OC 57.1 - Intrinsic activated thrombin generation for efficacy and monitoring of emicizumab

Tuesday, June 25, 2024

09:30 – 09:45 ICT

Room: 210 A-D

Presenting Author(s)

Henri M.H Spronk, PhD

Professor of Biochemistry of Atherothrombosis
Maastricht University
Maastricht, Limburg, Netherlands

Co-Author(s)

Rv

Rene van Oerle

researcher
MUMC
Maastricht, Limburg, Netherlands
Floor Heubel-Moenen

MD, PhD
Department of Hematology, Maastricht University Medical Center, Maastricht, The Netherlands
Maastricht, Limburg, Netherlands
PG

Peter Giesen

Director
CoagScope B.V.
Maastricht, Limburg, Netherlands
DH

Dave Hellenbrand

Laboratory specialist
MUMC+
Maastricht, Limburg, Netherlands
Amaury Monard

PhD candidate
Internal Medicine, Maastricht University Medical Center +, Maastricht, the Netherlands
Maastricht, Limburg, Netherlands
Paola van der Meijden

Associate Professor
MUMC+
Maastricht, Limburg, Netherlands
Tilman M. Hackeng, PhD

Professor
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University
Maastricht, Netherlands
Hugo ten Cate, MD, PHD

MD, PhD
Departments of Internal Medicine and Biochemistry, Maastricht University Medical Center+, Maastricht, The Netherlands
Maastricht, Limburg, Netherlands
Yvonne Henskens

Professor of the department of clinical chemistry
MUMC+
maastricht, Limburg, Netherlands

Background: Traditionally, severe hemophilia A (SHA) patients are treated with intravenous prophylactic Factor (F)VIII replacement concentrates to prevent spontaneous bleeding. Various extended half-life FVIII and non-factor products (such as emicizumab and Fitusiran) were introduced as alternatives. The Thrombin Generation Assay (TGA) is a potentially useful tool for monitoring the efficacy of various FVIII and non-FVIII replacement products in blood.

Aims: To investigate the applicability of intrinsically activated TGA in comparison to the commonly used extrinsically activated TGA.

Methods: The TGA assay was optimized and validated for the new PPP Reagent INT (contact activator, 4 µM phospholipids) for measuring octocog alfa and emicizumab.

Results: TG in normal plasma triggered by PPP Reagent INT (36 replicates) was characterized by a lag time of 5.39±0.22 min, an endogenous thrombin potential (ETP) of 1451±38 nM.min, a peak height of 420±9 nM and a velocity index of 254±25 nM/min. The overall variability of the assay was < 10%(CV) for all parameters, with a within-run and between-day variation < 5%(CV). PPP Reagent INT failed to induce TG in plasmas deficient for FXII, FXI, FIX, or FVIII, whereas normal profiles were obtained for FVII deficient plasma. Addition of octocog alfa or emicizumab to FVIII deficient plasma, dose dependently increased TG triggered with PPP Reagent INT. Both PPP Reagent LOW (low) and PPP Reagent (mid tissue factor) displayed poor sensitivity for the two replacement products. No dose dependent correlation was found between plasma emicizumab levels and extrinsic triggered TG in plasma from SHA subjects (n=58) treated with emicizumab. However, plasma emicizumab levels showed a good correlation with maximum thrombin (peak height) in the intrinsically activated TGA correlated with.

Conclusion(s): Intrinsically activated thrombin generation may be a suitable tool for monitoring different Hemophilia A replacement therapies. Future applicability of this PPP Reagent INT TGA in monitoring SHA patients requires further study.