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

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Management of Hemophilia B in surgical settings poses unique challenges due to the risk of excessive bleeding. This paper presents a series of two cases that demonstrate the effective use of perioperative extended half-life (EHL) factor IX products, specifically N9-GP (Refixia), in the surgical management of Hemophilia B. The cases include total knee replacement and total hip replacement. In each case, early initiation of EHL was observed to maintain adequate factor IX levels and control perioperative bleeding effectively, leading to successful surgical outcomes. These findings support the growing body of evidence suggesting the advantages of EHL perioperative treatment in patients with Hemophilia B, particularly in preparation for surgery. The implementation of EHL factor IX products as part of perioperative management plans may contribute to improved surgical outcomes and overall quality of life in Hemophilia B patients." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-73", "name": "Perioperative management in haemophilia with extended half-life factors:..." } } ] } Home Browse Perioperative management in haemophilia with extended half-life factors:... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Khurana H and Prasad Verma S. Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.12688/f1000research.142117.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Clinical Practice Article Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] Harshit Khurana 1 , Shailendra Prasad Verma 2 Harshit Khurana 1 , Shailendra Prasad Verma 2 PUBLISHED 17 Jan 2024 Author details Author details 1 Department of Geriatrics, Armed Forces Medical College, Pune, Pune, Maharashtra, 411040, India 2 Department of Clinical Hematology, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India Harshit Khurana Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing – Review & Editing Shailendra Prasad Verma Roles: Data Curation, Formal Analysis, Investigation, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Hemophilia B is a hereditary bleeding disorder characterized by deficient or defective coagulation factor IX, leading to a propensity for recurrent bleeding episodes, particularly in the joints. Management of Hemophilia B in surgical settings poses unique challenges due to the risk of excessive bleeding. This paper presents a series of two cases that demonstrate the effective use of perioperative extended half-life (EHL) factor IX products, specifically N9-GP (Refixia), in the surgical management of Hemophilia B. The cases include total knee replacement and total hip replacement. In each case, early initiation of EHL was observed to maintain adequate factor IX levels and control perioperative bleeding effectively, leading to successful surgical outcomes. These findings support the growing body of evidence suggesting the advantages of EHL perioperative treatment in patients with Hemophilia B, particularly in preparation for surgery. The implementation of EHL factor IX products as part of perioperative management plans may contribute to improved surgical outcomes and overall quality of life in Hemophilia B patients. READ ALL READ LESS Keywords Hemophilia, EHL, coagulation factor IX, perioperative extended half-life (EHL) factor IX, surgical management Corresponding Author(s) Shailendra Prasad Verma ( [email protected] ) Close Corresponding author: Shailendra Prasad Verma Competing interests: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given the final approval for the version to be published. The authors thank Dr. Mamta Jain of Medwiz Healthcare Communications for providing medical writing support in the preparation of this article, and Novo Nordisk, India, for the writing grant. The authors take full responsibility for the content and conclusions stated in this article. Novo Nordisk neither influenced the content of this publication nor was it involved in the study design, data collection, analysis, interpretation, or review. Grant information: Novo Nordisk, India provided a writing grant for this article. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Khurana H and Prasad Verma S. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Khurana H and Prasad Verma S. Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.12688/f1000research.142117.1 ) First published: 17 Jan 2024, 13 :73 ( https://doi.org/10.12688/f1000research.142117.1 ) Latest published: 17 Jan 2024, 13 :73 ( https://doi.org/10.12688/f1000research.142117.1 ) 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. Data availability No data are associated with this article. Acknowledgements We would like to acknowledge the contribution of the patients who consented to share their experiences for the benefit of others. Their willingness to participate in these case studies has made a significant contribution to our understanding of Hemophilia B management. The writing of this article was supported by a medical writer at Medwiz Healthcare Communications Private Ltd. References 1. Mannucci PM, Tuddenham EG: The hemophilias—from royal genes to gene therapy. N. Engl. J. Med. 2001; 344 (23): 1773–1779. PubMed Abstract | Publisher Full Text 2. White GC, Rosendaal F, Aledort LM, et al. : Definitions in hemophilia: recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb. Haemost. 