Platelet apoptosis in paediatric immune thrombocytopenia is ameliorated by intravenous immunoglobulin

Winkler, Jeannine; Kroiss, Sabine; Rand, Margaret L.; Azzouzi, Imane; Bang, K.W. Annie; Speer, Oliver; Schmugge, Markus

doi:10.1111/j.1365-2141.2011.08973.x

Cited by 55 publications

(74 citation statements)

References 37 publications

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“…Platelet apoptosis plays an important role in platelet clearance from the circulation, thus determines the life span of platelets. Enhanced platelet apoptosis has been implicated in a number of pathological processes, such as type 2 diabetes [7], immune thrombocytopenia [8], Bernard-Soulier syndrome [9] and thrombocytopenic purpura induced by Helicobacter pylori [10] or malaria [11].…”

Section: Introductionmentioning

confidence: 99%

P2Y12 protects platelets from apoptosis via PI3k‐dependent Bak/Bax inactivation

Zhang

et al. 2013

Journal of Thrombosis and Haemostasis

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Summary. Background: Platelet ADP receptor P2Y 12 is well studied and recognized as a key player in platelet activation, hemostasis and thrombosis. However, the role of P2Y 12 in platelet apoptosis remains unknown. Objectives: To evaluate the role of the P2Y 12 receptor in platelet apoptosis. Methods: We used flow cytometry and Western blotting to assess apoptotic events in platelets treated with ABT-737 or ABT-263, and stored at 37°C, combined with P2Y 12 receptor antagonists or P2Y 12 -deficient mice. Results: P2Y 12 activation attenuated apoptosis induced by ABT-737 in human and mouse platelets in vitro, evidenced by reduced phosphatidylserine (PS) exposure, diminished depolarization of mitochondrial inner transmembrane potential (DYm) and decreased caspase-3 activation. Through increasing the phosphorylation level of Akt and Bad, and changing the interaction between different Bcl-2 family proteins, P2Y 12 activation inactivated Bak/Bax. This antiapoptotic effect could be abolished by P2Y 12 antagonism or PI3K inhibition. We also observed the antiapoptotic effect of P2Y 12 activation in platelets stored at 37°C. P2Y 12 activation improved the impaired activation responses of apoptotic platelets stressed by ABT-737. In platelets from mice dosed with ABT-263 in vivo, clopidogrel or deficiency of P2Y 12 receptor enhanced apoptosis along with increased Bak/Bax activation. Conclusions: This study demonstrates that P2Y 12 activation protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation, which may be physiologically important to counter the proapoptotic challenge. Our findings that P2Y 12 blockade exaggerates platelet apoptosis induced by ABT-263 (Navitoclax) also imply a novel drug interaction of antagonists.

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Section: Introductionmentioning

confidence: 99%

P2Y12 protects platelets from apoptosis via PI3k‐dependent Bak/Bax inactivation

Zhang

et al. 2013

Journal of Thrombosis and Haemostasis

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“…Apart from inhibition of MK differentiation and platelet formation, anti-platelet antibody appears to induce apoptosis of platelets, which may be another factor contributing to the immunopathology of ITP 23,26,35 . Anti-platelet autoantibody has been shown to increase mitochondrial inner membrane potential (∆ ψ m ) depolarization, caspase-3,8,9 activation and phosphatidylserine exposure in platelets 23,35 , indicating a mitochondrion-dependent apoptosis pathway involved.…”

Section: Discussionmentioning

confidence: 99%

Low-level light treatment ameliorates immune thrombocytopenia

Yang

Zhang

2017

SPIE Proceedings

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Immune thrombocytopenia (ITP) is an immune-mediated acquired bleeding disorder characterized by abnormally low platelet counts. We reported here the ability of low-level light treatment (LLLT) to alleviate ITP in mice. The treatment is based on noninvasive whole body illumination 30 min a day for a few consecutive days by near infrared light (830 nm) transmitted by an array of light-emitting diodes (LEDs). LLLT significantly lifted the nadir of platelet counts and restored tail bleeding time when applied to two passive ITP models induced by anti-CD41 antibody. The anti-platelet antibody hindered megakaryocyte differentiation from the progenitors, impaired proplatelet and platelet formation, and induced apoptosis of platelets. These adverse effects of anti-CD41 antibody were all mitigated by LLLT to varying degrees, owing to its ability to enhance mitochondrial biogenesis and activity in megakaryocytes and preserve mitochondrial functions in platelets in the presence of the antibody. The observations argue not only for contribution of mitochondrial stress to the pathology of ITP, but also clinical potentials of LLLT as a safe, simple, and cost-effective modality of ITP.

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“…Gammagard could also have reduced apoptosis of the neuroblastoma cells, which has been observed in neurons exposed to α-synuclein [29]. IVIG products have been reported to exert anti-apoptotic effects in some systems [57][58][59] but not in others [60,61]. Studies in an animal model of synucleinopathy are indicated to determine if IVIG will exert neuroprotective effects in vivo.…”

Section: Discussionmentioning

confidence: 99%