In this video lecture, Dr. Frank Leebeek discusses:
- Current guideline recommendations for managing patients with von Willebrand disease undergoing minor and major surgical or dental procedures.
- How to select and dose desmopressin and von Willebrand factor replacement therapies while balancing effective hemostasis with the risk of excessive factor VIII levels.
- Practical perioperative considerations, including individualized treatment planning, pharmacokinetic-guided dosing, tranexamic acid use, and thromboprophylaxis.
Frank Leebeek obtained his medical degree and PhD degree at the Erasmus University in Rotterdam The Netherlands in 1990. He subsequently worked as a post-doctoral fellow for 2 years at the University of North Carolina at Chapel Hill, USA. He was trained as a haematologist at the Erasmus University Medical Center in Rotterdam, where he became a staff member and was appointed full professor in 2009. He is chair of the Department of Haematology since 2017. He is coordinating a research team on haemostasis and thrombosis with several research topics, mainly inherited bleeding disorders, including von Willebrand disease and haemophilia. He is steering committee member of several studies on new treatments for patients with bleedings disorders, including gene therapy. He is also the principal investigator of the Willebrand in the Netherlands (WiN) study and the WiN-Pro study.
He has been secretary of the Dutch Society of Thrombosis and Haemostasis, chairman of the Dutch Hemophilia Doctor’s Organisation, and board member of the Dutch Society of Haematology. He is currently executive board member of the European Hematology Association. He has been co-chair of the Scientific and Standardization Committee on von Willebrand Factor of the International Society on Thrombosis and Haemostasis. Dr Leebeek has (co-)authored over 480 scientific publications listed on PubMed, 20 book chapters and contributed to national and international treatment guidelines on haemophilia, von Willebrand’s disease and venous thrombosis.
(Video Lecture Summary)
Introduction
Dr. Frank Leebeek reviews the peri-procedural management of von Willebrand disease (vWD), focusing on strategies to prevent bleeding during surgical and dental procedures. Although vWD is the most common inherited bleeding disorder, perioperative management remains challenging because of the disease’s heterogeneity, differences among replacement products, and the need to balance adequate hemostasis with avoidance of excessive factor VIII levels and thrombotic complications.
Bleeding Risk During Surgery
Patients with vWD commonly experience mucocutaneous bleeding manifestations such as epistaxis, gingival bleeding, gastrointestinal bleeding, menorrhagia, and postpartum hemorrhage. Individuals with more severe disease may also develop joint and muscle bleeding.
Surgical and dental procedures represent a major bleeding challenge across all disease types. Drawing on data from the Willebrand in the Netherlands (WiN) study, Dr. Leebeek notes that postoperative bleeding is common not only in severe forms of vWD but also among patients with milder disease. A substantial proportion of patients require additional interventions, including repeat procedures, blood transfusions, or treatment with von Willebrand factor concentrates.
Guideline Recommendations for Perioperative Management
Dr. Leebeek reviews recommendations from the 2021 international guidelines for the management of vWD.
For minor procedures, the guidelines recommend increasing von Willebrand factor activity levels above 50 IU/dL using either desmopressin (DDAVP) or von Willebrand factor concentrate, together with tranexamic acid during and after the procedure. Patients with mild type 1 disease, baseline von Willebrand factor activity above 30 IU/dL, and a mild bleeding phenotype may be managed with tranexamic acid alone for selected minor interventions.
For major surgery, both factor VIII and von Willebrand factor activity levels should be maintained above 50 IU/dL for at least three days after surgery. Dr. Leebeek emphasizes that monitoring factor VIII alone is insufficient and that both factors should be followed throughout the perioperative period. The duration of replacement therapy should be individualized according to the procedure performed and the patient’s bleeding phenotype.
Choosing the Appropriate Hemostatic Therapy
Treatment selection depends largely on the type of vWD.
Patients with type 1 disease often respond well to desmopressin, which may be administered intravenously, subcutaneously, or intranasally, together with tranexamic acid. In type 2 disease, responsiveness to desmopressin varies, and many patients, particularly those with type 2A or 2B disease, require von Willebrand factor replacement. Patients with type 3 disease do not respond to desmopressin and should receive von Willebrand factor-containing concentrates.
