A functioning blood coagulation is essential for our survival – without it we would bleed to death from even small injuries. Now researchers have discovered a previously unrecognized regulatory mechanism of this hemorrhagic process. Accordingly, the glycoprotein V (GPV) located on the surface of blood platelets plays a crucial role in preventing the blood from clotting too much. The GPV protein controls the activity of an enzyme that produces long fibrin fibers at the end of the coagulation cascade. In this way, GPV prevents excessive clot formation. Knowledge of this process could help treat coagulation disorders, but could also be used to prevent strokes and heart attacks.
When our blood vessels are injured by cuts, abrasions, or contusions, it is vital that the bleeding is stopped and the wound is closed. In technical terms, this process is called haemostasis. This consists of two processes: When hemostasis, blood platelets (thrombocytes) adhere to the edges of the wound, form a plug and thus temporarily seal the injury. Blood clotting causes long fibers of fibrin to form, which clump together with the platelets, sealing the wound tightly. Both are important for stopping bleeding. However, if too many fibrin fibers are formed, this can lead to thrombosis, vascular occlusion and, in the worst case, stroke and heart attack. Therefore, tight regulation of fibrin formation is important. But how this works has only been partially clarified so far.
Central role for the glycoprotein V
Scientists around Sarah Beck from the University Hospital Würzburg have therefore taken a closer look at the process of fibrin formation and its actors. They focused on a protein on the surface of the blood platelets. This glycoprotein V (GPV) sits as a surface receptor on the blood platelets and is cut by the enzyme thrombin during blood clotting. This is an important player in blood clotting because it is responsible for the formation of fibrin fibers. Its activity is one of the decisive factors in determining whether coagulation is sufficient, excessive or too weak. So far, however, it was unclear whether GPV is also involved in this process and what physiological function this receptor has. To learn more about this, Beck and her team performed experiments on mice in which the GPV had been mutated in such a way that it could no longer be cleaved by thrombin.
“Although the platelets of these mice showed unaltered surface expression of GPV, their GPV was completely resistant to cleavage by thrombin,” the scientists explain. This had a surprising result: “Unexpectedly for us, these mice showed accelerated thrombus formation in arterial injuries,” report Beck and her colleagues. Further analysis suggested that the presence of the cleaved, soluble GPV in the blood apparently helps slow down fibrin formation. If the soluble GPV is missing, however, there is an excessive synthesis of the coagulation-promoting fibrin fibers. “We were thus able to uncover a new control point for the first time that regulates both hemostasis and the formation of thrombosis. This switching point is glycoprotein V, or GPV for short, which is found on the surface of blood platelets,” says senior author Bernhard Nieswandt from the University of Würzburg.
Opportunity for new therapies for blood clotting disorders
In further experiments, the research team was also able to uncover how glycoprotein V regulates excessive fibrin formation: it was already known from earlier studies that the enzyme thrombin attaches itself to the fibrin during the synthesis of these fibers. In this bound state, it is protected from anti-clotting factors in the blood and can do its work undisturbed. The current experiments now show that the GPV cleaved by the thrombin remains bound to the thrombin and thus disrupts its attachment to the fibrin. This hinders the further formation of new fibrin fibers – and thus also the formation of dangerous blood clots. In experiments with mice, the research team succeeded in preventing artificially triggered strokes through the targeted administration of dissolved GPV. Other forms of thrombus formation could also be prevented by this protein.
According to the scientists, these findings open up completely new possibilities for treating blood coagulation disorders. “Preventing thrombosis while maintaining hemostasis has long been a key goal of antithrombotic drug research,” the team explains. Although the anticoagulants available to date inhibit the formation of blood clots, they also disrupt the normal blood collection process, which is important for wound healing. Patients who have to take these drugs to prevent a heart attack or stroke therefore have an increased risk of internal and external bleeding. The use of dissolved GPV could now circumvent this problem because only excessive fibrin formation is inhibited, but not the rest of the coagulation cascade. Conversely, the newly discovered control function of GPV could also improve the treatment of coagulation disorders in hemophiliacs, for example by blocking GPV cleavage with antibodies. “In an experimental hemostasis model, our new antibody was actually able to restore hemostasis under conditions where hemostasis would otherwise not be possible,” reports Beck. Here, too, GPV offers great potential for new therapies.
Source: Sarah Beck (University Hospital Würzburg) et al., Nature Cardiovascular Research, two: 10.1038/s44161-023-00254-6)