Abstract
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: 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.
Keywords
VWF - VWD - DDAVP - VWF survival - VWF clearance
