What is von Willebrand disease?

What is Von Willebrand Disease?

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population equally in males and females, caused by deficiency or dysfunction of von Willebrand factor—a plasma protein essential for both platelet adhesion at injury sites and stabilization of factor VIII in circulation. 1

Pathophysiology

VWD causes bleeding through two distinct mechanisms 2:

• Impaired platelet adhesion: VWF normally mediates platelet attachment and aggregation at sites of vascular injury; when deficient or dysfunctional, the initial platelet plug cannot form properly, resulting in mucosal bleeding and easy bruising 2
• Secondary factor VIII deficiency: VWF serves as a carrier protein that protects factor VIII from premature clearance; reduced VWF leads to decreased factor VIII levels, impairing the coagulation cascade 1, 2

Classification System

VWD is categorized into three main types based on the nature of the VWF defect 1:

Type 1 (Partial Quantitative Deficiency)

• Accounts for approximately 75% of symptomatic cases 1, 3
• Partial reduction in VWF levels with normal protein structure 1
• Autosomal dominant inheritance with variable penetrance 4
• Mild to moderate bleeding symptoms 1

Type 2 (Qualitative Deficiency)

• Comprises nearly all remaining symptomatic cases 1
• Four subtypes exist: 2A, 2B, 2M, and 2N, each with distinct functional abnormalities 1
• Type 2A is the most common qualitative variant 1
• VWF protein is present but dysfunctional 5

Type 3 (Complete Quantitative Deficiency)

• Rare, affecting only 1 in 1,000 persons 1
• Virtually complete absence of VWF 1, 2
• Recessive inheritance pattern requiring two defective alleles 5
• Severe, life-threatening bleeding due to profound deficiency of both VWF functions 1, 2

Clinical Manifestations

The bleeding pattern in VWD is characteristically mucocutaneous 3, 6:

• Common symptoms: Easy bruising, nosebleeds (epistaxis), bleeding from minor wounds, prolonged bleeding after dental procedures 3, 6
• Women-specific: Heavy menstrual bleeding (menorrhagia) and postpartum hemorrhage 1, 6
• Procedure-related: Excessive bleeding following surgery, invasive procedures, traumatic injury, or childbirth 1
• Less frequent: Gastrointestinal bleeding, hematomas, or hemarthroses (particularly when factor VIII levels are significantly reduced) 5, 6

Bleeding severity ranges from mild in Type 1 to severe and life-threatening in Type 3 VWD 1.

Acquired von Willebrand Syndrome

A distinct entity from hereditary VWD, acquired von Willebrand syndrome (AVWS) occurs without personal or family history of bleeding 1:

• Associated with various medical conditions through different mechanisms 1
• Laboratory findings mirror those of hereditary VWD 1
• Should be considered when abnormal VWF test results and bleeding symptoms occur in patients lacking hereditary bleeding history 1

Diagnostic Considerations

A critical pitfall: VWD, particularly Type 1, is at risk of both overdiagnosis and underdiagnosis because VWF levels are influenced by factors outside the VWF gene, including ABO blood group, age, stress, pregnancy, inflammation, exercise, thyroid hormones, and estrogens 6, 4. The wide "normal" range of VWF measurements creates a continuous spectrum from normality to mild Type 1 cases, making clear distinction extremely difficult 4.

The diagnosis requires 1:

• Constellation of lifelong mucocutaneous bleeding symptoms 3
• Maternal history of bleeding disorder (supporting autosomal inheritance) 3
• Post-procedural bleeding history 3
• Array of specialized laboratory tests to characterize VWD type 5, 7

Prevalence Context

While VWD affects up to 1% of the general population, the prevalence of clinically relevant cases requiring treatment is substantially lower at approximately 100 per million inhabitants 1, 5. This discrepancy reflects the spectrum of disease severity and the challenge of distinguishing mild Type 1 cases from normal variation 4.