Non‐additive effect on thrombin generation when a plasma‐derived factor VIII/von Willebrand factor (FVIII/VWF) is combined with emicizumab in vitro

Abstract

Background: Emicizumab is an alternative non-factor approach for treating patients with hemophilia A. However, there is a potential risk of thrombotic events when emicizumab is concomitantly administered with pro-hemostatic therapies.Objectives: To assess the hemostatic effect in vitro when a plasma-derived factor VIII concentrate containing von Willebrand factor (pdFVIII/VWF) was added to hemophilia A plasma (HAp) in combination with emicizumab.Methods: HAp and HAp with FVIII inhibitors (HAp-i) samples with different concentrations of emicizumab (50 and 100 μg/mL) were combined with activated prothrombin complex concentrate at 0.5 to 1 U/mL, recombinant activated factor VII (rFVIIa) at 0.5 to 7 μg/mL, and pdFVIII/VWF at 0.1 to 4.5 IU/mL. Thrombin generation (TG; thrombin peak and endogenous thrombin potential) was determined using a Calibrated Automated Thrombogram assay.Results: When activated prothrombin complex concentrate was added to HAp and HAp-i with emicizumab, TG dramatically increased (multiplier effect > 4.5×). Addition of rFVIIa to HAp or HAp-i with emicizumab moderately increased TG in a concentration-related manner compared with rFVIIa alone. Addition of pdFVIII/VWF to HAp or HAp-i with emicizumab induced a TG response equivalent to those samples without emicizumab. In an in vitro model of immune tolerance induction with bleeds (HAp-i 15 Bethesda units), combination of pdFVIII/VWF, emicizumab, and rFVIIa did not trigger a multiplying effect on TG.Conclusions: pdFVIII/VWF showed a non-additive effect on TG when combined in vitro with emicizumab. This finding suggests that emicizumab has limited ability to promote factor X activation in the presence of pdFVIII/VWF, thus reducing the risk of thrombotic events.

Thrombin generation for monitoring hemostatic therapy in hemophilia A: A narrative review

“…On the contrary, a low dose of aPCC (25 IU/kg) already caused an exponential increase of TG in the presence of emicizumab, with TG values of multiple times the normal range. 60 This observation is in accordance with the observation of the HAVEN-1 study in which five patients experienced thrombotic complications when emicizumab was combined with high doses of aPCC. 50 This led to a black box warning for emicizumab to prevent combination of high doses of aPCC during a longer period (<100 IU/kg per 24 h).…”

“…However, when pdFVIII/VWF was added to plasmas with emicizumab, there was no difference observed in TG compared with plasma with only pdFVIII/VWF. This indicates that pdFVIII/VWF and emicizumab have non‐additive effects in the absence of inhibitors and thereby do not increase the thrombotic complication risk 60 . In this study, plasma was also spiked with aPCC and rFVIIa.…”

“…Although a therapeutic dose of rFVIIa showed an increase in TPH and ETP in plasma with emicizumab compared with plasma without rFVIIa, it remained within ranges observed in normal controls. On the contrary, a low dose of aPCC (25 IU/kg) already caused an exponential increase of TG in the presence of emicizumab, with TG values of multiple times the normal range 60 …”

Challenges of biological monitoring in a hemophilia A patient without inhibitors on emicizumab undergoing major orthopedic surgery: a case report

“…Since FVIII’s affinity for the specific binding sites of FIXa and FX is approximately 10-fold higher than that of emicizumab, this drug is rapidly displaced and thrombin generation is enhanced by circulating FVIII. 11 , 16 According to published data, the combination of emicizumab and rFVIII is not associated with a risk of thromboembolic complications, including thrombotic microangiopathy. However, due to the relatively small number of patients treated, few bleeding episodes, and short monitoring period, this hypothesis must still be confirmed by real-world clinical data.…”

Are there additive effects between emicizumab and factor VIII?

“…In their August 2020 publication in the Journal of Thrombosis and Haemostasis Bravo et al used an in vitro thrombin generation (TG) assay to investigate the interactions between plasma derived factor VIII/Von Willebrand Factor (pd FVIII/VWF) concentrate and emicizumab. 1 They concluded there was a non-additive effect on TG between pdFVIII/VWF concentrate and emicizumab. This stands in conflict to a separate investigation, also published in August 2020, which did demonstrate an additive effect.…”