2001; 85 (03): 560. Publisher Full Text 3. Walsh CE, Soucie JM, Miller CH: United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. Am. J. Hematol. 2015; 90 (5): 400–405. PubMed Abstract | Publisher Full Text 4. Kavakli K, Makris M, Zulfikar B, et al. : Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb. Haemost. 2006 Apr; 95 (4): 600–605. PubMed Abstract | Publisher Full Text 5. Poston JN, Kruse-Jarres R: Perioperative hemostasis for patients with hemophilia. Hematology Am. Soc. Hematol. Educ. Program. 2022 Dec 9; 2022 (1): 586–593. PubMed Abstract | Publisher Full Text | Free Full Text 6. Franchini M, Mannucci PM: Inhibitors of propagation of coagulation (factors VIII, IX and XI): a review of current therapeutic practice. Br. J. Clin. Pharmacol. 2011 Oct; 72 (4): 553–562. PubMed Abstract | Publisher Full Text | Free Full Text 7. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. : Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013; 19 (1): e1–e47. PubMed Abstract | Publisher Full Text 8. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. : Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N. Engl. J. Med. 2007; 357 (6): 535–544. PubMed Abstract | Publisher Full Text 9. Mahlangu J, Powell JS, Ragni MV, et al. : Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N. Engl. J. Med. 2014; 371 (26): 2313–2323. 10. Collins PW, Young G, Knobe K, et al. : Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014; 124 (26): 3880–3886. PubMed Abstract | Publisher Full Text | Free Full Text 11. Negrier C, Seuser A, Forsyth A, et al. : The benefits of exercise for patients with haemophilia and recommendations for safe and effective physical activity. Haemophilia. 2013 Jul; 19 (4): 487–498. PubMed Abstract | Publisher Full Text 12. Negrier C, et al. : Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood. 2011; 118 (10): 2695–2701. PubMed Abstract | Publisher Full Text 13. Santagostino E, et al. : Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016; 127 (14): 1761–1769. PubMed Abstract | Publisher Full Text | Free Full Text 14. Collins PW, et al. : Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J. Thromb. Haemost. 2009; 7 (3): 413–420. PubMed Abstract | Publisher Full Text 15. Ar MC, Balkan C, Kavaklı K: Extended Half-Life Coagulation Factors: A New Era in the Management of Hemophilia Patients. Turk. J. Haematol. 2019 Aug 2; 36 (3): 141–154. PubMed Abstract | Publisher Full Text 16. Escobar MA, et al. : Low-factor consumption for major surgery in haemophilia B with long-acting recombinant glycoPEGylated factor IX. Haemophilia. 2017; 23 (1): 67–76. PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 17 Jan 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of Geriatrics, Armed Forces Medical College, Pune, Pune, Maharashtra, 411040, India 2 Department of Clinical Hematology, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India Harshit Khurana Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing – Review & Editing Shailendra Prasad Verma Roles: Data Curation, Formal Analysis, Investigation, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Competing interests All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given the final approval for the version to be published. The authors thank Dr. Mamta Jain of Medwiz Healthcare Communications for providing medical writing support in the preparation of this article, and Novo Nordisk, India, for the writing grant. The authors take full responsibility for the content and conclusions stated in this article. Novo Nordisk neither influenced the content of this publication nor was it involved in the study design, data collection, analysis, interpretation, or review. Grant information Novo Nordisk, India provided a writing grant for this article. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 17 Jan 2024, 13:73 https://doi.org/10.12688/f1000research.142117.1 Copyright © 2024 Khurana H and Prasad Verma S. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Khurana H and Prasad Verma S. Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.12688/f1000research.142117.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 17 Jan 2024 Views 0 Cite How to cite this report: Olasupo OO. Reviewer Report For: Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.5256/f1000research.155620.r316871 ) The direct URL for this report is: https://f1000research.com/articles/13-73/v1#referee-response-316871 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 17 Oct 2024 Omotola O. Olasupo , Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.155620.r316871 Summary/ Overall Comments: The authors presented two cases demonstrating the effect of perioperative extended half-life (EHL) factor IX, N9-GP (Refixia), in the perioperative management of Hemophilia B. In these cases, early initiation of N9-GP was shown to maintain adequate ... Continue reading READ ALL Summary/ Overall Comments: The authors presented two cases demonstrating the effect of perioperative extended half-life (EHL) factor IX, N9-GP (Refixia), in the perioperative management of Hemophilia B. In these cases, early initiation of N9-GP was shown to maintain adequate factor IX levels and control perioperative bleeding. Below are some major points to consider to improve the manuscript. Title This report focuses on hemophilia B. The title should be rephrased to indicate hemophilia B. Hemophilia was spelt differently in the title versus across the manuscript. It is recommended to be consistent with the version of the spelling used across the report. While the sample size needed to label a study case series or case report may not be clearly defined, Patterson et al. suggest that case series should have at least five cases. 