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Article

Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways

1
Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420008, Russia
2
The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
3
Departments of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
4
Departments of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(7), 2556; https://doi.org/10.3390/ijms21072556
Received: 20 February 2020 / Revised: 4 April 2020 / Accepted: 5 April 2020 / Published: 7 April 2020
(This article belongs to the Special Issue Advances in Biological Functions of Platelet)
Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. HIT is caused by antibodies that recognize complexes of platelet factor 4 and heparin. The pathogenic mechanisms of this condition are not fully understood. In this study, we used flow cytometry, fluorimetry, and Western blot analysis to study the direct effects of pathogenic immune complexes containing platelet factor 4 on human platelets isolated by gel-filtration. HIT-like pathogenic immune complexes initially caused pronounced activation of platelets detected by an increased expression of phosphatidylserine and P-selectin. This activation was mediated either directly through the FcγRIIA receptors or indirectly via protease-activated receptor 1 (PAR1) receptors due to thrombin generated on or near the surface of activated platelets. The immune activation was later followed by the biochemical signs of cell death, such as mitochondrial membrane depolarization, up-regulation of Bax, down-regulation of Bcl-XL, and moderate activation of procaspase 3 and increased calpain activity. The results show that platelet activation under the action of HIT-like immune complexes is accompanied by their death through complex apoptotic and calpain-dependent non-apoptotic pathways that may underlie the low platelet count in HIT. View Full-Text
Keywords: platelets; heparin-induced thrombocytopenia; platelet death; apoptosis; caspase; calpain platelets; heparin-induced thrombocytopenia; platelet death; apoptosis; caspase; calpain
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MDPI and ACS Style

Mordakhanova, E.R.; Nevzorova, T.A.; Synbulatova, G.E.; Rauova, L.; Weisel, J.W.; Litvinov, R.I. Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways. Int. J. Mol. Sci. 2020, 21, 2556. https://doi.org/10.3390/ijms21072556

AMA Style

Mordakhanova ER, Nevzorova TA, Synbulatova GE, Rauova L, Weisel JW, Litvinov RI. Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways. International Journal of Molecular Sciences. 2020; 21(7):2556. https://doi.org/10.3390/ijms21072556

Chicago/Turabian Style

Mordakhanova, Elmira R., Tatiana A. Nevzorova, Gulnaz E. Synbulatova, Lubica Rauova, John W. Weisel, and Rustem I. Litvinov 2020. "Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways" International Journal of Molecular Sciences 21, no. 7: 2556. https://doi.org/10.3390/ijms21072556

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