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Abstract
Background: Free labile hemin acts as a damage-associated molecular pattern during acute and chronic hemolysis and muscle injury supporting platelet activation and thrombosis.
Aim: We investigated the anti-thrombotic potential of hydroxychloroquine on hemolysis-induced arterial thrombosis ex vivo, hemin-induced platelet activation, ferric-chloride (FeCl3)-induced arterial thrombosis and lung perfusion following hemin injection in mice.
Results: Erythrocyte lysis and endothelial cell activation cooperatively supported platelet aggregation and thrombosis at arterial shear stress. This thrombotic effect was reversed by hydroxychloroquine. In a purified system, hydroxychloroquine inhibited platelet build-up on immobilized von Willebrand factor in hemolyzed blood without altering initial platelet recruitment. Hydroxychloroquine inhibited hemin-induced platelet activation and phosphatidylserine exposure independently of reactive oxygen species generation. In the presence of hemin, hydroxychloroquine did not alter glycoprotein VI shedding but reduced C-type-lectin-like-2 expression on platelets. In vivo, hydroxychloroquine reversed pulmonary perfusion decline induced by exogenous administration of hemin. In arterial thrombosis models, hydroxychloroquine inhibited FeCl3-induced thrombosis in the carotid artery and reduced von Willebrand factor accumulation in the thrombi.
Conclusion: Hydroxychloroquine inhibited hemolysis-induced arterial thrombosis ex-vivo and improved pulmonary perfusion in hemin-treated mice, supporting a potential benefit of its use as an adjuvant therapy in hemolytic diseases to limit arterial thrombosis and to improve organ perfusion.
Aim: We investigated the anti-thrombotic potential of hydroxychloroquine on hemolysis-induced arterial thrombosis ex vivo, hemin-induced platelet activation, ferric-chloride (FeCl3)-induced arterial thrombosis and lung perfusion following hemin injection in mice.
Results: Erythrocyte lysis and endothelial cell activation cooperatively supported platelet aggregation and thrombosis at arterial shear stress. This thrombotic effect was reversed by hydroxychloroquine. In a purified system, hydroxychloroquine inhibited platelet build-up on immobilized von Willebrand factor in hemolyzed blood without altering initial platelet recruitment. Hydroxychloroquine inhibited hemin-induced platelet activation and phosphatidylserine exposure independently of reactive oxygen species generation. In the presence of hemin, hydroxychloroquine did not alter glycoprotein VI shedding but reduced C-type-lectin-like-2 expression on platelets. In vivo, hydroxychloroquine reversed pulmonary perfusion decline induced by exogenous administration of hemin. In arterial thrombosis models, hydroxychloroquine inhibited FeCl3-induced thrombosis in the carotid artery and reduced von Willebrand factor accumulation in the thrombi.
Conclusion: Hydroxychloroquine inhibited hemolysis-induced arterial thrombosis ex-vivo and improved pulmonary perfusion in hemin-treated mice, supporting a potential benefit of its use as an adjuvant therapy in hemolytic diseases to limit arterial thrombosis and to improve organ perfusion.
Original language | English |
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Journal | Journal of Thrombosis and Haemostasis |
Early online date | 24 Apr 2024 |
DOIs | |
Publication status | E-pub ahead of print - 24 Apr 2024 |
Keywords
- Hydroxychloroquine
- platelets
- thrombosis
- hemin
- hemolysis
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Mechanisms of mast cell-mediated inflammation exacerbating deep vein thrombosis
1/09/19 → 31/08/24
Project: Research