FXIa-Triggered Thrombin Generation to Predict Breakthrough Bleeding in Acquired Hemophilia A: Data from the GTH-AHA-EMI Study

Introduction Development of neutralizing autoantibodies against factor VIII (FVIII) leads to a severe bleeding disorder, acquired hemophilia A (AHA). Recently, it was shown that emicizumab – a bispecific humanized monoclonal antibody bridging FIXa and FX, thereby mimicking FVIIIa activity – prevented patients with AHA from bleeding*. However, some patients experienced clinically relevant breakthrough bleeds not predictable from clinical baseline characteristics [1].

Objectives: To assess potential biomarkers of breakthrough bleeding, including thrombin generation, emicizumab levels, residual FVIII activity, and concentration of other coagulation factors.

Method: Consecutive samples collected from twenty-eight patients enrolled in the GTH-AHA-EMI study were analyzed for emicizumab and FVIII concentration using chromogenic activity assay containing bovine and human factors, respectively. Thrombin generation assay (TGA) was performed using calibrated automated thrombogram (CAT). The intrinsic and extrinsic pathway of coagulation were initiated with low amounts of FXIa (FXIa-TGA) and tissue factor (TF-TGA), respectively. Enzyme-linked immunosorbent assay (ELISA) were used to measure factor IX, X, and XI concentrations.

Results: In FXIa-TGA, peak thrombin significantly increased with both emicizumab levels and FVIII activity. Higher FXIa-TGA peak and endogenous thrombin potential (ETP) values in patients were associated with significantly lower risk of bleeding as indicated by increment rate ratios below 1 (peak: 0.40 (0.17 – 0.84); ETP: 0.44 (0.20 – 0.88), both p<0.05). In TF-TGA, peak thrombin increased also with emicizumab concentration, but not with FVIII activity. TF-TGA parameters were not associated with bleeding rate. Factor IX, X and XI antigen levels were within normal ranges, remained stable over time and had no impact on either TGA assay. FVIII activity or emicizumab levels alone as well as inhibitor levels were not associated with bleeding rate.

Conclusion: This post-hoc analysis from the GTH-AHA-EMI clinical trial suggests thatFXIa-TGA parameters are related to both emicizumab levels and residual FVIII activity in AHA and can be a useful biomarker to indicate increased risk of bleeding despite emicizumab prophylaxis.

 

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Conflict of Interest:

SW reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures or consultancy from Biotest and Stago. FP, EE, and AK have nothing to disclose. OO reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures from CSL Behring and Roche–Chugai. PK reports institutional grants for research and studies from Ablynx–Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx–Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. CP reports institutional grants for research and studies from Chugai–Roche, Takeda, Zacros, and LeoPharma, and honoraria for lectures or consultancy from Bayer, Biomarin, Chugai–Roche, CSL Behring, Novo Nordisk, Pfizer, BMS, SOBI, and Takeda. RG reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. JO reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biogen Idec, Biomarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, SOBI, and Takeda. UJS reports institutional grants for research and studies from Octapharma, and honoraria for lectures or consultancy from Bayer, SOBI, CSL Behring, and Pfizer. WM reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, and Takeda–Shire, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda–Shire, and uniQure. KT-G reports honoraria for lectures or consultancy from Grifols, SOBI, Takeda, and Roche. KH reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, SOBI, and Takeda. HE reports institutional grants for research and studies from Bayer, CSL Behring, and Pfizer, and honoraria for lectures or consultancy from Bayer Vital, BioMarin, Biotest, CSL Behring, Novo Nordisk, Pfizer, Roche, and Sobi PM reports institutional grants for research and studies from Baxter Innovations, Bayer, LFB, SOBI, Octapharma, Pfizer, and Roche, and honoraria for lectures or consultancy from Alexion, AstraZeneca, Biotest, CSL Behring, Shire, Octapharma, Pfizer, Roche, and Takeda. CH reports honoraria for lectures or consultancy from Bayer, SOBI, Roche, Pfizer, and Takeda. PK reports institutional grants for research and studies from Ablynx–Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx–Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. RG reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. RK reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Octapharma, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Biomarin, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche–Chugai, Sanofi, SOBI, and Takeda. AT reports institutional grants for research and studies from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda. CH reports honoraria for lectures or consultancy from Bayer, SOBI, Roche, Pfizer, and Takeda.

• References

• 1 Tiede A. 1 et al. 2023; Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study. The Lancet Haematology Volume 10 (11) e913-e921

Publication History

Article published online:
13 February 2025