Intrinsic apoptosis circumvents the functional decline of circulating platelets, but does not cause the storage lesion
- Pleines, I; Lebois, M; Gangatirkar, P; Au, AE; Lane, RM; Henley, KJ; Kauppi, M; Corbin, J; Cannon, P; Bernardini, J; Alwis, I; Jarman, KE; Ellis, S; Metcalf, D; Jackson, SP; Schoenwaelder, SM; Kile, BT; Josefsson, EC;
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- Journal Article in press
- The circulating life span of blood platelets is regulated by the pro-survival protein BCL-XL. It restrains the activity of BAK and BAX, the essential pro-death mediators of intrinsic apoptosis. Disabling the platelet intrinsic apoptotic pathway in mice by deleting BAK and BAX results in a doubling of platelet life span and concomitant thrombocytosis. Apoptotic platelets expose phosphatidylserine (PS) via a mechanism that is distinct from that driven by classical agonists. Whether there is any role for apoptotic PS in platelet function in vivo, however, is unclear. Apoptosis has also been associated with the platelet storage lesion (PSL), the constellation of biochemical deteriorations that occur during blood bank storage. In this study, we investigated the role of BAK/BAX-mediated apoptosis in hemostasis and thrombosis, and in the development of the PSL. We show that while intrinsic apoptosis is rapidly induced during storage at 37 degrees C, it is not detected when platelets are kept at the standard storage temperature of 22 degrees C. Remarkably, loss of BAK and BAX did not prevent the development of the PSL at either temperature. BAK/BAX-deficient mice exhibited increased bleeding times and unstable thrombus formation. This phenotype was not caused by impaired PS exposure, but associated with a defect in granule release from aged platelets. Strikingly, rejuvenation of BAK/BAX-deficient platelets in vivo completely rescued the observed hemostatic defects. Thus, apoptotic culling of old platelets from the bloodstream is essential to maintain a functional, hemostatically reactive platelet population. Inhibiting intrinsic apoptosis in blood banked platelets is unlikely to yield significant benefit.
- WEHI Research Division(s)
- Cancer And Haematology; Systems Biology And Personalised Medicine; Cell Signalling And Cell Death
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Creation Date: 2018-05-31 09:17:47Last Modified: 2018-05-31 09:35:00