Von Willebrand disease classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nazia Fuad M.D.

Overview

Von Willebrand disease may be classified as acquired or inherited. There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Hemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects in Von Willebrand factor.

Classification

Classification of von Willebrand disease,

Types	Quantitative Deficiency of VWF	Comments
Type 1	Partial quantitative deficiency of VWF	Accounts for 60%-70% of patients with VWD Bleeding severity mild to severe AD inheritance Factor VIII levels low,
Type 3	Complete deficiency of VWF	Rare, 1%–2% of all cases Clinically similar to hemophilia A with joint and soft tissue bleeding Severe mucosal bleeding AR inheritance VWF activity and RIPA absent or decreased Factor VIII levels low, 1-10%
	Qualitative Deficiency of VWF
Type 2	Qualitative deficiency of VWF	25%–30% of cases
Type 2A	Qualitative variants with the absence of high and intermediate-molecular-weight VWF multimers	Accounts for approximately one-tenth to one-fifth of patients with VWD Moderate to severe bleeding AD or AR inheritance VWF activity and RIPA decreased Factor VIII levels may be normal or reduced
Type 2B	Qualitative variants with increased affinity for platelet GpIb	Accounts for approximately 5% of patients with VWD The increase in binding of larger VWF multimers to platelet GP Ib results in sequestration of the platelets and VWF Thrombocytopenia Moderate to severe bleeding AD inheritance VWF activity decreased RIPA increased Factor VIII levels may be normal or reduced
Type 2M	Qualitative variants with decreased binding of VWF to GP Ib, resulting in decreased platelet adhesion	Uncommon Moderate to severe bleeding AD or AR inheritance VWF activity and RIPA decreased Factor VIII levels may be normal or decreased
Type 2N	Qualitative variants with remarkably decreased affinity for FVIII	Uncommon Clinically similar to hemophilia A with joint, soft tissue, urinary bleeding AR inheritance VWF activity and RIPA normal Factor VIII levels low (5 to 15%)

Von Willebrand disease may be classified as inherited and acquired

Inherited

• VWD is caused by mutations at the VWF locus and is usually classified into three main types according to quantitative (Types 1 and 3) or qualitative (Types 2A, 2B, 2M, 2N) abnormalities.
• Type 1 VWD
  • Refers to partial quantitative deficiency of VWF.
• Type 2 VWD
  • Refers to qualitative deficiency of VWF.

• • Type 2A
    • This is an abnormality of the synthesis or proteolysis of the vWF multimers.
    • This results in the presence of small multimer units in circulation.
    • Factor VIII binding is normal.
    • Ristocetin co-factor activity is low.
  • Type 2B
    • There is a increase binding of vWF to platelets
    • There is rapid clearance of the platelets and the large vWF multimers.
    • A mild thrombocytopenia may occur.
    • The large vWF multimers are absent in the circulation
    • Factor VIII binding is normal.
    • The RiCof:vWF antigen assay is low.
  • Type 2M
    • This is caused by decreased or absent binding of vWF to GPIb on the platelets.
    • Factor VIII binding is normal.
    • Type 2N (Normandy)
    • This is a deficiency of the binding of vWF to factor VIII.
    • This type has a normal vWF antigen level and normal functional test results.
    • Factor VIII is low.
    • Patient has the clinical findings of hemophilia A but a pedigree suggesting autosomal, rather than X-linked, inheritance.

• Type 3 VWD
  • Virtually complete deficiency of VWF.
  • Most severe form of vWD
  • Patients have severe mucosal bleeding.
  • Low levels of factor VIII

Acquired von Willebrand disease

• Acquired vWD can occur in patients with autoantibodies.
• In such cases the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
• This form of vWD occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding (Heyde's syndrome).

• Acquired vWF has also been described in Wilms' tumour, hypothyroidism and mesenchymal dysplasias.