- Email: [email protected]
Prospective study of continuous infusion with Beriate® P in patients with severe haemophilia A undergoing surgery – a subgroup analysis
Thrombosis Research 134 (2014) S43–S47
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Prospective study of continuous infusion with Beriate® P in patients with severe haemophilia A undergoing surgery – a subgroup analysis Günter Auerswald ⁎, Andrea Bade, Julia Johne, Kirstin Haubold, David Overberg, Sylvia Masurat, Carolin Moorthi Centre for Thrombosis and Haemostasis, Professor-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany
a r t i c l e
i n f o
Available online 21 December 2013 Keywords: Haemophilia A Beriate® P Continuous infusion Inhibitors Coagulation disorders Surgery
a b s t r a c t Introduction: Inhibitor development in severe haemophilia A patients is currently the most serious complication of factor VIII (FVIII) treatment. Although continuous infusion (CI) of FVIII concentrate during surgical procedures in haemophilia A patients has been shown to be beneficial, some publications suggest that CI increases the risk of inhibitor generation. We conducted a prospective subgroup analysis to investigate if CI of the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate® P during surgery increases the risk of inhibitor formation. Materials and methods: Patients with severe haemophilia A (FVIII:C b1%) were included if they presented with a negative history of previous inhibitors, had ≥50 exposure days, and had been scheduled for a planned surgical procedure. A bolus infusion (30–50 IU/kg body weight) of Beriate® P was administered intravenously and followed by CI at a rate of 3–4 IU/kg body weight/hour. Dose adjustments were subsequently made based on daily measurements of plasma FVIII activity. Results: Five patients (aged 8–34 years) with severe haemophilia A were included. The surgical procedures ranged from teeth extraction to internal fixation of a fracture. There was no inhibitor generation with CI of Beriate® P in patients undergoing surgery, and we did not observe any complications due to re-bleeding or virus transmission. Conclusion: Beriate® P was efficacious, safe, and well tolerated during CI. © 2013 Published by Elsevier Ltd.
Introduction Haemophilia is an X-linked coagulation disorder that, due to its mode of inheritance, mainly affects males, and is estimated to occur at a rate of 1 in 5,000 live male births for haemophilia A [1] and 1 in 20,000 for haemophilia B worldwide [2]. The majority of haemophilia A patients present with a severe deficiency, which is defined as plasma factor VIII (FVIII) clotting activity (FVIII:C) levels below 1% [1]. Control of bleeding episodes in individuals with haemophilia A or B is achieved with the administration of coagulation factors, either plasmaderived or recombinant. Usually, these factors are given intermittently as bolus infusions to achieve haemostasis; however, there has been increasing interest in the use of continuous infusions (CI) of clotting factors for surgery in order to maintain a more constant or physiological concentration, thereby reducing the risk of bleeding from excessively low trough levels [3].
Abbreviations: BU, Bethesda Units; CI, continuous infusion; ED, exposure day; FVIII, factor VIII; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PTP, previously treated patient; PUP, previously untreated patient; PVC, polyvinylchloride; SD, standard deviation. ⁎ Corresponding author at: Centre for Thrombosis and Haemostasis, ProfessorHess-Kinderklinik, Klinikum Bremen-Mitte, St. Jürgen Str. 1, 28177 Bremen, Germany. Tel.: +49 421 497 3655x5410; fax: +49 421 497 4631. E-mail address: [email protected] (G. Auerswald). 0049-3848/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.thromres.2013.10.009
The idea of using CI of anti-haemophilic factor was first proposed in 1954 by Professor Kenneth Brinkhous in his seminal article in the Bulletin of The New York Academy of Medicine [4]. However, it was not until 1970 that the first systematic study assessing the effects of CI with FVIII as a cryoprecipitate or glycine-precipitate fraction was published [5]. In this study by McMillan et al., which assessed the effects of CI of FVIII under various conditions in five children with haemophilia A, the investigators reported that FVIII activity in glycine-precipitated fractions was stable at room temperature for up to 27 hours and that CI at a rate of 17 mL/hour of different concentrations produced levels of FVIII activity that were proportional to the dose rate and became relatively steady at 12–18 hours [5]. Subsequent pharmacokinetic studies reported similar findings [6–11]. In one such early study, Hathaway et al. established that higher FVIII concentrations could be achieved by CI compared with intermittent administration during surgery, and that CI of FVIII concentrate at a dose of 0.04 IU/kg body weight/hour intravenously could result in an increase in FVIII:C plasma levels of 1% [6]. Several factors associated with FVIII concentrates when given as a CI are important; most notably, the stability and sterility of the prepared solution. Current labelling recommends using most reconstituted FVIII products either immediately or within 1–3 hours after reconstitution (Beriate® P, however, can be used for up to 8 hours after reconstitution according to the prescribing information). Nevertheless, several studies have found that FVIII products can remain stable for longer periods of
S44
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
time after reconstitution. Schulman et al. for example, investigated the stability of 15 commonly available FVIII concentrates (including Beriate® P, CSL Behring, Marburg, Germany), and reported that FVIII activity was maintained for several days or even weeks for some of the products [12]. We subsequently have repeated these investigations with Beriate® P and Haemate® P and found stability within defined ranges for 4 days at 20–25 °C for Beriate® P in reconstituted and even diluted (1:3 with physiological saline) formulations (Fig. 1 [13]). Results for Haemate® P (dilution 1:2 in physiological saline) were similar. Tests for microbiological contamination (Staphylococcus auerus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis) at the end of this period proved to be negative [13]. Since the initial feasibility studies outlined above, the successful use of CI with FVIII has been reported in haemophilia A patients during surgical procedures [11,14–22], for the induction of immune tolerance therapy [23], for inhibitor management [24], and in primary or secondary prophylaxis [25]. When administered correctly, CI is associated with favourable haemostatic effects compared with intermittent bolus injections [26]. The advantages of CI include the maintenance of a constant FVIII concentration and a decrease in the amount of factor administered as a result of reduced factor clearance [15]. Pharmacoeconomic calculations have estimated cost savings with CI compared with bolus infusions to be in the range of 20–50% of factor concentrate used [15]. Several potential safety issues associated with CI are worthy of consideration. Prolonged therapy with factor concentrates requires the use of venous access devices, which have been associated with the development of infection, thrombosis, and thrombophlebitis [3]. Moreover, some studies have indicated that CI may be associated with an increased risk of inhibitor development [27–29]. Since data from our centre do not show an increased incidence of inhibitor generation when using CI in patients with coagulation disorders undergoing surgery, we recently undertook a prospective study to determine the rate of inhibitor formation in a surgical population of patients with haemophilia A, haemophilia B and von Willebrand disease who were being managed with CI [30]. In the current paper, we describe a subgroup analysis of patients with haemophilia A who received CI with the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate® P. Data were extracted and analyzed to provide an overview of the efficacy and safety of Beriate® P as CI in haemophilia A patients.
