• Robert J Freishtat, Joanne Natale, Angela S Benton, Joanna Cohen, Matthew Sharron, Andrew A Wiles, Wai-Man Ngor, Bahar Mojgani, Margaret Bradbury, Andrew Degnan, Reecha Sachdeva, Lindsay M Debiase, Svetlana Ghimbovschi, Matthew Chow, Clarice Bunag, Ervand Kristosturyan, and Eric P Hoffman.
• Division of Emergency Medicine, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA. rfreishtat@cnmcresearch.org
• Am. J. Respir. Crit. Care Med. 2009 Mar 15; 179 (6): 467-73.

RationaleSepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood.ObjectivesBecause recent evidence shows that platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis.MethodsWe studied megakaryocytes and platelets from a murine-induced sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B.Measurements And Main ResultsPlatelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. Platelets from septic granzyme B null (-/-) mice showed no lymphotoxicity.ConclusionsOur findings establish a conceptual advance in sepsis: Septic megakaryocytes produce platelets with acutely altered mRNA profiles, and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy.

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