What is type 2 von Willebrand disease (vWD)?

By William Aird

Type 2 VWD is characterized by a qualitative abnormalities in the VWF protein. Different subtypes reflect which protein-protein interactions are affected. In some cases, reduced binding to a physiologic binding partner may be caused by defective multimerization rather than a defect in a specific protein binding domain:

  • Accounts for about 20% of cases of vWD.
  • Autosomal dominant inheritance.
  • Subtypes include:
    • Type 2A:
      • Most common subtype.
      • Accounts for 10 to 15 percent of VWD cases.
      • Deficiency of large (intermediate and high-molecular-weight) multimers due to either:
        • Decreased multimer assembly
        • Increased proteolysis
      • Impaired von Willebrand factor (vWF) binding to collagen and platelets.
    • Type 2B:
      • Accounts for approximately 5 percent of VWD cases.
      • Gain-of-function mutation which causes increased vWF binding to platelet GPIb alpha with rapid clearance of platelet-vWF complex.
      • Enhanced binding tom platelets leads to accelerated clearance or sequestration of platelets and of the bound HMW VWF multimers, resulting in deficiency of high-molecular-weight multimers and thrombocytopenia (the latter occurring in 40% of affected patients).
      • Phenocopy of platelet type vWD.
    • Type 2M (M for multimer):
      • Loss-of-function mutation which decreases vWF binding to platelet GPIb alpha or collagen.
      • Normal vWF multimer distribution.
    • Type 2N (N for Normandy, the location where it was discovered):
      • Loss-of-function mutations in vWF that cause decreased vWF binding to factor VIII with abnormally increased clearance of factor VIII.
      • May mimic mild hemophilia A.
  • Most cases caused by missense mutations, which are usually limited to specific functional domains.
  • Ratio of von Willebrand factor ristocetin cofactor activity to von Willebrand factor antigen (vWF:RCo to vWF:Ag) typically < 0.7, with exception of type 2N and collagen-binding variant of type 2M.

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