Materials and Methods Study Design Patients were included in the analysis of this substudy if they had severe haemophilia A (FVIII:C b1%), were ≤50 years of age, had no previous history of inhibitors, provided evidence of ≥50 exposure days (EDs), had documentation regarding their hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV) virus, and human immunodeficiency virus (HIV) type 1 or 2 status, and were scheduled for a minor or major surgical procedure. Study exclusion criteria included a contraindication to Beriate® P, a known hypersensitivity to Beriate® P, thrombophilia, or a confirmed or suspected pregnancy. The larger study was designed as a prospective study and patients were recruited from paediatric, otolaryngology, oral surgery, urology, orthopaedic, and gynaecology departments (Professor-Hess-Kinderklinik, Bremen). That study was approved prior to initiation by the Institutional Review Board of the Medical Chamber of Bremen. All subjects or their parents provided informed consent prior to study enrolment. Patients were evaluated clinically prior to surgery; a full medical history was obtained, and a complete laboratory evaluation was performed, including red blood cell count, prothrombin time, partial thromboplastin time, fibrinogen, FVIII activity in plasma (FVIII:C), FVIII inhibitor status (FVIII inhibitor), bleeding time, serological markers for HAV, HBV, HCV, and HIV-1 and -2, and, if indicated, investigation of FVIII recovery. Thirty to 60 minutes prior to surgery, a bolus injection of Beriate® P of approximately 30–50 IU/kg body weight was administered. At the start of surgery, CI was initiated at a rate of 3–4 IU/kg body weight/ hour in line with data from the literature [15]. Dose adjustments were subsequently made on the basis of daily measurements of plasma FVIII activity. Inhibitors were measured according to the Nijmegen modification of the Bethesda method. Inhibitors were investigated either in the local laboratory of our hospital or by a reference laboratory (Prof. Dr. Budde, Hamburg, Germany). Testing for inhibitors took place at baseline (prior to the start of the infusion) and 3–4 weeks after surgery. The presence of inhibitors was defined as Bethesda Units (BU) ≥0.6. Lowand high-titre inhibitors were defined as ≤5 and N5 BU, respectively. The evaluation of safety parameters included the number of bleeds during CI, the number of thromboses and other adverse events, and incidence of virus transmission. The incidence of adverse events was evaluated either directly in the clinic or 3–4 weeks after discharge. Haemostatic efficacy was rated as either “excellent” (no bleeding complications or excessive loss of blood), “good” (mild bleeding, no further treatments needed), “fair” (bleeding requiring further factor substitution) or “poor” (excessive bleeding requiring transfusion of red blood cells). The primary objective of the study was to investigate the incidence of inhibitors as a consequence of CI in our patients. Secondary objectives included evaluating the efficacy and safety of CI. Statistics We applied descriptive statistical procedures for data analysis. Demographic data are presented as means ± standard deviations; however, where the median values differed substantially from the mean values, medians plus ranges are also presented. Results
Fig. 1. Stability (factor VIII clotting activity [FVIII:C]) of Beriate® P after reconstitution, storage at 20–25 °C: mean values of three different batches with standard deviations [13]. One-stage clotting assay (dashed line), chromogenic assay (solid line). h, hours; d, days.
A total of five patients who had received Beriate® P CI were included in this analysis. All patients were male with severe haemophilia A (FVIII: C b 1%) (Table 1). The mean age of the patients was 21.2 ± 8.5 years (range 8–34). The surgical procedures evaluated were tonsillectomy
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
and adenectomy (n = 2), meniscectomy (n = 1), wisdom teeth extractions (n = 1) and internal fixation of an elbow fracture (n = 1). FVIII concentrate was administered with regular syringe pumps through a peripheral vein. All patients were observed for up to 4 weeks postoperatively and then every 4–6 months for over 1 year. Routine observation is ongoing. Figs. 2–6 show the plasma FVIII:C levels during CI with Beriate® P and consequent adaptations of CI dosing. For patient 1 (Fig. 2), who underwent a tonsillectomy and adenectomy, coagulation parameters were controlled until Day 27 (not all data shown). FVIII:C returned to b1% by 3days after the last Beriate® P infusion. The patient was negative for inhibitors and the last red blood cell count was normal. Surgery was performed without any adverse events during the peri-operative or post-operative period. Patient 2 (Fig. 3) also had a tonsillectomy and adenectomy performed without any adverse effects on red- or white cell counts, liver parameters or inhibitor titres (measured on Day 6 and Week 5 post-surgery; not all data shown). Surgery was uncomplicated and the peri-/postoperative periods uneventful. Patient 3 (Fig. 4) also had no pathological findings and no evidence of inhibitor development 5 weeks after surgery (not all data shown). Patient 4 (Fig. 5) had four wisdom teeth removed with a normal post-operative course and no evidence of abnormal laboratory parameters or inhibitor development. Patient 5 (Fig. 6) underwent internal fixation of an elbow fracture and had normal laboratory parameters when measured 6 weeks after the operation. No inhibitors developed. Splint removal was performed after 6 months, with a bolus of 2,000 IU of Beriate® P administered during the procedure. The clinical course for this patient was without adverse events, and again, no inhibitors were detected. In all five patients, no virus transmission occurred. Furthermore, during 20 years on the market, there have been no proven cases of virus transmission with Beriate® P. Over the current observation period of more than 1 year, there have been no reported side effects attributable to Beriate® P, including viral transmission (hepatitis A, B and C, HIV-1/2) or development of inhibitors. In two patients, small swelling at the infusion site was reported after 4 days; the infusion site was changed before occlusion and swelling subsided. Discussion
S45
Fig. 2. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 1) with severe haemophilia A undergoing tonsillectomy and adenectomy. Tranexamic acid was concomitantly administered peri-operatively at a dose of 10 mg/kg body weight three times daily up to Day 14. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
minimum are undesirable and result in the need for large quantities of FVIII to be infused peri-operatively. The results of this study confirm those of previously reported studies [11,14–22,31] demonstrating that CI is an effective and well-tolerated means of providing excellent haemostatic control during surgery. As would be expected, the dosing of Beriate® P varied between patients, with higher doses and longer periods of treatment required for the more complex surgical procedures. The levels of factor concentrate required with CI infusion were from 20% to more than 50% lower than those required with bolus dosing. This requirement for reduced dosing with CI has the advantage of lowering not only the costs of treatment but also the potential risk of treatment peaks. A further advantage of continuous factor concentrate infusion is the favourable titration that minimizes the risk of bleeding complications. In our study, we found no evidence of an increased risk of inhibitor development associated with CI. These findings contrast with those of other authors who have reported an association between inhibitor formation and treatment with CI for surgery or bleeding [27–29]. The
The availability of safe and effective plasma-derived and recombinant coagulation factor concentrates means that surgical indications for individuals with haemophilia are now similar to those of the general population. Most surgical centres have traditionally replaced FVIII with intermittent bolus therapy; however, the very high peak levels of FVIII required to ensure that trough levels remain above a certain
Table 1 Demographics of patients and type of surgery.
