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 (VWF)—a plasma glycoprotein essential for platelet adhesion at sites of vascular injury and for carrying and stabilizing coagulation factor VIII. 1

Pathophysiology

VWF is a large multimeric glycoprotein with two critical hemostatic functions 1, 2:

• Mediates platelet adhesion and aggregation at sites of blood vessel injury by forming a bridge between platelets and damaged vessel walls 1
• Binds and stabilizes factor VIII (FVIII) in circulation, protecting it from premature degradation and clearance 1, 3

Deficiency or dysfunction of VWF results in impaired primary hemostasis and may also cause decreased FVIII levels, leading to secondary coagulation defects 1.

Classification

VWD is classified into three main types based on pathophysiology 1:

Type 1 VWD (Most Common)

• Partial quantitative deficiency of VWF 1
• Accounts for approximately 75% of symptomatic cases 1
• VWF levels typically between 30-50 IU/dL represent the mildest defects 4

Type 2 VWD (Qualitative Defects)

• Qualitative dysfunction of VWF with four distinct subtypes 1:
  • Type 2A: Most common variant among Type 2 cases 1
  • Type 2B: Gain-of-function mutation causing increased platelet binding 1
  • Type 2M: Defective platelet binding without loss of high molecular weight multimers 1
  • Type 2N: Defective FVIII binding 1

Type 3 VWD (Rare and Severe)

• Virtually complete quantitative deficiency with undetectable VWF levels 1, 4
• Extremely rare, affecting only approximately 1 in 1,000 persons 1
• Associated with severe, life-threatening bleeding 1, 4

Clinical Manifestations

The hallmark of VWD is mucocutaneous bleeding 1, 3:

Common bleeding symptoms include 1:

• Nosebleeds (epistaxis)
• Easy bruising (ecchymoses)
• Gingival bleeding
• Prolonged bleeding from minor wounds
• Heavy menstrual bleeding (menorrhagia) or postpartum hemorrhage in women

More severe bleeding manifestations 1:

• Excessive bleeding with surgery or invasive procedures (including dental extractions)
• Gastrointestinal or urinary tract bleeding
• Hematomas or hemarthroses (particularly when FVIII levels are very low)
• Hemoptysis
• Central nervous system bleeding (rare but life-threatening)

Symptom severity correlates with VWD type 1:

• Type 1: Mild bleeding symptoms
• Type 2: Variable, depending on subtype
• Type 3: Severe, life-threatening bleeding including hemarthroses and muscle hematomas

Acquired von Willebrand Syndrome

Acquired von Willebrand syndrome (AVWS) is less common than hereditary VWD and should be suspected in patients with 1:

• Abnormal VWF test results and bleeding symptoms
• No personal or family history of bleeding consistent with hereditary disease
• Associated medical conditions known to cause AVWS 1

AVWS typically results from various mechanisms including autoantibodies, increased VWF clearance, or consumption associated with underlying medical conditions 1.

Epidemiology and Inheritance

• Prevalence: Up to 1% of the U.S. and world populations 1
• Inheritance pattern: Affects males and females in approximately equal proportions 1
• Clinical significance: While prevalence may be high, clinically significant bleeding requiring diagnosis and treatment is less common 1

Key Clinical Pitfalls

Important considerations when evaluating for VWD 1, 5:

• Bleeding symptoms are common in the general population; not all bleeding indicates a bleeding disorder
• VWF levels can be influenced by blood type, stress, inflammation, and hormones, potentially causing diagnostic confusion
• Enhanced VWF clearance plays a critical role in both Type 1 and Type 2 VWD etiology, which has implications for treatment selection 5
• The mildest forms of Type 1 VWD (VWF levels 30-50 IU/dL) usually do not cause significant bleeding 4