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

Abstract

Critical clinical questions remain unanswered regarding diagnosis and management of patients with low von Willebrand factor (VWF) levels (30-50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with low VWF levels. Despite marginally reduced plasma VWF levels, International Society of Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH BAT) confirmed significant bleeding phenotypes in the majority of LoVIC patients. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30 to 50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma factor VIII to VWF antigen (VWF:Ag) ratios were significantly increased in LoVIC patients compared with controls ( < .0001). In contrast, VWF propeptide to VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF collagen binding activity levels were both significantly reduced compared with controls ( < .05). In response to 1-desamino-8-D-arginine vasopressin (DDAVP), peak VWF:Ag levels exceeded 100 IU/dL in 88% of patients and was sustained >100 IU/dL after 4 hours in 72% of 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, 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 www.clinicaltrials.gov as #NCT03167320.

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

“…It is unclear why the majority (91%) of cases are female given that the bleeding score was similar after the female specific bleeding issues (PPH and menorrhagia) had been deducted. It is known from an Irish study of 126 patients, with low VWF (0.3‐0.5 IU/mL), that 89% were women and the median age was 39 and that when gynaecological bleeding was removed the bleeding score remained elevated, which resembles our collection . Mean age of presentation was 38.4 years (men 33.2, women 38.8; Table ).…”

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

“…Consistently, only 65–75% of the patients with plasma VWF < 30 IU dL −1 have VWF sequence variations, and this frequency decreases progressively as the VWF level rises to > 30 IU dL −1 . A recent study in unequivocal bleeders with ‘low VWF’ (30–50 IU dL −1 ) found no correlation between BS and VWF levels, and most patients had normal VWF propeptide/VWF:Ag ratios and sustained response of VWF:Ag and VWF:RCo to desmopressin (DDAVP), consistent with decreased VWF synthesis or secretion . This suggests that most bleeders with ‘low VWF’ have type 1 VWD, and are not just individuals with VWF situated within the 2.5th percentile distribution .…”

Controversies in the diagnosis of Type 1 von Willebrand disease

“…Conversely, moderately reduced VWF levels (35‐50 IU/dL) show low heritability, rarely exhibit linkage to the VWF locus, and are not always associated with significant bleeding . However, data from the Low VWF Ireland Cohort (LoVIC) study shows that 77% of females with VWF levels between 30 and 50 IU/dL had positive ISTH‐BAT scores . The latter highlights the gender differences with respect to the diagnosis of VWD.…”

“…A recent publication looked at predictors of VWD diagnosis for those individuals with borderline VWF levels (30‐60 IU/dL) . The authors used a multivariable logistic regression model which was fitted with gender, age, bleeding score, family history, VWF:RCo and ABO blood group as predictors, to predict VWD diagnosis.…”