a
Characteristic
Value
Patients with severe haemophilia A Mean age ± SD (range), years Mean weight ± SD, kg Median weight (range), kg Mean height ± SD, cm Median height (range), cm Mean body mass index, kg/m2 Type of surgery, n (%) Tonsillectomy and adenectomy Meniscectomy Teeth extraction Internal fixation of elbow fracture
5 males (Caucasian) 21.2 ± 8.5 (8–34) 72.0 ± 26.3 78.0 (29.0–98.0) 170.0 ± 20.8 176.0 (134.0–188.0) 24.9 2 (40) 1 (20) 1 (20) 1 (20)
Quantitative demographic data are listed as means ± standard deviations. If means deviated from median values, median values and ranges are also listed. SD, standard deviation.
Fig. 3. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 2) with severe haemophilia A undergoing tonsillectomy and adenectomy. Tranexamic acid was concomitantly administered peri-operatively at a dose of 10 mg/kg body weight three times daily. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
S46
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
Fig. 6. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 5) undergoing internal fixation of an elbow fracture. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours. Fig. 4. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 3) with severe haemophilia A undergoing meniscectomy. No tranexamic acid was administered. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
reason for this difference might be explained in part by variances in study populations. The potential increased inhibitor risk in patients with b 50 EDs undergoing surgery and receiving CI, led us to include only subjects with severe haemophilia A who had ≥50 EDs. Such strict inclusion and exclusion criteria may have ensured that the risk of inhibitor development was minimized, and could explain why we did not observe the development of inhibitors in any of our patients. These observations are in line with suggestions from Bidlingmaier et al., who recommend CI only in patients with ≥20 EDs [21]. The question of whether CI is associated with a higher risk of inhibitor development than bolus administration will only be addressed adequately in a randomized, controlled trial in which the two modes of administration are compared directly. Plasma-derived FVIII concentrates, such as Beriate® P offer a number of practical advantages over recombinant products when used in CI regimens. The higher volumes associated with plasma-derived FVIII concentrates – which may be viewed as a disadvantage in everyday clinical practice – is a major advantage in CI regimens, as the reconstituted product does not need dilution. Reconstitution of FVIII concentrates with low volumes can cause pump problems and, since
most widely used pumps are unable to handle infusion of small volumes, mini-pumps are required, which are expensive, less readily available, and may be associated with thrombophlebitis at the injection site [32]. DiMichele et al. conducted a comparative study of continuously infused plasma-derived versus recombinant FVIII products and found significant differences in recovery between plasma-derived and recombinant products [33]. Both monoclonal antibody-purified plasma-derived FVIII products evaluated showed a stable recovery of 84–109% during the 8-hour infusion, whereas the two recombinant FVIII products, when reconstituted in normal saline, showed an early drop in recovery to 57–76%. When the recombinant FVIII products were restudied with the addition of 10 mg/mL of human albumin to the bags, no improvement in recovery was observed [33]. McLeod et al. reported significant (42%) loss of FVIII activity when recombinant FVIII concentrates were diluted and stored in polyvinylchloride (PVC)-based containers after just 48 hours of storage [34]. An even greater loss of activity was found for polyethylene compared with PVC containers in an investigation of CI using a recombinant FVIII product conducted by Hurst et al. [35]. The problem of reduced activity appears to be especially acute with recombinant FVIII products in which no albumin is added as a stabilizer. This is true for all recombinant FVIII products currently available on the German market. In the most recent investigation, published in 2010, Revel-Vilk et al. confirmed loss of FVIII activity for a recombinant FVIII concentrate even when dilutions were moderate [36]. Similar observations have been described by other investigators [37,38]. In summary, in our study, Beriate® P was found to have an excellent efficacy and safety profile when used as a continuous infusion during surgery. Haemostasis was achieved in all patients, wound healing was uncomplicated, no re-surgeries were required, no virus transmissions or thromboses occurred, and no inhibitor generation was observed. The practical advantages of plasma-derived over recombinant FVIII products – including the ability to use regular perfusers rather than mini-pumps – suggest that products such as Beriate® P have an important role to play in the peri-operative management of individuals with severe haemophilia A who have had at least 20–50 prior EDs. Conflict of Interest Statement
Fig. 5. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 4) undergoing extraction of four wisdom teeth. Over the period of 10 days, tranexamic acid was concomitantly administered at a dose of 10 mg/kg body weight three times daily. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
G.A. has received an unrestricted investigators grant from CSL Behring, and honoraria for speaker presentations and congress attendance from CSL Behring, Bayer, Baxter, Novo Nordisk and Biotest. A.B. has received financial support from CSL Behring, Bayer and Baxter. K.H., D.O. and J.J. have received financial support from Bayer and CSL Behring. C.M. has received financial support from Bayer and Baxter.
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
Acknowledgements The authors gratefully acknowledge the invaluable support from Dr. Mathias Jürs, CSL Behring, Hattersheim am Main, Germany.
