Because of asymmetric cleavage in the VWF A2 domain, ADAMTS13 degradation results in larger and smaller size monomeric forms of 176 kDa (C-terminal peptide Bortezomib cost sequence) and 140 kDa (N-terminal peptide sequence) respectively (Fig. 1 [9]). On agarose

gels these represent the two satellite bands, flanking the major band of all VWF multimers [10, 11] forming a so-called VWF triplet. The slower and faster migrating triplet bands thus either contain or lack one 140 kDa N-terminal peptide sequence compared to the intermediate VWF triplet band, respectively [9]. The variable part of individual VWF triplets resides in the N-terminal protein part comprising the A1 domain, which contains binding sites for heparin, coagulation factor VIII and GPIb and, hence, is highly relevant to VWF function. As the properties

of individual VWF triplet bands have not been investigated so far, normal plasma-derived VWF has been separated into sub-fractions with a similar multimeric composition, but different triplet band patterns [12]. PD0325901 supplier Heparin affinity column separation was used, followed by size exclusion chromatography to obtain VWF preparations with a similar multimer profile, but distinct pattern of triplet bands, resulting in different affinities to GPIb and different capabilities to promote GPIb-dependent platelet adhesion under high-shear flow conditions. The results suggest that different functional properties of individual triplet bands are not only relevant for heparin affinity, but also for GPIb binding affinity, pointing to a distinct role of the VWF triplet band composition regarding GPIb-dependent platelet adhesion to VWF. The larger size, slower migrating VWF triplet bands appear to be functionally more active in supporting thrombus formation on collagen MCE type III surfaces, implicating that the altered triplet band composition, regularly observed

in type 2 VWD patients, may contribute to an altered VWF-dependent platelet adhesion at high-shear flow. Angiogenesis is a complex process describing the formation of new blood vessels. A role for VWF in controlling angiogenesis has recently been described [13] and possibly explains many, but not all the clinical observations of this complication in VWD. Angiodysplasia, a clinical manifestation of angiogenesis, has been a recognized feature of acquired and inherited VWD for many years. The best known example is acquired VWD in Heyde’s syndrome which described the association of aortic stenosis and gastrointestinal (GI) bleeding from angiodysplasia [14]. Most patients with severe aortic stenosis have acquired VWD due to the unfolding of the VWF as it passes the stenosed valve, making it more susceptible to cleavage by ADAMTS13. Affected individuals can bleed from the GI tract, the cause of which is often due to colonic angiodysplasia.