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

Abstract

AbstractA 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: k 0, associated with the VWF release phase; k 1, illustrating the phase of conversion from high- to low-molecular-weight VWF multimers; and k e, associated with the VWF elimination phase. The amount of VWF released (D) was also measured. k e and D were significantly higher in O than in non-O blood group controls; k 1 was also higher, but less markedly so. All the parameters were accelerated in type Vicenza, especially k e (p < 0.0001), which explains the significant reduction in VWF half-life. In types 2B and 2A-II, k 1 was one order of magnitude higher than in controls, which explains their loss of large VWF multimers. All parameters except k e 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.