References [1] DiMichele D, Neufeld EJ. Hemophilia. A new approach to an old disease. Hematol Oncol Clin North Am 1998;12:1315–44. [2] Konkle BA, Josephson NC, Nakaya Fletcher SM, Thompson AR. Hemophilia B. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Stephens K, editors. GeneReviews™. Seattle: University of Washington; 2011 [Available from: http://www.ncbi.nlm.nih. gov/books/NBK1495/ [last accessed Sept 12, 2013]]. [3] Stachnik JM, Gabay MP. Continuous infusion of coagulation factor products. Ann Pharmacother 2002;36:882–91. [4] Brinkous KM. Hemophilia. Bull N Y Acad Med 1954;30:325–42. [5] McMillan CW, Webster WP, Roberts HR, Blythe WB. Continuous intravenous infusion of factor VIII in classic haemophilia. Br J Haematol 1970;18:659–67. [6] Hathaway WE, Christian MJ, Clarke SL, Hasiba U. Comparison of continuous and intermittent factor VIII concentrate therapy in haemophilia A. Am J Hematol 1984;17:85–8. [7] Blatt PM, White II GC, McMillan CW, Roberts HR. Treatment of anti-factor VIII antibodies. Thromb Haemost 1977;38:514–23. [8] Levin J, Ness PM, Bell WR. Continuous infusion of factor VIII concentrate for therapy of haemophilia A. Blood 1981;58:220a. [9] Hermens WTH. Dose calculation of human factor VIII and factor IX concentrates for infusion therapy. In: Brinkhous KM, Hemker HC, editors. Handbook of hemophilia. New York: Elsevier; 1975. p. 569–89. [10] Bona RD, Weinstein RA, Weisman SJ, Bartolomeo A, Rickles FR. The use of continuous infusion of factor concentrates in the treatment of hemophilia. Am J Hematol 1989;32:8–13. [11] Weinstein RE, Bona RD, Rickles FR. Continuous infusion of mononclonal antibodypurified factor VIII. Am J Hematol 1991;36:211–2. [12] Schulman S, Gitel S, Martinowitz U. Stability of factor VIII concentrates after reconstitution. Am J Hematol 1994;45:217–23. [13] Metzner HJ, Watzka B, Müller HG, Klockmann U, Hermentin P, Höinghaus R, et al. Stabilität von Faktor VIII-Präparaten: Voraussetzung für die kontinuierliche Infusion. Die Gelben Hefte 1997;37:183–90. [14] Flora S, Hambley H, Thumpston J, Clark J. Continuous infusion of highly purified factor VIII (Monoclate M). Am J Hematol 1992;40:157. [15] Martinowitz U, Schulman S, Gitel H, Horozowski H, Heim M, Varon D. Adjusted dose continuous infusion of factor VIII in patients with haemophilia A. Br J Haematol 1992;82:729–34. [16] Hawkins TE, Green GJ, Romeril K, Milicich GS, Carter JM. Treatment of haemophilia A by continuous factor VIII infusion. Aust N Z J Med 1995;25:37–9. [17] Hay CR, Doughty HI, Savidge GF. Continuous infusion of factor VIII for surgery and major bleeding. Blood Coagul Fibrinolysis 1996;7(Suppl. 1):S15–9. [18] Travis SF, Burns N, Greenbaum BH, Stark E. Postoperative management of hemophilia A and low titer inhibitor at home using factor VIII continuous infusion. Clin Pediatr 1996;35:40–2. [19] Rochat C, McFadyen ML, Schwyzer R, Gillham A, Cruickshank A. Continuous infusion of intermediate-purity factor VIII in haemophilia A patients undergoing elective surgery. Haemophilia 1999;5:181–6.
S47
[20] Dingli D, Gastineau DA, Gilchrist GS, Nichols WL, Wilke JL. Continuous factor VIII infusion therapy in patients with haemophilia A undergoing surgical procedures with plasma-derived or recombinant factor VIII concentrates. Haemophilia 2002;8:629–34. [21] Bidlingmaier C, Deml MM, Kurnik K. Continuous infusion of factor concentrates in children with haemophilia A in comparison with bolus injections. Haemophilia 2006;12:212–7. [22] Martinowitz U, Luboshitz J, Bashari D, Ravid B, Gorina E, Regan L, et al. Stability, efficacy, and safety of continuously infused sucrose-formulated recombinant factor VIII (rFVIII-FS) during surgery in patients with severe haemophilia. Haemophilia 2009;15:676–85. [23] Tamura K, Kanazawa T, Suzuki M, Shioya A, Morikawa A. Successful induction of immune tolerance by continuous infusion of recombinant factor VIII in a haemophilia A patient with high-inhibitor titres. Haemophilia 2006;12:100–2. [24] Rubinger M, Houston DS, Schwetz N, Woloschuk DM, Israels SJ, Johnston JB. Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors. Am J Hematol 1997;56:112–8. [25] Goldsmith JC. Rationale and indications for continuous infusion of antihemophilic factor (factor VIII). Blood Coagul Fibrinolysis 1996;7(Suppl. 1):S3–6. [26] Varon D, Martinowitz U. Continuous infusion therapy in haemophilia. Haemophilia 1998;4:431–5. [27] von Auer Ch, Oldenburg J, von Depka M, Escuriola-Ettinghausen C, Kurnik K, Scharrer I. Inhibitor development in patients with hemophilia A after continuous infusion of FVIII concentrates. Ann N Y Acad Sci 2005;1051:498–505. [28] Sharathkumar A, Kirby M, Freedman M, Abdelhaleem M, Chitayat D, Teshima IE, et al. J Thromb Haemost 2003;1:1228–36. [29] Eckhardt CL, Menke LA, van Ommen CH, van der Lee JH, Geskus RB, Kamphuisen PW, et al. Intensive peri-operative use of factor VIII and the Arg593 → Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost 2009;7:930–7. [30] Auerswald G, Bade A, Haubold K, Overberg D, Masurat S, Moorthi C. No inhibitor development after continuous infusion of factor concentrates in subjects with bleeding disorders undergoing surgery: a prospective study. Haemophilia 2013;19:438–44. [31] Auerswald G. Continuous infusion of factor VIII concentrate after surgery in children with hemophilia. Die Gelben Hefte 1997;37:191–8. [32] Martinowitz U, Schulman S. Review of pumps for continuous infusion of coagulation factor concentrates: what are the options? Blood Coagul Fibrinolysis 1996;7(Suppl. 1):S27–33. [33] DiMichele DM, Lasak ME, Miller CH. In vitro factor VIII recovery during the delivery of ultrapure factor VIII concentrate by continuous infusion. Am J Hematol 1996;51:99–103. [34] McLeod AG, Walker IR, Zheng S, Hayward CP. Loss of factor VIII activity during storage in PVC containers due to adsorption. Haemophilia 2000;6:89–92. [35] Hurst D, Zabor S, Malianni D, Miller D. Evaluation of recombinant factor VIII (Kogenate) stability for continuous infusion using a minipump infusion device. Haemophilia 1998;4:785–9. [36] Revel-Vilk S, Blanchette V, Schmugge M, Clark DS, Lillicrap D, Rand ML. In vitro and in vivo stability of undiluted recombinant factor VIII for continuous infusion use in haemophilia A. Haemophilia 2010;16:72–9. [37] Parti R, Ardosa J, Yang L, Mankarious S. In vitro stability of recombinant human factor VIII (Recombinate™). Haemophilia 2000;6:513–22. [38] Neidhardt E, Koval R, Burke E, Warne N. In vitro evaluation of B-domain deleted recombinant factor VIII (ReFacto®) stability during simulated continuous infusion administration. Haemophilia 2005;11:319–25.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Prospective study of continuous infusion with Beriate® P in patients with severe haemophilia A undergoing surgery – a subgroup analysis Günter Auerswald ⁎, Andrea Bade, Julia Johne, Kirstin Haubold, David Overberg, Sylvia Masurat, Carolin Moorthi Centre for Thrombosis and Haemostasis, Professor-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany
a r t i c l e
i n f o
Available online 21 December 2013 Keywords: Haemophilia A Beriate® P Continuous infusion Inhibitors Coagulation disorders Surgery
a b s t r a c t Introduction: Inhibitor development in severe haemophilia A patients is currently the most serious complication of factor VIII (FVIII) treatment. Although continuous infusion (CI) of FVIII concentrate during surgical procedures in haemophilia A patients has been shown to be beneficial, some publications suggest that CI increases the risk of inhibitor generation. We conducted a prospective subgroup analysis to investigate if CI of the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate® P during surgery increases the risk of inhibitor formation. Materials and methods: Patients with severe haemophilia A (FVIII:C b1%) were included if they presented with a negative history of previous inhibitors, had ≥50 exposure days, and had been scheduled for a planned surgical procedure. A bolus infusion (30–50 IU/kg body weight) of Beriate® P was administered intravenously and followed by CI at a rate of 3–4 IU/kg body weight/hour. Dose adjustments were subsequently made based on daily measurements of plasma FVIII activity. Results: Five patients (aged 8–34 years) with severe haemophilia A were included. The surgical procedures ranged from teeth extraction to internal fixation of a fracture. There was no inhibitor generation with CI of Beriate® P in patients undergoing surgery, and we did not observe any complications due to re-bleeding or virus transmission. Conclusion: Beriate® P was efficacious, safe, and well tolerated during CI. © 2013 Published by Elsevier Ltd.
