Perioperative management of acute type A aortic dissection using extended half-life factor IX (Alprolix) in a patient with severe hemophilia B: a case report

Abstract

Background

Emergency surgery for acute type A aortic dissection (ATAAD) in patients with severe hemophilia B is extremely rare, and perioperative coagulation management is a major challenge.

Case presentation

A 63-year-old man with severe hemophilia B (factor IX activity < 1%) was diagnosed with ATAAD and underwent emergency surgery. Replacement therapy with an extended half-life factor IX product (eftrenonacog alfa; Alprolix) was administered targeting a factor IX activity of 80–100%, and total arch replacement was performed. Cardiopulmonary bypass was performed under standard heparinization conditions. Since rapid measurement of factor IX activity was not possible, postoperative replacement therapy was based primarily on the clinical assessment of hemostasis, with serial activated partial thromboplastin time measurements providing supportive information, whereas intraoperative anticoagulation was managed using standard activated clotting time monitoring. Intra- and postoperative bleeding volumes were within ranges comparable to those observed in standard complex aortic surgery, and the postoperative course was uneventful.

Conclusions

The use of an extended half-life factor IX product may be a practical option for perioperative coagulation management during emergency aortic surgery in patients with severe hemophilia B.

Background

Severe hemophilia B is a rare inherited bleeding disorder, and emergency cardiovascular surgery in affected patients presents substantial challenges in perioperative coagulation management. Although surgical treatment for acute type A aortic dissection (ATAAD) has been reported in patients with hemophilia [1, 2], published reports of perioperative management using intermittent administration of an extended half-life factor IX product in patients with severe hemophilia B remain extremely limited. We report a patient with severe hemophilia B who successfully underwent emergency total arch replacement using eftrenonacog alfa.

Case presentation

A 63-year-old man presented to a local hospital with sudden onset of chest and back pain. Contrast-enhanced computed tomography revealed an acute Stanford type A aortic dissection with a patent false lumen and an entry tear distal to the origin of the left subclavian artery. The patient was subsequently transferred to our institution for emergency surgery.

His medical history included severe hemophilia B, diagnosed at the age of 30 years following an evaluation for prolonged activated partial thromboplastin time (APTT). Factor IX activity was < 1%, and he had not been receiving regular prophylactic replacement therapy.

On admission, he was alert and hemodynamically stable. His body weight was 63 kg. Laboratory findings showed hemoglobin 13.5 g/dL, platelet count 295,000/µL, APTT 53.8 s, fibrinogen 427 mg/dL, and factor IX activity < 1%.

Surgical procedure

Based on the World Federation of Hemophilia guidelines and considering the high bleeding risk associated with cardiopulmonary bypass (CPB) and circulatory arrest, a target factor IX activity of 80–100% was set, and 5000 IU (approximately 80 IU/kg) of eftrenonacog alfa (Alprolix; Bioverativ Therapeutics Inc. Waltham, MA, USA) was administered. The dosing regimen was determined in consultation with hematologists, taking into account the pharmacokinetic characteristics of eftrenonacog alfa and the expected reduction in coagulation factor activity during CPB.

Surgery was performed via median sternotomy. CPB was established with arterial inflow via the right axillary and right femoral arteries and venous drainage via the right atrium. Circulatory arrest was initiated at a rectal temperature of 28 °C, with bilateral selective cerebral perfusion.

Distal anastomosis was performed in zone 2 between the left common carotid and left subclavian arteries, and a J Graft Open stent (25 × 120 mm; Japan Lifeline Co., Tokyo, Japan) was deployed. Total arch replacement was completed using a four-branched J-graft (24 mm; Japan Lifeline Co.).

Before systemic heparinization, the baseline activated clotting time (ACT) was 164 s. Standard-dose heparinization was performed, and the ACT was maintained at > 500 s throughout the CPB. Protamine reversal was performed in a standard manner, resulting in recovery of the ACT to 137 s. An additional dose of eftrenonacog alfa was administered 6 h after the initial dose. Satisfactory hemostasis was achieved after weaning from CPB.

