Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices

Neufeld, Ellis J.; Solimeno, Luigi Piero; Quon, Doris; Walsh, Chris; Seremetis, Stephanie; Cooper, David L.; Iyer, N.C.; Hoxer, Christina Stentoft; Giangrande, Paul

doi:10.1111/hae.13279

Cited by 12 publications

(19 citation statements)

References 58 publications

(92 reference statements)

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“…Only a few decades ago, surgery in hemophiliacs was considered difficult and was associated with significant risks, such as uncontrolled bleeding, hemolytic complications associated with impure factor concentrates, transmission of bloodborne infections, and problems with wound healing [8,9]. With advancements in the treatment of hemophilia and the ability to replete deficient factor levels, surgery can be performed more safely.…”

Section: Discussionmentioning

confidence: 99%

Vascularized Free Tissue Transfer in a Patient with Hemophilia B: Case Report and Literature Review

Qaisi

Kierce

Murphy

2019

Case Reports in Surgery

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Hemophilia is a blood disorder characterized by impairment of the coagulation cascade leading to an increased bleeding risk (Kauffman, 2014). As such, surgical management of these patients can become difficult and well-defined surgical guidelines are not yet in place (Assoumane et al., 2017). Close monitoring of perioperative factor levels may be even more crucial for those undergoing microvascular free tissue transfer. This is because either a hypercoagulable or hypocoagulable bleeding state has the potential to further increase the risk of vascular compromise to the flap. We report a successful case of mandibular reconstruction using a free fibular flap in a patient with severe hemophilia B and the protocols we used, as well as a review of the literature of similar cases. In the literature, we identified 6 cases of microvascular free tissue transfer in patients with hemophilia; two of these cases had complications which were both related to excess bleeding. It is crucial that these cases be managed in a multidisciplinary fashion in close consultation with a hematologist. The role of venothromboembolism (VTE) prophylaxis in the hemophilic patient undergoing free tissue transfer is discussed.

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Section: Discussionmentioning

confidence: 99%

Vascularized Free Tissue Transfer in a Patient with Hemophilia B: Case Report and Literature Review

Qaisi

Kierce

Murphy

2019

Case Reports in Surgery

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“…An international multi‐center observational cohort study was performed in which data were collected from 118 severe and moderate hemophilia B patients from five Hemophilia Treatment Centers in the Netherlands and five in the United Kingdom. Patients of all ages, who had undergone a minor or major elective surgical procedure between 1 January 2000 and 1 December 2015, were included . Details of the study data have been reported previously .…”

Section: Methodsmentioning

confidence: 99%

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery

Preijers

Hazendonk

Liesner

et al. 2018

Journal of Thrombosis and Haemostasis

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Meer FJM, Meijer K, Fijnvandraat K, Leebeek FWG, Collins PW, Cnossen MH, Mathôt RAA, for the OPTI-CLOT study group. Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery. J Thromb Haemost 2018; 16: 2196-207. Essentials• Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. • We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. • Population PK parameter values for clearance and V1 were 284 mL h À1 70 kg À1 and 5450 mL70 kg À1 . • Perioperative PK parameters differ from those during non-surgical prophylactic treatment.Summary. Background: Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under-and overdosing occurs frequently during surgery. Aim: The objective was to quantify and explain the interpatient variability of perioperatively administered plasmaderived (pd) and recombinant (r) FIX concentrates. Methods: Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NON-MEM. Results: Measured perioperative FIX level vs. time profiles were adequately described using a threecompartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h À1 70 kg À1 (18%); V1, 5450 mL70 kg À1 (19%); Q2, 110 mL h À1 70 kg À1 ; V2, 4800 mL70 kg À1 ; Q3, 1610 mL h À1 70 kg À1 ; V3, 2040 mL70 kg À1 . From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions: The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery.

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“…The risk of surgery-related bleeding has been reduced by standard FIX products, but comparisons with nonacog beta pegol or EHL products in the perioperative setting are limited by the relative scarcity of literature on bleeding risks in patients with hemophilia B. 31 – 34 Moreover, there is great variability in defining bleeding risk and a lack of robust evidence on surgical outcomes. 34 Nevertheless, perioperative use of nonacog beta pegol requires lower consumption and fewer injections than that reported for standard FIX products.…”

Section: Clinical Efficacy Of Glycopegylated Rfixmentioning

confidence: 99%

“… 31 – 34 Moreover, there is great variability in defining bleeding risk and a lack of robust evidence on surgical outcomes. 34 Nevertheless, perioperative use of nonacog beta pegol requires lower consumption and fewer injections than that reported for standard FIX products. 23 …”

Section: Clinical Efficacy Of Glycopegylated Rfixmentioning

confidence: 99%

GlycoPEGylated recombinant factor IX for hemophilia B in context

Santagostino

Mancuso

2018

DDDT

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Decisions over hemophilia treatment selection and switching involve balancing many clinical and patient-related factors. The current standard of care for patients with hemophilia B is prophylaxis with plasma-derived or recombinant factor IX (rFIX) concentrates. However, several extended half-life (EHL) rFIX products have recently been developed to improve treatment convenience and clinical outcomes for these patients. Nonacog beta pegol, an rFIX product that combines the FIX protein with a 40 kDa polyethylene glycol moiety, has been evaluated in 115 previously treated patients with hemophilia B (including 25 children) in the paradigm clinical trial program. FIX activity levels and pharmacokinetics were monitored throughout these trials and showed that nonacog beta pegol offers significant pharmacological improvements over standard FIX products. Once-weekly prophylaxis with nonacog beta pegol 40 IU/kg resulted in fewer bleeds in all patients (median annualized bleeding rate of 1.0 across all ages), resolved 90% of target joints, and improved health-related quality of life. No patients developed FIX inhibitors, and there were no thromboembolic events or unexpected safety concerns. Nonacog beta pegol was also safe and effective in the perioperative setting. These findings show that nonacog beta pegol is highly effective, while also offering more convenient dosing than standard FIX products. Nonacog beta pegol represents a significant advance in the current context of treatment for hemophilia B, offering effective management across several treatment modalities and settings, and potentially easing the treatment burden for patients of all ages. Meanwhile, the development of novel treatment strategies, such as gene therapy, anti-tissue factor pathway inhibitor antibodies, and RNA interference therapy, may provide patients with additional therapeutic options, which would require reassessment of the role of EHL products in the future.

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Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices

Cited by 12 publications

References 58 publications

Vascularized Free Tissue Transfer in a Patient with Hemophilia B: Case Report and Literature Review

Vascularized Free Tissue Transfer in a Patient with Hemophilia B: Case Report and Literature Review

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery

GlycoPEGylated recombinant factor IX for hemophilia B in context

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