kinase C, Erk MAPK, and caspases were not involved. Inhibition of p38 MAPK during platelets storage also markedly improved the posttransfusion recovery and hemostatic function of stored platelets in vivo. Moreover, p38 MAPK inhibition during storage of human platelets improved the adhesion of these cells to collagen under flow. Inhibition of p38 MAPK also prevented TACE-dependent shedding of GPIb⍺ from platelets undergoing mitochondrial injury, a model for PSL. Phosphorylation of p38 MAPK was observed upon platelet storage and mitochondrial injury.

In summary, our data suggest that inhibition of p38 MAPK or TACE during storage may significantly improve the quality of stored platelets.

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