Hypothetical mechanism of the effects of dimerization defects on vWF multimer assembly.

In heterozygous individuals with either the vWD 2A/IID or vWD 3 mutation, normal vWF (symbols with shaded and black half circles) is released from the ER in the form of dimers, and aberrant vWF (symbols with shaded and white half circles) is released in the form of monomers. The symbols' black half circles represent an intact dimerization site, whereas their shaded half circles represent the amino-terminal multimerization site. White half circles represent the defective dimerization site in mutant vWF monomers. On inclusion of aberrant monomers during the ongoing multimerization process in the Golgi and post-Golgi region, further polymerization is blocked, resulting in the observed lack of HMWM. Apposition of an aberrant monomer at only one site results in a multimer with an odd number of individual subunits, represented by the extra intervening bands (marked by odd numbers) between individual multimers. The original multimer pattern shown on the right is from the coexpression product of recombinant mutant 2A/IID with recombinant WT vWF shown in Figure 5B.