Thrombin‐triggered platelet apoptosis

Leytin, Valery; Allen, David J.; Mykhaylov, Sergiy; Lyubimov, Elena; Freedman, John

doi:10.1111/j.1538-7836.2006.02200.x

Cited by 156 publications

(194 citation statements)

References 42 publications

(109 reference statements)

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“…It has become recognized that PS exposure on platelets can occur as a result of platelet activation or via apoptosis [12][13][14][15][16]31]. Dissipation of DC m is an early apoptotic event that occurs before PS exposure in nucleated cells; in platelets, it occurs rapidly upon stimulation with agonists, addi- tion of hydrophobic local anesthetics, or application of shear stress, but it is not associated with the PS exposure that occurs on platelets directly stimulated to be apoptotic with the BH3 mimetic ABT-737 [12][13][14]16,58,59].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to PS exposure, activated platelets undergo membrane blebbing (microparticle (MP) formation), cell shrinkage, and extension of filopodia. As well, there is depolarization of mitochondrial inner membrane potential (DC m ), an early apop-totic event that precedes PS exposure, and activation and translocation of Bcl-2 family members and activation of caspase-9 and -3 [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

et al. 2010

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In the Bernard-Soulier syndrome (BSS), the giant platelets are said to have increased phosphatidylserine (PS) surface exposure in the resting state and shortened survival in the circulation. When normal platelets are activated, they undergo many biochemical and morphological changes, some of which are apoptotic. Herein, we investigated apoptotic-like events in BSS platelets upon activation, specifically, PS exposure, microparticle (MP) formation, cell shrinkage, and loss of mitochondrial inner membrane potential (DC m ). Platelets from two unrelated BSS patients were examined in whole blood; agonists used were collagen, thrombin, PAR1-or PAR4-activating peptides (APs), or combinations of collagen with thrombin, and the PAR-APs. Flow cytometry was used to measure PS exposure (annexin A5 binding), platelet-derived MPs (forward scatter; events <0.75 lm size), and DC m (TMRM fluorescence). PS exposure was increased on resting and activated BSS platelets, and this was independent of the platelet size. MP formation by BSS platelets was generally enhanced. Cell shrinkage occurred on activation to form smaller, PS-exposing platelets in BSS and controls. A proportion of PS-exposing BSS and control platelets exhibited DC m loss, but unlike controls, there was also loss of DC m in the BSS platelets not exposing PS. Thus, BSS platelets undergo apoptotic-like events upon activation, with PS exposure and MP formation being enhanced. These events may play a role in the shortened survival in BSS, as well as affecting thrombin generation. Am. J. Hematol. 85:584-592, 2010. V

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

et al. 2010

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“…21 For example, Bcl-2 family proteins can be posttranscriptionally regulated and caspases activated in agonist-stimulated platelets. 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.…”

Section: Functional Necrosismentioning

confidence: 99%

Procoagulant platelets: are they necrotic?

Jackson

Schoenwaelder

2010

Blood

140

141

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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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“…As an example, externalization of membrane PS residues occur in neurons during anoxia (Maiese, 2001, Maiese and Boccone, 1995, nitric oxide exposure (Chong, et al, 2003f, Maiese, et al., 1997, and during the administration of agents that induce the production of reactive oxygen species, such as 6-hydroxydopamine (Salinas, et al, 2003). Membrane PS externalization on platelets also has been associated with clot formation in the vascular cell system (Leytin, et al, 2006). The translocation of membrane PS residues from the inner cellular membrane to the outer surface is a necessary component under most conditions for the removal of apoptotic cells , Maiese and Vincent, 2000a, Maiese and Vincent, 2000b.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Erythropoietin and Oxidative Stress

Maiese

Chong

Hou

et al. 2008

CNR

108

113

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Unmitigated oxidative stress can lead to diminished cellular longevity, accelerated aging, and accumulated toxic effects for an organism. Current investigations further suggest the significant disadvantages that can occur with cellular oxidative stress that can lead to clinical disability in a number of disorders, such as myocardial infarction, dementia, stroke, and diabetes. New therapeutic strategies are therefore sought that can be directed toward ameliorating the toxic effects of oxidative stress. Here we discuss the exciting potential of the growth factor and cytokine erythropoietin for the treatment of diseases such as cardiac ischemia, vascular injury, neurodegeneration, and diabetes through the modulation of cellular oxidative stress. Erythropoietin controls a variety of signal transduction pathways during oxidative stress that can involve Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription pathways, Wnt proteins, mammalian forkhead transcription factors, caspases, and nuclear factor κB. Yet, the biological effects of erythropoietin may not always be beneficial and may be poor tolerated in a number of clinical scenarios, necessitating further basic and clinical investigations that emphasize the elucidation of the signal transduction pathways controlled by erythropoietin to direct both successful and safe clinical care. KeywordsAlzheimer's disease; Akt; angiogenesis; apoptosis; cancer; cardiac; caspases; diabetes; endothelial; erythropoietin; forkhead; FoxO; GSK-3β; inflammation; mitochondria; NF-κB; renal; STATs; Wnt OXIDATIVE STRESSInitial work in pathways that can lead to oxidative stress by early investigators observed that increased metabolic rates could be detrimental to animals in an elevated oxygen environment. More current studies point to the potential aging mechanisms and accumulated toxic effects for an organism that are tied to oxidative stress (Maiese, et al., 2008a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in organisms, or at least the rate of oxygen consumption in organisms, has intrigued several investigators. Pearl proposed that increased exposure to oxygen through an increased metabolic rate could lead to a shortened life span (Pearl, 1928). Subsequent work by multiple investigators has furthered this hypothesis by demonstrating that increased metabolic rates could be detrimental to animals in an elevated oxygen environment . When one moves to more current work, oxygen free radicals and mitochondrial DNA mutations have become associated with oxidative stress injury, aging mechanisms, and accumulated toxicity for an organism (Yui and Matsuura, 2006).Oxygen free radicals can be generated in elevated quantities during the reduction of oxygen and subsequently lead to cell injury and apoptosis. Oxidative stress occurs as a result of the development of reactive oxygen species that consist of oxygen free radicals and other chemical entities. These agents can involve superoxide free radicals, hydrogen peroxide, sin...

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Thrombin‐triggered platelet apoptosis

Cited by 156 publications

References 42 publications

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

Procoagulant platelets: are they necrotic?

Erythropoietin and Oxidative Stress

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