OC 47.1 - Evaluation of plasmin generation in severe haemophilia A patients treated with novel therapies

Monday, June 24, 2024

14:45 – 15:00 ICT

Room: 210 A-D

Presenting Author(s)

Phway P. Thwin, MSc, ASCPi, MIBMS

Senior Biomedical Scientist
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital NHS Foundation Trust
London, England, United Kingdom

Co-Author(s)

AR

Anne Riddell

Laboratory Manager
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust. London, United Kingdom
London, England, United Kingdom
PL

Philip Lane

Research Scientist
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust. London, United Kingdom
London, England, United Kingdom
JI

Janette Itaas

Clinical Nurse Specialist
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital NHS Foundation Trust
London, England, United Kingdom
Ilaria De Simone, PhD

PostDoc
Synapse Research Institute
Maastricht, Limburg, Netherlands
Dana Huskens, PhD

PhD, Senior Research Project Leader
Synapse Research Institute
Maastricht, Limburg, Netherlands
Bd

Bas de Laat

General Director
Synapse Research Institute
Maastricht, Limburg, Netherlands
Pratima Chowdary, MD

Professor of Haemophilia, Centre Director
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital
London, England, United Kingdom
Paul Batty, MBBS PhD

Associate Professor
Cancer Institute, University College London, London, UK
London, England, United Kingdom

Background: Hyperfibrinolysis has been reported to contribute to bleeding in severe haemophilia A (SHA). Whether novel therapeutics for the treatment of HA affect fibrinolysis is not clear. Measuring plasmin generation (PG) may provide information on the effect of novel therapies on fibrinolysis, and potential for treatment failure.

Aims: To evaluate PG kinetics pre and post treatment with an extended half-life recombinant factor VIII concentrate (rFVIII-EHL) and factor VIII (FVIII) bispecific antibody (FVIII-bsAb) in SHA

Methods: A calibrated plasmin generation assay (PGA) was performed on samples from healthy volunteers (n=35), SHA patients treated with rFVIII-EHL, turoctocog alfa pegol (n=19) and SHA patients treated with FVIII-bsAb, emicizumab (n=19), after informed consent and ethics approval. PG was activated using tissue factor, phospholipid and tissue plasminogen activator, 2-macroglobulin-complex calibrator and substrate containing fluorogenic PG substrate and calcium chloride. PG parameters: lag time (LT), endogenous plasmin potential (EPP), peak, time to peak (TtPeak) and velocity were measured. A percentage normal relative to reference plasma was also calculated.

Results: There were no statistical differences in core PG parameters (EPP, peak and velocity) between HV and pre-treatment SHA (FVIII ≤5 IU/dL) samples (Table 1). A significant weak correlation (r=0.348, p=0.040) was seen in HV between EPP and FVIII levels (FVIII:62-220 IU/dL). Interestingly, no correlation (r= 0.052, p=0.831) was observed between EPP and FVIII levels (FVIII:97-171 IU/dL) in post-EHL rFVIII treatment samples. EPP differed significantly (p=0.031) between pre and post rFVIII-EHL samples; however, differences fell within the normal range. Plasmin peak differed significantly (p=0.031) between pre and steady state emicizumab samples. In steady state emicizumab samples, significant correlation was noted between emicizumab level and PG parameters: EPP(r= -0.534), peak(r= -0.497) and velocity (r= -0.498) (Figure 1).

Conclusion(s): No hyperfibrinolysis was observed in pre-treatment SHA samples compared to HV. There were alterations in PG kinetics in SHA after emicizumab treatment which warrants further investigation.