Enhanced VWF clearance in low VWF pathogenesis: limitations of the VWFpp/VWF:Ag ratio and clinical significance

Abstract

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.

Low von Willebrand Disease: A Bleeding Disorder of Unknown Cause?

“…Furthermore, VWFpp clearance kinetics may also vary between individual patients with low VWF and type 1 VWD. 50 Taken together, these data demonstrate that enhanced VWF clearance plays an important role in low VWF pathogenesis. Although the biological mechanisms responsible for pathological VWF clearance in patients without VWF sequence variants has not been defined, previous studies have reported altered VWF glycosylation in subsets of patients with both low VWF and type 1 VWD, respectively.…”

“…47,48 Interestingly, Doherty et al recently reported that the sensitivity of the steady-state VWFpp/VWF:Ag ratio for identifying increased VWF clearance in patients with low VWF was significantly reduced compared to gold-standard desmopressin fall-off rates. 50 This likely reflects the fact that the reduction in plasma VWF half-life in low VWF patients ($6 hours) is not as marked as that observed in type 1C patients (2$4 hours). Furthermore, VWFpp clearance kinetics may also vary between individual patients with low VWF and type 1 VWD.…”

“…47 48 Similarly, recent studies have shown that pathological enhanced VWF clearance also contributes to low VWF pathogenesis in some patients. 50 51 The ASH/ISTH/WFH/NHF guidelines recommend that enhanced VWF clearance in patients be assessed by measurement of sequential plasma VWF levels following desmopressin infusion. 6 12 The proposed threshold for defining pathological increased VWF clearance is a fall in plasma VWF:Ag levels >30% between +1 hour and +4 hours after desmopressin.…”

“…6 Recent data from the LoVIC study have demonstrated that ∼20% of patients with low VWF demonstrate enhanced VWF clearance based on these criteria. 50 51 As an alternative approach, previous studies have successfully used a VWF propeptide (VWFpp)/VWF:Ag ratio > 3 to identify patients with type 1C VWD. 47 48 Interestingly, Doherty et al recently reported that the sensitivity of the steady-state VWFpp/VWF:Ag ratio for identifying increased VWF clearance in patients with low VWF was significantly reduced compared to gold-standard desmopressin fall-off rates.…”

Von Willebrand Factor Multimer Analysis and Classification: A Comprehensive Review and Updates

“…Recently, a higher proportion of patients with type 1 were found to have abnormal VWFpp:VWF:Ag ratios, suggesting that VWD type 1C may be more common than previously suspected. 64 65…”