Abstract
Background
In patients with moderate to severe qualitative and quantitative von Willebrand disease (VWD), even minor surgical procedures can be associated with a risk of life-threatening bleeding. Treatment strategies vary according to the levels of von Willebrand factor (VWF) and Factor VIII (FVIII). The aim of this study was to evaluate the effectiveness and the safety of Voncento® (CSL Behring, Marburg, Germany), a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), during surgeries performed in patients with inherited VWD.
Materials and methods
The OPALE study, a French multicentre observational study, was carried out from May 2016 to May 2019. It evaluated and analysed patients with inherited VWD (any type) requiring treatment with Voncento® who underwent surgery.
Results
In total, 92 patients were enrolled, and 66 patients underwent 100 surgical procedures: 69 minor and 31 major surgeries conducted in 30 patients with type 1, 50 patients with type 2, and 20 patients with type 3 VWD. During minor surgeries, the median number of infusions was one (range: 1–9), the pre-operative loading dose was 41 IU VWF:RCo kg−1 (range: 18–147), and the total dose was 63 (range: 18–594). During major surgeries, the number of infusions was 4 (range: 1–23), the pre-operative loading dose was 43 (range: 25–66) IU VWF: RCo kg−1, and the total dose was 155 (range: 40–575). The median FVIII:C levels ranged from 78 to 165 IU dL−1 during 5 days after minor surgeries and from 86 and 167 IU dL−1 during 11 days after major surgeries. VW:RCo levels ranged between 35 and 65 IU dL−1 and between 34 and 76 IU dL−1 after minor and major surgeries, respectively. The overall clinical effectiveness was qualified as “excellent” or “good” in 99% of patients. No thrombotic events related to Voncento® were recorded.
Discussion
The present study suggests that Voncento® is an effective and well-tolerated therapy for the peri-operative management of patients with all VWD types.
Keywords: bleeding, von Willebrand disease, surgery, FVIII/VWF concentrates, Voncento®
INTRODUCTION
Inherited von Willebrand disease (VWD) is considered the most common bleeding disorder. Its prevalence is approximately 1% in the general population but symptomatic patients are rarer (0.01%)1. It is caused by a partial or total quantitative deficiency (type 1 and type 3) or by a qualitative defect (type 2) of von Willebrand factor (VWF), a large multimeric protein that is required for platelet adhesion and serves as factor VIII (FVIII) carrier. Type 2 VWD is further divided into four subgroups (2A, 2B, 2M, and 2N) that are distinguished according to the nature of the VWF defect2. In patients with moderate to severe qualitative and quantitative VWD, even relatively minor surgical procedures can be associated with a risk of life-threatening excessive bleeding3. As VWD clinical severity and laboratory diagnosis are heterogeneous, treatment strategies for surgical procedures vary according to the type of VWF functional impairment and the levels of VWF and FVIII4,5. Most patients with type 1 VWD can be treated with the synthetic vasopressin analogue desmopressin (DDAVP; 2-desamino-8-D-arginine vasopressin), whereas patients with type 3 VWD and most patients with type 2 VWD require concentrates containing VWF. Plasma-derived FVIII concentrates, which were initially developed for the treatment of haemophilia, contain large amounts of VWF and are used in patients for whom DDAVP treatment is considered ineffective or is contraindicated. Voncento® (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived FVIII/VWF concentrate that has been registered in France since 2015 for the treatment and prevention of bleeding events in patients with inherited VWD. This concentrate was registered in Australia in 2000 and is used there under the name Biostate® (CSL Behring). This plasma-derived product has preserved high molecular weight (HMW) multimers which are important for haemostatic efficacy6. In Voncento®, the ratio of FVIII to VWF activity is 1:2.4. A comparative pharmacokinetic study between Biostate® and AHF (High Purity; CSL Behring) factor in patients with VWD demonstrated favourable increase of FVIII coagulant activity (FVIII:C), VWF ristocetin co-factor activity (VWF:RCo), VWF antigen levels (VWF:Ag), and VWF HMW multimers in plasma following Biostate® (Voncento®) infusion6. Around the same time, a retrospective study on a small cohort of patients with VWD undergoing invasive procedures or elective surgery reported that Biostate® was effective for bleeding prevention7, as did a subsequent smaller but prospective study8.
