Introduction Emicizumab prophylaxis reduces bleeding in people with hemophilia A (PwHA), offering hemostatic activity equivalent to ~15% of normal factor VIII activity (FVIII:C) level. Thus, additional FVIII supplementation would be required at breakthrough bleeding or surgery. A standard dosage of FVIII product does not account for baseline coagulant potential of emicizumab, however.

Aim The CAGUYAMA study (jRCTs051210137) aimed to assess global coagulation function in PwHA without inhibitors receiving emicizumab and FVIII concomitantly, and to determine an appropriate FVIII dose for clinical management.

Methods and Analyses The multicenter, open-label, non-randomized trial (CAGUYAMA study) enrolled 100 PwHA without inhibitors. Total 32 events involving FVIII administration (30±5 U/kg) for breakthrough bleeding or surgery were analyzed. Each event included blood sampling at pre and post FVIII administration.

The primary endpoint was change in adjusted maximum coagulation rate (Ad|min1|) by clot waveform analysis (CWA). CWA was initiated by a diluted mixture of PT and APTT reagents (Nogami K. JTH 2018). The degree of improvement in maximum coagulation rate (IMCR%) was defined relative to healthy controls (100%) and untreated PwHA (0%).

Secondary endpoints included clinical hemostatic assessment, thrombin generation assay (TGA), and rotational thromboelastometry (ROTEM; non-activated mode), performed with or without anti-emicizumab antibodies (anti-Emi-Ab) to isolate FVIII effects alone. TGA was evaluated using peak thrombin; ROTEM was evaluated using clotting time (CT) as primary outcome. Exploratory endpoints included correlation between emicizumab concentration and coagulation parameters.

Results A total of 100 PwHA (mean age 31 years) from 13 institutions were enrolled (mean follow-up: 26.5 months). Among 32 events, 47% were bleeding episodes (e.g., joint, muscle, gastro-intestine) and 53% were surgeries (e.g., tooth extraction, synovectomy).

Mean administered FVIII dose was 30.8±3.3 U/kg, yielding the FVIII:C of 77.1±20.4% and in vivo recovery of 2.5±0.7 %/U/kg. The IMCR% calculated by CWA increased from 39.4% (pre-FVIII) to 92.1% (post-FVIII). With the addition of anti-Emi-Abs, the IMCR% was 3.2% (pre-FVIII) and 78.6% (post-FVIII), indicating that calculated FVIII effect was 52.7% in the presence of emicizumab and 75.4% in its absence. All events achieved effective clinical hemostasis.

In TGA triggered by ellagic acid and tissue factor, peak thrombin (IMCR%) by FVIII administration increased from 249 nM (55.4%; pre) to 348 nM (88.0%; post). With the addition of anti-Emi-Abs, the IMCR% was 6.4% (pre) and 74.6% (post), indicating that calculated FVIII effect was 32.6% in the presence of emicizumab and 68.2% in its absence.

In addition, ROTEM analysis (11 events) revealed that the CT decreased from 1,190±169 s (pre) to 1,158±301 s (post) (control: 938±128 s). With the addition of anti-Emi-Abs, the CT was changed from 5,213±2,915 s to 1,459±447 s.

At enrollment of this study, CWA and TGA confirmed emicizumab's contribution to baseline hemostasis as follows; Ad|min1| decreased from 5.4 (37.2%) to 4.0 (0.9%) and peak thrombin from 238 nM (51.9%) to 92.7 nM (4.3%) by the addition of anti-Emi-Abs. Plasma emicizumab concentration was 51.2±17.8 µg/mL, and a moderate positive correlation was observed with baseline Ad|min1| in CWA (r=0.42), but not with peak thrombin in TGA (r=0.05), suggesting CWA seemed to better reflect emicizumab-driven hemostatic function. No abnormalities in platelets counts, coagulation or fibrinolysis laboratory markers were observed during the follow-up.

Conclusion In PwHA receiving emicizumab prophylaxis, FVIII supplementation at 30±5 U/kg was safe and effective for breakthrough bleeding and surgical hemostasis. These findings could support clinical use of FVIII with consideration of emicizumab's baseline effect.

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2025
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