Optimal design of infusion tests for the identification of physiological models of acquired von Willebrand syndrome

Abstract

Acquired von Willebrand syndrome (AVWS) is a bleeding disorder resembling inherited Von Willebrand disease (VWD) characterised by a qualitative and/or quantitative deficiency of von Willebrand factor (VWF) that occurs in patients with no personal or family history of bleeding as a result of underlying pathological conditions. To treat AVWS patients, desmopressin (DDAVP) and plasma-derived VWF concentrates are the primary therapies for spontaneous acute bleeding episodes and for preventing bleeding during invasive or surgical procedures. Pharmacokinetic (PK) models have been recently developed and applied to characterize VWD and AVWS, but these models cannot be calibrated from infusion tests data, and their calibration requires stressful 24-hours long tests to be carried out on subjects to achieve a satisfactory estimation of the individual haemostatic parameters. The objectives of this paper are: i) to present a new physiological model of VWD including exogenous infusion of plasma-derived VWF concentrates, suitable to describe AVWS; ii) to validate the newly proposed model from clinical data; iii) to quantify the information that can be obtained from clinical tests using different VWF concentrates by applying model-based design of experiments (MBDoE) techniques. Results show that the newly developed model calibrated from infusion data allows to estimate precisely the full set of haemostatic parameters for a subject affected by AVWS preserving the same level of information obtained from conventional tests. Most importantly, results demonstrate that the overall duration of infusion tests for the identification of key haemostatic parameters can significantly be reduced from 24 h to 2.5 h.