The Von Willebrand factor/ADAMTS13 axis in ischemic stroke

Speaker: Simon de Meyer
Department: Department of Thrombosis, KU Leuven, Belgium
Location: Erasmuc MC Rotterdam
Date: May 15, 2017
Author: Teun Huijben

Simon de Meyer studied Industrial Engineering and Bio-engineering and obtained his PhD in Leuven focusing on the von Willebrand disease. Later he did post-doctoral research for three year at Harvard University. Afterwards he returned to Leuven to take an associate professorship at the Faculty of Biomedical Science in the department of Thrombosis.

Simon starts his talk by explaining the basic principles of a stroke. During a stroke a small clot of blood (thrombus) gets trapped in some small blood vessel, thereby obstructing the blood. This obstruction can lead to tissue damage which is especially dangerous when it happens in the brain or heart muscle. A typical stroke exists of two phases. The first phase is called the acute phase during which the thrombus is blocking the blood flow. The second phase is the diffusive phase in which the thrombus has been resolved, but the surrounding tissue still suffers from the period of reduced oxygen supply.

The problem with strokes is that they are unpredictable and there are almost no effective therapies. The best known therapy is the drug tPA (tissue plasminogen activator) that helps the rapid resolving of the thrombus. The disadvantages of tPA are that it can cause dangerous bleedings in other places in the body, you can becomeĀ tPA resistant and it can be neurotoxic. Because it has to be given in less than 4.5 hours after the stroke, only 10% of the patients can have the drug on time, and only 50% of them reacts positively to it. All of this together makes tPA not the best option to treat strokes.

Another therapy is thrombectomy which is removal of the thrombus with a mechanical device. Besides that it is a good alternative to tPA is also gives us the advantages of collecting fresh human thrombi to study their composition. And this is exactly the part Simon is most interested in: of which cells/components is the thrombus made off and can this explain the different behaviour of thrombi during tPA treatment?

They study the thrombi by making sections, stain them with different dyes and look at them with the microscope. Besides the fact that all thrombi look very different, also the percentages fibrin, red blood cells, neutrophils and platelets differ enormously between different thrombi. They knew that Von Willebrand factor (VWF) is very important during wound healing and the formation of thrombi. Because VWF binds to both the collagen as to the platelets, providing a scaffold to form a blood clot. Using this knowledge they started looking at the VWF in the thrombi and found that this differed a lot between different thrombi. They also found that the concentration of VWF in the thrombi negatively correlated with the percentage of red blood cells in the thrombi, strongly suggesting that the VWF is important in the formation and composition of the thrombus.

It was known that the protein ADAMTS13 cuts VWF. So the hypothesis of Simon and his colleagues was that using ADAMTS13 promotes thrombus resolution in a stroke. To test this they used a mouse model in which thrombi were introduced by opening the skulls and adding a chemical that activates the blood clotting pathways. When the thrombi were formed and the mouse visibly suffered from a stroke, ADAMTS13 was added. And as expected, the thrombus was resolved, the blood flow increased and the damaging effects reduced. Even when ADAMTS13 was added more than 1 hour after the stroke, it was still helpful in reducing the injuries.

However, when the thrombus is resolved and the blood flow is restored, the problems are not over. It is known that after a stroke the surrounding tissue and vessels are getting more damaged for a while. Simon and his group showed that VWF knock-out mice experience less damage after a stroke, suggesting that VWF stimulates tissue damaging. Here ADAMTS13 treatment has the same effects as during the acute phase, it reduces the injury.

In the future, Simon will try to further quantify the effects of tPA, ADAMTS13 and nuclease (a promising drug he mentioned in the last part of the talk) hoping to find the perfect cocktail to treat patients suffering from strokes.

After all, I really enjoyed Simons talk and he explained patiently and very clear all the experiments leading to his conclusions. Although this is not directly my field of interested it was enjoyable and educational.

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