Increased Clearance Explains the Ultra-Large Multimers in Von Willebrand Disease Type 2M Vicenza; Lessons from Recombinant VWF Vicenza and Modeling of Multimer Catabolism.

Abstract The pathogenesis of VWD Vicenza has remained elusive. VWD Vicenza is characterized by low plasma but normal platelet VWF concentration, the presence of ultra-large plasma multimers, and a heterozygous R1205H mutation. VWF Vicenza is reported to have a decreased half-life in the circulation. When we expressed rVWF Vicenza R1205H in 293T cells, it was secreted with wild type efficiency and multimer distribution, suggesting that the primary defect is accelerated clearance. To evaluate this hypothesis, we developed a pharmacokinetic model of VWF multimer catabolism. The initial assumptions are: 1. Secretion occurs at a fixed rate with the initial “ultra-large” multimer distribution seen in platelet alpha granules. 2. Cleavage of multimers occurs with a probability p that increases with increasing multimer size. 3. Clearance occurs with a time constant determined by the plasma half life and is independent of multimer size. Modeled multimer distributions were compared to those determined experimentally for patient plasma samples. The effects of DDAVP infusion also were modeled and compared to published data (Casonato et al, Blood2002; 99:180). For p = 7.5 x 10−4 min−1 and a half life of 12 h, the modeled multimer patterns were comparable to the observed steady-state distribution of normal VWF. Decreasing the half life to 2 hours produces a low plasma concentration of “ultra-large” multimers typical of VWD Vicenza without a change in any other parameter. Conversely, increasing the probability of cleavage by only thirty percent produces typical VWD 2A multimer distributions. The model also reproduces the triplet patterns of normal and type 2A VWF. Finally, the DDAVP simulations reproduced the time course of VWF plasma concentrations and multimer distributions of DDAVP-treated patients. We conclude that increased clearance alone can explain the ultra-large multimer distribution of VWD Vicenza. Similar modeling should allow the estimation of VWF cleavage and clearance rates in other variants of VWD and in other clinical situations including thrombotic thrombocytopenic purpura. Figure Figure Figure Figure