Phosphatidylserine surface expression and integrin αIIbβ3 activity on thrombin/convulxin stimulated platelets/particles of different sizes

Rukoyatkina, Natalia; Begonja, Antonija Jurak; Geiger, Jörg; Eigenthaler, Martin; Walter, Ulrich; Gambaryan, Stepan

doi:10.1111/j.1365-2141.2008.07506.x

Cited by 23 publications

(23 citation statements)

References 43 publications

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“…This circumstance is of special interest in view of the previous report demonstrating different integrin expression on platelets of different sizes. 25 Analysis of the integrin activation kinetics (Figures II and III in the online-only Data Supplement) revealed that most platelets originally had activated integrin in agreement with a previous report 7 but that all Ca-positive cells lost PAC-1 binding as soon as they became PS positive.…”

Section: Ps+/ca-platelets Have Activated α Iib β 3 Retain High Levesupporting

confidence: 70%

“…To test whether the PS-positive subpopulations are caspasedependent, 25 we carried out experiments on platelet activation using a pan-caspase inhibitor Z-VAD-FMK. No effect of this inhibitor on the formation of the PS-positive subpopulations was detected ( Figure VI in the online-only Data Supplement).…”

Section: Cell Death-related Phenomena In the Platelet Subpopulationsmentioning

confidence: 99%

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Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α _IIb β ₃

Topalov

Yakimenko²,

Canault³

et al. 2012

ATVB

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Objective— Phosphatidylserine (PS) externalization by platelets upon activation is a key event in hemostasis and thrombosis. It is currently believed that strong stimulation of platelets forms 2 subpopulations, only 1 of which expresses PS. Methods and Results— Here, we demonstrate that physiological stimulation leads to the formation of not 1 but 2 types of PS-expressing activated platelets, with dramatically different properties. One subpopulation sustained increased calcium level after activation, whereas another returned to the basal low-calcium state. High-calcium PS-positive platelets had smaller size, high surface density of fibrin(ogen), no active integrin α IIb β 3 , depolarized mitochondrial membranes, gradually lost cytoplasmic membrane integrity, and were poorly aggregated. In contrast, the low-calcium PS-positive platelets had normal size, retained mitochondrial membrane potential and cytoplasmic membrane integrity, and combined retention of fibrin(ogen) with active α IIb β 3 and high proaggregatory function. Formation of low-calcium PS-positive platelets was promoted by platelet concentration increase or shaking and was decreased by integrin α IIb β 3 antagonists, platelet dilution, or in platelets from kindlin-3–deficient and Glanzmann thrombasthenia patients. Conclusion— Identification of a novel PS-expressing platelet subpopulation with low calcium regulated by integrin α IIb β 3 can be important for understanding the mechanisms of PS exposure and thrombus formation.

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Section: Ps+/ca-platelets Have Activated α Iib β 3 Retain High Levesupporting

confidence: 70%

Section: Cell Death-related Phenomena In the Platelet Subpopulationsmentioning

confidence: 99%

Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α _IIb β ₃

Topalov

Yakimenko²,

Canault³

et al. 2012

ATVB

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“…The mechanisms of Thr/Cvx-induced platelet activation and pro-coagulant activity are well characterised 13, 30, 31, 32 and we used this model as a positive control to compare PKA/PKG effects on platelet apoptosis induced by other stimuli.…”

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confidence: 99%

Protein kinase A activation by the anti-cancer drugs ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition and apoptosis

et al. 2017

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Chemotherapy-induced thrombocytopenia is a common bleeding risk in cancer patients and limits chemotherapy dose and frequency. Recent data from mouse and human platelets revealed that activation of protein kinase A/G (PKA/PKG) not only inhibited thrombin/convulxin-induced platelet activation but also prevented the platelet pro-coagulant state. Here we investigated whether or not PKA/PKG activation could attenuate caspase-dependent apoptosis induced by the anti-cancer drugs ABT-737 (the precursor of navitoclax) and thymoquinone (TQ), thereby potentially limiting chemotherapy-induced thrombocytopenia. This is particularly relevant as activation of cyclic nucleotide signalling in combination chemotherapy is an emerging strategy in cancer treatment. However, PKA/PKG-activation, as monitored by phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), did not block caspase-3-dependent platelet apoptosis induced by the compounds. In contrast, both substances induced PKA activation themselves and PKA activation correlated with platelet inhibition and apoptosis. Surprisingly, ABT-737- and TQ-induced VASP-phosphorylation was independent of cAMP levels and neither cyclases nor phosphatases were affected by the drugs. In contrast, however, ABT-737- and TQ-induced PKA activation was blocked by caspase-3 inhibitors. In conclusion, we show that ABT-737 and TQ activate PKA in a caspase-3-dependent manner, which correlates with platelet inhibition and apoptosis and therefore potentially contributes to the bleeding risk in chemotherapy patients.

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“…Resting platelets were used to set baseline gates, with MPs excluded from platelet analysis. Platelet size was expressed as median forward scatter (FSC); although other factors can influence FSC, it is widely used as an estimate of cell size, including platelet size [31][32][33][34]. To compensate for the large size of BSS platelets, binding of annexin A5 to equivalent-sized control and BSS platelets was examined, i.e.…”

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confidence: 99%

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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Phosphatidylserine surface expression and integrin αIIbβ3 activity on thrombin/convulxin stimulated platelets/particles of different sizes

Cited by 23 publications

References 43 publications

Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α _IIb β ₃

Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α _IIb β ₃

Protein kinase A activation by the anti-cancer drugs ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition and apoptosis

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

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Phosphatidylserine surface expression and integrin αIIbβ3 activity on thrombin/convulxin stimulated platelets/particles of different sizes

Cited by 23 publications

References 43 publications

Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α IIb β 3

Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α IIb β 3

Protein kinase A activation by the anti-cancer drugs ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition and apoptosis

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

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Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α _IIb β ₃

Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α _IIb β ₃