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Blood, 1 December 2003, Vol. 102, No. 12, pp. 4229-4235.
Prepublished online as a Blood First Edition Paper on August 7, 2003; DOI 10.1182/blood-2003-04-1305.
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TRANSFUSION MEDICINE
Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro–aged or –injured mouse platelets
Wolfgang Bergmeier,
Peter C. Burger,
Crystal L. Piffath,
Karin M. Hoffmeister,
John H. Hartwig,
Bernhard Nieswandt, and
Denisa D. Wagner
From the CBR Institute for Biomedical Research, Inc., and the Department of Pathology, Harvard Medical School, and the Division of Hematology/Department of Medicine, Brigham and Women's Hospital, Boston, MA; and the Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Germany.
Platelet transfusions are a crucial component of support for patients with severe thrombocytopenia. Storage of platelet concentrates, however, is associated with a reduction in platelet posttransfusion recovery and hemostatic function. In this study, we established a model of mitochondrial injury that resembles platelet storage lesion. Mitochondrial injury, provoked by incubation of platelets with carbonyl cyanide m-chlorophenylhydrazone (CCCP), led to reduced posttransfusion recovery in mice, an effect that directly correlated with the duration of treatment. Damaged platelets were characterized by shape change, disruption of membrane asymmetry, surface expression of P-selectin, and profound proteolysis of GPIb . Using our model, we identified a key role for endogenous metalloproteinase(s) in platelet clearance, as their inhibition markedly improved posttransfusion recovery of both the mitochondria-injured and in vitro-aged mouse platelets. Metalloproteinase inhibition also prevented proteolysis of GPIb on damaged platelets, thereby improving the hemostatic function of these cells in vivo. We propose that inhibition of metalloproteinase activity during storage could significantly improve the effectiveness of platelet transfusions. Surface expression of GPIb might be a powerful marker to determine the quality of platelet concentrates, because it reflects metalloproteinase activity in vitro. (Blood. 2003;102: 4229-4235)
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