In this video lecture, Dr. Saskia Schols discusses:
- How DDAVP increases endogenous von Willebrand factor and factor VIII levels, including dosing, response testing, and safety considerations.
- Which VWD subtypes are most likely to respond and why DDAVP is contraindicated in type 2B disease.
- How phenotype, genotype, VWF clearance, and baseline laboratory values can help predict an individual patient’s DDAVP response.
Dr. Saskia Schols studied medicine at Maastricht University from 2000 till 2006. During the last year of her study, she received a Kootstra fellowship grant, a price for young medical doctors to perform scientific research during the first year after graduation. As part of her PhD traineeship, she worked in the laboratories of Professor Shaun Jackson in Melbourne, Australia, and Professor Wolfgang Bergmeier in Philadelphia, USA. After defending her PhD thesis in 2010, she started the specialty training in internal medicine at the Maastricht University Medical Center. From 2013 until 2016, she was trained as a fellow in the Department of Hematology of the Maastricht University Medical Center.
After graduating as an internist-hematologist, she started her current position as an internist-hematologist in the Hemophilia Treatment Center (HTC) Nijmegen-Eindhoven-Maastricht, located in Nijmegen. Next to her participation in patient care in the HTC and other benign hematological disorders (hemoglobinopathies, paroxysmal nocturnal hemoglobinuria, and iron metabolism disorders), she performs scientific research and supervises several PhD students. In 2017 she became the principal investigator of the nationwide Rare Bleeding Disorders in The Netherlands study (RBIN study). Since then, many peer-reviewed papers have been published from this study. Dr. Schols also participates in other nationwide collaborative studies, such as the Willebrand in the Netherlands study, Hemophilia in the Netherlands study and the Symphony consortium. Since 2021, Dr. Schols is a board member of the Dutch Society of Hemophilia Treating Physicians (NVHB), and in 2026 she became chairperson. In 2024, she established the EAHAD working group of “very rare coagulation factor deficiencies (VRCFD)”.
(Video Lecture Summary)
Introduction
Dr. Saskia Schols reviews the use of desmopressin (DDAVP) in von Willebrand disease (VWD). She explains its mechanism of action, appropriate dosing, expected biologic response, and important safety considerations. She also reviews several studies examining how VWD subtype, genotype, multimer pattern, VWF clearance, and baseline laboratory values influence treatment response and help guide patient selection.
Correcting the Hemostatic Defect in VWD
The goal of VWD treatment is to correct two related defects in hemostasis. Reduced VWF activity impairs platelet adhesion at sites of vascular injury, while reduced factor VIII levels compromise fibrin clot formation. Two primary treatment approaches are available: DDAVP, which stimulates release of endogenous VWF and factor VIII from endothelial Weibel-Palade bodies, and plasma-derived or recombinant VWF-containing concentrates, which replace these proteins directly. Antifibrinolytic agents such as tranexamic acid are often used alongside DDAVP to further support hemostasis.
How DDAVP Works
DDAVP is a synthetic analogue of vasopressin that selectively activates V2 receptors. Administration results in the release of VWF, factor VIII, and tissue plasminogen activator from endothelial storage granules into the circulation. This produces a typical three- to fivefold increase in plasma VWF activity and factor VIII levels. DDAVP may be administered intravenously, subcutaneously, or intranasally, with the standard intravenous or subcutaneous dose being 0.3 μg/kg.
Testing the Individual Response
Dr. Schols recommends performing a DDAVP test before relying on the drug for treatment of bleeding or invasive procedures. Testing establishes the patient’s biologic response and helps predict clinical efficacy. A complete response is generally defined as VWF activity and factor VIII levels exceeding 50 IU/dL, while a partial response reflects at least a threefold increase without reaching this threshold. Patients who meet neither criterion are considered nonresponders. Peak responses are usually observed about 30 minutes after administration and last approximately six to eight hours.
