What is the significance of Von Willebrand (VW) Normandy and the VWF (Von Willebrand Factor):RCoF (Von Willebrand Factor Ristocetin Cofactor)/VWF:Ag (Von Willebrand Factor Antigen) ratio?

From the Guidelines

Von Willebrand disease (VWD) Normandy is a specific variant of VWD characterized by normal or near-normal von Willebrand factor antigen (VWF:Ag) levels but decreased VWF ristocetin cofactor activity (VWF:RCo), with a VWF:RCo/VWF:Ag ratio less than 0.6-0.7 typically indicating this variant. The VWF:RCo/VWF:Ag ratio is a key diagnostic parameter for VWD Normandy, representing a qualitative defect in VWF function rather than a quantitative deficiency.

• Patients with VWD Normandy often present with mild to moderate bleeding symptoms despite having seemingly adequate VWF antigen levels.
• Diagnosis requires specialized laboratory testing including VWF:RCo activity, VWF:Ag levels, and calculation of their ratio, as routine coagulation tests are not sensitive to detect loss of VWF high-molecular-weight (HMW) multimers 1.
• Treatment typically involves desmopressin (DDAVP) as first-line therapy for minor bleeding episodes or procedures, which can temporarily increase VWF levels, with VWF-containing concentrates being necessary for more severe bleeding or when DDAVP is contraindicated.
• Genetic testing can confirm the diagnosis by identifying specific mutations in the VWF gene associated with this variant, with the reduced ratio reflecting the impaired function of the VWF protein despite adequate quantity, specifically affecting its ability to bind to platelets and facilitate platelet adhesion at sites of vascular injury. The most recent and highest quality study 1 highlights the importance of specialized laboratory tests, including VWF:RCo activity, VWF:Ag levels, and calculation of their ratio, in diagnosing VWD Normandy, and emphasizes the need for a comprehensive approach to diagnosis and treatment.
• The study also notes that a low VWF:RCo/Ag ratio (<0.7) may indicate a decrease in HMW multimers and is considered a surrogate marker for reduction or loss of HMW multimers.
• In addition, the study discusses the challenges of diagnosing acquired von Willebrand syndrome (AVWS) in patients on extracorporeal membrane oxygenation (ECMO) support, and highlights the need for close collaboration between hematologists and intensivists in diagnosing and managing AVWS in these patients.

From the Research

Significance of Von Willebrand (VW) Normandy and VWF:RCoF/VWF:Ag Ratio

• The VWF:RCoF/VWF:Ag ratio is significant in diagnosing and classifying von Willebrand disease (VWD) types, particularly type 1 and type 2 2, 3, 4, 5.
• A normal VWF:RCoF/VWF:Ag ratio is typically seen in type 1 VWD, while a decreased ratio is often associated with type 2 VWD, especially type 2A and 2B 2, 5.
• The ratio can also help differentiate between type 1 and type 2 VWD, as well as between different subtypes of type 2 VWD, such as type 2M and type 2N 2, 5.
• Desmopressin (DDAVP) trials can be used to assess the response of VWF parameters, including the VWF:RCoF/VWF:Ag ratio, to diagnose and classify VWD types 3, 5, 6.
• The VWF:RCoF/VWF:Ag ratio can also be used to monitor the response to treatment with FVIII/VWF concentrates in patients with VWD 2, 3.

Von Willebrand Factor (VWF) Parameters

• VWF parameters, including VWF:Ag, VWF:RCo, and VWF:CB, are essential in diagnosing and classifying VWD types 2, 3, 4, 5.
• The response of VWF parameters to DDAVP can help differentiate between type 1 and type 2 VWD, as well as between different subtypes of type 2 VWD 3, 5.
• VWF multimer analysis can also be used to diagnose and classify VWD types, particularly type 2 VWD 4, 5, 6.
• The VWF propeptide to VWF:Ag ratio can be used to predict a shorter than normal half-life for VWF:Ag in patients with VWD type 1 Vicenza and type 1/2E 4.

Diagnostic and Therapeutic Implications

• The diagnosis and classification of VWD types are crucial for determining the appropriate treatment and management strategy 2, 3, 5, 6.
• The VWF:RCoF/VWF:Ag ratio and other VWF parameters can be used to monitor the response to treatment and adjust the treatment plan as needed 2, 3.
• Desmopressin trials and VWF multimer analysis can be used to diagnose and classify VWD types, and to guide treatment decisions 3, 5, 6.
• Genetic testing can also be used to diagnose and classify VWD types, particularly type 2B and type 2N VWD 6.