Perioperative management in haemophilia with extended half-life factors: a case series

Introduction

Hemophilia B is an X-linked recessive bleeding disorder caused by deficient or dysfunctional coagulation factor IX, which is essential for normal blood clotting.¹ It is the second most common type of hemophilia, accounting for approximately 20% of all hemophilia cases.² Patients with hemophilia B experience recurrent and spontaneous bleeding episodes, especially in joints and muscles, which can lead to chronic pain, joint damage, and significant morbidity.³

Surgical procedures in patients with hemophilia B pose unique challenges due to the increased risk of perioperative and postoperative bleeding.^4,5 This risk is further amplified in surgeries involving highly vascularized areas or those that involve major joints. Uncontrolled bleeding in these patients can lead to significant complications such as prolonged hospital stay, increased healthcare costs, and in some cases, life-threatening situations.⁶

Over the years, the management of hemophilia B has evolved significantly with the development of recombinant factor IX products, allowing for safer and more effective prophylaxis.⁷ Perioperative treatment involves regular intravenous infusions of factor IX concentrates to maintain a minimum level of factor IX activity, thereby preventing spontaneous bleeding episodes.⁸

The advent of extended half-life (EHL) factor IX products, such as glycoPEGylated factor IX, has further revolutionized the management of hemophilia B.⁹ These novel products offer longer-lasting protection against bleeding, reducing the frequency of infusions required and improving patients’ quality of life.^10–15

Despite these advancements, performing major surgery on individuals with hemophilia B continues to present challenges. This is because it necessitates repeated bolus dosing and/or continuous infusion to maintain sufficient levels of factor IX (FIX) in the bloodstream, ensuring proper haemostasis until the wound heals. Given the pharmacokinetic (PK) properties of existing FIX products, it is necessary to closely monitor FIX levels during both the intra- and postoperative periods. This monitoring helps adjust replacement therapy to achieve and sustain the required FIX levels.¹⁶

In this paper, we present a series of cases highlighting the successful use of perioperative treatment in hemophilia B patients undergoing various surgical procedures. We aim to shed light on the effectiveness of EHL and prompt a broader discussion on its potential benefits in the surgical management of hemophilia B.

Cases

Case 1: Perioperative treatment in total hip replacement surgery

The first case involves a 27-year-old Indian male student pursuing his education. The patient was diagnosed with Hemophilia B at the age of 5 years without any relevant family history of Hemophilia. The patient had been suffering from arthropathy, with significant pain and functional limitation in both knees, elbows, hip, and left ankle. The patient’s Hemophilia B and resultant arthropathy were severe enough to result in walking difficulty, necessitating the use of single support.

Due to the severity of his condition, the patient was advised to undergo a total hip replacement (THR) for his left hip. Recognizing the heightened risk of bleeding associated with Hemophilia B, the patient was treated with Nonacog Beta Pegol (N9GP), 40 IU/Kg once weekly for six months prior to his scheduled surgery. His pre-operative and post-operative X ray images are shown in Figures 1 and 2.

Figure 1. Pre-operative X ray.

Figure 2. Post-operative X ray.

During the hospitalization period, a total of 5 doses of EHL therapy were administered. The first dose, given preoperatively, was 80 IU/kg and resulted in an excellent haemostatic response. The second and third doses of 40 IU/kgBW were given on the first and fourth day postoperatively, respectively. The final two doses were administered between the 7th and 12th day, marking the end of the treatment. The patient did not experience any adverse effects, and his overall recovery was good.

Case 2: Perioperative treatment in total knee replacement surgery

This case represents a 29-year-old Indian male computer engineer diagnosed with Hemophilia B. The patient presented with persistent pain, swelling, and functional limitation in his right knee joint, which has progressively worsened over the last 3 years. Diagnostic investigations revealed severe right knee haemophilic arthropathy, leading to the clinical decision to perform a total knee replacement (TKR).

Given the patient’s history of Hemophilia B, a perioperative treatment regimen was implemented to mitigate the risk of perioperative bleeding. The patient was administered N9-GP (Refixia), a recombinant human coagulation factor IX glyco-pegylated product. The dosing schedule was strategically designed to optimize haemostatic coverage during the perioperative period. The treatment regimen started with a preoperative dose of 80 IU/kg, followed by two postoperative doses of 40 IU/kg at 1-3 day intervals within the first week of surgery. Weekly doses were subsequently administered until bleeding cessation.

The desired factor IX levels were meticulously monitored to ensure effective haemostatic coverage throughout the postoperative period (Table 1). Intra-operative images are depicted in Figure 3 and post operative X ray is shown in Figure 4.

Table 1. Administration of Refixia (EHL F-IX) and the corresponding factor IX levels during the postoperative period after the patient underwent TKR surgery.

