Long-Term Anticoagulation in a Severe Hemophilia A Patient Receiving Efanesoctocog Alpha Prophylaxis: A Case Report

Therapeutic innovations in the last decades have significantly improved the life expectancy of patients with hemophilia (PWH). As a result, the prevalence of age-related diseases, such as cardiovascular conditions requiring anticoagulation, has increased within this population.[1] In patients with severe hemophilia, anticoagulation must be approached with caution and requires multidisciplinary consensus, given the delicate balance between the hemorrhagic risk associated with anticoagulation and the antithrombotic protection conferred by factor VIII (FVIII) or factor IX (FIX) deficiency.[2]

Efanesoctocog alfa (EFA; Altuvoct® or Altuviiio®, Sanofi-Sobi) is a novel recombinant FVIII composed of a B-domain-deleted, Fc-fusion FVIII linked to the D′D3 domain of von Willebrand factor and 2 XTEN polypeptides, which confer an ultra-extended half-life (EHL) of 38 to 47 hours. It is indicated for prophylaxis, on-demand treatment, and perioperative management in patients with hemophilia A.[3] [4] [5] We present a case of a patient with severe hemophilia A (SHA) treated with both EFA and long-term anticoagulation. Initially, he was enrolled in a prospective phase 3b study lasting 24 months, evaluating the effect of a weekly infusion of 50 IU/kg of EFA on physical activity (ClinicalTrials.gov: NCT05817812). However, the patient was excluded from the study due to the requirement for long-term anticoagulation with apixaban, prescribed for atrial fibrillation (AF). He was subsequently authorized to continue EFA prophylaxis under a compassionate use program. We reviewed the literature to assess whether long-term anticoagulation may be appropriate for patients with SHA receiving EFA prophylaxis.

Our 70-year-old, 79-kg patient, who provided written consent, suffers from SHA and multiple comorbidities. His SHA, caused by an intron 22 inversion mutation of the F8 gene and with no history of FVIII inhibitor, is managed at the Hemophilia Centre of Strasbourg University Hospital. His medical history includes posttransfusional chronic hepatitis C, which was successfully treated with ledipasvir and sofosbuvir. He also suffers from cardiovascular conditions, such as well-controlled hypertension and AF (secondary to mitral and aortic regurgitation without stenosis), treated with flecainide since 2018. Additionally, he has undergone several surgeries, including bilateral ankle arthrodesis and multiple knee replacements (three on the left knee and one on the right knee) due to advanced hemophilic arthropathy. Before starting EFA, he had received several secondary prophylaxis regimens (plasma-derived FVIII, conventional recombinant FVIII, and EHL recombinant FVIII products).

Twelve months after starting EFA prophylaxis (weekly infusion of 50 IU/kg) and 3 days following an infusion, he presented with a painful and swollen right knee. Arthrocentesis performed 1 hour after an infusion of 30 IU/kg of EFA confirmed a prosthetic joint infection.

Forty-eight hours later, the arthritis was treated with joint lavage, synovectomy, and replacement of the prosthesis's mobile components. As recommended in the summary of product characteristics for Altuvoct®, the procedure was performed after an infusion of 50 IU/kg of EFA, and no major bleeding was observed (hemoglobin loss <1 g/dL). The postoperative protocol included two EFA infusions of 30 IU/kg, administered 3 and 6 days after the procedure, totaling 110 IU/kg. The efficacy was judged as excellent.[6]

Factor VIII activity (FVIII:C) of EFA was measured daily and remained consistently above the recommended perioperative targets for major surgery ([Fig. 1]).[7] All FVIII:C were measured with a one-stage clotting assay (OSA) deemed suitable for EFA (Immunodeficient VIII and CK-Prest, on a STA-R Max analyzer, all Diagnostica Stago, Asnières-sur-Seine, France).[8]

Fig. 1 Course of FVIII:C of EFA during the perioperative period. EFA, efanesoctocog alfa; FVIII, factor VIII.

As a precautionary measure and based on the current recommendations of the relevant French professional society,[9] the anesthesiologist decided to discontinue flecainide in preparation for the major surgery, despite the patient having previously experienced an episode of AF. Unfortunately, this resulted in AF within the following 12 hours. As AF persisted for 48 hours following the procedure, the patient was started on bisoprolol in combination with flecainide. He was also discharged on levofloxacin and rifabutin once Staphylococcus lugdunensis was identified in joint fluid cultures.

The patient's HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly) and CHA₂DS₂-VA (Congestive heart failure, Hypertension, Age ≥75 years (2 points), Diabetes mellitus, prior Stroke/transient ischaemic attack/arterial thromboembolism (2 points), Vascular disease, Age 65–74 years) scores were both 3 (see below for more details on the scores). After a collaborative and thorough assessment of the thrombotic and bleeding risks, thromboprophylaxis with enoxaparin (4,000 IU once daily) was initiated. Once the wound had healed properly, 3 weeks later, enoxaparin was switched to full-dose apixaban (5 mg twice daily) for long–term anticoagulation.

The patient was seen for follow-up once a week for a month, then once a month (systematically just before an EFA infusion) at the Hemophilia Centre of Strasbourg University Hospital, to closely monitor the occurrence of bleeding events, which were assessed through detailed patient interviews and thorough physical examinations.

