PB0810 - A novel role for subtle enhanced VWF clearance in Low VWF pathogenesis highlights limitations of VWFpp/VWF:Ag ratio assessment of clearance.

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Dearbhla Doherty, MB BCh BAO

Research fellow
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Dublin 2, Dublin, Ireland

Co-Author(s)

MB

Mary Byrne

Coagulation Laboratory Chief
National Coagulation Centre, St James's Hospital, Dublin
Dublin, Dublin, Ireland
MN

Margaret Nolan

Clinical Research Coordinator
National Coagulation Centre, St James's Hospital, Dublin 8
Dublin, Dublin, Ireland
JO

Jamie M. O’Sullivan, PhD

StAR Research Lecturer
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Dublin, Dublin, Ireland
KR

Kevin Ryan

Consultant Haematologist
National Coagulation Centre, St James's Hospital, Dublin
Dublin, Dublin, Ireland
Niamh O'Connell, MD

St. James Hospital
Dublin, Ireland
SH

Sandra Haberichter

Director, Hemostasis, Senior Investigator
Versiti Blood Research Institute
Milwaukee, Wisconsin, United States
Pamela A. Christopherson

Research Program Coordinator
Versiti Blood Research Institute
Milwaukee, Wisconsin, United States
Jorge DiPaola, MD

Professor of Pediatrics & Molecular Genetics and Genomics
Department of Pediatrics, School of Medicine, Washington University
St. Louis, Missouri, United States
Paula James, MD

Professor
Department of Medicine, Queen's University, Kingston, ON, Canada
Kingston, Ontario, Canada
Michelle Lavin, MD, PhD

Consultant Haematologist
National Coagulation Centre, St. James Hospital and Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Physicians and Surgeons in Ireland (RCSI)
Dublin, Dublin, Ireland
JO

James S. O'Donnell, MB, PhD

Professor of Haematology
Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland,Dublin, Ireland
Dublin, Dublin, Ireland

Background: Markedly enhanced VWF clearance represents an important pathogenic mechanism in Type 1C and Type 2 VWD. In contrast, previous studies suggest that reduced VWF biosynthesis is more important in patients with VWF levels in the 30-50 IU/dL range.

Aims: VWF clearance was investigated in the Low VWF Ireland cohort (LoVIC) using the recent 2021 ASH/ISTH/NHF/WFH guideline recommendation for increased clearance diagnosis (plasma VWF:Ag fall-off >30% from peak at 4 hours following desmopressin).

Methods: Low VWF patients (n=75) were recruited following ethical approval and informed consent. Following intravenous desmopressin (DDAVP), blood samples were drawn for VWF:Ag, VWF:RCo and FVIII:C at baseline (T0), 1 (T1) and 4 hours (T4).

Results: Based on ASH guideline criteria, 15/75 (20%) of Low VWF patients demonstrated enhanced VWF clearance (Figure 1). Low VWF patients with enhanced clearance demonstrated (i) significantly higher initial increases in plasma VWF:Ag levels at T1 (median 3.84 vs 2.89-fold, p< 0.0001) and (ii) significantly greater fall-offs in plasma VWF:Ag, VWF:RCo and FVIII:C levels between T1 and T4 (median 1.53 vs 1.20-fold for VWF:Ag, p< 0.0001) (Figure 1). Thus, within the Low VWF cohort, there is a subgroup in whom desmopressin triggers enhanced endothelial release of VWF-FVIII, which then undergoes enhanced plasma clearance. The steady-state VWFpp/VWF:Ag ratio has been used to identify patients with Type 1C VWD. Interestingly, in the Low VWF cohort, we observed a marked discordance between VWFpp/VWF:Ag ratios and DDAVP fall-off data. Even using the blood group O VWFpp/VWF:Ag 97.5th percentile cut-off (> 2.15), only 12% (9/75) of Low VWF patients were identified as suspected enhanced clearance.

Conclusion(s): Our findings define a novel role for subtle enhanced VWF clearance in Low VWF pathogenesis. Furthermore, our data highlight important limitations of the VWFpp/VWF:Ag ratio in identifying increased clearance in patients with mild to moderate reductions in plasma VWF levels.