Comparing thrombin generation in hemophilia A and patients with non-valvular atrial fibrillation on oral anticoagulation

Introduction: Recently published guidelines on antithrombotic treatment in persons with hemophilia (PWH) appraised the literature on whether PWH are naturally anticoagulated: Only two studies compared thrombin generation (TG) in PWH and patients on vitamin K antagonists (VKA), both analyzing endogenous thrombin potential (ETP) and limited by arbitrary stratifications [1]. Here, we aimed to compare TG in PWHA at varying factor (F) VIII concentrations with patients on VKA and rivaroxaban.

Method: We sampled plasma from 1) PWHA of all severities participating in our biobank and 2) from participants on VKA or rivaroxaban of our hospital-based registry on patients with non-valvular atrial fibrillation (AF). TG was measured by a commercially available assay (Technothrombin, Technoclone) and FVIII levels by chromogenic substrate assay (Biophen, Hyphen Biomed). Rivaroxaban concentrations were quantified by LC-MS/MS [2]. We regressed 1) TG parameters on FVIII and 2) INR or rivaroxaban concentrations on TG parameters in PWHA and VKA or rivaroxaban samples, respectively. Estimating TG parameters in 1) and INR or rivaroxaban concentrations at those values in 2), respectively, allowed us to compare INR or rivaroxaban concentrations and FVIII in a continuous fashion, computing 95% bootstrap confidence intervals (95% CI).

Results: We collected a total of 510 samples from 112 PWHA and 189 AF patients treated with VKA (n=121) or rivaroxaban (n=68). The median (IQR) FVIII activity and INR values in the respective cohorts was 13 IU/dL (3-38) and 2.0 (1.7-2.4). The median rivaroxaban concentration measured among AF patients treated with rivaroxaban was 92.6 ng/mL (33.0-192.2). TG curve parameters showed substantial variability among all three cohorts, and, accordingly, their relationship with FVIII, INR, and rivaroxaban and ability to differentiate between changes was only modest. Importantly, TG curves clustered distinctly between cohorts ([Fig. 1]). As such, different TG parameters lead to varying apparent comparison estimates. Comparing INR and FVIII by ETP revealed an estimated mean INR equivalence of 2.1 (95% CI, 1.9-2.3) in PWHA<1 IU/dL followed by an immediate decline and plateau ([Fig. 2]). In contrast, a comparison by thrombin peak height (TPH) lead to a mean INR equivalence of 2.5 (2.3-2.7) at<1 IU/dL with a less steep decline. Comparing PWHA and AF patients on rivaroxaban by ETP and TPH lead to an estimated mean rixaroxaban concentration equivalence of 284.8 (210.0-357.7) and 229.7 ng/mL (180.6-280.4) at<1 IU/dL FVIII activity, respectively.

Fig. 1 Thrombin generation parameters by sample cohort. Thrombin generation parameters showed distinct clustering between the three cohorts of PWHA (blue), AF patients treated with VKA (red), and AF patients treated with rivaroxaban (yellow). Abbreviations: AF, atrial fibrillation; ETP, endogenous thrombin potential; PC (%), principal component (explained variation); PWHA, persons with hemophilia A; VI, velocity index, VKA, vitamin K antagonists; TPH, thrombin peak height; TTP, time-to-peak.

Fig. 2 Relationship of ETP and TPH with FVIII, INR, and rivaroxaban. Scatter plots displaying the relationship of ETP and TPH with FVIII in PWHA (blue); with INR in VKA-treated AF patients (red); and with drug concentration in rivaroxaban-treated AF patients (yellow). The rightmost column shows mean INR- (purple) and rivaroxaban-equivalence (green) for increasing FVIII activity levels. Error bars/bands display 95% confidence intervals (CI). Abbreviations: AF, atrial fibrillation; ETP, endogenous thrombin potential; FVIII, factor VIII; INR, international normalized ratio; TPH, thrombin peak height; ρ, Spearman’s rank correlation; τ, Kendall rank correlation.

Conclusion: TG showed substantial variability and differed distinctly between PWHA, VKA-treated, and rivaroxaban-treated AF patients. Our data was incompatible with a guideline-concluded threshold of 10 IU/dL for indicating natural anticoagulation in PWHA similar to therapeutic INR in VKA patients. Our study suggests comparisons by individual TG parameters between PWHA and anticoagulated patients to be overly simplistic.

 

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Conflict of Interest:

Cihan Ay received honoraria for lectures and/or participation in advisory boards from Biotest, Bayer, CSL Behring, Novo Nordisk, Roche, Sobi, and Takeda. Oliver Königsbrügge has received honoraria for lectures and participation in advisory boards from Roche, CSL Behring, Pfizer and BMS. Daniel Kraemmer has received honoraria for lectures and participation in advisory boards from CSL Behring and Pfizer. Ingrid Pabinger has been a consultant for CSL Behring and has received honoraria for lectures and participation in advisory boards from CSL Behring, Pfizer, Roche, and Takeda. Peter Quehenberger has no conflict of interest to declare. Judit Rejtő has no conflicts of interest to declare.

• References

• 1 Schutgens R. et al. 2023; ‘Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance’. Hemasphere. 7 (06) e900
• 2 Königsbrügge O. et al. 2018; ‘Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation’. Clin Exp Med. 18 (03) 325-336

Publication History

Article published online:
13 February 2025