Ferrari, M;
Galvanin, F;
Barolo, M;
Daidone, V;
Padrini, R;
Bezzo, F;
Casonato, A;
(2018)
A Mechanistic Model to Quantify von Willebrand Factor Release, Survival and Proteolysis in Patients with von Willebrand Disease.
Thrombosis and Haemostasis
, 118
(2)
pp. 309-319.
10.1160/TH17-05-0375.
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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.
| Type: | Article |
|---|---|
| Title: | A Mechanistic Model to Quantify von Willebrand Factor Release, Survival and Proteolysis in Patients with von Willebrand Disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1160/TH17-05-0375 |
| Publisher version: | http://dx.doi.org/10.1160/TH17-05-0375 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | VWF, VWD, DDAVP, VWF survival, VWF clearance |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Chemical Engineering |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10041135 |
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