Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways
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 und...
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doaj-101d9672fd4d446da505d8766477fc1d2020-11-25T02:35:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01212556255610.3390/ijms21072556Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic PathwaysElmira R. Mordakhanova0Tatiana A. Nevzorova1Gulnaz E. Synbulatova2Lubica Rauova3John W. Weisel4Rustem I. Litvinov5Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420008, RussiaInstitute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420008, RussiaInstitute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420008, RussiaThe Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartments of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAInstitute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420008, RussiaHeparin-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-X<sub>L</sub>, 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.https://www.mdpi.com/1422-0067/21/7/2556plateletsheparin-induced thrombocytopeniaplatelet deathapoptosiscaspasecalpain |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Elmira R. Mordakhanova Tatiana A. Nevzorova Gulnaz E. Synbulatova Lubica Rauova John W. Weisel Rustem I. Litvinov |
spellingShingle |
Elmira R. Mordakhanova Tatiana A. Nevzorova Gulnaz E. Synbulatova Lubica Rauova John W. Weisel Rustem I. Litvinov Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways International Journal of Molecular Sciences platelets heparin-induced thrombocytopenia platelet death apoptosis caspase calpain |
author_facet |
Elmira R. Mordakhanova Tatiana A. Nevzorova Gulnaz E. Synbulatova Lubica Rauova John W. Weisel Rustem I. Litvinov |
author_sort |
Elmira R. Mordakhanova |
title |
Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways |
title_short |
Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways |
title_full |
Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways |
title_fullStr |
Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways |
title_full_unstemmed |
Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways |
title_sort |
platelet activation in heparin-induced thrombocytopenia is followed by platelet death via complex apoptotic and non-apoptotic pathways |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-04-01 |
description |
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-X<sub>L</sub>, 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. |
topic |
platelets heparin-induced thrombocytopenia platelet death apoptosis caspase calpain |
url |
https://www.mdpi.com/1422-0067/21/7/2556 |
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