How does the clot form?

There has been a continued improvement in knowledge about the cellular mechanisms leading to blood clot formation “As soon as a blood vessel wall is damaged”, explains Dr Cécile Oury (FRS-FNRS- Research Associate,  GIGA-Cardiovascular Sciences at the University of Liege), “blood platelets play a crucial role: a serie of reactions activates platelets so that they stick to the injured area, which result in the formation of a clot to ‘plug the hole’ in the vessel. This physiological process, called hemostasis, is required for the maintenance of the integrity of the circulatory system; otherwise we would bleed to death after the occurrence of the first hemorrhage. In a normal situation, the clot disappears spontaneously. Thrombosis is the abnormal pathological situation where the clot does not dissipate and form a thrombus”.

Actually, the most widely used drugs to prevent arterial thrombosis act to limit platelet activation and aggregation. The best known and most popular is aspirin. Taken on a daily basis in small doses, often combined with clopidogrel (marketed under the brand name Plavix), aspirin therapy reduces the risk of cardiovascular events by 25%. “This is not enough”, says Dr Souad Rahmouni (FRS-FNRS- Research Associate, GIGA-Signal Transduction at the University of Liege), “in addition, this treatment has serious side effects such as stomach ulcers and excessive bleeding” It is little to say that finding novel anti-thrombotic agents with a more favorable safety profile is a pressing medical need.

Finding a new target

It is in this context that the two scientists from GIGA have identified a new target, a protein called DUSP3. This protein, which is produced inside the platelets, is a member of the “phosphatases” family. Proteins from this family play, usually, an inhibitory role in cellular activity. Surprisingly, and according to the GIGA team’s new findings, DUSP3 acts as a positive regulator of platelet activity: it stimulates, rather than inhibits, platelet activity. To investigate further DUSP3 function in platelets, the scientists used a genetically modified mouse (known as knock-out mice or KO), in this case, DUSP3-KO.

Cécile Oury explains, “We have discovered that platelet activity is inhibited in DUSP3-KO mice, lacking DUSP3 protein. These mice are more resistant to experimentally-induced thrombosis when compared to normal mice. Interestingly, these mice do not bleed more than normal mice, indicating that primary hemostasis mechanisms are preserved. Therefore, if we can pharmacologically block the activity of this protein, we will have found a new and probably safe anti-thrombotic strategy”