The total operative time, CPB time, aortic cross-clamp time, selective cerebral perfusion time, and circulatory arrest time were 456, 246, 159, 82, and 59 min, respectively. The intraoperative blood loss was 1343 mL. The patient received 6 units of red blood cells, 12 units of fresh frozen plasma, and 20 units of platelets.

Postoperative course

Postoperative drainage was low (225 mL), and no additional transfusion was required, except for autologous salvaged blood. The patient was extubated on postoperative day (POD) 3 and discharged from the intensive care unit on POD 5.

Because rapid measurement of factor IX activity was unavailable at our institution, postoperative replacement therapy was based primarily on clinical assessment of hemostasis, with serial APTT measurements used only as supportive information. Every 24 h from PODs 1 to 3, 5000 IU of eftrenonacog alfa was administered, followed by 3000 IU every 48 h on PODs 4 and 6.

Invasive procedures, including the removal of temporary pacing wires and drains, were performed during the factor replacement therapy (Fig. 1).

Fig. 1.

Perioperative coagulation management. Changes in activated partial thromboplastin time (APTT) and dosing schedule of extended half-life factor IX (eftrenonacog alfa) from the preoperative period to postoperative day (POD) 6. Baseline factor IX activity was < 1%. Because rapid measurement of factor IX activity was not possible, serial APTT measurements are presented as supportive information together with clinical assessment of hemostasis. APTT remained relatively stable with intermittent dosing. Intraoperative blood loss was 1.343 mL, and postoperative drainage on POD 1 was 225 mL, followed by serosanguineous drainage from PODs 2 to 4. The timing of clinical events associated with bleeding risk is indicated

Postoperative contrast-enhanced computed tomography revealed no anastomotic complications, bleeding, or residual malperfusion, and the patient was discharged in good condition.

Discussion

Hemophilia is an X-linked inherited bleeding disorder, with hemophilia B accounting for approximately 3.8 per 100,000 males. Severe hemophilia B, defined as factor IX activity < 1%, is particularly rare [3].

Advances in replacement therapy have improved the life expectancy of patients with hemophilia, resulting in an increased incidence of age-related cardiovascular diseases [4]. However, most reported cases of cardiac surgery in patients with hemophilia involve elective procedures, and emergency surgery for ATAAD remains uncommon. To our knowledge, reports describing emergency total arch replacement for ATAAD in patients with severe hemophilia B managed with an extended half-life factor IX product remain extremely limited. Additionally, the perioperative management of severe hemophilia B during emergency aortic surgery requiring CPB and circulatory arrest remains challenging. Such management requires the maintenance of adequate coagulation factor levels. Current guidelines recommend maintaining factor IX activity at 80–100% during major surgery [5]. However, during CPB, coagulation factors are reduced owing to hemodilution and consumption, necessitating careful perioperative management and additional dosing.

Previous reports demonstrated that appropriate perioperative replacement therapy is essential for safe cardiac surgery in patients with hemophilia [6]. Conventional standard half-life factor IX products often require frequent or continuous infusions to maintain stable plasma levels. In contrast, extended half-life factor IX products, such as eftrenonacog alfa, allow for less frequent dosing and more stable factor activity owing to their prolonged circulation time [7]. These pharmacokinetic advantages may be particularly beneficial in emergency cardiovascular surgery, in which continuous infusion is often impractical. Previous reports of emergency ATAAD surgery in patients with hemophilia described successful management using continuous infusion of standard half-life coagulation factor concentrates with serial factor activity monitoring, without major bleeding complications [1, 2]. Both reported patients had mild hemophilia. In the present case, the patient had severe hemophilia B (factor IX activity < 1%) and was managed with intermittent administration of an extended half-life factor IX product without continuous infusion or serial factor IX activity measurements. No excessive bleeding or re-exploration for bleeding was required. Although direct comparison is limited by differences in patient characteristics and surgical procedures, this case suggests that intermittent administration of an extended half-life factor IX product may be a feasible perioperative management strategy for emergency cardiovascular surgery. The prolonged half-life of eftrenonacog alfa may also facilitate perioperative replacement therapy in emergency settings where continuous infusion is impractical.

