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Von Willebrand Disease (VWD)
Part 1: NHLBI Diagnosis Guidelines

Introduction & Clinical Assessment Recommendations



VWF Structure and Domains1

Slide 5

May 2011

The VWF protein amino acid sequence, shown at the top of this diagram, is aligned with the VWF gene cDNA at the bottom, and domains of VWF are shown in the middle.

The VWF protein has a propeptide, at the top left, that is cleaved during multimerization of the protomer. Near the middle of the mature protomer is the cleavage site for ADAMTS13, the plasma protease that degrades circulating VWF multimers to down-regulate VWF activity. Deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura, known as TTP. Domains of the mature VWF protomer include binding sites for ligands including factor VIII, the platelet surface glycoprotein Ib (GP Ib) complex in the A1 domain, collagen, and platelet GP IIb/IIIa. Also shown are the locations of disulfide bonds near the carboxyl terminus (at the right), and near the amino terminus (at the left), by which VWF is first dimerized then multimerized during its synthesis. Mutations causing dysfunctional or Type 2 VWD variants generally correspond to the functional domains as shown in the bottom diagram of VWF cDNA. Type 2A mutations either impair VWF multimerization (Type 2A1) or enhance multimer proteolysis (Type 2A2), whereas Types 2B or 2M mutations affect platelet GP Ib interactions, and Type 2N mutations impair FVIII binding.

VWF Structure and Domains1

 


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