title: Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro-aged or -injured mouse platelets.
abstract: 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 GPIbalpha. 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 GPIbalpha 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 GPIbalpha might be a powerful marker to determine the quality of platelet concentrates, because it reflects metalloproteinase activity in vitro.
authors.affiliation: The CBR Institute for Biomedical Research, Inc., 800 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bergmeier
authors.forename: Peter C
authors.initials: PC
authors.lastname: Burger
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Piffath
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hoffmeister
authors.forename: John H
authors.initials: JH
authors.lastname: Hartwig
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000473:pathology*; D001793:Blood Preservation / Q000379:methods*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016922:Cellular Senescence / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000473:pathology; D010979:Platelet Function Tests; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D017713:Platelet Transfusion / Q000592:standards*
chemical_list: D004791:Enzyme Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D045726:Metalloproteases