Enhanced VWF clearance in Low VWF pathogenesis - limitations of VWFpp/VWF:Ag ratio and clinical significance.

Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of Type 1 and Type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (30-50 IU/dL range; Low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to Low VWF pathobiology. Low VWF patients were recruited to the LoVIC study following ethical approval and informed consent. Desmopressin was administered intravenously in 75 patients and blood samples drawn at baseline, 1 and 4 hour time-points. As defined by recent ASH/ISTH/NHF/WFH guidelines, 20% of our Low VWF cohort demonstrated significantly enhanced VWF clearance. Importantly from a clinical perspective, this enhanced VWF clearance was seen following desmopressin infusion, but did not affect the steady-state VWFpp/VWF:Ag ratio in most cases. This discrepancy between VWFpp/VWF:Ag ratio and desmopressin fall-off rates in patients with mild quantitative VWD may reflect alteration in VWFpp clearance kinetics. Finally, our data further demonstrate that bleeding scores are significantly lower in Low VWF patients with enhanced VWF clearance compared to those in whom reduced VWF biosynthesis represents the principle pathogenic mechanism. This trial was registered at www.clinicaltrials.gov as #NCT03167320.