Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels

Michelle Lavin, Sonia Aguila, Sonja Schneppenheim, Niall Dalton, Kenneth L. Jones, Jamie M. O'Sullivan, Niamh M. O'Connell, Kevin Ryan, Barry White, Mary Byrne, Marie Rafferty, Mairead M. Doyle, Margaret Nolan, Roger J.S. Preston, Ulrich Budde, Paula James, Jorge Di Paola and James S. O'Donnell

Key points

  • Patients registered with Low VWF have significant bleeding phenotypes that cannot be explained by concomitant bleeding disorders.

  • Low VWF levels in the range 30-50 IU/dL are predominantly due to reduced VWF synthesis/secretion rather than enhanced clearance.


Critical clinical questions remain unanswered regarding diagnosis and management of patients with Low VWF levels (30–50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with Low VWF. Interestingly, despite their marginally reduced plasma VWF levels, ISTH BAT and Condensed MCMDM-1 VWD scores both confirmed significant bleeding phenotypes in the majority of LoVIC patients. For example, among female patients with Low VWF, 77% had ISTH BAT scores ≥6. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30-50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma FVIII:C/VWF:Ag ratios were significantly increased in LoVIC patients compared to controls (p<0.0001). In contrast, increased plasma VWF:pp/VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF:Ag and platelet-VWF:CB levels were both significantly reduced compared to controls (p<0.05). In response to DDAVP, peak VWF levels exceeded 100 IU/dL in 88% of patients. Importantly, the DDAVP response was sustained (VWF:Ag and VWF:RCo both remained >100 IU/dL after 4 hours in 72% subjects). In conclusion, our novel data suggest that Low VWF levels can be associated with significant bleeding, and are predominantly due to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in some individuals with Low VWF, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. This trial was registered at #NCT03167320.

  • Submitted May 30, 2017.
  • Accepted September 1, 2017.