In the framework of a multicentre observational study evaluating effectiveness and safety of Voncento® to prevent bleeding in patients with VWD, the aim of the present analysis was to evaluate this treatment in patients undergoing surgical procedures in real-life settings.
MATERIALS AND METHODS
Patients
The Observatoire des Patients présentant une Maladie de Willebrand et traités par Voncento® (OPALE) study is a French multicentre observational study to evaluate patients with inherited VWD (any type) requiring treatment with Voncento®. The study was conducted from May 2016 to May 2019 in 14 French Bleeding Disorder Centres: Nantes, Lyon, Paris-Bicètre (2 centres), Besançon, Paris-Necker, Le Chesnay, Strasbourg, Paris-Lariboisière, Brest, Caen, Nancy, Eaubonne, Paris-Cochin.
The current analysis focuses on the patients included in the OPALE study who underwent surgical procedures during the study period. At baseline, the following patient data were recorded: age, sex, weight, blood group, VWD type and plasma FVIII:C, VWF:RCo, and VWF:Ag levels. VWD was diagnosed and classified by each investigator according to the clinical and laboratory criteria published by the International Society of Thrombosis and Haemostasis (ISTH)4. For the patients with type 1 VWD, lack of response or a contraindication to desmopressin were inclusion criteria in this study. The molecular analysis performed by the French national reference centre for VWD confirmed the VWD type in all patients. For patients with haemophilia, surgical procedures were defined as major if they met any of following criteria: orthopaedic intervention involving joints, >3 molar extractions, any gynaecological procedure, any procedure with a high risk of bleeding, and surgical opening into the large body cavities9; all other surgeries were classified as minor.
Pre-operative loading dose (IU kg−1), total dose (IU kg−1), number of exposure days (ED), and treatment duration with Voncento® (days) were recorded. The initial pre-operative dose, maintenance dose, and treatment duration were chosen by each investigator, without using pharmacokinetic data. Data on associated treatments potentially interacting with haemostasis, such as tranexamic acid, antithrombotic agents, and non-steroidal anti-inflammatory drugs, administered during and after surgery were also noted. Monitoring of FVIII:C and VWF:RCo levels before each infusion were prescribed according to each physician’s routine practice, and values were collected when available. The clinical effectiveness was evaluated by each investigator as “any” to “excellent”, and adverse events were also recorded by each investigator. An institutional review board approved the study in accordance with French regulations. Patients or the parents/guardian of children signed full informed consent.
RESULTS
Patients’ characteristics
In total, 92 patients were enrolled in the OPALE study of whom 66 underwent surgery and are described in the present analysis. Median age was 45 (range: 4–86) years, and 66.7% were women. Twenty-three patients (34.8%) had type 1, 37 (56.1%) patients had type 2 (n=10 type 2M, n=6 type 2N, n=13 type 2A, n=5 with type 2B, n=2 type 2B/2N, and n=1 type 3/2N), and 6 (9.1%) had type 3 VWD. The demographic characteristics are summarised in Table I. At baseline, the median VWF:RCo level was 12 (range: 3–83) IU dL−1, that of VWF:Ag was 22.5 (range: 1–88) IU dL−1, that of FVIII:C was 26.5 (range: 1–63) IU dL−1, and platelet count was 211 (range: 11–351)×109/L. Data according to the VWD type are available in Table II. Among the patients with type 2, 6 patients with type 2N VWD had normal VWF:RCo levels.
Table I.
Demographic characteristics of patients with von Willebrand disease undergoing surgery
| Total n=66 |
Type 1 n=23 |
Type 2 n=37 |
Type 3 n=6 |
|
|---|---|---|---|---|
|
| ||||
| Sex, n(%) | ||||
| Male | 22 (33.3%) | 8 (34.8%) | 11 (29.7%) | 3 (50.0%) |
| Female | 44 (66.7%) | 15 (65.2%) | 26 (70.3%) | 3 (50.0%) |
|
| ||||
| Blood group O, n (%) | 31 (48.4%) | 14 (60.9%) | 15 (42.9%) | 2 (33.3%) |
|
| ||||
| Median age, years (range) | 45 (4–86) | 44 (5–86) | 44 (5–86) | 30.5 (5–66) |
|
| ||||
| Median body weight, kg (range) | 67.0 (16.3–117 kg) | 68.0 (17.0–117 kg) | 68.0 (16.3–105.0 kg) | 56.3 (21.0–90.0 kg) |
n: number
Table II.
Baseline factor levels according to the type of von Willebrand disease
| Total n=66 |
Type 1 n=23 |
Type 2 n=37 |
Type 3 n=6 |
||
|---|---|---|---|---|---|
| Type 2A, 2B, 2M n=31 |
Type 2N n=6 |
||||
| VWF:RCo, IU dL−1 | 12.0 (3–83) | 14.5 (4–35) | 10 (3–37) | 68 (29–83) | Undetectable |
| VWF:Ag, IU dL−1 | 22.5 (1–88) | 15.0 (6–47) | 25 (6–78) | 67 (38–88) | Undetectable |
| FVIII:C, IU dL−1 | 26.5 (1–63) | 27.0 (8–62) | 31 (6–63) | 18 (12–22) | 1.0 (1–2) |
| Platelets, ×109/L | 211 (11–351) | 255 (143–351) | 189 (11–305) | 220 (197–259) | 158 (80–284) |
VWD: von Willebrand disease; n: number. Results are expressed as median values (range).
Surgical procedures and Voncento® treatment
During the study period, the 66 patients underwent a total of 100 surgical procedures (n=69 minor and n=31 major surgeries; n=30 in patients with type 1, n=50 in patients with type 2, and n=20 in patients with type 3 VWD) using Voncento® to prevent bleeding complications. Minor surgeries were mainly dental (27 of 69, 39%) and digestive (15 of 69, 22%) procedures, while orthopaedic procedures represent 18 of 31 (58%) major surgeries. Forty-seven patients underwent one surgical intervention, 18 patients had 2–5, and one patient with major comorbidities had 10 surgical procedures.
During minor surgeries, the median number of infusions was one (range: 1–9), the median pre-operative loading dose was 41 (range: 18–147) IU VWF:RCo kg−1, and the median total dose was 63 (range: 18–594) IU VWF:RCo kg−1. The median number of ED was one (range: 1–8) and the duration of treatment was one day (range: 1–11). Data according to the VWD type are available in Table III.
Table III.
Treatment modalities and duration during minor surgeries
| n (%) | Total 69 (100%) |
Type 1 19 (28%) |
Type 2 34 (49%) |
Type 3 16 (23%) |
|---|---|---|---|---|
| N of infusions* | 1 (1–11) | 1 (1–4) | 1 (1–6) | 3 (1–11) |
| Loading dose IU VWF: RCo kg−1* | 41 (18–147) | 36 (27–66) | 42 (19–147) | 53 (18–75) |
| Total dose, IU VWF: RCo kg−1* | 63 (18–594) | 38 (27–180) | 55 (19–280) | 119 (28–594) |
| Exposure, days | 1 (1–8) | 1 (1–4) | 1 (1–6) | 2 (1–8) |
| Duration, days* | 1 (1–11) | 1 (1–4) | 1 (1–11) | 2 (2–8) |
n: number.
Results are expressed as median values (range).
During major surgeries, the median number of infusions was 4 (range: 1–23), the median pre-operative loading was 43 (range: 25–66) IU VWF: RCo kg−1, and the median total dose was 155 (range: 40–575) IU VWF: RCo kg−1. The median number of ED was 4 (range: 1–26) while the median treatment duration was 4 days (range: 1–26). Data according to VWD type are available in Table IV.
Table IV.
Treatment modalities and duration during major surgeries
| n (%) | Total 31 (100%) |
Type 1 11 (35%) |
Type 2 16 (52%) |
Type 3 4 (13%) |
|---|---|---|---|---|
| N of infusions* | 4 (1–23) | 4 (1–7) | 4 (1–15) | 19.5 (8–23) |
| Loading dose IU VWF: RCo kg−1* | 43 (25–66) | 42 (25–58) | 43 (26–52) | 59.5 (44–66) |
| Total dose, IU VWF: RCo kg−1* | 155 (40–575) | 126 (42–450) | 130.5 (40–310) | 492 (330–575) |
| Exposure, days | 4 (1–22) | 4 (1–6) | 3.5 (1–8) | 18.5 (7–22) |
| Duration, days* | 4 (1–26) | 4 (1–6) | 4 (1–9) | 22 (15–26) |
n: number; VWD: von Willebrand disease. Results are expressed as median values (range).
Tranexamic acid was prescribed in 38 of 69 (55%) minor surgeries, and in 11 of 31 (34%) major surgeries, and in 74% (20 of 27) of dental procedures. Eight patients received an antithrombotic agent during 2 of 23 orthopaedic procedures, 3 of 17 digestive procedures, one of 11 gynaecological procedures, and 2 of 27 dental surgeries.
Laboratory monitoring of replacement therapy
In total, plasma FVIII:C were monitored throughout the post-operative period for 60 surgical procedures (n=30 [43%] minor, and n=30 [97%] major surgeries including 18 orthopaedic procedures) and VWF:RCo levels for 34 surgical procedures (n=15 [22%] minor and n=19 [61%] major surgeries) (Figure 1).
Figure 1.
Median (range) post-operative FVIII:C and von Willebrand Factor (VWF):RCo levels
After (A) minor and (B) major surgery.
After minor surgeries, the median FVIII:C levels ranged between 78 and 165 IU dL−1 during the first 5 days post surgery, while the median VW:RCo levels ranged between 35 and 65 IU dL−1 (Figure 1A). The highest FVIII:C levels were observed at day 1 and 3 post surgery (277 and 214 IU dL−1, respectively), while the lowest VWF:RCo level recorded from day 1 to day 5 was 35 IU dL−1. After major surgeries, the median FVIII:C levels varied between 86 and 167 IU dL−1 during 11 days post surgery, while median VW:RCo levels ranged between 34 and 76 IU dL−1 (Figure 1B). The highest FVIII:C levels were observed on day 2 and day 3 post surgery (288 and 290 IU dL−1, respectively), while the lowest VWF:RCo level recorded from day 1 to day 8 was 21 IU dL−1.
Clinical outcomes and safety
The overall clinical effectiveness was qualified as ‘excellent’ or ‘good’ in 99% of patients and ‘moderate’ in one minor surgery. No bleeding complications were recorded. Six adverse events were reported: headaches (n=2), vomiting (n=1), discomfort (n=1), atrial fibrillation (n=1), and deep vein thrombosis (n=1). The latter occurred in a 53-year-old woman with type 2N VWD and a Body Mass Index >31 kg/m2 who underwent total hip replacement and developed deep vein thrombosis 10 days after the last infusion of Voncento® and despite thromboprophylaxis. In this patient, FVIII:C level was <150 IU/dL during Voncento® treatment (doses received at days 0, 1 and 3 were 40, 26, and 26 IU VWF:RCo kg−1, respectively). This episode was evaluated as being unrelated to the Voncento® treatment by the investigator.
DISCUSSION
The results of this large prospective study corroborate the findings of two previous series showing the effectiveness and safety of Voncento® to prevent bleeding in patients with VWD undergoing surgical procedures7,8.
The findings reported here indicate that patients receive a wide range of pre-operative loading doses; there is also heterogeneity regarding total dose and duration of treatment for both minor and major surgeries. In addition, Voncento® was found to be effective for 18 surgeries (minor: 9; major: 9) (data not shown) despite lower doses than those recommended by the guidelines for the treatment of patients with VWD during surgical procedures (30–60 IU VWF:RCo kg- for minor surgery and 40–60 IU VWF:RCo kg-1 for major surgery)10. Similarly, total doses and the number of exposure days were lower than those reported in series using other factor concentrates, such as Wilate® (Octapharma, Lachen, Switzerland), Humate-P® (CSL Behring), or Wilfactin® (LFB SA, Les Ulis, France)11–13. However, these studies cannot be compared in terms of loading and total dose because of the heterogeneity of FVIII content. The heterogeneity in treatment regimens has been highlighted by a European survey based on a review of the literature, which meant the authors were unable to establish factor level thresholds to prevent risk of bleeding during surgical procedures in patients with VWD14. Interestingly, with the exception of patients with type 3 VWD who received higher median loading and total doses in both minor and major surgeries, there was no difference in treatment characteristics according to the type of VWD as reported elsewhere with other factor concentrates11–13.
