New insights into mechanisms of venous thrombosis hold therapeutic potential

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Cardiovascular diseases are the most common cause of death in industrialized nations. In addition to heart attacks and strokes, these also include clot formation in the venous system, such as deep vein thrombosis and pulmonary embolism. Current treatment concepts are mainly limited to the inhibition of the coagulation system ("blood thinners") and the mechanical or medicinal dissolution of venous clots. In contrast, blood platelets, which are the most important therapeutic structure in arterial thrombosis, have not yet been part of therapy concepts for venous thrombosis.

Researchers led by Privatdozent Dr. Rainer Kaiser, Dr. Badr Kilani and Privatdozent Dr. Leo Nicolai from the Medical Clinic I of the LMU Hospital have now described for the first time the important contribution of a particularly activated form of blood platelets, the so-called procoagulant platelets, in the formation of venous thrombi. To this end, the researchers used blood samples from patients who had presented to the emergency department at LMU Hospital with suspected leg vein thrombosis or pulmonary embolism. Patients who were later diagnosed with venous thrombosis or pulmonary embolism showed high levels of a particularly activated platelet subtype, known as procoagulant platelets, at the time of inclusion in the study. This subpopulation of platelets is characterized by a balloon-shaped form and the strong binding of coagulation factors on their surface. The scientists also discovered that procoagulant platelets are also directly involved in the formation of clots in pulmonary embolisms and could be detected in thrombi aspirated from the pulmonary arteries of particularly severely ill patients. The researchers also detected procoagulant platelets in a mouse model of deep vein thrombosis.

In the second part of the study, the scientists investigated whether inhibiting the procoagulant activation of blood platelets can influence venous clot formation. In fact, two mouse lines that are unable to form procoagulant platelets showed a significantly reduced tendency to thrombosis. As part of a therapeutic approach, Kaiser, Kilani and Nicolai finally used a clinically approved drug from the class of carbonic anhydrase inhibitors, which can inhibit procoagulant activation. The researchers were able to show that animals treated with the drug methazolamide exhibited significantly fewer thromboses. In contrast to conventional antiplatelet and anticoagulant drugs, treatment with methazolamide had no effect on bleeding time after traumatic vascular injury.

The results of this study identify the procoagulant activation of platelets as an important mediator in the development of leg vein thrombosis and pulmonary embolism. This new mechanism of clot formation brings platelets into the focus of venous thrombosis: While previous therapeutic approaches primarily inhibit coagulation proteins in the blood and are associated with increased bleeding rates, the new study results could pave the way for targeted inhibition of platelets using clinically already approved agents in everyday clinical practice. In addition, the detection of increased numbers of procoagulant platelets in the circulation could contribute to the development of new diagnostic algorithms for venous thrombosis.

The translational study led by the three young scientists was published today in the internationally renowned journal Blood.

Procoagulant platelet activation promotes venous thrombosis: Rainer Kaiser, Robin Dewender, Maité Mulkers, Julia Stermann, Dario Rossaro, Lea Di Fina, Lukas Li, Christoph Gold, Michael Schmid, Lily Kääb, Luke Eivers, Sezer Akgöl, Keyang Yue, Lisa Maria Kammerer, Quentin Loew, Afra Anjum, Raphael Escaig, Anastassia Akhalkatsi, Lisa Sophia Laun, Jan Kranich, Thomas Brocker, Tonina T Mueller, Angelina Kraechan, Jonas Gmeiner, Kami Pekayvaz, Manuela Thienel, Steffen Massberg, Konstantin Stark, Badr Kilani, Leo Nicolai;

Blood.2024025476.