OC 66.4 - Increased Endothelial Secretion and Reduced Circulatory Clearance Contribute to Elevated Plasma von Willebrand Factor Levels in Multiple Myeloma

Tuesday, July 12, 2022

3:30 PM – 3:45 PM

Location: ExCel Center, ICC Capital Suite Room 10&11

Presentation Format: In-Person

Presenting Author(s)

Claire Comerford, MB Bch BAO

Haematology SpR/Postgraduate Student
Royal College of Surgeons in Ireland
Dublin, Dublin, Ireland

Co-Author(s)

SP

Sukhraj Pal Singh Dhami

Postdoctoral Researcher
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Dublin, Dublin, Ireland
PM

Philip Murphy

Consultant Haematologist
Department of Haematology, Beaumont Hospital, Dublin, Ireland
Dublin, Dublin, Ireland
SP

Sean Patmore

Postgraduate Student
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Dublin, Dublin, Ireland
SW

Soracha Ward

Postdoctoral
RCSI
Dublin, Dublin, Ireland
UB

Ulrich Budde

Professor of Haematology
Medilys Laborgesellschaft mbH, Department of Hämostaseology, Hamburg, Germany
Hamburg, Hamburg, Germany
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
SG

Siobhan Glavey

Consultant Haematologist
Department of Haematology, Beaumont Hospital, Dublin, Ireland
Dublin, Dublin, Ireland
JQ

John Quinn

Consultant Haematologist
Department of Haematology, Beaumont Hospital, Dublin, Ireland
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

Background: Multiple myeloma (MM) is associated with one of the highest rates of cancer associated thrombosis, with both venous and arterial events reported. The biological basis for this remains poorly understood. Elevated plasma von Willebrand Factor antigen (VWF:Ag) levels are an independent risk factor for thrombosis and poorer survival in other malignancies.

Aims: To systematically characterise VWF:Ag and activity in MM patients and provide novel mechanistic insight into the biology of thrombotic risk in MM.

Methods: Plasma samples were collected from 105 patients with MM/precursor MM. 10 primary bone marrow (BM)MM samples were obtained. VWF:Ag and propeptide (VWFpp) were measured using ELISA. Endothelial cells (ECs) were co-cultured with human myeloma cell line (HMCLs) or primary MM cell supernatant.

Results: Elevated plasma VWF:Ag levels were observed in newly diagnosed/relapsed MM compared with precursor MM (332.7IU/dL vs 133.1IU/dL; p< 0.0001). VWF:Ag correlated with markers of disease activity, including paraprotein level. Highest levels were observed with poorest response to MM therapy (402IU/dL vs 154.4IU/dL; p< 0.05). Ultralarge VWF multimers were present in relapsed MM, suggesting increased thrombotic risk associated with treatment refractory disease. Increased VWFpp levels were observed across the cohort, indicating acute endothelial activation. However, impaired circulatory clearance of VWF is also suspected, with reduced VWFpp/VWF:Ag ratios (0.69 vs 1.48; p< 0.0001) and increased VWF half-life evident. We also observed VWF multimers locally within the BM niche. Supporting this, supernatant from both HMCL and primary MM cells promoted endothelial secretion of VWF, which was shown to directly interact with MM cells.

Conclusion(s): Our findings provide novel mechanistic insight into contributory roles of both increased secretion and reduced clearance of VWF underpinning elevated VWF levels in MM. We also demonstrate multimeric VWF within the BM niche, raising the possibility that VWF may not only contribute to the prothrombotic phenotype but could also be implicated in local disease progression.