At the same time, a local pharmacokinetic study (at steady state) conducted at the start of apixaban treatment demonstrated a recovery of 3.48 IU/dL:IU/kg, a half-life of 50 hours calculated using WAPPS-Hemo (Web-Accessible Population Pharmacokinetic Service-Hemophilia, McMaster University), and a trough level of 16 IU/dL. To prevent interference of apixaban with FVIII:C, it was first adsorbed onto activated charcoal (DOAC Stop, Haematex). During the follow-up, the trough FVIII:C under EFA therapy remained stable, between 13 and 16 IU/dL, always measured after apixaban removal (FVIII:C was between 9 and 12 IU/dL on the native sample; [Table 1]). All FVIII activities were measured using the same OSA described previously. To ensure the absence of overdose, apixaban trough (44 ng/mL) and peak (333 ng/mL) concentrations were assessed after 2 months of treatment and were within the expected range (19–209 ng/mL and 73–438 ng/mL, respectively).[10] To date (after 8 months), the patient has experienced no major bleeding, with only rare (three) episodes of minor gum bleeding.

Table 1 Evolution of trough FVIII:C under apixaban in native and activated charcoal-treated samples

Weeks after apixaban introduction		1	2	3	4	8	20
Trough FVIII:C (IU/dL)	NS	12	10	9	9	11	9
	ACS	16	14	13	14	14	13

Abbreviations: ACS, activated charcoal-treated sample; FVIII, factor VIII; NS, native sample.

To date, only 14 major surgeries under EFA therapy have been reported, all demonstrating an excellent hemostatic response (particularly with no need for blood transfusion) and no safety concerns or inhibitor development. In our patient, surgical management was similarly straightforward and uneventful, due to the simplicity of the recommended dosing regimen and the satisfactory hemostasis achieved with this treatment.[3] [11]

However, the patient's management was complicated by AF, which remains the most frequent arrhythmia in both PWH and the general population. International guidelines for the management of AF recommend anticoagulation for stroke prevention when the thrombotic risk, as assessed by the CHA₂DS₂-VA score, is ≥2, while accounting for the bleeding risk, evaluated using the HAS-BLED score. These scores may serve as general guides for PWH, but no specific predictive thresholds are recommended. Therefore, expert-provided balance of thrombotic and bleeding risk must be prioritized. Moreover, it should be considered carefully, taking into account the recommended minimum trough FVIII or FIX levels. Consequently, after assessing the thrombotic and bleeding balance, a collegial decision was made to anticoagulate the patient. Once wound healing was achieved, full-dose apixaban therapy was initiated, as direct oral anticoagulants (DOACs) are the first-line therapy for AF in the general population. Moreover, international guidelines recommend using DOACs over vitamin K antagonists in PWH with AF due to their favorable safety profile and the ability to individualize treatment regimens. While on full-dose DOAC therapy, FVIII or FIX trough levels should be maintained above 20 IU/dL.[12] [13] This target may be achieved with EFA, given its ultra-EHL. Indeed, with weekly administration, EFA can maintain normal to near-normal FVIII levels for several days, with a mean trough level of 15 IU/dL, occasionally reaching or exceeding 20 IU/dL.[3]

Our patient has not experienced any major bleeding to date (after 8 months, only rare episodes of minor gum bleeding were reported), even though his trough FVIII:C did not exceed 16 IU/dL. The pharmacokinetic data of our patient (half-life, trough level) were consistent with those reported in the XTEND-1 study, in which SHA patients received the same prophylactic regimen.[3] The use of global hemostasis assays, such as viscoelastic or thrombin generation assays, could have provided an interesting complement to the overall assessment of the patient's bleeding risk; however, these tests were unfortunately not available in our laboratory.

The titration of EFA by the manufacturer is performed using Actin FSL (Siemens). However, several OSAs have been shown to reliably monitor EFA, such as CK-Prest, with a slight overestimation observed at very low levels.[8] More recently, OSA and chromogenic substrate assays (CSAs) specifically calibrated for EFA have demonstrated accurate activity assessment, underscoring the importance of a commercially available, product-specific calibrator to minimize assay variability.[14] [15] Clinicians and pathologists should be aware that DOACs may falsely decrease FVIII:C when using an OSA or a CSA. Activated charcoal, such as DOAC Stop, significantly mitigates the effects of DOACs without interfering with FVIII:C measurement.[16] Therefore, FVIII:C may be measured after neutralizing DOACs, even though this practice is not mentioned in the last international guidelines.[7]

In conclusion, managing anticoagulation in patients with SHA remains a complex challenge, requiring multidisciplinary collaboration. Given its ability to maintain normal to near-normal FVIII levels for several days, with trough levels that occasionally reach or exceed 20 IU/dL, the standard EFA prophylaxis regimen may facilitate the implementation of long-term anticoagulation in selected patients.

Authors' Contributions

L.S., A.H., and D.D. designed the study, analyzed the data, and wrote the paper. A-C.G., S.K., J.W., O.F., and C.R-O. contributed to the acquisition and interpretation of the data and critically reviewed the manuscript. All authors approved the final version.

Ethical Approval

The study was approved by our institution's ethics board. The authors followed the CARE (CAse REports) guidelines.

Data Availability Statement

The data that support the findings of this case report are available upon request from the corresponding author.

Publikationsverlauf

Eingereicht: 28. Juli 2025

Angenommen: 25. August 2025

Artikel online veröffentlicht:
04. September 2025

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