Glycoprotein VI, or GPVI for short, is a surface receptor found exclusively on platelets and their precursor cells, megakaryocytes in the bone marrow. GPVI is primarily responsible for binding collagen at the site of an injured blood vessel, which triggers the activation and aggregation of platelets. GPVI therefore has a role in so-called haemostasis, the process of stopping bleeding. However, excessive activation of the GPVI receptor can lead to the formation of pathological thrombi and thus to vascular occlusions, which impede blood flow to vital organs. A heart attack or stroke may result.
Prof. Dr. Bernhard Nieswandt first described the function of the GPVI receptor in 2001 in the Journal of Experimental Medicine. Through his research, the head of the Department of Experimental Biomedicine I at Würzburg University Hospital (UKW) and research group leader at the Rudolf Virchow Center (RVZ) of the University of Würzburg (JMU) laid the foundation in recent years for the development and clinical testing of so-called GPVI inhibitors. Just a few weeks ago, Boehringer Ingelheim and Lower Franconian biotech company EMFRET Analytics signed a cooperation and licensing agreement for the preclinical development programme of the GPVI-blocking antibody EMA601. Its development has been significantly supported by Würzburg University Medicine (see press release on the signing of the agreement and the history of EMA601). In 2024, Nieswandt and his team, led by first author Dr. Stefano Navarro, demonstrated in the European Heart Journal that EMA601 blocks the GPVI signalling pathway in platelets extremely effectively, thereby preventing thrombosis and thrombo-inflammatory disease processes without impairing vital blood clotting.
Current study shows unexpected alternative to GPVI inhibitors
Navarro and Nieswandt, together with their colleagues and Emfret Analytics, now present another promising approach to preventing thrombosis and thrombo-inflammatory diseases while preserving normal blood clotting in the high-ranking journal “Signal Transduction and Targeted Therapy”.
Instead of inhibiting GPVI activity by blocking it, they reduced its density on the platelet surface. Although a GPVI deficiency protected mice against thrombosis, it could impair haemostasis when combined with other platelet aggregation inhibitors such as high doses aspirin.
Using a humanized mouse model and human platelets, the Experimental Biomedicine I team has now found that certain antibodies with low binding strength- in this case JAQ1 antibodies-reduce the number of GPVI receptors on platelets by approximately half. To the researchers’ surprise, receptor depletion consistently stopped halfway. Thus, rather than generating GPVI-deficient platelets, JAQ1 appeared to consistently create an entirely new platelet state, a stable “GPVI-low” phenotype (GPVI^LO).
GPVI^LO is a new, distinct platelet phenotype
“For me, the most surprising finding was that partial receptor loss is not simply an intermediate state between normal platelets and GPVI deficiency,” explains first author Dr. Stefano Navarro. “Instead, it resulted in a distinct platelet phenotype that maintained haemostatic function while at the same time retaining strong antithrombotic efficacy.”
Remarkably, despite the lower number of receptors, the platelets were still able to adhere to injured blood vessels and stop bleeding. In contrast to complete GPVI depletion, haemostatic function remained intact even in combination with high-dose aspirin when GPVI was partially reduced. At the same time, the signals contributing to the formation and stabilisation of blood clots, as well as the procoagulant activity of the platelets, were significantly reduced.
Targeted control of receptor density could become a therapeutic principle
The study thus opens up a new approach for the development of safer drugs to prevent thrombosis. Instead of completely switching off GPVI, targeted control of receptor density itself could become a therapeutic principle in the future by selectively suppressing pathological signalling pathways. In experimental models, GPVI^LO platelets provided reliable protection against arterial thrombosis and inflammatory lung injury.
“Our data suggest that the biological function of GPVI depends not only on its activity but also on its abundance on the platelet surface. This opens up a new pharmacological concept in which receptor density itself becomes a therapeutic target,” explains Bernhard Nieswandt. “Long-term anti-GPVI therapy could go beyond the prevention of thrombotic diseases and also contribute to the treatment of inflammatory disease states such as ischaemic stroke, acute lung injury and potentially cancer metastases.”
Contact:
Prof. Dr. Bernhard Nieswandt
Experimentelle Biomedizin I, Universitätsklinikum Würzburg
Rudolf-Virchow-Zentrum, Universität Würzburg
Josef-Schneider-Str. 2, Haus D15, 97080 Würzburg
Telefon:+49 931 31-80405
E-Mail: bernhard.nieswandt@uni-wuerzburg.de