A Mechanistic Model to Quantify von Willebrand Factor Release, Survival and Proteolysis in Patients with von Willebrand Disease

A reduced von Willebrand factor (VWF) synthesis or survival, or its increased proteolysis, alone or in combination, contributes to the development of von Willebrand disease (VWD).We describe a new, simple mechanistic model for exploring how VWF behaves in well-defined forms of VWD after its 1-desamino-8-D-arginine vasopressin (DDAVP)-induced release from endothelial cells. We aimed to ascertain whether the model can consistently predict VWF kinetic changes. The study involved 9 patients with VWD types Vicenza (a paradigmatic form with a reduced VWF survival), 8 type 2B, 2 type 2A-I, 1 type 2A-II (associated with an increased VWF proteolysis), and 42 normal controls, whose VWF levels were measured after a 24-hour-long DDAVP test. The rate constants considered were: k0, associated with the VWF release phase; k1, illustrating the phase of conversion from high- to low-molecular-weight VWF multimers; and ke, associated with the VWF elimination phase. The amount of VWF released (D) was also measured. ke and D were significantly higher in O than in non-O blood group controls; k1 was also higher, but less markedly so. All the parameters were accelerated in type Vicenza, especially ke (p < 0.0001), which explains the significant reduction in VWF half-life. In types 2B and 2A-II, k1 was one order of magnitude higher than in controls, which explains their loss of large VWF multimers. All parameters except ke were lower in type 2A-I.The proposed mechanistic model clearly describes the altered biochemical pathways in well-characterized VWD, prompting us to suggest that it might help clarify elusive forms of VWD too