Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosis
Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious prothrombotic adverse event after vaccination with adenovector-based COVID-19 vaccines. Laboratory findings indicate that anti–platelet factor 4 (PF4) immunoglobulin G antibodies are the causing factor for the...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924007377 |
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| author | Jan Zlamal Vera M. Ripoll Christine S.M. Lee Filip Toma Karina Althaus Flavianna Rigoni Andreas Witzemann Shane Whittaker David Capraro Günalp Uzun Tamam Bakchoul Vivien M. Chen |
| author_facet | Jan Zlamal Vera M. Ripoll Christine S.M. Lee Filip Toma Karina Althaus Flavianna Rigoni Andreas Witzemann Shane Whittaker David Capraro Günalp Uzun Tamam Bakchoul Vivien M. Chen |
| author_sort | Jan Zlamal |
| collection | DOAJ |
| description | Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious prothrombotic adverse event after vaccination with adenovector-based COVID-19 vaccines. Laboratory findings indicate that anti–platelet factor 4 (PF4) immunoglobulin G antibodies are the causing factor for the onset of thromboembolic events in VITT. However, molecular mechanisms of cellular interactions, signaling pathways and involvement of different cell types in VITT antibody–mediated thrombosis are not fully understood. Moreover, uncertainty exists regarding current treatment protocols because the sole anticoagulation was shown to be inefficient to prevent thrombosis progression in severe VITT cases. In this study, we demonstrate that platelet spleen tyrosine kinase (SYK) modulates anti-PF4 VITT-mediated thrombus formation in an ex vivo model of immunothrombosis. Our study showed that the selective inhibition of SYK can abrogate VITT antibody–driven procoagulant platelet formation, activation of plasmatic coagulation as well as platelet-leukocyte interplay. Most importantly, the specific inhibition of SYK in platelets but not in neutrophils prevented VITT antibody–induced multicellular thrombus formation, without perturbing the platelet function. Our findings indicate that the specific targeting of platelet SYK might be a promising therapeutic approach to prevent thrombotic complications in patients with antibody-mediated immunothrombosis. |
| format | Article |
| id | doaj-art-e5f8154bd02a44dc89b4b8833504715e |
| institution | OA Journals |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-e5f8154bd02a44dc89b4b8833504715e2025-08-20T02:16:44ZengElsevierBlood Advances2473-95292025-04-01981772178510.1182/bloodadvances.2024014167Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosisJan Zlamal0Vera M. Ripoll1Christine S.M. Lee2Filip Toma3Karina Althaus4Flavianna Rigoni5Andreas Witzemann6Shane Whittaker7David Capraro8Günalp Uzun9Tamam Bakchoul10Vivien M. Chen11Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, GermanyANZAC Research Institute, Sydney Local Health District, Sydney, New South Wales, Australia; Department of Haematology, Concord Repatriation General Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia; Concord Clinical School, The University of Sydney, Sydney, New South Wales, AustraliaANZAC Research Institute, Sydney Local Health District, Sydney, New South Wales, Australia; Department of Haematology, Concord Repatriation General Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia; Concord Clinical School, The University of Sydney, Sydney, New South Wales, Australia; Division of Genome Science and Cancer, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, AustraliaInstitute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, GermanyInstitute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, GermanyInstitute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, GermanyInstitute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, GermanyANZAC Research Institute, Sydney Local Health District, Sydney, New South Wales, Australia; Department of Haematology, Concord Repatriation General Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia; Concord Clinical School, The University of Sydney, Sydney, New South Wales, AustraliaANZAC Research Institute, Sydney Local Health District, Sydney, New South Wales, AustraliaInstitute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, GermanyInstitute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany; Correspondence: Tamam Bakchoul, University Hospital of Tübingen, Otfried-Müller Strasse 4/1, 72076 Tübingen, Germany;ANZAC Research Institute, Sydney Local Health District, Sydney, New South Wales, Australia; Department of Haematology, Concord Repatriation General Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia; Concord Clinical School, The University of Sydney, Sydney, New South Wales, AustraliaAbstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious prothrombotic adverse event after vaccination with adenovector-based COVID-19 vaccines. Laboratory findings indicate that anti–platelet factor 4 (PF4) immunoglobulin G antibodies are the causing factor for the onset of thromboembolic events in VITT. However, molecular mechanisms of cellular interactions, signaling pathways and involvement of different cell types in VITT antibody–mediated thrombosis are not fully understood. Moreover, uncertainty exists regarding current treatment protocols because the sole anticoagulation was shown to be inefficient to prevent thrombosis progression in severe VITT cases. In this study, we demonstrate that platelet spleen tyrosine kinase (SYK) modulates anti-PF4 VITT-mediated thrombus formation in an ex vivo model of immunothrombosis. Our study showed that the selective inhibition of SYK can abrogate VITT antibody–driven procoagulant platelet formation, activation of plasmatic coagulation as well as platelet-leukocyte interplay. Most importantly, the specific inhibition of SYK in platelets but not in neutrophils prevented VITT antibody–induced multicellular thrombus formation, without perturbing the platelet function. Our findings indicate that the specific targeting of platelet SYK might be a promising therapeutic approach to prevent thrombotic complications in patients with antibody-mediated immunothrombosis.http://www.sciencedirect.com/science/article/pii/S2473952924007377 |
| spellingShingle | Jan Zlamal Vera M. Ripoll Christine S.M. Lee Filip Toma Karina Althaus Flavianna Rigoni Andreas Witzemann Shane Whittaker David Capraro Günalp Uzun Tamam Bakchoul Vivien M. Chen Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosis Blood Advances |
| title | Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosis |
| title_full | Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosis |
| title_fullStr | Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosis |
| title_full_unstemmed | Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosis |
| title_short | Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody–induced immunothrombosis |
| title_sort | platelet spleen tyrosine kinase is a key regulator of anti pf4 antibody induced immunothrombosis |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924007377 |
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