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Thrombin Generation is a Better Predictor for Factor VIII Replacement Therapy Effect Than Factor VIII Activity Levels

1Radboud University Medical Center, Hematology, Nijmegen, the Netherlands, 2Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, the Netherlands, 3Amsterdam UMC, University of Amsterdam, Clinical Pharmacology, Amsterdam, the Netherlands, 4Enzyre BV, Nijmegen, the Netherlands

Abstract Number: PB0903

Meeting: ISTH 2020 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in hemophilia A (HA) patients mainly consists of measuring plasma FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG), thereby providing a novel pharmacodynamic measurement tool relating dose-to-effect.

Aims: To determine dose-effect responses after a FVIII replacement therapy bolus in HA patients by measuring TG profiles.

Methods: Pharmacodynamic studies with a single bolus of 25-50 IE/kg standard half-life FVIII were performed in 26 HA patients with simultaneous determination of plasma FVIII activity levels and TG using the NHA at 10 time points. The study was approved by the Radboudumc ethics-committee. Patients gave written informed consent. TG parameters (lag time (LT), time to thrombin peak (TTP), thrombin peak height (TPH) and thrombin potential (TP)) were calculated and are presented as absolute values as medians (interquartile range).

Results: Median baseline FVIII concentration was 1.0% (< 1.0-6.0), with a LT 15 of minutes (6.8-23.3), TTP 28.5 minutes (15.5-36), TPH 22 nM (15-35), and TP 404 nM/min (undetectable-876). After FVIII replacement therapy, FVIII concentration increased to 72% (62-82) at 15 minutes and TG parameters normalized. LT was restored to 3 minutes (2.8-3.5), TTP to 8.5 minutes (7.8-9.3), TPH increased to 222 nM (159-255) and TP to 1834 nM/min (1546-2353), figure 1. Twenty-four hours after infusion, FVIII concentration was 15% (10-26), while increased TG parameters remained high [LT 4.7 minutes (3.5-5.3), TTP 12.3 minutes (10.8-14.6), THP 73 nM (58.5-126.3), TP 1394 nM/min (1066-1677)].

Conclusions: HA patients with equal FVIII activity levels show clear differences in TG (TPH, TTP, TP and LT). After FVIII replacement, TG normalizes (TPH, TTP and LT) and thrombin potential remains normal up to 24 hours. We suggest that thrombin generation measurements better predict the dose effect relation in HA patients compared to solely FVIII activity levels.


[Thrombin generation parameters (right y-axis) and FVIII concentration (left y-axis) after a bolus of standard half-life FVIII replacement therapy]

To cite this abstract in AMA style:

Valke LLFG, Bukkems LH, Blijlevens NMA, Mathôt RAA, Van Heerde WL, Schols SEM. Thrombin Generation is a Better Predictor for Factor VIII Replacement Therapy Effect Than Factor VIII Activity Levels [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/thrombin-generation-is-a-better-predictor-for-factor-viii-replacement-therapy-effect-than-factor-viii-activity-levels/. Accessed September 22, 2023.

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