Dr. Leebeek also reviews recommended treatment durations, noting that replacement may be needed for only one day after dental extraction but may extend to three to five days after minor surgery and seven to ten days after major surgery.
von Willebrand Factor Concentrates and Factor VIII Accumulation
An important focus of the lecture is the selection of replacement products. Dr. Leebeek explains that currently available von Willebrand factor concentrates differ substantially in their composition, particularly in the ratio of von Willebrand factor to factor VIII and in their multimer distribution.
Because von Willebrand factor stabilizes endogenous factor VIII, repeated administration of combined factor VIII/von Willebrand factor concentrates can result in progressive accumulation of factor VIII during the postoperative period. This increase may raise thrombotic risk, particularly in patients with additional risk factors.
For patients who already have adequate endogenous factor VIII levels or who are at increased risk of thrombosis, pure von Willebrand factor concentrates may help avoid excessive postoperative factor VIII concentrations.
Practical Considerations for Pure von Willebrand Factor Therapy
When using purified von Willebrand factor concentrates, clinicians must recognize that endogenous factor VIII requires time to recover after replacement.
Dr. Leebeek explains that administering purified von Willebrand factor six to twelve hours before elective surgery allows endogenous factor VIII levels to rise sufficiently for safe surgery. In urgent procedures where immediate hemostasis is required, recombinant factor VIII may be administered alongside purified von Willebrand factor to provide adequate perioperative factor VIII activity.
Careful monitoring of both von Willebrand factor and factor VIII remains essential regardless of the replacement product used.
Pharmacokinetic-Guided Dosing
Traditional perioperative dosing has often resulted in factor VIII levels substantially exceeding target ranges. Dr. Leebeek discusses emerging pharmacokinetic-guided dosing strategies that integrate the kinetics of both von Willebrand factor and factor VIII.
Although early pharmacokinetic studies did not demonstrate clear clinical benefit, newer population-based pharmacokinetic models account for the interaction between von Willebrand factor and endogenous factor VIII. These models aim to achieve target von Willebrand factor levels while limiting excessive postoperative factor VIII accumulation.
He describes the ongoing TWIN study in the Netherlands, which is evaluating this individualized dosing approach in surgical patients with vWD.
Managing Older Adults with Type 1 von Willebrand Disease
Another challenge is the management of older patients with type 1 vWD. Von Willebrand factor levels frequently increase with age, and many patients eventually reach levels within the normal laboratory range.
Despite this normalization, observational studies suggest that bleeding risk may persist, particularly during surgical procedures. Dr. Leebeek therefore recommends reconsidering, rather than removing, the diagnosis of vWD in these patients. Treatment decisions should continue to be guided by the patient’s current bleeding phenotype rather than laboratory values alone.
In older adults, desmopressin should be used cautiously because of cardiovascular comorbidities, and replacement therapy should avoid unnecessarily high factor VIII concentrations.
Thromboprophylaxis After Surgery
Whether patients with vWD should receive postoperative thromboprophylaxis remains an area of ongoing debate.
Although individuals with untreated vWD may have some protection from thrombosis, replacement therapy can normalize or even elevate factor VIII and von Willebrand factor levels during the postoperative period. Dr. Leebeek notes that postoperative venous thromboembolism has been reported, particularly when factor levels become markedly elevated.
For patients undergoing major surgery who also have additional thrombotic risk factors, such as cancer or obesity, thromboprophylaxis should be considered while replacement therapy is being administered. However, he acknowledges that practices vary considerably among treatment centers because high-quality evidence remains limited.
Conclusion
Dr. Leebeek concludes that successful perioperative management of von Willebrand disease requires an individualized treatment plan for every patient and every procedure. Appropriate target levels for both von Willebrand factor and factor VIII should be established, replacement therapy tailored to the disease subtype and surgical risk, and tranexamic acid incorporated whenever appropriate. Close collaboration among hematologists, surgeons, anesthesiologists, and patients helps optimize hemostasis while minimizing bleeding and thrombotic complications.