Perioperative Monitoring with Global Coagulation Test in Severe Hemophilia a without Inhibitor on Emicizumab Prophylaxis Undergoing Orthopedic Surgery

INTRODUCTION

Emicizumab is a bispecific antibody used to prevent bleeding episodes in patients with severe hemophilia A (PwHA) without inhibitor. However, using FVIII to manage breakthrough bleeding or invasive procedures in patients without inhibitors remains necessary. Current guidelines recommend using chromogenic FVIII (FVIII:C) levels based on bovine reagents to monitor the hemostatic response to the combination of both drugs. However, the perioperative hemostatic management of PwHA undergoing prophylaxis with emicizumab and FVIII remains challenging.

Here we describe the hemostatic management and monitoring using global coagulation test of two PwHA without inhibitor on emicizumab prophylaxis undergoing orthopaedic surgery with FVIII.

METHODS

Perioperative monitoring for two patients was performed, measuring FVIII:C levels using bovine-derived reagents. Samples for global coagulation test were collected in tubes with Corn Trypsin Inhibitor to prevent activation of the contact pathway. Clotting time (CT) was evaluated by Rotational Thromboelastometry (ROTEM®) using whole blood activated by a low concentration of tissue factor (TF) solution (final dilution 1:50,000 of EXTEM reagent) plus recalcification. Thrombin Peak (TP) was assessed by thrombin generation test (TGT) in plasma, also using a low amount of TF and phospholipids (PPP-LOW, Stago).

ROTEM and TGT were performed in samples collected before and after FVIII administration during the perioperative process. Samples obtained before FVIII dosing were also spiked in vitro with equivalent therapeutic amounts of FVIII products.

RESULTS

Patient 1 is a 55-year-old male with severe HA under EMI prophylaxis (1.5 mg/week). He underwent an ankle arthrodesis with osteosynthesis due to severe hemophilic arthropathy. Plasma-derived FVIII/FVW concentrate (pdFVIII/FVW) was used to provide effective hemostatic coverage during the procedure. He received the first dose before surgery and the last dose on day +7 after surgery. The postoperative course was uneventful, and he was discharged on day +4.

Patient 2 is a 52-year-old male with a medical history of HIV infection, lymphoma in complete remission and severe HA on EMI prophylaxis (6 mg every four weeks). He was referred to an orthopaedic surgeon due to cubital tunnel syndrome secondary to hemophilic arthropathy that required surgery. A single dose (50 Ul/kg) of extended half-life recombinant FVIII (rFVIII EHL) concentrate was administered before intervention. He was discharged on day +2 in the absence of bleeding complications. He received an additional dose of rFVIII EHL on day +3 after the surgery.

Table 1 shows FVIII:C levels in both patients. Both global coagulation tests showed that treatment with emicizumab was insufficient for complete normalization of hemostatic parameters. Clotting time was longer, and thrombin generation was reduced in emicizumab-treated patients compared to healthy controls before the intervention (Figure 1).

We observed an improvement and normalization of CT and TP values after administering both FVIII products (plasma-derived or recombinant with EHL) during the perioperative period. This improvement was similar to that obtained with in vitro spiking of equivalent doses of FVIII (Figure 1). Additionally, a correlation between FVIII:C levels and CT and TP values was also observed.

CONCLUSIONS The global coagulation test were used to evaluate the hemostatic response to FVIII treatment in PwHA on emicizumab prophylaxis during invasive procedures. Considering that both tests provide a more comprehensive assessment of the hemostatic state of the interaction of emicizumab and FVIII, these tests may complement FVIII levels in complex cases of bleeding or surgery.

Funding: ISCIII-FEDER PI19/00631; Catedra UAM-Roche

Alvarez Roman:Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Novo-Nordisk: Consultancy, Honoraria, Research Funding; CSL-Behring: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding. Butta:Roche: Speakers Bureau; Novo-Nordisk: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; CSL-Bering: Research Funding. Hermans:oche, Novo Nordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Spark, Octapharma, CSL Behring: Research Funding; oche, Novo Nordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Spark, Octapharma, CSL Behring: Honoraria; oche, Novo Nordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Spark, BioMarin, Octapharma, CSL Behring: Consultancy. Jiménez-Yuste:Roche, Novo Nordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Spark, BioMarin, Octapharma, CSL Behring: Consultancy; Roche, NovoNordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Octapharma, CSL Behring: Research Funding; Roche, NovoNordisk, Sanofi, Sobi, Takeda, Grifols, Bayer, Pfizer, Spark, Octapharma, CSL Behring: Honoraria.