von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor

The bleeding disorder von Willebrand disease (VWD) is caused by mu-tations of von Willebrand factor (VWF), a multimeric glycoprotein es-sential for platelet-dependent primary haemostasis. VWD type 2A-associated mutations each disrupt VWF biosynthesis and function at different stages, depending on the VWF domain altered by the mu-tation. These effects cause considerable heterogeneity in phenotypes and symptoms. To characterise the molecular mechanisms underlying the specific VWF deficiencies in VWD 2A/IIC, IID and IIE, we investi-gated VWF variants with patient-derived mutations either in the VWF pro-peptide or in domains D3 or CK. Additionally to static assays and molecular dynamics (MD) simulations we used microfluidic ap-proaches to perform a detailed investigation of the shear-dependent function of VWD 2A mutants. For each group, we found distinct char-acteristics in their intracellular localisation visualising specific defects in biosynthesis which are correlated to respective multimer patterns