Innovative Technique Shows Promise as a Treatment for Thrombosis and Rare Bleeding Disorder Von Willebrand Disease

When a wound occurs, various processes ensure that the blood clots and the wound closes. A key player in this process is the Von Willebrand factor (VWF). This protein helps blood platelets stick together and adhere to the damaged vessel wall, forming a blood clot. A deficiency of VWF can lead to Von Willebrand disease. Patients with this condition have a mutation in the section of DNA (gene) responsible for producing VWF. As a result, they produce insufficient or malfunctioning VWF, making them prone to excessive bleeding and bruising. On the other hand, an excess of VWF increases the risk of thrombosis, where blood vessels become blocked due to blood clots.

Current Treatments Are Insufficient

Existing treatments for clotting disorders, such as aspirin and the anticoagulant clopidogrel, inhibit platelet aggregation. However, these medications do not work for everyone and can cause side effects, such as unwanted bleeding. Current therapies for Von Willebrand disease primarily focus on reducing bleeding symptoms without addressing the underlying problem.

An Innovative Technique

Researcher Yvonne Jongejan has developed an innovative technique that can treat both thrombosis and Von Willebrand disease. Her method targets RNA, the messenger that translates genetic information into proteins. RNA does this by creating copies of a specific DNA segment (gene), known as messenger RNA (mRNA).

To influence the production of VWF, Jongejan used small interfering RNAs (siRNAs). These small RNA fragments are programmed to bind to the mRNA, cutting it apart and thereby reducing VWF production. "This effectively ‘switches off’ the gene responsible for VWF production, leading to a decrease in the protein’s levels," she explains.

Preventing Complete Loss of VWF Production

To prevent patients from completely losing VWF production and experiencing bleeding complications, the researcher focused on common hereditary differences within a section of the gene known as alleles. Jongejan explains: “A gene consists of two alleles: one inherited from the father and one from the mother. Patients with Von Willebrand disease have a mutation in only one of these alleles, while the other remains healthy. In this disease, the new technique selectively inhibits VWF production from the ‘faulty’ allele, ensuring that the healthy copy can still produce VWF. Although the total amount of VWF is reduced, the remaining VWF should be fully functional, improving its activity and effectiveness.”

She continues: “In thrombosis, there is no genetic mutation involved. By targeting an inherited difference between the two alleles with siRNAs, we can reduce the total amount of VWF by half, thereby lowering the risk of thrombosis.” She successfully tested this method in the laboratory: “VWF production decreased without causing bleeding issues.”

Translating the Technique to Human Applications

The next step is to transition the technique from the laboratory to human applications. After completing her PhD research, Jongejan began a new study to further develop this technique. It will still take some time before this method becomes available as a treatment or therapy. “But now we know which pieces of the puzzle we need to use,” she says.

Jongejan defended her PhD on December 18. Her supervisors were Professor Jeroen Eikenboom, an expert in Von Willebrand disease, and thrombosis and hemostasis researcher Bart van Vlijmen.