Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage

von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease

“…In a recent expression study, it was shown that type 2A mutations are often characterized by a combination of intracellular retention, defective multimerization, loss of regulated secretion, and increased proteolysis by ADAMTS13. 25 Our data support that this increased clearance is an important component. This also suggests that these ratios may discriminate between type 1 and type 2 VWD, which has been stated before.…”

“…by guest www.bloodjournal.org From this will not be picked up by the VWFpp/VWF:Ag ratio. The VWF type 2A mutations will often lead to a combination of pathophysiological mechanisms such as those reported by Jacobi et al 25 In addition to increased susceptibility for ADAMTS13 proteolysis, the mutant VWF may also have a shortened half-life resulting in an increased VWFpp/ VWF:Ag ratio. We found no differences between 2A VWD with defects in multimerization (and possibly enhanced ADAMTS13-mediated proteolysis) and 2M VWD with normal multimer patterns.…”

Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States

“…17 Multimer distribution was assayed by quantitative gel electrophoresis. 18 Ligand binding assays were performed as previously described, including VWF binding to type III collagen (VWF:CB3), 16 VWF binding to type IV collagen (VWF:CB4), 19 and VWF binding to mutant platelet GPIb (VWF:GPIbM). 20,21 VWF propeptide (VWFpp) was measured to evaluate for VWF clearance defects.…”

Von Willebrand Disease: Range of the Disease, and Management

“…The defect results in two different pathogenic mechanisms, one that results in defective synthesis of highmolecular-weight multimers and the other in an enhanced propensity for ADMATS-13 mediated proteolysis. Others have suggested genetic mutations that result in complex abnormalities including synthesis, storage, release, and proteolytic processing [11].…”