Date	Refixia (EHL RX)	Desired dose of Refixia	Desired dose of SHL F-IX	Desired F-IX level	Factor IX levels (60-160%)
(Day0-Surgery Day)	4000 IU	4800 IU once	4800 U daily	80%	83.3% (Cepha Screen Reagent)
Day4	2000 IU	3600 IU once	3600 U daily	60%	63.8%
Day7	1000 IU	-	2400 U daily	40%	59%
Day10	1000 IU	2400 IU daily	2400 U daily	40%	46%
Day15	1000 IU	1200 IU daily	1200 U daily	20%	63.8%
Day22	1000 IU	1000 IU once	1200 U twice weekly	10-15%	22%
1 month later	Received 1000 IU 4 doses	1000 IU weekly	1200 U twice weekly	10-15%	16-23%
2 months later	Received 1000 IU 5 doses	1000 IU weekly	1200 U twice weekly	10-15%	7-19%
3 months later	1000 IU once in 10 days × 2 doses	1000 IU weekly	1200 U twice weekly	10-15%	11%
Total	21 doses-1000 IU	25 doses	100 doses-600 U	Approximately 40%	-

Figure 3. Intra-operative images.

Figure 4. Post operative X ray.

The measured factor IX levels closely followed the desired levels, ranging between 16% and 83.3%, signifying the effectiveness of the N9GP or EHL regimen.

Notably, no additional dosing was required intraoperatively, and haemostasis was successfully achieved. The patient’s recovery was uneventful, and the outcomes were encouraging, with no excessive bleeding or other severe complications observed. This case underscores the potential of EHL treatment in enhancing surgical outcomes in patients with Hemophilia B undergoing major orthopaedic procedures. It stresses the importance of diligent perioperative management, including personalized dosing strategies and close monitoring of clotting factor levels, to ensure optimal haemostatic control.

Discussion

Nonacog beta pegol is a recombinant factor IX (rFIX) compound that is synthesized by expressing the human factor IX gene sequence in Chinese hamster ovary (CHO) cells, without the use of any human or additional animal materials. To the FIX activation peptide, a 40-kilodalton polyethylene glycol (PEG) moiety is attached via site-directed glycoPEGylation. During the coagulation process, the activation peptide, along with the PEG, is cleaved, resulting in the production of native-activated factor IX.

In a single-dose pharmacokinetic trial, nonacog beta pegol demonstrated a five-fold increase in terminal half-life compared to standard factor IX products. This extended half-life enabled the administration of once-weekly regimen in adults and adolescents with hemophilia B, ensuring sustained high levels of factor IX activity. Additionally, this treatment approach was deemed safe and effective for managing and preventing bleeding episodes.¹⁶

The case studies presented in this paper highlight the potential of perioperative treatment with Extended Half-Life (EHL) therapies such as N9-GP (Refixia) and GlycoPEGylated Factor IX in improving surgical outcomes for patients with Hemophilia B. These cases depict various surgical scenarios ranging from total knee replacement to hip replacement. Across these diverse surgical interventions, EHL therapies provided effective haemostatic control, underlining their utility in a broad spectrum of surgical contexts.

A common thread observed across these cases is the successful management of perioperative haemostasis with the use of EHL therapy. This aligns with the findings of several previous studies that have reported the advantages of EHL over standard half-life (SHL) factor IX products due to their longer half-life and lower clearance, allowing for reduced dosing frequency and sustained factor IX activity.^12,13

The ability to maintain factor IX levels within the desired range during the postoperative period, as observed in Case 2, is a crucial factor in preventing postoperative bleeding, which is a significant concern in haemophilic patients undergoing surgery. This is supported by other studies, which have shown that maintaining factor IX levels above a certain threshold significantly reduces the risk of bleeding complications.¹⁴

Interestingly, the benefits of EHL therapy extended beyond the immediate perioperative period. For instance, in Case 1, EHL therapy was initiated six months prior to the scheduled total hip replacement surgery, and this approach was effective in ensuring excellent haemostatic response throughout the surgical process.

While our case series and existing literature support the use of EHL therapies in the surgical management of Hemophilia B, it is important to recognize that each patient presents a unique clinical scenario. Therefore, the decision on the timing and dosing of perioperative treatment should be individualized based on the patient’s specific condition, surgical procedure, and other relevant factors.

The successful outcomes observed in these cases underscore the potential of EHL therapy as a perioperative strategy in improving surgical outcomes for Hemophilia B patients. However, larger controlled studies are required to further validate these findings and to explore the optimal timing and dosing strategies for EHL therapy in different surgical scenarios.

Conclusion

The two cases presented herein provide compelling evidence supporting the use of extended half-life (EHL) perioperative in the management of surgical patients with Hemophilia B. The administration of EHL products, particularly N9-GP (Refixia), showed promising results in maintaining adequate factor IX levels and controlling perioperative bleeding, thus leading to successful surgical outcomes in all cases.

In clinical practice, these results underscore the importance of individualized treatment plans and the need for a multidisciplinary approach in managing Hemophilia B patients who require surgery. The appropriate timing, dosing, and monitoring of perioperative treatment are crucial elements that can significantly impact surgical outcomes.

In conclusion, the implementation of perioperative treatment in surgical management strategies for Hemophilia B patients is likely to improve surgical outcomes and the overall quality of life for these patients. The use of EHL factor IX products, as demonstrated in these case studies, could potentially revolutionize the therapeutic approach towards Hemophilia B.

Consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patients.