Type 2B VWD substitutions trigger enhanced macrophage-mediated clearance that is attenuated by the BT200 aptamer
Type 2B von Willebrand disease (VWD) is characterized by missense variants in exon 28 of the von Willebrand factor (VWF) gene that encodes the VWF-A1 domain. These missense mutations result in single amino acid residue substitutions that cause activation of VWF-A1 and promote spontaneous interaction with platelet GPIba;. Importantly, enhanced VWF clearance has been shown to play a key pathogenic…
Type 2B von Willebrand disease (VWD) is caused by missense variants in exon 28 of the von Willebrand factor (VWF) gene. These mutations result in single amino acid substitutions that activate VWF-A1 and promote spontaneous interaction with platelet GPIba. Enhanced VWF clearance plays a significant role in 90% of Type 2B VWD patients, although the underlying mechanisms are not well understood.
In this study, researchers examined various Type 2B amino acid substitutions within the VWF-A1 domain, including R1306W, R1308C, W1313C, and R1379L. They discovered that these variants exhibit significantly increased macrophage binding. Specifically, type 2B VWD variants show heightened interaction with LRP1 extracellular cluster II and IV.
The K1405-K1408 lysine cluster in the VWF-A1 domain facilitates this increased LRP1 interaction for type 2B VWD variants. Additionally, these variants display enhanced interaction with the macrophage MGL receptor. Importantly, the study found that the increase in macrophage binding for type 2B variants is significantly reduced in the presence of the BT200 aptamer.
These findings could have direct clinical implications for understanding the heterogeneity and treatment of Type 2B VWD.
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