 |
| Treatment with soluble GPV prevents the formation of a vascular-closing thrombus in an experimental mouse model for thrombosis formation (right). On the left is a vascular-closing thrombus of an untreated mouse. Image Credit: Sarah Beck / University Hospital Würzburg |
The platelet glycoprotein V is an important switching point for hemostasis and thrombus formation. This new finding could have great clinical potential.
If our blood vessels are injured by cuts or abrasions or bruises, it is vital that the bleeding is stopped and the wound closed. In technical terms, this process is called hemostasis. This consists of two processes: the hemostasis, in which platelets (platelets) attach to the wound edges, form a plug and temporarily seal the injury. And the blood clotting or coagulation cascade, in which long fibers are formed from fibrin, which together with the platelets seal the wound firmly.
However, if fibrin is formed in excess, for example in chronic wounds, vascular occlusions, so-called thrombosis, can occur. Strict regulation of fibrin formation is therefore important. However, how coagulation is limited has not yet been fully understood.
In an international project coordinated by Würzburg University Medicine, researchers have now deciphered a central regulatory mechanism for fibrin formation and derived new therapeutic approaches from it. The results are released in the renowned journal Nature Cardiovascular Research.
GPV controls the activity of thrombin and fibrin formation
In the study, the working group around study director Professor Bernhard Nieswandt came to fundamentally new findings.
“For the first time, we were able to uncover a new switching point that regulates both hemostasis and the formation of thrombosis. This switching point is the glycoprotein V, or GPV for short, which is located on the surface of platelets. GPV controls the activity of the enzyme thrombin, which is responsible for the formation of fibrin,” explains Bernhard Nieswandt, head of the chair for experimental biomedicine I and board member of the Rudolf Virchow Center - Center for Integrative and Translational Bioimaging (RVZ) at the University of Würzburg.
Thrombin is a crucial enzyme in blood clotting and its activity must therefore be controlled very precisely in terms of time and space. So far it was known that the surface receptor GPV is cut by thrombin during the activation of the platelets. This releases GPV as a soluble receptor form.
However, the physiological function of this receptor was largely unknown. Using genetic and pharmacological approaches, researchers have shown that thrombin-mediated cleavage of GPV limits the formation of fibrin. By keeping the soluble GPV bound to thrombin, it changes the activity of thrombin so that it can form less fibrin.
"Knowledge will change textbook knowledge"
Experiments on experimental thrombose models have shown that soluble GPV prevents, among other things, the formation of vascular-closing thrombi and provides clear protection against experimental stroke and the associated brain damage.
Bernhard Nieswandt is convinced that these new findings will expand the knowledge of the textbook. He thanks the participating scientists from the RVZ and the University Hospital Würzburg (UKW), who were supported by colleagues from Mainz, Maastricht and the USA.
Antibodies against GPV offer great clinical potential
In another approach, the research group generated antibodies against GPV that prevent thrombin-mediated cutting off of GPV.
“In our studies we were able to show that these antibodies increase thrombin activity and that there is an increased fibrin formation. Our idea was therefore to use these antibodies in connection with a disturbed hemostasis to increase fibrin formation,” said Professor David Stegner, head of the Vascular Imaging Working Group at the RVZ and one of the final authors of the study.
In addition to genetic causes, impaired hemostasis can also be attributed to pharmacologically-related impairments in the number or function of platelets. This is the case, for example, after taking platelet aggregation inhibitors such as clopidogrel, which are used to prevent a heart attack or stroke and to treat circulatory disorders.
“In an experimental model for hemostasis, our new antibody was actually able to restore hemostasis under conditions where hemostasis is otherwise not possible. This indicates support for hemostasis by improving thrombin-dependent fibrin formation,” adds Dr. Sarah Beck, scientist at the Würzburg Institute for Experimental Biomedicine and first author of the study. “Anti-GPV treatment could have great clinical potential and is a starting point that we will pursue in the future."
Published in journal: Nature Cardiovascular Research
Source/Credit: University of Würzburg
Reference Number: med032423_02