Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery: Comment

We were interested to read the recently published paper in the Journal of Thrombosis and Haemostasis by Peyvandi et al1 The phase 3 study evaluates the efficacy and safety of recombinant von Willebrand factor (rVWF) in patients with severe von Willebrand disease (VWD) undergoing elective surgery. The paper provides supporting evidence for the use of rVWF to achieve hemostasis during surgical procedures; however, there are a number of unanswered questions that need further clarification in order to understand the clinical implications fully and provide guidance to clinicians.

In general, treatment strategies for VWD vary by the type and severity of disease; when acute bleeding or trauma occurs, or to prevent bleeding in the surgical setting, patients are treated with desmopressin or VWF-containing concentrates. Prophylaxis has been successfully used to treat patients with hemophilia,2 and although it is logical to assume that this success could translate to severe VWD, there is limited documented experience on the long-term benefit of prophylaxis in these patients.3 Data from the prophylaxis network showed that patients with type 1 and type 2 VWD were rarely treated prophylactically, and although patients with type 3 VWD were more likely to be treated prophylactically, it was only used in 28.7% and 12.2% of patients in Europe and the United States, respectively.4

We are in a new era of treatment for VWD and there is a need to understand how rVWF should be used in the perioperative period. Treatment of surgical bleeds is challenging and is dependent on each patient's current treatment strategy. As described previously, the majority of patients with VWD are treated on demand; therefore, factor VIII (FVIII) levels prior to surgery may be low, and in the Peyvandi study,1 patients were treated with a loading dose of rVWF (40-60 IU/kg) 12-24 h prior to the surgical procedure to allow endogenous levels of FVIII:C to rise to ≥30 IU/dL for minor/oral surgery or ≥60 IU/dL for major surgery. FVIII levels were assessed within 3 h of the start of surgery and rVWF was to be coadministered with rFVIII within 1 to 2 h prior to surgery to meet recommended peak plasma levels of FVIII (minor/oral, 40-50 IU/dL; major, 80-100 IU/dL). However, in 2/10 patients undergoing major surgery, FVIII was supplemented even when FVIII:C levels ≥100 IU/dL were achieved, while in a further2 patients FVIII was not given despite plasma levels <80 IU/dL. Postoperatively, one patient received a further six doses of FVIII despite preoperative FVIII:C levels >100 IU/dL. This is not consistent with recommendations provided to investigators in this study as described by Peyvandi and colleagues and may lead to confusion as to the appropriate management of patients with VWD undergoing surgery in clinical practice.

Furthermore, confusion already exists in the literature; there is no consensus on the management of patients with VWD undergoing surgery, including dosage and optimum levels of VWF and FVIII during the perioperative period. U.S. guidelines recommend loading doses of VWF of 40 to 60 IU/kg for major surgery and 30 to 60 IU/kg for minor surgery, with maintenance doses of 20 to 40 IU/kg every 8 to 24 h and every 12 to 48 h, respectively.5 The therapeutic goal is to maintain FVIII levels >50 IU/dL for 7 to 14 days in patients undergoing major surgery and 3 to 5 days for those undergoing minor surgery. In contrast, UK guidelines do not provide recommendations on doses of VWF and FVIII; rather they recommend that FVIII levels should be monitored regularly in all major and the majority of minor surgical procedures, and that during major surgical procedures FVIII plasma levels should be maintained ≥100 IU/dL, and should be sustained >50 IU/dL in the postoperative period.6

In addition, patients are generally admitted to hospital on the day of surgery and treatment with VWF loading doses 12 to 24 h prior to the surgical procedure is not usual clinical practice. Discussion on how this could be addressed in a real-life setting, including its impact on patients and costs such as additional days in hospital, is missing. Furthermore, loading doses up to a day prior to the start of surgery is only feasible with elective surgeries. There is a need to understand how these data can translate to emergency surgery, and guidance related to the use of rVWF in the perioperative period for these surgeries would be useful, particularly with respect to the need for concomitant FVIII. A previous study of a plasma-derived VWF concentrate containing very low FVIII levels provided guidance for both scheduled and unscheduled surgeries.7 All patients received a 50- to 60-IU/kg loading dose of VWF concentrate 1 h prior to surgery according to local clinical practices. Following this, treatment regimens differed depending on the type of surgery. For scheduled procedures, patients received an infusion of VWF concentrate (50 or 60 IU/kg) 12 to 24 h prior to the procedure in order to allow endogenous FVIII to attain plasma levels of ≥60 IU/dL at the time of surgery. For unscheduled procedures, the preoperative VWF dose was coadministered with a priming dose of FVIII in order to attain a FVIII peak of at least 60 IU/dL. Similar to emergency surgery, FVIII may also need to be coadministered for patients treated on demand who are experiencing a severe bleed. As the majority of patients with VWD are treated on demand, guidance in this situation would be helpful.

These studies indicate that surgery can be successfully performed by providing adequate and timely hemostasis during the perioperative procedure. However, further guidance may still be warranted for emergency surgeries. In the Peyvandi study,1 pharmacokinetic analysis (see Figure 1) showed that following a loading dose of rVWF it takes up to 12 h for FVIII levels to rise to target levels (≥30 IU/dL for minor/oral surgery or ≥60 IU/dL for major surgery). However, for emergency surgeries it may not be possible to wait for FVIII levels to rise before starting the procedure. Furthermore, there may not be time to assess FVIII levels prior to surgery as indicated by Peyvandi et al1 Thus, in this situation additional FVIII administration would be warranted.

In addition to the uncertainties described previously, the impact of rVWF on bleeding events and transfusion requirements during surgery is lacking. Actual intraoperative blood loss relative to predicted blood loss is provided in the Supplementary Information and that one patient with type 3 VWD undergoing a total knee replacement received an intraoperative transfusion of packed red blood cells (500 mL volume) is stated. However, it would be helpful for the authors to elaborate on further outcome criteria and add more details on transfusion requirements if any.

The study supports the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery but results should not be generalized to all surgical settings. This study was performed on a mixed population of patients with different types of VWD, including several patients with FVIII levels close to target levels; therefore, further studies of selected groups of patients are needed to understand fully how to use these products in all clinical situations. In this new era of treatment for VWD there is a need for guidance on how rVWF should be used in the perioperative period for all types of patients and surgeries.

CONFLICT OF INTERESTS

W. M. has received personal fees from CSL Behring, LFB, Octapharma, and Takeda/Shire.

AUTHOR CONTRIBUTIONS

W. M. was involved in the conception and preparation of the original draft of the manuscript and revising it critically for content and providing final approval of the version to be published.