OC 63.2 - Inter-individual FVIII clearance heterogeneity in PWH in the iPATH study – biological determinants and clinical importance.

Tuesday, July 12, 2022

3:00 PM – 3:15 PM

Location: ExCel Center, ICC Capital Suite Room 7&12

Presentation Format: In-Person

Presenting Author(s)

Einas Elsheikh, MRCP-UK,FRCPath

Clinical Research Fellow
Royal College of Surgeons Ireland, St James Hospital, Dublin8
Dublin 8, Ireland

Co-Author(s)

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
NL

Niamh Larkin

Advanced Nurse Practitioner
St. James's Hospital, Dublin
Dublin, Dublin, Ireland
Niamh O'Connell, MD

St. James Hospital
Dublin, Ireland
KR

Kevin Ryan

Consultant Haematologist
National Coagulation Centre, St James's Hospital, Dublin
Dublin, Dublin, Ireland
MB

Mary Byrne

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

Evelyn Singleton

National Coordinator of coagulation factor concentrates,Clinical nurse manager (CNM3)
National Coagulation Centre ,St James's Hospital,Dublin8
Dublin, Dublin, Ireland
PF

Padraic G. Fallon

Professor
Trinity College Dublin
Dublin, Dublin, Ireland
Jill M. Johnsen, MD

Associate Professor, Division of Hematology
University of Washington, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
Seattle, Washington, United States
Steven W. Pipe, MD

Professor of Pediatrics and Pathology
University of Michigan, Ann Arbor, MI, USA
Ann Arbor, Michigan, United States
Peter L. Turecek, PhD, PharmD

Professor
Baxalta Innovations GmbH, a Takeda company
Vienna, Wien, Austria
JO

James O'Donnell

Professor, Vascular Biology-RCSI, Consultant haematologist ,St James's Hospital ,Dublin
Royal College of Surgeons Ireland, St James Hospital , Dublin8
Dublin, Dublin, Ireland

Background: Significant inter-individual variation in FVIII clearance has been described in patients with severe haemophilia A (PWH). However the mechanisms underlying this heterogeneity and its clinical significance remain poorly defined.

Aims: We studied in vivo clearance of rFVIII (Advate) in a large population of Irish PWH using MyPKFit and investigated factors influencing half-life and clinical outcomes.

Methods: Patients were recruited from the National Coagulation Centre in Dublin. All patients provided written informed consent. Clinical data were collected retrospectively from electronic medical records and patients diaries for the period from January 2013 through January 2018.

Results: 54 PWH were enrolled median age 36 years, range( 18-75). Overall, median annualized bleed rate (ABR) was 3.7, median Haemophilia Joint Health Score (HJHS) was 26 (range 0-51), median FVIII dose was 52.4 IU/kg/week (range 5.7-128.6). Although the median rFVIII half-life was 11.4 hours, marked inter-patient variability was observed (range 7.7-20.1 hours). FVIII half-life correlated significantly with endogenous plasma VWF:Ag levels (r=0.5378, p< 0.0001). In keeping with this finding, FVIII half-life was significantly reduced in group O compared to non-O PWH (p=0.02). In addition, FVIII half-life increased significantly with age (p < 0.0001). Interestingly, FVIII usage was reduced in older PWH, despite the fact HJHS and ABR both increased progressively with age. Finally, we observed that dose of FVIII prophylaxis used in PWH correlated inversely with FVIII half-life despite the fact that PK-driven FVIII dosing was not used in Ireland in the study period. We hypothesize that PWH with faster FVIII clearance have increased bleed rates that lead to higher intensity FVIII prophylaxis over time.

Conclusion(s): These data highlight that multiple factors contribute to marked inter-individual variation in rFVIII clearance in PWH. Moreover, this clearance heterogeneity has direct translational relevance. Further studies will be required to define the biological mechanisms underpinning this variability, and to develop personalised treatment regimens for PWH.