Global Coagulation Potentials and Breakthrough Bleeds in Emicizumab-Treated Hemophilia a Patients Were Similar to Mild Hemophilia a Patients
Authors: Nakajima Yuto , Mizumachi Kuniyoshi , Shimonishi Naruto , Furukawa Shoko , Ogiwara Kenichi , Takeyama Masahiro , Shima Midori , Nogami Keiji 
Published: November 2021

Abstract
Emicizumab prophylaxis dramatically reduces bleeding events in severe patients with hemophilia A (PwHA) with and without FVIII inhibitors. Recently, some real-world experiences on PwHA with emicizumab prophylaxis have been reported. The effectiveness of emicizumab could be attributed to an earlier report that the coagulant potential in emicizumab at clinical dosage appeared to correspond to 10-15 IU/dL of factor VIII activity (FVIII:C) (Muto, JTH 2014), indicating that emicizumab enables to transform severe PwHA to mild PwHA. However, the comparison of coagulation potential and bleeding characteristics in PwHA receiving emicizumab (Emi-PwHA) and mild PwHA (PwMHA) remains to be investigated. Here, we examined the clinical and laboratory characteristics in Emi-PwHA and PwMHA. Clinical data of bleeding episodes and coagulation potentials were collected from 64 Emi-PwHA and 15 PwMHA (median FVIII:C 13 IU/dL [IQR 8.5-17.0]). Comprehensive coagulation function was evaluated using Ca 2+-triggered rotational thromboelastometry (ROTEM) and/or ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Furthermore, we compared the features of breakthrough bleeds in two groups.
We first compared with the clinical characteristics and coagulation function between the Emi-PwHA with and without the experience of breakthrough bleeds. The age, treatment period, annual bleeding rates (ABR), the percentage of inhibitor-positive, and prophylaxis regimen were not significantly different between both groups. There was no significant difference in ROTEM and CWA-based coagulation potential between Emi-PwHA with and without breakthrough bleeds (median; CT+CFT 1,703s [IQR 1,547-1,849] and 1,837s [IQR 1,671-2,216], Ad|min1| 4.92 [IQR 4.63-5.27] and 4.78 [IQR 4.4-5.11], respectively).
We examined clinical data and ROTEM-based coagulation function between the Emi-PwHA and PwMHA. The age in PwMHA (median 25 years [IQR 20-49]) was older than that in Emi-PwHA (median 13 years [IQR 6-25]; p=0.004). The ABR and coagulation function in Emi-PwHA (median; ABR 0 [IQR 0-0.4], CT+CFT 1,795s [IQR 1,659-2,135]) were not significantly different from that in PwMHA (median; ABR 0.3 [IQR 0-0.49], CT+CFT 2,077s [IQR 1,627-2,449]), suggesting that the global coagulation potential in Emi-PwHA was equivalent to that in PwMHA.
We next investigated bleeding features in Emi-PwHA (19 cases) and PwMHA (12 cases). Bleeding patterns of them were similar and divided into 3 groups; spontaneous, early post-traumatic (bleeding associated with trauma within 1-2 days) and late post-traumatic (bleeding involved with trauma within 1-2 weeks). Emi-PwHA experienced spontaneous (5/19), early post-traumatic (14/19) and late post-traumatic (3/19) bleedings, and PwMHA experienced spontaneous (4/12), early post-traumatic (7/12) and late post-traumatic (5/12) bleedings. Some patients of them had both spontaneous and early post-traumatic bleeding or both early and late post-traumatic bleeding. The majority of their bleedings was trauma-induced.
Severe bleeding symptoms such as muscle bleeds, hemarthrosis or fracture in Emi-PwHA were required FVIII (total 60-200 IU/kg) and hospitalization for 3-5 days. In contrast, those severe breakthrough bleedings in PwMHA were required higher doses of FVIII (total 140-705 IU/kg) and hospitalization for 1-2 weeks. Although the coagulation potential in Emi-PwHA was similar to that in PwMHA, the treatment period and hospitalization for breakthrough bleeds in PwMHA appeared to be longer than those in Emi-PwHA. We speculated that this discrepancy might be due to the difference of physical activities or preventive managements for bleeding because Emi-PwHA was originally severe PwHA.
In conclusion, the coagulation potential and bleeding characteristics in Emi-PwHA appeared to be similar to PwMHA, suggesting that emicizumab-mediated coagulation potential reflected the mild type in clinical severity.

Disclosures
Nakajima: Chugai Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical company: Research Funding. Mizumachi: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shimonishi: CSL Bering: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Furukawa: Chugai Pharmaceutical Co., Ltd.: Research Funding. Ogiwara: Chugai Pharmaceutical Co., Ltd.: Research Funding. Takeyama: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shima: Fujimoto Seiyaku: Consultancy, Speakers Bureau; Sanofi S.A.: Speakers Bureau; BioMarin Pharmaceutical Inc.: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk A/S: Honoraria, Speakers Bureau; Takeda: Research Funding; CSL Behring: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau.