What is the inheritance pattern and treatment of Von Willebrand's disease (VWD)?

From the Guidelines

Von Willebrand disease is typically inherited in an autosomal dominant pattern, and treatment depends on the severity and type of the disease, with desmopressin (DDAVP) being the first choice for mild cases, as it enhances platelet adherence and aggregate growth, as seen in studies such as 1. The disease is characterized by easy bruising, nosebleeds, or other mucosal bleeding, and patients may be at risk of bleeding following surgery or invasive procedures, traumatic injury, or childbirth, as noted in 1.

Key Points to Consider

• The three main types of VWD are Type 1 (partial quantitative deficiency), Type 2 (qualitative deficiency) with four subtypes (2A, 2B, 2M, 2N), and Type 3 (virtually complete quantitative deficiency), with Type 1 accounting for ~75% of symptomatic persons, as described in 1.
• For mild cases, desmopressin (DDAVP) is often used, administered as a nasal spray (150-300 mcg) or intravenously (0.3 mcg/kg), as it stimulates the release of stored von Willebrand factor (vWF) and factor VIII, as seen in 1.
• For more severe cases or when DDAVP is ineffective, vWF replacement therapy is necessary, using products like Humate-P, Wilate, or Vonvendi at doses typically ranging from 40-60 IU/kg.
• Antifibrinolytic medications such as tranexamic acid (1-1.5 g orally three times daily) or aminocaproic acid may be added to help stabilize clots, as part of a comprehensive treatment plan.

Treatment Approach

The specific treatment approach varies based on the patient's vWF levels, the type of von Willebrand disease, and the clinical situation, so individualized care under hematology guidance is essential, taking into account the latest guidelines and studies, such as 1 and 1. Some key considerations include:

• The use of desmopressin to enhance platelet adherence and aggregate growth, as seen in 1.
• The role of vWF replacement therapy in more severe cases, as described in 1.
• The potential benefits of antifibrinolytic medications in stabilizing clots, as part of a comprehensive treatment plan.

From the FDA Drug Label

Desmopressin acetate injection 4 mcg/mL is indicated for patients with mild to moderate classic von Willebrand’s disease (Type I) with factor VIII levels greater than 5% Those von Willebrand’s disease patients who are least likely to respond are those with severe homozygous von Willebrand’s disease with factor VIII coagulant activity and factor VIII von Willebrand factor antigen levels less than 1%. Desmopressin acetate injection is not indicated for the treatment of severe classic von Willebrand’s disease (Type I) and when there is evidence of an abnormal molecular form of factor VIII antigen.

The inheritance of von Willebrand's disease is not directly addressed in the provided drug label. However, regarding treatment, desmopressin acetate injection is indicated for patients with mild to moderate classic von Willebrand’s disease (Type I) with factor VIII levels greater than 5%. It is not indicated for severe classic von Willebrand’s disease (Type I) or when there is evidence of an abnormal molecular form of factor VIII antigen 2.

From the Research

Von Willebrand Disease Inheritance

• Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative or qualitative defects in von Willebrand factor (VWF) 3
• VWD has several categories, including types 1 and 3, which have partial or total VWF quantitative deficiencies, and type 2, which has VWF quality issues 3

Treatment Options for Von Willebrand Disease

• Desmopressin (DDAVP) is the treatment of choice for most patients with type 1 VWD, which accounts for approximately 70 to 80 per cent of all cases with the disease 4
• Desmopressin raises endogenous factor VIII and von Willebrand factor three- to fivefold, thereby transiently correcting both the intrinsic coagulation and primary hemostasis defects 4
• Plasma-derived VWF/FVIII products may also be substituted exogenously, and treatment with plasma-derived or recombinant VWF concentrates without FVIII is also possible 3
• Recombinant VWF (vonicog alfa, Vonvendi) was approved by the U.S. Food and Drug Administration (FDA) in December 2015 and may have an important role in the management of VWD 5

Desmopressin Efficacy and Safety

• The relationship between desmopressin dose, its plasma concentration, and the VWF:Act response in type 1 VWD patients has been quantified in a pharmacokinetic-pharmacodynamic (PK-PD) model 6
• Simulations demonstrated that after 0.3 mcg/kg desmopressin intravenously, >90% patients with a VWF:Act baseline of ≥0.20 IU/mL attain a VWF:Act >0.5 IU/ml up to ≥4 h after administration 6
• Desmopressin is not effective in VWD type 3 and in severe forms of VWD 1 and 2, and it can induce transient thrombocytopenia in patients with VWD type 2B 7

Treatment Considerations

• A test dose of DDAVP at the time of diagnosis is recommended to establish the individual patterns of biological response and to predict clinical efficacy during bleeding and surgery 7
• The results of several retrospective studies on the use of DDAVP in VWD management have been reported, but more studies are needed to determine the most effective method for managing VWD 3