Procoagulant platelet activation promotes venous thrombosis

Platelets are key players in cardiovascular disease and platelet aggregation represents a central pharmacological target, particularly in secondary prevention. However, inhibition of adenosine diphosphate and thromboxane signaling has low efficacy in preventing venous thromboembolism, necessitating...

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Published in:	Blood
Main Authors:	Kaiser, Rainer, Dewender, Robin, Mulkers, Maité, Stermann, Julia, Rossaro, Dario, Di Fina, Lea, Li, Lukas, Gold, Christoph, Schmid, Michael, Kääb, Lily, Eivers, Luke, Akgöl, Sezer, Yue, Keyang, Kammerer, Lisa Maria, Loew, Quentin, Anjum, Afra, Escaig, Raphael, Akhalkatsi, Anastassia, Laun, Lisa Sophia, Kranich, Jan, Brocker, Thomas, Mueller, Tonina T, Kraechan, Angelina, Gmeiner, Jonas, Pekayvaz, Kami, Thienel, Manuela, Massberg, Steffen, Stark, Konstantin, Kilani, Badr, Nicolai, Leo
Format:	Journal Article
Language:	English
Published:	United States 23-10-2024
Online Access:	Get full text
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Summary:	Platelets are key players in cardiovascular disease and platelet aggregation represents a central pharmacological target, particularly in secondary prevention. However, inhibition of adenosine diphosphate and thromboxane signaling has low efficacy in preventing venous thromboembolism, necessitating the inhibition of the plasmatic coagulation cascade in this disease. Anticoagulation carries a significantly higher risk of bleeding complications, highlighting the need of alternative therapeutic approaches. We hypothesized that procoagulant activation (PA) of platelets promotes venous thrombus formation and that targeting PA could alleviate venous thrombosis. Here, we found elevated levels of procoagulant platelets in the circulation of patients with deep vein thrombosis (DVT) and pulmonary embolism, and in mice developing DVT following inferior vena cava stenosis. Further, we detected procoagulant activation of recruited platelets within murine and human venous thrombi. Mice with platelet-specific deficiency in central pathways of procoagulant activation - cyclophilin D and transmembrane protein 16F - were more resistant towards low flow-induced venous thrombosis. Finally, we found that a clinically approved carbonic anhydrase inhibitor, methazolamide, reduced platelet procoagulant activity and alleviated murine thrombus formation without affecting trauma-associated hemostasis. These findings identify an essential role of platelet procoagulant function in venous thrombosis and delineate novel pharmacological strategies targeting platelets in preventing venous thromboembolism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-4971 1528-0020 1528-0020
DOI:	10.1182/blood.2024025476