Repeat Dosing and Tachyphylaxis
Repeated DDAVP dosing is limited by tachyphylaxis because endothelial stores of VWF become depleted after administration. For this reason, repeat doses should generally not be given more than twice at intervals of 12 to 24 hours. This limitation should be considered when planning treatment for prolonged bleeding episodes or major procedures.
Response by VWD Subtype
Patients with mild type 1 VWD generally demonstrate the strongest responses to DDAVP. The drug is contraindicated in type 2B VWD because it may worsen thrombocytopenia by releasing abnormal VWF with enhanced platelet binding. It is also ineffective in type 3 VWD, where little or no endogenous VWF is available for release. Responses in type 2A, 2M, and 2N VWD are often reduced or variable, making individual response testing particularly important.
Safety and Adverse Effects
DDAVP remains a widely accepted treatment because it is effective, relatively inexpensive, and generally well tolerated. The most common adverse effects are flushing and headache, while rare but serious complications include hyponatremia, cerebral edema, and seizures. Appropriate patient selection and careful fluid management help minimize these risks.
Multimer Pattern and Genetic Variants
Dr. Schols reviews findings from the European MCMDM-1VWD study evaluating DDAVP response in patients with type 1 VWD. Patients with complete responses generally had higher baseline VWF activity, VWF antigen, and factor VIII levels. Most partial or nonresponders had abnormal VWF multimer patterns, whereas complete responders more often had normal multimers. Response was also associated with the location of the genetic variant. Patients with variants in the D1, D2, or D4 domains more frequently achieved complete responses, whereas variants in the D3 or A1 through A3 domains were more often associated with partial or absent responses. Although patients with normal multimer patterns tended to have longer response duration and VWF half-life, considerable variability remained even among individuals carrying the same variant.
DDAVP Response and Bleeding Phenotype
The Willebrand in the Netherlands (WiN) study further examined DDAVP response in patients with type 1 VWD. Most patients demonstrated a complete response, while nonresponders had substantially higher bleeding scores. Higher post-DDAVP VWF and factor VIII levels, particularly factor VIII measured three hours after administration, were associated with lower bleeding scores. These findings suggest that both the magnitude and duration of the DDAVP response contribute to differences in bleeding phenotype among patients with type 1 VWD.
VWF Clearance and Response Duration
The lecture also highlights the importance of VWF clearance. Patients with an elevated VWF propeptide-to-antigen ratio, indicating increased clearance, had lower VWF and factor VIII levels several hours after DDAVP administration and experienced higher bleeding scores. An adequate initial response may therefore not provide sustained hemostatic protection, emphasizing the value of measuring later time points after treatment.
Genotype and Family Response Patterns
A subsequent WiN study evaluated DDAVP responses in patients with type 1 and type 2 VWD, including those with and without identifiable genetic variants. Patients with type 1 VWD who lacked a detectable VWF variant showed the best responses, while complete response rates declined among patients with type 1 disease carrying a variant and were lowest in type 2 VWD. Although responses varied across different mutations, family members carrying the same variant generally demonstrated similar responses, suggesting that genotype and family history can help inform treatment decisions.
A Predictive Model for DDAVP Testing
Dr. Schols concludes by reviewing a Dutch study that developed a predictive model for DDAVP testing. Patients with type 1 VWD whose historically lowest VWF activity ranged from 30 to 50 IU/dL consistently responded well and may not require formal DDAVP testing. Patients with lower baseline levels should generally undergo testing, with additional four-hour measurements when necessary to assess response durability. Patients with type 2A or 2M VWD require more comprehensive testing because responses are less predictable. This model aims to reduce unnecessary testing while ensuring that patients with uncertain responses are appropriately evaluated.
Conclusion
Dr. Schols concludes that DDAVP remains a well-established treatment for VWD, with the important exception of type 2B disease. Response is influenced by baseline VWF levels, multimer pattern, genotype, VWF synthesis, and clearance, and later measurements are often as informative as the initial rise in VWF. As predictive models continue to evolve, they may help identify patients who can safely receive DDAVP without extensive testing while reserving comprehensive response studies for those in whom treatment remains uncertain.