1,2 This report can be labeled a case report, considering two cases were reported. Introduction The use of “various surgical procedures” suggests that a variety of surgeries were being described. Specifying the two surgeries conducted (total hip and knee replacement) will be more accurate. Use the non-proprietary name of the product nonacog beta pegol (or its shortened form N9-GP) across the manuscript. Methods If this report is deemed a case series, the use of a standard reporting guideline, such as The Preferred Reporting Of CasE Series in Surgery (PROCESS) guidelines, will be helpful to ensure all necessary elements are reported. 3 If this is considered a case report, similar reporting guidelines such as the CARE guidelines (for CAse REports) can be considered. 4,5 Was the study registered prospectively? If so, state the research registry number. State whether the case series is: (1) prospective/retrospective, (2) single/multi-centre, and if (3) cases are consecutive/non-consecutive. Also, provide relevant dates. More details are needed on the setting(s) in which the surgeries were conducted (e.g. teaching/district general hospital, community, or private practice). More details are needed on study participants e.g. demographics, comorbidities, history of inhibitors, previous exposure to N9-GP, exposure to other hemostatic agents before and within the perioperative period, severity of hemophilia B (mild, moderate, or severe) Provide details on how hemostatic response (excellent, good, fair, inadequate) was defined. Provide details on how overall recovery was defined. What is the follow-up time in the postoperative period for the assessment of overall recovery? Conclusions This report (being a case report or a case series) does not provide compelling evidence to support the use of extended half-life (EHL) in the perioperative management of Hemophilia B, as mentioned by the authors. The conclusions need to be reviewed and more rigorous study designs are recommended to make such conclusions. Is the background of the cases’ history and progression described in sufficient detail? No Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the conclusion balanced and justified on the basis of the findings? No References 1. Patterson P, Weaver M, Clark S, Yealy D: Case reports and case series in prehospital emergency care research. Emergency Medicine Journal . 2010; 27 (11): 807-809 Publisher Full Text 2. Abu-Zidan FM, Abbas AK, Hefny AF: Clinical "case series": a concept analysis. Afr Health Sci . 2012; 12 (4): 557-62 PubMed Abstract 3. Agha R, Sohrabi C, Mathew G, Franchi T, et al.: The PROCESS 2020 Guideline: Updating Consensus Preferred Reporting Of CasE Series in Surgery (PROCESS) Guidelines. International Journal of Surgery . 2020; 84 : 231-235 Publisher Full Text 4. Alsaywid B, Abdulhaq N: Guideline on writing a case report. Urology Annals . 2019; 11 (2). Publisher Full Text 5. CARE Case Report Guidelines. CARE Case Report Guidelines. 2024. Reference Source Competing Interests: No competing interests were disclosed. Reviewer Expertise: Health research methodology, clinical epidemiology, hemostasis, thrombosis, evidence-based medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Olasupo OO. Reviewer Report For: Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.5256/f1000research.155620.r316871 ) The direct URL for this report is: https://f1000research.com/articles/13-73/v1#referee-response-316871 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Phua CW. Reviewer Report For: Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.5256/f1000research.155620.r262650 ) The direct URL for this report is: https://f1000research.com/articles/13-73/v1#referee-response-262650 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 16 May 2024 Chai W Phua , Division of Hematology and Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.155620.r262650 Summary of the Article The article under review presents two case studies demonstrating the use of glycoPEGylated, extended half-life, recombinant FIX (Nonacog Beta Pegol, N9GP) in the perioperative management of Hemophilia B during major orthopedic surgeries—total knee replacement and total hip replacement. It ... Continue reading READ ALL Summary of the Article The article under review presents two case studies demonstrating the use of glycoPEGylated, extended half-life, recombinant FIX (Nonacog Beta Pegol, N9GP) in the perioperative management of Hemophilia B during major orthopedic surgeries—total knee replacement and total hip replacement. It details the clinical context with radiographic images, the administration of N9GP, the monitoring of coagulation factor levels, and the outcomes, which indicate effective bleeding control and successful surgical results. Assessment of Article Quality Relevance and Importance : The topic is relevant, focusing on the significant challenges in managing hemophilia patients undergoing surgery, including real-world experience with N9GP. The surgical management of hemophilia presents a complex challenge due to the unique nature of each surgical case, varied patient responses to factor replacement therapies, and differing laboratory capabilities across treatment centers. This necessitates highly