Introduction Haemophilia is an X-linked coagulation disorder that, due to its mode of inheritance, mainly affects males, and is estimated to occur at a rate of 1 in 5,000 live male births for haemophilia A [1] and 1 in 20,000 for haemophilia B worldwide [2]. The majority of haemophilia A patients present with a severe deficiency, which is defined as plasma factor VIII (FVIII) clotting activity (FVIII:C) levels below 1% [1]. Control of bleeding episodes in individuals with haemophilia A or B is achieved with the administration of coagulation factors, either plasmaderived or recombinant. Usually, these factors are given intermittently as bolus infusions to achieve haemostasis; however, there has been increasing interest in the use of continuous infusions (CI) of clotting factors for surgery in order to maintain a more constant or physiological concentration, thereby reducing the risk of bleeding from excessively low trough levels [3].
Abbreviations: BU, Bethesda Units; CI, continuous infusion; ED, exposure day; FVIII, factor VIII; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PTP, previously treated patient; PUP, previously untreated patient; PVC, polyvinylchloride; SD, standard deviation. ⁎ Corresponding author at: Centre for Thrombosis and Haemostasis, ProfessorHess-Kinderklinik, Klinikum Bremen-Mitte, St. Jürgen Str. 1, 28177 Bremen, Germany. Tel.: +49 421 497 3655x5410; fax: +49 421 497 4631. E-mail address: [email protected] (G. Auerswald). 0049-3848/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.thromres.2013.10.009
The idea of using CI of anti-haemophilic factor was first proposed in 1954 by Professor Kenneth Brinkhous in his seminal article in the Bulletin of The New York Academy of Medicine [4]. However, it was not until 1970 that the first systematic study assessing the effects of CI with FVIII as a cryoprecipitate or glycine-precipitate fraction was published [5]. In this study by McMillan et al., which assessed the effects of CI of FVIII under various conditions in five children with haemophilia A, the investigators reported that FVIII activity in glycine-precipitated fractions was stable at room temperature for up to 27 hours and that CI at a rate of 17 mL/hour of different concentrations produced levels of FVIII activity that were proportional to the dose rate and became relatively steady at 12–18 hours [5]. Subsequent pharmacokinetic studies reported similar findings [6–11]. In one such early study, Hathaway et al. established that higher FVIII concentrations could be achieved by CI compared with intermittent administration during surgery, and that CI of FVIII concentrate at a dose of 0.04 IU/kg body weight/hour intravenously could result in an increase in FVIII:C plasma levels of 1% [6]. Several factors associated with FVIII concentrates when given as a CI are important; most notably, the stability and sterility of the prepared solution. Current labelling recommends using most reconstituted FVIII products either immediately or within 1–3 hours after reconstitution (Beriate® P, however, can be used for up to 8 hours after reconstitution according to the prescribing information). Nevertheless, several studies have found that FVIII products can remain stable for longer periods of
S44
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
time after reconstitution. Schulman et al. for example, investigated the stability of 15 commonly available FVIII concentrates (including Beriate® P, CSL Behring, Marburg, Germany), and reported that FVIII activity was maintained for several days or even weeks for some of the products [12]. We subsequently have repeated these investigations with Beriate® P and Haemate® P and found stability within defined ranges for 4 days at 20–25 °C for Beriate® P in reconstituted and even diluted (1:3 with physiological saline) formulations (Fig. 1 [13]). Results for Haemate® P (dilution 1:2 in physiological saline) were similar. Tests for microbiological contamination (Staphylococcus auerus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis) at the end of this period proved to be negative [13]. Since the initial feasibility studies outlined above, the successful use of CI with FVIII has been reported in haemophilia A patients during surgical procedures [11,14–22], for the induction of immune tolerance therapy [23], for inhibitor management [24], and in primary or secondary prophylaxis [25]. When administered correctly, CI is associated with favourable haemostatic effects compared with intermittent bolus injections [26]. The advantages of CI include the maintenance of a constant FVIII concentration and a decrease in the amount of factor administered as a result of reduced factor clearance [15]. Pharmacoeconomic calculations have estimated cost savings with CI compared with bolus infusions to be in the range of 20–50% of factor concentrate used [15]. Several potential safety issues associated with CI are worthy of consideration. Prolonged therapy with factor concentrates requires the use of venous access devices, which have been associated with the development of infection, thrombosis, and thrombophlebitis [3]. Moreover, some studies have indicated that CI may be associated with an increased risk of inhibitor development [27–29]. Since data from our centre do not show an increased incidence of inhibitor generation when using CI in patients with coagulation disorders undergoing surgery, we recently undertook a prospective study to determine the rate of inhibitor formation in a surgical population of patients with haemophilia A, haemophilia B and von Willebrand disease who were being managed with CI [30]. In the current paper, we describe a subgroup analysis of patients with haemophilia A who received CI with the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate® P. Data were extracted and analyzed to provide an overview of the efficacy and safety of Beriate® P as CI in haemophilia A patients.
