Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion

Irina Pleines, Marion Lebois, Pradnya Gangatirkar, Amanda E. Au, Rachael M. Lane, Katya J. Henley, Maria Kauppi, Jason Corbin, Ping Cannon, Jonathan Bernardini, Imala Alwis, Kate E. Jarman, Sarah Ellis, Donald Metcalf, Shaun P. Jackson, Simone M. Schoenwaelder, Benjamin T. Kile, Emma C. Josefsson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The circulating life span of blood platelets is regulated by the prosurvival protein BCL-XL. It restrains the activity of BAK and BAX, the essential prodeath 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 although intrinsic apoptosis is rapidly induced during storage at 37°C, it is not detected when platelets are kept at the standard storage temperature of 22°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 was 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.

Original languageEnglish
Pages (from-to)197-209
Number of pages13
JournalBlood
Volume132
Issue number2
DOIs
Publication statusPublished - 12 Jul 2018

Cite this

Pleines, I., Lebois, M., Gangatirkar, P., Au, A. E., Lane, R. M., Henley, K. J., ... Josefsson, E. C. (2018). Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion. Blood, 132(2), 197-209. https://doi.org/10.1182/blood-2017-11-816355
Pleines, Irina ; Lebois, Marion ; Gangatirkar, Pradnya ; Au, Amanda E. ; Lane, Rachael M. ; Henley, Katya J. ; Kauppi, Maria ; Corbin, Jason ; Cannon, Ping ; Bernardini, Jonathan ; Alwis, Imala ; Jarman, Kate E. ; Ellis, Sarah ; Metcalf, Donald ; Jackson, Shaun P. ; Schoenwaelder, Simone M. ; Kile, Benjamin T. ; Josefsson, Emma C. / Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion. In: Blood. 2018 ; Vol. 132, No. 2. pp. 197-209.
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title = "Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion",
abstract = "The circulating life span of blood platelets is regulated by the prosurvival protein BCL-XL. It restrains the activity of BAK and BAX, the essential prodeath 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 although intrinsic apoptosis is rapidly induced during storage at 37°C, it is not detected when platelets are kept at the standard storage temperature of 22°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 was 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.",
author = "Irina Pleines and Marion Lebois and Pradnya Gangatirkar and Au, {Amanda E.} and Lane, {Rachael M.} and Henley, {Katya J.} and Maria Kauppi and Jason Corbin and Ping Cannon and Jonathan Bernardini and Imala Alwis and Jarman, {Kate E.} and Sarah Ellis and Donald Metcalf and Jackson, {Shaun P.} and Schoenwaelder, {Simone M.} and Kile, {Benjamin T.} and Josefsson, {Emma C.}",
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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 2018, 'Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion' Blood, vol. 132, no. 2, pp. 197-209. https://doi.org/10.1182/blood-2017-11-816355

Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion. / Pleines, Irina; Lebois, Marion; Gangatirkar, Pradnya; Au, Amanda E.; Lane, Rachael M.; Henley, Katya J.; Kauppi, Maria; Corbin, Jason; Cannon, Ping; Bernardini, Jonathan; Alwis, Imala; Jarman, Kate E.; Ellis, Sarah; Metcalf, Donald; Jackson, Shaun P.; Schoenwaelder, Simone M.; Kile, Benjamin T.; Josefsson, Emma C.

In: Blood, Vol. 132, No. 2, 12.07.2018, p. 197-209.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion

AU - Pleines, Irina

AU - Lebois, Marion

AU - Gangatirkar, Pradnya

AU - Au, Amanda E.

AU - Lane, Rachael M.

AU - Henley, Katya J.

AU - Kauppi, Maria

AU - Corbin, Jason

AU - Cannon, Ping

AU - Bernardini, Jonathan

AU - Alwis, Imala

AU - Jarman, Kate E.

AU - Ellis, Sarah

AU - Metcalf, Donald

AU - Jackson, Shaun P.

AU - Schoenwaelder, Simone M.

AU - Kile, Benjamin T.

AU - Josefsson, Emma C.

PY - 2018/7/12

Y1 - 2018/7/12

N2 - The circulating life span of blood platelets is regulated by the prosurvival protein BCL-XL. It restrains the activity of BAK and BAX, the essential prodeath 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 although intrinsic apoptosis is rapidly induced during storage at 37°C, it is not detected when platelets are kept at the standard storage temperature of 22°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 was 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.

AB - The circulating life span of blood platelets is regulated by the prosurvival protein BCL-XL. It restrains the activity of BAK and BAX, the essential prodeath 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 although intrinsic apoptosis is rapidly induced during storage at 37°C, it is not detected when platelets are kept at the standard storage temperature of 22°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 was 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.

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DO - 10.1182/blood-2017-11-816355

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SN - 0006-4971

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