What is Von Willebrand (vWD) disease type 1?

Von Willebrand Disease Type 1

Von Willebrand Disease Type 1 is a partial quantitative deficiency of von Willebrand factor (VWF), accounting for approximately 75% of all von Willebrand disease cases, and is characterized by mild to moderate mucocutaneous bleeding. 1

Definition and Pathophysiology

Von Willebrand Disease Type 1 is defined by:

• Partial quantitative deficiency of von Willebrand factor (VWF)
• VWF levels typically between 15-50% of normal 2
• Normal structure and function of the VWF that is present
• Normal ratio of VWF activity to VWF antigen (VWF:RCo/VWF:Ag ratio >0.7) 1

VWF is a crucial adhesive glycoprotein that plays important roles in:

• Primary hemostasis (platelet adhesion and aggregation)
• Secondary hemostasis (carrying and stabilizing Factor VIII in circulation) 3

Clinical Presentation

Patients with Type 1 VWD typically present with:

• Mucocutaneous bleeding (most common manifestation) 2
• Nosebleeds
• Easy bruising
• Prolonged bleeding from minor wounds
• Menorrhagia or postpartum hemorrhage in women
• Bleeding after surgery or dental procedures
• Less commonly: gastrointestinal bleeding

The severity of symptoms generally correlates with the degree of VWF deficiency, with symptoms being milder than in other VWD types.

Diagnostic Challenges

Type 1 VWD presents several diagnostic challenges:

• Variable penetrance of bleeding symptoms
• VWF levels show low heritability
• VWF levels fluctuate (acute phase reactant)
• Low VWF levels are weak risk factors for bleeding 4
• High prevalence of blood group O (which naturally has lower VWF levels) 5

This has led some to question whether mild Type 1 VWD represents a true disease entity or simply the lower end of the normal distribution of VWF levels 4.

Laboratory Diagnosis

Diagnosis requires:

1. Core laboratory tests 1:

   • VWF antigen (VWF:Ag) - reduced
   • VWF ristocetin cofactor activity (VWF:RCo) - reduced proportionally to antigen
   • Factor VIII coagulant activity (FVIII:C) - may be normal or reduced
   • VWF:RCo/VWF:Ag ratio - normal (>0.7)
   • Normal multimer pattern

2. Supporting tests:

   • Complete blood count (CBC)
   • Prothrombin time (PT)
   • Activated partial thromboplastin time (aPTT) - may be normal or prolonged

3. Important considerations:

   • Repeat testing is recommended (up to 3 times) due to variability in VWF levels 1
   • Testing should be performed using a standardized bleeding assessment tool (BAT) 1

Genetic Basis

Unlike other VWD types where specific mutations are well-characterized:

• The molecular basis of Type 1 VWD is largely undefined 3
• Missense mutations in mild Type 1 VWD with normal multimers are mainly located in:
  • Regulatory sequence region
  • D1/D2 propeptide region
  • D' VWF-FVIII binding site region
  • D4, B1-B3 and C1-C2 domains 5

Treatment

Management of Type 1 VWD includes:

1. First-line treatment: Desmopressin (DDAVP) 1, 3

   • Stimulates release of endogenous VWF from endothelial storage sites
   • Effective for most patients with mild to moderate Type 1 VWD
   • Patients typically show good/normal responses to DDAVP 5

2. For severe cases or when DDAVP is ineffective:

   • VWF-containing factor concentrates (plasma-derived or recombinant) 1, 2

3. Adjunctive therapies:

   • Fibrinolytic inhibitors (tranexamic acid, aminocaproic acid)
   • Topical hemostatic agents
   • Hormonal therapies for menorrhagia 2

Important Clinical Considerations

• Target VWF activity levels for surgical procedures: ≥50 IU/dL 1
• For pregnancy: maintain VWF:RCo ≥50 IU/dL for vaginal delivery and ≥80 IU/dL for cesarean section 1
• Avoid concomitant use of aspirin or other platelet antiaggregants 1
• Document response to interventions to guide future management 1

Type 1 VWD, while being the most common form of VWD, requires careful diagnosis to avoid both over-diagnosis and under-diagnosis, as many individuals with low VWF levels may not have clinically significant bleeding tendencies.