Materials and Methods Study Design Patients were included in the analysis of this substudy if they had severe haemophilia A (FVIII:C b1%), were ≤50 years of age, had no previous history of inhibitors, provided evidence of ≥50 exposure days (EDs), had documentation regarding their hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV) virus, and human immunodeficiency virus (HIV) type 1 or 2 status, and were scheduled for a minor or major surgical procedure. Study exclusion criteria included a contraindication to Beriate® P, a known hypersensitivity to Beriate® P, thrombophilia, or a confirmed or suspected pregnancy. The larger study was designed as a prospective study and patients were recruited from paediatric, otolaryngology, oral surgery, urology, orthopaedic, and gynaecology departments (Professor-Hess-Kinderklinik, Bremen). That study was approved prior to initiation by the Institutional Review Board of the Medical Chamber of Bremen. All subjects or their parents provided informed consent prior to study enrolment. Patients were evaluated clinically prior to surgery; a full medical history was obtained, and a complete laboratory evaluation was performed, including red blood cell count, prothrombin time, partial thromboplastin time, fibrinogen, FVIII activity in plasma (FVIII:C), FVIII inhibitor status (FVIII inhibitor), bleeding time, serological markers for HAV, HBV, HCV, and HIV-1 and -2, and, if indicated, investigation of FVIII recovery. Thirty to 60 minutes prior to surgery, a bolus injection of Beriate® P of approximately 30–50 IU/kg body weight was administered. At the start of surgery, CI was initiated at a rate of 3–4 IU/kg body weight/ hour in line with data from the literature [15]. Dose adjustments were subsequently made on the basis of daily measurements of plasma FVIII activity. Inhibitors were measured according to the Nijmegen modification of the Bethesda method. Inhibitors were investigated either in the local laboratory of our hospital or by a reference laboratory (Prof. Dr. Budde, Hamburg, Germany). Testing for inhibitors took place at baseline (prior to the start of the infusion) and 3–4 weeks after surgery. The presence of inhibitors was defined as Bethesda Units (BU) ≥0.6. Lowand high-titre inhibitors were defined as ≤5 and N5 BU, respectively. The evaluation of safety parameters included the number of bleeds during CI, the number of thromboses and other adverse events, and incidence of virus transmission. The incidence of adverse events was evaluated either directly in the clinic or 3–4 weeks after discharge. Haemostatic efficacy was rated as either “excellent” (no bleeding complications or excessive loss of blood), “good” (mild bleeding, no further treatments needed), “fair” (bleeding requiring further factor substitution) or “poor” (excessive bleeding requiring transfusion of red blood cells). The primary objective of the study was to investigate the incidence of inhibitors as a consequence of CI in our patients. Secondary objectives included evaluating the efficacy and safety of CI. Statistics We applied descriptive statistical procedures for data analysis. Demographic data are presented as means ± standard deviations; however, where the median values differed substantially from the mean values, medians plus ranges are also presented. Results
Fig. 1. Stability (factor VIII clotting activity [FVIII:C]) of Beriate® P after reconstitution, storage at 20–25 °C: mean values of three different batches with standard deviations [13]. One-stage clotting assay (dashed line), chromogenic assay (solid line). h, hours; d, days.
A total of five patients who had received Beriate® P CI were included in this analysis. All patients were male with severe haemophilia A (FVIII: C b 1%) (Table 1). The mean age of the patients was 21.2 ± 8.5 years (range 8–34). The surgical procedures evaluated were tonsillectomy
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
and adenectomy (n = 2), meniscectomy (n = 1), wisdom teeth extractions (n = 1) and internal fixation of an elbow fracture (n = 1). FVIII concentrate was administered with regular syringe pumps through a peripheral vein. All patients were observed for up to 4 weeks postoperatively and then every 4–6 months for over 1 year. Routine observation is ongoing. Figs. 2–6 show the plasma FVIII:C levels during CI with Beriate® P and consequent adaptations of CI dosing. For patient 1 (Fig. 2), who underwent a tonsillectomy and adenectomy, coagulation parameters were controlled until Day 27 (not all data shown). FVIII:C returned to b1% by 3days after the last Beriate® P infusion. The patient was negative for inhibitors and the last red blood cell count was normal. Surgery was performed without any adverse events during the peri-operative or post-operative period. Patient 2 (Fig. 3) also had a tonsillectomy and adenectomy performed without any adverse effects on red- or white cell counts, liver parameters or inhibitor titres (measured on Day 6 and Week 5 post-surgery; not all data shown). Surgery was uncomplicated and the peri-/postoperative periods uneventful. Patient 3 (Fig. 4) also had no pathological findings and no evidence of inhibitor development 5 weeks after surgery (not all data shown). Patient 4 (Fig. 5) had four wisdom teeth removed with a normal post-operative course and no evidence of abnormal laboratory parameters or inhibitor development. Patient 5 (Fig. 6) underwent internal fixation of an elbow fracture and had normal laboratory parameters when measured 6 weeks after the operation. No inhibitors developed. Splint removal was performed after 6 months, with a bolus of 2,000 IU of Beriate® P administered during the procedure. The clinical course for this patient was without adverse events, and again, no inhibitors were detected. In all five patients, no virus transmission occurred. Furthermore, during 20 years on the market, there have been no proven cases of virus transmission with Beriate® P. Over the current observation period of more than 1 year, there have been no reported side effects attributable to Beriate® P, including viral transmission (hepatitis A, B and C, HIV-1/2) or development of inhibitors. In two patients, small swelling at the infusion site was reported after 4 days; the infusion site was changed before occlusion and swelling subsided. Discussion
S45
Fig. 2. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 1) with severe haemophilia A undergoing tonsillectomy and adenectomy. Tranexamic acid was concomitantly administered peri-operatively at a dose of 10 mg/kg body weight three times daily up to Day 14. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
minimum are undesirable and result in the need for large quantities of FVIII to be infused peri-operatively. The results of this study confirm those of previously reported studies [11,14–22,31] demonstrating that CI is an effective and well-tolerated means of providing excellent haemostatic control during surgery. As would be expected, the dosing of Beriate® P varied between patients, with higher doses and longer periods of treatment required for the more complex surgical procedures. The levels of factor concentrate required with CI infusion were from 20% to more than 50% lower than those required with bolus dosing. This requirement for reduced dosing with CI has the advantage of lowering not only the costs of treatment but also the potential risk of treatment peaks. A further advantage of continuous factor concentrate infusion is the favourable titration that minimizes the risk of bleeding complications. In our study, we found no evidence of an increased risk of inhibitor development associated with CI. These findings contrast with those of other authors who have reported an association between inhibitor formation and treatment with CI for surgery or bleeding [27–29]. The
The availability of safe and effective plasma-derived and recombinant coagulation factor concentrates means that surgical indications for individuals with haemophilia are now similar to those of the general population. Most surgical centres have traditionally replaced FVIII with intermittent bolus therapy; however, the very high peak levels of FVIII required to ensure that trough levels remain above a certain
Table 1 Demographics of patients and type of surgery.
