What is von Willebrand disease?

Von Willebrand Disease: An Overview

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the general population, characterized by deficiency or dysfunction of von Willebrand factor (VWF), which mediates platelet adhesion and carries factor VIII, resulting in excessive mucocutaneous bleeding. 1, 2

Pathophysiology

VWD results from defects in VWF, a multimeric plasma glycoprotein that serves two critical functions:

• Mediates platelet adhesion and aggregation at sites of vascular injury (primary hemostasis)
• Carries and stabilizes coagulation factor VIII (FVIII) in circulation (secondary hemostasis) 1, 2

Classification

VWD is classified into three main types based on the nature of VWF defects:

1. Type 1 (~75% of cases)

   • Partial quantitative deficiency of VWF
   • Autosomal dominant inheritance

2. Type 2

   • Qualitative defects in VWF
   • Further subdivided into:
     • Type 2A: Decreased platelet adhesion due to selective deficiency of high-molecular-weight VWF multimers
     • Type 2B: Increased affinity for platelet glycoprotein Ib
     • Type 2M: Defective platelet adhesion despite normal VWF multimer distribution
     • Type 2N: Decreased affinity for factor VIII
   • Predominantly autosomal dominant inheritance

3. Type 3

   • Complete or near-complete absence of VWF
   • Rare (approximately 1 in 1,000)
   • Autosomal recessive inheritance 2, 3

Clinical Presentation

Common bleeding symptoms include:

• Nosebleeds (epistaxis)
• Easy bruising
• Gingival bleeding
• Bleeding from small wounds
• Menorrhagia or postpartum bleeding in women

Less common but significant symptoms:

• Gastrointestinal bleeding
• Hematomas or hemarthroses
• Bleeding with surgery or invasive procedures
• Urinary bleeding
• Hemoptysis
• Central nervous system bleeding (rare) 1, 4

Diagnosis

Diagnosis of VWD requires:

1. Clinical assessment for bleeding phenotype

   • Typically mucocutaneous and provoked bleeding

2. Laboratory testing:

   • VWF antigen (VWF:Ag)
   • VWF ristocetin cofactor activity (VWF:RCo)
   • Factor VIII coagulation activity (FVIII)
   • Complete blood count
   • Coagulation profile

3. Additional specialized testing may include:

   • VWF multimer analysis
   • VWF collagen binding
   • Genetic testing 1, 2, 5

Important diagnostic considerations:

• Prothrombin Time (PT) is typically normal in VWD
• Activated Partial Thromboplastin Time (aPTT) may be prolonged in severe cases due to decreased FVIII levels, but is often normal in mild cases 2

Treatment

Treatment approaches depend on VWD type, severity, and clinical situation:

1. Desmopressin (DDAVP)

   • First-line therapy for Type 1 VWD with FVIII levels >5%
   • Stimulates release of endogenous VWF
   • Not effective in Type 3 and generally less effective in Type 2 VWD
   • Can be administered 30 minutes prior to procedures 2, 6

2. VWF/FVIII concentrates

   • Used when desmopressin is ineffective or contraindicated
   • First-line for Type 3 VWD and most Type 2 variants
   • Target VWF activity level ≥50 IU/dL
   • Available as plasma-derived or recombinant products 2, 4

3. Antifibrinolytic agents

   • Adjunctive therapy for mucosal bleeding
   • Can be used alone for minor bleeding or with other treatments 7, 4

4. Hormone therapy

   • For management of heavy menstrual bleeding in women
   • First choice for menorrhagia in women who don't desire pregnancy 7

Special Considerations

1. Women with VWD:

   • 5-20% of women with menorrhagia have undiagnosed VWD
   • VWF levels typically rise during pregnancy, often improving symptoms
   • Postpartum hemorrhage risk requires monitoring and possible prophylaxis 7, 5

2. Surgical management:

   • Minor procedures: Can often be managed with desmopressin and/or antifibrinolytics
   • Major surgery: Requires VWF replacement therapy
   • Factor levels should be maintained above 100 IU/dL during surgery and for 7-10 days postoperatively 2, 7

3. Acquired von Willebrand syndrome:

   • Can occur in conditions like severe aortic stenosis (20% of patients)
   • May develop in patients with continuous-flow mechanical circulatory support devices due to shear forces affecting VWF multimers 2

VWD remains underdiagnosed despite being common, particularly in women with menorrhagia. Proper diagnosis requires specialized laboratory testing and expertise, and patients with suspected VWD should be referred to a hematologist or hemophilia treatment center for definitive diagnosis and management.