VWF and von Willebrand disease (hereditary or acquired): It can be concluded that regardless of their location within the VWF A2 domain the subset of VWD mutations that do not result in the intracellular retention of VWF (type 2A VWD group 2) disrupt the domain folding stability and cooperativity, causing spatial separation of the N- and C- termini leading to enhanced proteolysis by the regulating protease, ADAMTS13.