Although factor level monitoring was performed according to each physician’s routine practice, FVIII:C were recorded in nearly all patients and VWF:RCo levels in almost two-thirds of patients undergoing major surgery. Several different guidelines for laboratory monitoring of replacement therapy in patients with VWD undergoing surgery are available and the frequency of this monitoring remains a question of debate10,15,16. Some authors recommend FVIII:C quantification to monitor thrombotic risk associated with FVIII:C >150 IU dL−1, which is considered a venous thromboembolism risk threshold15. Here, FVIII:C was quantified in several patients at least up to day 7 after major surgery, and the median FVIII:C levels was <160 IU dL−1 (range: 80–230 IU dL−1). In our study, the post-operative FVIII:C levels after the use of Voncento®, a plasma-derived FVIII/VWF product with a ratio of FVIII to VWF activity of 1:2.4, are similar to those reported in a prospective study using a highly purified VWF concentrate without FVIII; the post-operative FVIII:C median levels were above 150 IU dL−1 (range: 70–300 IU dL−1) at day 4 post surgery13.
No thrombotic event was reported among the 31 major surgical interventions, including several orthopaedic and gynaecological procedures. As in the first series using Biostate®7,8, and in studies using other VWF concentrates, the present study confirms the safety of Voncento® with regards to the risk of thrombosis associated with high FVIII:C level. Gill et al. suggested that the high transient levels of FVIII and/or VWF in patients undergoing surgery and treated with factor concentrates do not usually result in thrombotic complication17. The median treatment duration herein, even for major surgery, was lower than that recommended by the US guidelines10; this also could have contributed to Voncento® effectiveness and safety. In addition, tranexamic acid was prescribed relatively rarely after major surgeries (34%) avoiding perhaps increased thrombotic risk. Tranexamic acid was mainly prescribed for minor interventions (55%) and for dental procedures (74%) as described by Leebeek et al.18. However, the value of this treatment in association with factor concentrates should be confirmed in large, randomised and prospective studies.
The present study does have certain limitations. For example, the choice of the definition of minor and major surgeries remains arguable because it is based on the bleeding risk in patients with haemophilia, which could differ to that in patients with VWD (except for type 3 VWD). Furthermore, it is also of note that there are also no consistent recommendations for major or minor surgery for patients with haemophilia9. As for haemophilia, clear and consistent definitions are desirable to provide guidance on the appropriate treatment and to improve the accuracy of trial data in order to facilitate the interpretation of surgical outcomes. Another limitation is the large heterogeneity of surgery types and treatment modalities. Moreover, because the volume of the blood loss was not reported in this prospective study, the evaluation of the haemostatic effects was only qualitative. Thus, additional studies are needed to determine the minimal effective dose and the frequency and duration of treatment with Voncento® (and the other available factor concentrates) to maintain haemostasis in post-operative settings.
CONCLUSIONS
The present study suggests that Voncento®, a plasma-derived FVIII/VWF concentrate (ratio 1:2.4) is an effective and well-tolerated therapy for the peri-operative management of major and minor surgical procedures in patients with all VWD types.
ACKNOWLEDGEMENTS
We thank Philip Robinson (DRCI, Hospices Civils de Lyon) for his advice.
Footnotes
AUTHORSHIP CONTRIBUTIONS
LR, Rd’O, AH, MT designed the research study, performed the research, analysed the data, and wrote the paper. VP, GM, EDR, DD, NIB, BPP, AB-D, SC, BF, AH performed the research and reviewed the manuscript. HC, DB analysed the data and wrote the paper. All authors read and approved the final manuscript.
The Authors declare that they have no conflicts of interest and that this work was funded by an unconditional grant from CSL Behring.
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