In the present case, clinically satisfactory hemostasis was achieved with intermittent administration of an extended half-life factor IX product, during complex aortic surgery requiring CPB and circulatory arrest. Although serial factor IX activity measurements were unavailable, no excessive bleeding, re-exploration for bleeding, or major complications occurred, suggesting that this strategy may provide practical perioperative coagulation management in emergency settings.

Although direct measurement of factor IX activity remains the standard for perioperative monitoring, it was not feasible in this case because the assays were outsourced and could not be performed rapidly. Therefore, postoperative coagulation management was based primarily on clinical assessment of hemostasis, with serial APTT measurements providing supportive information, whereas intraoperative anticoagulation during cardiopulmonary bypass was monitored with standard ACT monitoring. Although serial APTT measurements provided supportive information regarding perioperative coagulation status, APTT should not be regarded as a surrogate marker for factor IX activity. APTT is influenced by multiple factors, including deficiencies of other intrinsic coagulation factors, heparin exposure, lupus anticoagulant, and assay reagents; therefore, it does not accurately reflect circulating factor IX activity. Furthermore, APTT should be interpreted with caution in the perioperative setting because cardiopulmonary bypass itself alters coagulation through hemodilution and coagulation factor consumption. In the present case, APTT values remained relatively stable throughout the postoperative period and were consistent with favorable clinical outcome. However, these findings should not be interpreted as validating APTT as a substitute for factor IX activity measurement. The intended perioperative hemostatic target was a factor IX activity of 80–100% in accordance with the current WFH guidelines. Because rapid factor IX assays were unavailable, no predefined APTT target was adopted. Instead, replacement therapy was guided primarily by the planned dosing regimen and clinical assessment of hemostasis, with serial APTT measurements serving as supportive information.

Despite severe hemophilia B, perioperative transfusion requirements in the present case were within the range reported in contemporary ATAAD surgery [8]. Direct comparison with previous reports is difficult because of differences in patient characteristics, surgical procedures, and institutional transfusion practices. No re-exploration for bleeding was required, indicating that satisfactory perioperative hemostasis was achieved despite the underlying severe coagulation disorder. Taken together, this case suggests that intermittent administration of an extended half-life factor IX product may provide practical perioperative coagulation management in patients with severe hemophilia B undergoing emergency cardiac surgery. Further clinical experience is required to establish the optimal dosing strategy and monitoring protocol.

A limitation of this report is that serial factor IX activity measurements were unavailable; therefore, achievement and maintenance of the intended target factor IX activity could not be directly confirmed. Nevertheless, intermittent administration of eftrenonacog alfa was associated with favorable clinical hemostasis. This strategy may represent a practical approach for managing patients with hemophilia undergoing emergency cardiac surgery.

Abbreviations

ACT

Activated clotting time

APTT

Activated partial thromboplastin time

CPB

Cardiopulmonary bypass

ATAAD

Acute type A aortic dissection

POD

Postoperative day

Authors’ contributions

Tessho Kitamura contributed to patient management and manuscript drafting.

Yutaro Ryu contributed to data collection and literature review.

Shun Nakaji and Shinichiro Taniguchi supervised the study and critically revised the manuscript.

All authors read and approved the final manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Ethical approval was waived by our institution for this case report. Written informed consent to participate was obtained from the patient.

Consent for publication

Written informed consent for publication of the case report and accompanying images was obtained from the patient.

Competing interests

The authors declare that they have no competing interests.