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. 2026 Jan 2;10(1):103333. doi: 10.1016/j.rpth.2025.103333

Figure 1.

Figure 1

Differences in mechanisms of action between factor (F)VIII and denecimig in relation to the thrombin generation assay (TGA). TGA thrombogram in hemophilia A (HA) plasma alone or supplemented with denecimig or FVIII initiated with the triggers (A) activated FXI (FXIa; 8 mU/mL) or (B) tissue factor (TF; 1 pM). The right panels show the kinetic hypothesis of trigger-specific thrombin generation. FVIII and denecimig mode of action in a TGA initiated with FXIa and TF. “First” and “second” indicate sequential steps for each condition. FVIII activation is hypothesized to be the rate-limiting step for TGA triggered with FXIa, whereas activated FIX (FIXa) activation is the rate-limiting step for TGA triggered with TF. A denecimig concentration of 4.4 μg/mL was selected from the trough concentration range in the FRONTIER2 study (4.1 [95% CI, 3.83; 4.56] to 4.5 [95% CI, 4.23; 4.89] μg/mL) [14]. A FVIII concentration of 30 International Units (IU)/dL was selected because it produces a similar peak height and endogenous thrombin potential (area under the curve) for the 2 trigger conditions (FXIa and TF). Furthermore, it has been shown that denecimig had an additive effect on these parameters when the FVIII concentration was ≤30 IU/dL [34]. FIIa, thrombin; FVIIa, activated factor VII; FVIIIa, activated factor VIII; FXa, activated factor.