Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function

Schoenwaelder, Simone M.; Yao, Yuan; Josefsson, Emma C.; White, M. J. D.; Yu, Yao; Mason, Kylie D.; O’Reilly, Lorraine A.; Henley, Katya J.; Ono, Akiko; Hsiao, Sarah; Willcox, Abbey; Roberts, Andrew W.; Huang, David C.S.; Salem, Haitham; Kile, Benjamin T.; Jackson, Shaun P.

doi:10.1182/blood-2009-01-200345

Cited by 281 publications

(345 citation statements)

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“…22,23 However, recent analysis of Bak/Bax-deficient mouse platelets has revealed that agonist-induced platelet procoagulant function occurs independent of apoptosis. 12 Consistent with this, several studies have demonstrated that caspase inhibitors do not block the procoagulant function of activated platelets. 12,24,25 There is a growing body of evidence demonstrating that many of the biochemical processes regulating agonist-induced platelet procoagulant function are more typical of necrosis ( Figure 3).…”

Section: Functional Necrosismentioning

confidence: 70%

“…12 Consistent with this, several studies have demonstrated that caspase inhibitors do not block the procoagulant function of activated platelets. 12,24,25 There is a growing body of evidence demonstrating that many of the biochemical processes regulating agonist-induced platelet procoagulant function are more typical of necrosis (Figure 3). For example, procoagulant platelet function is initiated by high, sustained levels of cytosolic Ca 2ϩ23 , leading to opening of the MPTP and mitochondrial dysfunction.…”

Section: Functional Necrosismentioning

confidence: 99%

“…1,11 Many of the features of apoptosis (membrane fragmentation, cytoskeletal disruption, microvesiculation, caspase activation and phosphatidylserine [PS] exposure) are observed during prolonged platelet storage ex vivo and during the conversion of activated platelets to a procoagulant state, raising the possibility that apoptosis may also regulate platelet function. However, recent studies have demonstrated that the molecular events underlying agonistinduced platelet procoagulant function can occur independently of apoptotic cell death, 12 raising the possibility that alternative cell death pathways contribute to platelet procoagulant function (Table 1).…”

Section: Introductionmentioning

confidence: 99%

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Procoagulant platelets: are they necrotic?

Jackson

Schoenwaelder

2010

Blood

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Apoptosis and necrosis represent distinct cell death processes that regulate mammalian development, physiology and disease. Apoptosis characteristically leads to the silent destruction and removal of cells in the absence of an inflammatory response. In contrast, necrotic cell death can induce physiologic inflammatory responses linked to tissue defense and repair. Although anucleate, platelets undergo programmed cell death, with apoptosis playing an important role in clearing effete platelets from the circulation. While it has long been recognized that procoagulant platelets exhibit characteristic features of dying cells, recent studies have demonstrated that platelet procoagulant function can occur independent of apoptosis. A growing body of evidence suggest that the biochemical, morphologic and functional changes underlying agonist-induced platelet procoagulant function are broadly consistent with cell necrosis, raising the possibility that distinct death pathways regulate platelet function and survival. In this article, we will discuss the mechanisms underlying apoptotic and necrotic cell death pathways and examine the evidence linking these pathways to the platelet procoagulant response. We will also discuss the potential contribution of these pathways to the platelet storage lesion and propose a simplified nomenclature to describe procoagulant platelets. IntroductionUntil the early 1970s it was thought that all cells die as a result of necrosis (Table 1); a form of cell death that is prominent when tissues undergo extensive damage from trauma or disease. This concept changed dramatically in 1972 after the landmark observations of Kerr and colleagues, 9 who described a new form of cell death, termed apoptosis (Table 1). Since then, the genetic and biochemical processes responsible for apoptotic cell death have been extensively investigated. It is now well defined that apoptosis is a key process underlying human development, normal physiology and a range of common human diseases. 10 In contrast, the concepts underlying necrosis have become less clear-cut. While it has long been assumed that necrosis is predominantly a pathologic process resulting from tissue injury, there is growing evidence that cells can orchestrate their own demise through programmed cell necrosis in a manner that initiates physiologic inflammatory and repair responses. [2][3][4][6][7][8] Although anucleate, platelets have the capacity to undergo programmed cell death (Table 1). This has been most clearly demonstrated with platelet apoptosis; a process that is important for clearance of effete platelets from the circulation. 1,11 Many of the features of apoptosis (membrane fragmentation, cytoskeletal disruption, microvesiculation, caspase activation and phosphatidylserine [PS] exposure) are observed during prolonged platelet storage ex vivo and during the conversion of activated platelets to a procoagulant state, raising the possibility that apoptosis may also regulate platelet function. However, recent studies have demonstrated that the m...

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Section: Functional Necrosismentioning

confidence: 70%

Section: Functional Necrosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Procoagulant platelets: are they necrotic?

Jackson

Schoenwaelder

2010

Blood

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142

141

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“…Phosphatidylserine (PS) exposure on the surface of activated platelets is known to be essential for the assembly of coagulation factor complexes,57 and its appearance on the cell surface is associated with several physiologic and pathologic phenomena 58, 59. Hence, we determined whether e‐cigarette exposure modulates the surface levels of phosphatidylserine.…”

Section: Resultsmentioning

confidence: 99%

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

Qasim

Karim

Silva‐Espinoza

et al. 2018

JAHA

100

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BackgroundCardiovascular disease is the main cause of death in the United States, with smoking being the primary preventable cause of premature death, and thrombosis being the main mechanism of cardiovascular mortality in smokers. Due to the perception that electronic/e‐cigarettes are “safer/less harmful” than conventional cigarettes, their usage—among a variety of ages—has increased tremendously during the past decade. Notably, there are limited studies regarding the negative effects of e‐cigarettes on the cardiovascular system, which is also the subject of significant debate.Methods and ResultsWe employed a passive e‐VapeTM vapor inhalation system and developed an in vivo whole‐body e‐cigarette mouse exposure protocol that mimics real‐life human exposure scenarios/conditions and investigated the effects of e‐cigarettes and clean air on platelet function and thrombogenesis. Our results show that platelets from e‐cigarette–exposed mice are hyperactive, with enhanced aggregation, dense and α granule secretion, activation of the αIIbβ3 integrin, phosphatidylserine expression, and Akt and ERK activation, when compared with clean air–exposed platelets. E‐cigarette–exposed platelets were also found to be resistant to inhibition by prostacyclin, relative to clean air. Furthermore, the e‐cigarette–exposed mice exhibited a shortened thrombosis occlusion and bleeding times.ConclusionsTaken together, our data demonstrate for the first time that e‐cigarettes alter physiological hemostasis and increase the risk of thrombogenic events. This is attributable, at least in part, to the hyperactive state of platelets. Thus, the negative health consequences of e‐cigarette exposure should not be underestimated and warrant further investigation.

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“…He proposed that the Bcl-x L :Bak interaction is critical for determining platelet lifespan. Because Bak has a longer half-life than Bcl-x L , Dr Huang suggested that investigation of the stability of Bcl-x L , particularly the unstructured loop region between the first and second α-helices of Bcl-x L , may be important for understanding how this pro-survival protein regulates platelet lifespan [21].…”

Section: Cell Death -Good Bad and The Mechanismsmentioning

confidence: 99%

From molecules and cells to diseases: West meets East for medical research in Tianjin

Liu

2009

Cell Res

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Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function

Cited by 281 publications

References 16 publications

Procoagulant platelets: are they necrotic?

Procoagulant platelets: are they necrotic?

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

From molecules and cells to diseases: West meets East for medical research in Tianjin

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