tailored surgical plans that are not easily standardized. Constructive Comments Strengths: The case studies provide insights into practical applications, adding valuable real-world evidence to the literature on Hemophilia B management. The suggested product monograph dosing regimen of N9GP successfully managed major orthopedic surgical procedures. Areas for Improvement: The rationale for choosing these specific cases for publication should be clarified. Were these instances the first applications of N9GP in the context of major orthopedic surgeries? Detailing Case Histories: The descriptions of the cases would benefit from a more comprehensive presentation of each patient’s medical background. This should include: Describe the severity of Hemophilia (mild, moderate, or severe). Detailed prior treatment modalities (prophylaxis vs. on-demand), including exposure days to factor products if known, informing about inhibitors' potential development. Documentation of target joints, HJHS scores and annualized bleeding rates to provide context on the disease impact. Information on prior pharmacokinetic testing with N9GP, if available. The status of inhibitors to factor IX and whether testing was conducted before the surgical intervention to assess the risk of an immune response to N9GP. Were follow-up testing done? Specifics in Case 1 Presentation: For Case 1, additional specifics can deepen the understanding of perioperative management: Were any specific laboratory assessments conducted preoperatively or postoperatively? Details of these assessments can help validate the efficacy of the treatment protocol. Explanation of the six-month preoperative treatment with N9GP. Was this aimed at optimizing joint condition, reducing bleed rates, or achieving a specific pharmacokinetic profile? The duration of the hospital stay, any transfusion requirements, significant hemoglobin drop and details about postoperative prophylaxis or return to on-demand treatment. Discuss any thromboprophylaxis measures taken, considering the hypercoagulable state post-surgery. Any long-term outcomes or follow-up data post-surgery to assess sustained benefits or complications (i.e. inhibitor testing) A more precise definition of the surgical response and a clear justification for the chosen dosing regimen, particularly aiming to achieve peak factor levels of 100% pre-operatively and maintaining at least 50% trough levels post-operatively. Specifics in Case 2 Presentation : As with Case 1, the specifics listed above have pertinence and could further enhance the case presentation. Table 1: The presentation in Table 1 needs improvement for better clarity and understanding. It should specify whether the factor IX levels shown are intended to represent peak or trough levels. The total dosing reported appears to be inconsistent. If the table aims to compare the utilization of standard half-life versus extended half-life factor IX products, presenting the data in terms of total dosing per kilogram could provide a clearer comparison and illustrate the benefits of EHL in reducing the frequency and volume of doses. If the lower doses used achieved the desired levels of FIX, this warrants highlighting in the text. Detail the rationale for the 3-month dosing regimen. Was this specifically pre-planned to maintain factor levels for rehabilitation, or did it transition into a regular prophylaxis schedule post-surgery? Specifics in Discussion: To enhance the discussion section of your paper and provide a more compelling analysis of Extended Half-Life versus Standard Half-Life factor products including maintaining stable factor levels throughout surgical procedures, reduced dosing frequency, and sustained protection. These benefits enhance patient outcomes and help mitigate some logistical and laboratory constraints associated with shorter half-life products. Reflect on how the cases presented illustrate the benefits of N9GP. Conclusion The paper provides insight into the real-world experience of N9GP in major surgical procedures. The case studies contribute to existing knowledge, highlighting the safety and efficacy of EHL products in surgical settings. With some enhancements, the paper could further its impact. The review supports the article be with revisions, as suggested. Is the background of the cases’ history and progression described in sufficient detail? Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the conclusion balanced and justified on the basis of the findings? Partly Competing Interests: Over the past 3 years, I have received research funding from Roche and honoraria from Abbvie, Sanofi, CSL, Beigene, AstraZeneca, Recordati, FORUS Therapeutics, Bayer, Octapharma, Janssen, Roche Reviewer Expertise: Hematologic Disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Phua CW. Reviewer Report For: Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.5256/f1000research.155620.r262650 ) The direct URL for this report is: https://f1000research.com/articles/13-73/v1#referee-response-262650 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 17 Jan 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 17 Jan 24 read read Chai W Phua , London Health Sciences Centre, London, Canada Omotola O. Olasupo , McMaster University, Hamilton, Canada Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Olasupo O. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 Oct 2024 | for Version 1 Omotola O. Olasupo , Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada 0 Views copyright © 2024 Olasupo O. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Summary/ Overall Comments: The authors presented two cases demonstrating the effect of perioperative extended half-life (EHL) factor IX, N9-GP (Refixia), in the perioperative management of Hemophilia B. In these cases, early initiation of N9-GP was shown to maintain adequate factor IX levels and control perioperative bleeding. Below are some major points to consider to improve the manuscript. Title This report focuses on hemophilia B. The title should be rephrased to indicate hemophilia B. Hemophilia was spelt differently in the title versus across the manuscript. It is recommended to be consistent with the version of the spelling used across the report. While the sample size needed to label a study case series or case report may not be clearly defined, Patterson et al. suggest that case series should have at least five cases. 1,2 This report can be labeled a case report, considering two cases were reported. Introduction The use of “various surgical procedures” suggests that a variety of surgeries were being described. Specifying the two surgeries conducted (total hip and knee replacement) will be more accurate. Use the non-proprietary name of the product nonacog beta pegol (or its shortened form N9-GP) across the manuscript. Methods If this report is deemed a case series, the use of a standard reporting guideline, such as The Preferred Reporting Of CasE Series in Surgery (PROCESS) guidelines, will be helpful to ensure all necessary elements are reported. 3 If this is considered a case report, similar reporting guidelines such as the CARE guidelines (for CAse REports) can be considered. 4,5 Was the study registered prospectively? If so, state the research registry number. State whether the case series is: (1) prospective/retrospective, (2) single/multi-centre, and if (3) cases are consecutive/non-consecutive. Also, provide relevant dates. More details are needed on the setting(s) in which the surgeries were conducted (e.g. teaching/district general hospital, community, or private practice). More details are needed on study participants e.g. demographics, comorbidities, history of inhibitors, previous exposure to N9-GP, exposure to other hemostatic agents before and within the perioperative period, severity of hemophilia B (mild, moderate, or severe) Provide details on how hemostatic response (excellent, good, fair, inadequate) was defined. Provide details on how overall recovery was defined. What is the follow-up time in the postoperative period for the assessment of overall recovery? Conclusions This report (being a case report or a case series) does not provide compelling evidence to support the use of extended half-life (EHL) in the perioperative management of Hemophilia B, as mentioned by the authors. The conclusions need to be reviewed and more rigorous study designs are recommended to make such conclusions. Is the background of the cases’ history and progression described in sufficient detail? No Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the conclusion balanced and justified on the basis of the findings? No References 1. Patterson P, Weaver M, Clark S, Yealy D: Case reports and case series in prehospital emergency care research. Emergency Medicine Journal . 2010; 27 (11): 807-809 Publisher Full Text 2. Abu-Zidan FM, Abbas AK, Hefny AF: Clinical "case series": a concept analysis. Afr Health Sci . 2012; 12 (4): 557-62 PubMed Abstract 3. Agha R, Sohrabi C, Mathew G, Franchi T, et al.: The PROCESS 2020 Guideline: Updating Consensus Preferred Reporting Of CasE Series in Surgery (PROCESS) Guidelines. International Journal of Surgery . 2020; 84 : 231-235 Publisher Full Text 4. Alsaywid B, Abdulhaq N: Guideline on writing a case report. Urology Annals . 2019; 11 (2). Publisher Full Text 5. CARE Case Report Guidelines. CARE Case Report Guidelines. 2024. Reference Source Competing Interests No competing interests were disclosed. Reviewer Expertise Health research methodology, clinical epidemiology, hemostasis, thrombosis, evidence-based medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Olasupo OO. Peer Review Report For: Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.5256/f1000research.155620.r316871) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-73/v1#referee-response-316871 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Phua C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 16 May 2024 | for Version 1 Chai W Phua , Division of Hematology and Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada 0 Views copyright © 2024 Phua C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Summary of the Article The article under review presents two case studies demonstrating the use of glycoPEGylated, extended half-life, recombinant FIX (Nonacog Beta Pegol, N9GP) in the perioperative management of Hemophilia B during major orthopedic surgeries—total knee replacement and total hip replacement. It details the clinical context with radiographic images, the administration of N9GP, the monitoring of coagulation factor levels, and the outcomes, which indicate effective bleeding control and successful surgical results. Assessment of Article Quality Relevance and Importance : The topic is relevant, focusing on the significant challenges in managing hemophilia patients undergoing surgery, including real-world experience with N9GP. The surgical management