a
Characteristic
Value
Patients with severe haemophilia A Mean age ± SD (range), years Mean weight ± SD, kg Median weight (range), kg Mean height ± SD, cm Median height (range), cm Mean body mass index, kg/m2 Type of surgery, n (%) Tonsillectomy and adenectomy Meniscectomy Teeth extraction Internal fixation of elbow fracture
5 males (Caucasian) 21.2 ± 8.5 (8–34) 72.0 ± 26.3 78.0 (29.0–98.0) 170.0 ± 20.8 176.0 (134.0–188.0) 24.9 2 (40) 1 (20) 1 (20) 1 (20)
Quantitative demographic data are listed as means ± standard deviations. If means deviated from median values, median values and ranges are also listed. SD, standard deviation.
Fig. 3. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 2) with severe haemophilia A undergoing tonsillectomy and adenectomy. Tranexamic acid was concomitantly administered peri-operatively at a dose of 10 mg/kg body weight three times daily. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
S46
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
Fig. 6. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 5) undergoing internal fixation of an elbow fracture. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours. Fig. 4. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 3) with severe haemophilia A undergoing meniscectomy. No tranexamic acid was administered. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
reason for this difference might be explained in part by variances in study populations. The potential increased inhibitor risk in patients with b 50 EDs undergoing surgery and receiving CI, led us to include only subjects with severe haemophilia A who had ≥50 EDs. Such strict inclusion and exclusion criteria may have ensured that the risk of inhibitor development was minimized, and could explain why we did not observe the development of inhibitors in any of our patients. These observations are in line with suggestions from Bidlingmaier et al., who recommend CI only in patients with ≥20 EDs [21]. The question of whether CI is associated with a higher risk of inhibitor development than bolus administration will only be addressed adequately in a randomized, controlled trial in which the two modes of administration are compared directly. Plasma-derived FVIII concentrates, such as Beriate® P offer a number of practical advantages over recombinant products when used in CI regimens. The higher volumes associated with plasma-derived FVIII concentrates – which may be viewed as a disadvantage in everyday clinical practice – is a major advantage in CI regimens, as the reconstituted product does not need dilution. Reconstitution of FVIII concentrates with low volumes can cause pump problems and, since
most widely used pumps are unable to handle infusion of small volumes, mini-pumps are required, which are expensive, less readily available, and may be associated with thrombophlebitis at the injection site [32]. DiMichele et al. conducted a comparative study of continuously infused plasma-derived versus recombinant FVIII products and found significant differences in recovery between plasma-derived and recombinant products [33]. Both monoclonal antibody-purified plasma-derived FVIII products evaluated showed a stable recovery of 84–109% during the 8-hour infusion, whereas the two recombinant FVIII products, when reconstituted in normal saline, showed an early drop in recovery to 57–76%. When the recombinant FVIII products were restudied with the addition of 10 mg/mL of human albumin to the bags, no improvement in recovery was observed [33]. McLeod et al. reported significant (42%) loss of FVIII activity when recombinant FVIII concentrates were diluted and stored in polyvinylchloride (PVC)-based containers after just 48 hours of storage [34]. An even greater loss of activity was found for polyethylene compared with PVC containers in an investigation of CI using a recombinant FVIII product conducted by Hurst et al. [35]. The problem of reduced activity appears to be especially acute with recombinant FVIII products in which no albumin is added as a stabilizer. This is true for all recombinant FVIII products currently available on the German market. In the most recent investigation, published in 2010, Revel-Vilk et al. confirmed loss of FVIII activity for a recombinant FVIII concentrate even when dilutions were moderate [36]. Similar observations have been described by other investigators [37,38]. In summary, in our study, Beriate® P was found to have an excellent efficacy and safety profile when used as a continuous infusion during surgery. Haemostasis was achieved in all patients, wound healing was uncomplicated, no re-surgeries were required, no virus transmissions or thromboses occurred, and no inhibitor generation was observed. The practical advantages of plasma-derived over recombinant FVIII products – including the ability to use regular perfusers rather than mini-pumps – suggest that products such as Beriate® P have an important role to play in the peri-operative management of individuals with severe haemophilia A who have had at least 20–50 prior EDs. Conflict of Interest Statement
Fig. 5. Clinical course of continuous infusion (CI) of Beriate® P in a patient (patient 4) undergoing extraction of four wisdom teeth. Over the period of 10 days, tranexamic acid was concomitantly administered at a dose of 10 mg/kg body weight three times daily. b.w., body weight; FVIII:C, factor VIII clotting activity; h, hours.
G.A. has received an unrestricted investigators grant from CSL Behring, and honoraria for speaker presentations and congress attendance from CSL Behring, Bayer, Baxter, Novo Nordisk and Biotest. A.B. has received financial support from CSL Behring, Bayer and Baxter. K.H., D.O. and J.J. have received financial support from Bayer and CSL Behring. C.M. has received financial support from Bayer and Baxter.
G. Auerswald et al. / Thrombosis Research 134 (2014) S43–S47
Acknowledgements The authors gratefully acknowledge the invaluable support from Dr. Mathias Jürs, CSL Behring, Hattersheim am Main, Germany.
References [1] DiMichele D, Neufeld EJ. Hemophilia. A new approach to an old disease. Hematol Oncol Clin North Am 1998;12:1315–44. [2] Konkle BA, Josephson NC, Nakaya Fletcher SM, Thompson AR. Hemophilia B. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Stephens K, editors. GeneReviews™. Seattle: University of Washington; 2011 [Available from: http://www.ncbi.nlm.nih. gov/books/NBK1495/ [last accessed Sept 12, 2013]]. [3] Stachnik JM, Gabay MP. Continuous infusion of coagulation factor products. Ann Pharmacother 2002;36:882–91. [4] Brinkous KM. Hemophilia. Bull N Y Acad Med 1954;30:325–42. [5] McMillan CW, Webster WP, Roberts HR, Blythe WB. Continuous intravenous infusion of factor VIII in classic haemophilia. Br J Haematol 1970;18:659–67. [6] Hathaway WE, Christian MJ, Clarke SL, Hasiba U. Comparison of continuous and intermittent factor VIII concentrate therapy in haemophilia A. Am J Hematol 1984;17:85–8. [7] Blatt PM, White II GC, McMillan CW, Roberts HR. Treatment of anti-factor VIII antibodies. Thromb Haemost 1977;38:514–23. [8] Levin J, Ness PM, Bell WR. Continuous infusion of factor VIII concentrate for therapy of haemophilia A. Blood 1981;58:220a. [9] Hermens WTH. Dose calculation of human factor VIII and factor IX concentrates for infusion therapy. In: Brinkhous KM, Hemker HC, editors. Handbook of hemophilia. New York: Elsevier; 1975. p. 569–89. [10] Bona RD, Weinstein RA, Weisman SJ, Bartolomeo A, Rickles FR. The use of continuous infusion of factor concentrates in the treatment of hemophilia. Am J Hematol 1989;32:8–13. [11] Weinstein RE, Bona RD, Rickles FR. Continuous infusion of mononclonal antibodypurified factor VIII. Am J Hematol 1991;36:211–2. [12] Schulman S, Gitel S, Martinowitz U. Stability of factor VIII concentrates after reconstitution. Am J Hematol 1994;45:217–23. [13] Metzner HJ, Watzka B, Müller HG, Klockmann U, Hermentin P, Höinghaus R, et al. Stabilität von Faktor VIII-Präparaten: Voraussetzung für die kontinuierliche Infusion. Die Gelben Hefte 1997;37:183–90. [14] Flora S, Hambley H, Thumpston J, Clark J. Continuous infusion of highly purified factor VIII (Monoclate M). Am J Hematol 1992;40:157. [15] Martinowitz U, Schulman S, Gitel H, Horozowski H, Heim M, Varon D. Adjusted dose continuous infusion of factor VIII in patients with haemophilia A. Br J Haematol 1992;82:729–34. [16] Hawkins TE, Green GJ, Romeril K, Milicich GS, Carter JM. Treatment of haemophilia A by continuous factor VIII infusion. Aust N Z J Med 1995;25:37–9. [17] Hay CR, Doughty HI, Savidge GF. Continuous infusion of factor VIII for surgery and major bleeding. Blood Coagul Fibrinolysis 1996;7(Suppl. 1):S15–9. [18] Travis SF, Burns N, Greenbaum BH, Stark E. Postoperative management of hemophilia A and low titer inhibitor at home using factor VIII continuous infusion. Clin Pediatr 1996;35:40–2. [19] Rochat C, McFadyen ML, Schwyzer R, Gillham A, Cruickshank A. Continuous infusion of intermediate-purity factor VIII in haemophilia A patients undergoing elective surgery. Haemophilia 1999;5:181–6.
S47
[20] Dingli D, Gastineau DA, Gilchrist GS, Nichols WL, Wilke JL. Continuous factor VIII infusion therapy in patients with haemophilia A undergoing surgical procedures with plasma-derived or recombinant factor VIII concentrates. Haemophilia 2002;8:629–34. [21] Bidlingmaier C, Deml MM, Kurnik K. Continuous infusion of factor concentrates in children with haemophilia A in comparison with bolus injections. Haemophilia 2006;12:212–7. [22] Martinowitz U, Luboshitz J, Bashari D, Ravid B, Gorina E, Regan L, et al. Stability, efficacy, and safety of continuously infused sucrose-formulated recombinant factor VIII (rFVIII-FS) during surgery in patients with severe haemophilia. Haemophilia 2009;15:676–85. [23] Tamura K, Kanazawa T, Suzuki M, Shioya A, Morikawa A. Successful induction of immune tolerance by continuous infusion of recombinant factor VIII in a haemophilia A patient with high-inhibitor titres. Haemophilia 2006;12:100–2. [24] Rubinger M, Houston DS, Schwetz N, Woloschuk DM, Israels SJ, Johnston JB. Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors. Am J Hematol 1997;56:112–8. [25] Goldsmith JC. Rationale and indications for continuous infusion of antihemophilic factor (factor VIII). Blood Coagul Fibrinolysis 1996;7(Suppl. 1):S3–6. [26] Varon D, Martinowitz U. Continuous infusion therapy in haemophilia. Haemophilia 1998;4:431–5. [27] von Auer Ch, Oldenburg J, von Depka M, Escuriola-Ettinghausen C, Kurnik K, Scharrer I. Inhibitor development in patients with hemophilia A after continuous infusion of FVIII concentrates. Ann N Y Acad Sci 2005;1051:498–505. [28] Sharathkumar A, Kirby M, Freedman M, Abdelhaleem M, Chitayat D, Teshima IE, et al. J Thromb Haemost 2003;1:1228–36. [29] Eckhardt CL, Menke LA, van Ommen CH, van der Lee JH, Geskus RB, Kamphuisen PW, et al. Intensive peri-operative use of factor VIII and the Arg593 → Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost 2009;7:930–7. [30] Auerswald G, Bade A, Haubold K, Overberg D, Masurat S, Moorthi C. No inhibitor development after continuous infusion of factor concentrates in subjects with bleeding disorders undergoing surgery: a prospective study. Haemophilia 2013;19:438–44. [31] Auerswald G. Continuous infusion of factor VIII concentrate after surgery in children with hemophilia. Die Gelben Hefte 1997;37:191–8. [32] Martinowitz U, Schulman S. Review of pumps for continuous infusion of coagulation factor concentrates: what are the options? Blood Coagul Fibrinolysis 1996;7(Suppl. 1):S27–33. [33] DiMichele DM, Lasak ME, Miller CH. In vitro factor VIII recovery during the delivery of ultrapure factor VIII concentrate by continuous infusion. Am J Hematol 1996;51:99–103. [34] McLeod AG, Walker IR, Zheng S, Hayward CP. Loss of factor VIII activity during storage in PVC containers due to adsorption. Haemophilia 2000;6:89–92. [35] Hurst D, Zabor S, Malianni D, Miller D. Evaluation of recombinant factor VIII (Kogenate) stability for continuous infusion using a minipump infusion device. Haemophilia 1998;4:785–9. [36] Revel-Vilk S, Blanchette V, Schmugge M, Clark DS, Lillicrap D, Rand ML. In vitro and in vivo stability of undiluted recombinant factor VIII for continuous infusion use in haemophilia A. Haemophilia 2010;16:72–9. [37] Parti R, Ardosa J, Yang L, Mankarious S. In vitro stability of recombinant human factor VIII (Recombinate™). Haemophilia 2000;6:513–22. [38] Neidhardt E, Koval R, Burke E, Warne N. In vitro evaluation of B-domain deleted recombinant factor VIII (ReFacto®) stability during simulated continuous infusion administration. Haemophilia 2005;11:319–25.