of hemophilia presents a complex challenge due to the unique nature of each surgical case, varied patient responses to factor replacement therapies, and differing laboratory capabilities across treatment centers. This necessitates highly tailored surgical plans that are not easily standardized. Constructive Comments Strengths: The case studies provide insights into practical applications, adding valuable real-world evidence to the literature on Hemophilia B management. The suggested product monograph dosing regimen of N9GP successfully managed major orthopedic surgical procedures. Areas for Improvement: The rationale for choosing these specific cases for publication should be clarified. Were these instances the first applications of N9GP in the context of major orthopedic surgeries? Detailing Case Histories: The descriptions of the cases would benefit from a more comprehensive presentation of each patient’s medical background. This should include: Describe the severity of Hemophilia (mild, moderate, or severe). Detailed prior treatment modalities (prophylaxis vs. on-demand), including exposure days to factor products if known, informing about inhibitors' potential development. Documentation of target joints, HJHS scores and annualized bleeding rates to provide context on the disease impact. Information on prior pharmacokinetic testing with N9GP, if available. The status of inhibitors to factor IX and whether testing was conducted before the surgical intervention to assess the risk of an immune response to N9GP. Were follow-up testing done? Specifics in Case 1 Presentation: For Case 1, additional specifics can deepen the understanding of perioperative management: Were any specific laboratory assessments conducted preoperatively or postoperatively? Details of these assessments can help validate the efficacy of the treatment protocol. Explanation of the six-month preoperative treatment with N9GP. Was this aimed at optimizing joint condition, reducing bleed rates, or achieving a specific pharmacokinetic profile? The duration of the hospital stay, any transfusion requirements, significant hemoglobin drop and details about postoperative prophylaxis or return to on-demand treatment. Discuss any thromboprophylaxis measures taken, considering the hypercoagulable state post-surgery. Any long-term outcomes or follow-up data post-surgery to assess sustained benefits or complications (i.e. inhibitor testing) A more precise definition of the surgical response and a clear justification for the chosen dosing regimen, particularly aiming to achieve peak factor levels of 100% pre-operatively and maintaining at least 50% trough levels post-operatively. Specifics in Case 2 Presentation : As with Case 1, the specifics listed above have pertinence and could further enhance the case presentation. Table 1: The presentation in Table 1 needs improvement for better clarity and understanding. It should specify whether the factor IX levels shown are intended to represent peak or trough levels. The total dosing reported appears to be inconsistent. If the table aims to compare the utilization of standard half-life versus extended half-life factor IX products, presenting the data in terms of total dosing per kilogram could provide a clearer comparison and illustrate the benefits of EHL in reducing the frequency and volume of doses. If the lower doses used achieved the desired levels of FIX, this warrants highlighting in the text. Detail the rationale for the 3-month dosing regimen. Was this specifically pre-planned to maintain factor levels for rehabilitation, or did it transition into a regular prophylaxis schedule post-surgery? Specifics in Discussion: To enhance the discussion section of your paper and provide a more compelling analysis of Extended Half-Life versus Standard Half-Life factor products including maintaining stable factor levels throughout surgical procedures, reduced dosing frequency, and sustained protection. These benefits enhance patient outcomes and help mitigate some logistical and laboratory constraints associated with shorter half-life products. Reflect on how the cases presented illustrate the benefits of N9GP. Conclusion The paper provides insight into the real-world experience of N9GP in major surgical procedures. The case studies contribute to existing knowledge, highlighting the safety and efficacy of EHL products in surgical settings. With some enhancements, the paper could further its impact. The review supports the article be with revisions, as suggested. Is the background of the cases’ history and progression described in sufficient detail? Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the conclusion balanced and justified on the basis of the findings? Partly Competing Interests Over the past 3 years, I have received research funding from Roche and honoraria from Abbvie, Sanofi, CSL, Beigene, AstraZeneca, Recordati, FORUS Therapeutics, Bayer, Octapharma, Janssen, Roche Reviewer Expertise Hematologic Disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Phua CW. Peer Review Report For: Perioperative management in haemophilia with extended half-life factors: a case series [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :73 ( https://doi.org/10.5256/f1000research.155620.r262650) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-73/v1#referee-response-262650 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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