von Willebrand

Overview of von Willebrand Disease (vWD)

• Definition: The most common inherited bleeding disorder, characterized by a quantitative (amount) or qualitative (functional) defect in von Willebrand factor (vWF)
• Prevalence: Estimated to affect 1-3% of the population, though many cases are mild and undiagnosed
• Key Features:
  • Mucocutaneous bleeding: Easy bruising, nosebleeds (epistaxis), gum bleeding, menorrhagia (heavy menstrual bleeding)
  • Prolonged bleeding after cuts, dental procedures, or surgery
• Genetic Basis: vWD is usually inherited as an autosomal dominant trait, although autosomal recessive inheritance is possible in some subtypes.
• Treatment: Varies depending on the type and severity of vWD, and may include desmopressin, vWF/FVIII concentrates, and antifibrinolytic agents

von Willebrand Factor (vWF): Structure and Function

• vWF Structure:
  • A large, multimeric glycoprotein found in plasma, platelets, and subendothelial connective tissue
  • Synthesized by endothelial cells and megakaryocytes
  • Monomers of vWF are assembled into dimers, which then polymerize to form large multimers
  • The size and structure of vWF multimers are critical for its function
• vWF Functions:
  • **Platelet Adhesion:
    • vWF binds to exposed collagen in the subendothelium of damaged blood vessels
    • vWF then binds to the platelet glycoprotein Ib/IX/V (GPIb/IX/V) receptor on the platelet surface, mediating initial platelet adhesion
    • This interaction is crucial for platelet plug formation at sites of vascular injury, especially under high shear stress conditions
  • **Factor VIII Carrier:
    • vWF binds to factor VIII (FVIII), a coagulation protein
    • vWF protects FVIII from degradation and prolongs its half-life in the circulation
    • Decreased vWF can lead to decreased FVIII levels

Classification of vWD

• Type 1 vWD: (60-80% of cases)

  • Partial quantitative deficiency of vWF
  • vWF is present, but in reduced amounts
  • All vWF multimers are present, but in decreased concentration
  • Inheritance: Usually autosomal dominant

• Type 2 vWD: (20-30% of cases)

  • Qualitative defects in vWF function
  • vWF is present in normal or near-normal amounts, but its ability to perform its functions is impaired
  • Subtypes:
    • Type 2A:
      • Decreased high-molecular-weight vWF multimers
      • Impaired platelet adhesion
      • Often caused by increased proteolysis or abnormal multimer assembly
    • Type 2B:
      • Increased affinity of vWF for platelets
      • Spontaneous binding of vWF to platelets, leading to clearance of both vWF and platelets from the circulation, resulting in thrombocytopenia
      • Ristocetin-induced platelet aggregation (RIPA) is enhanced at low concentrations of ristocetin
    • Type 2M:
      • Decreased binding of vWF to platelets or collagen
      • Normal vWF multimer distribution
      • Differentiation of subtypes depends on which binding activity is affected (platelets or collagen)
    • Type 2N:
      • Decreased binding of vWF to factor VIII
      • Markedly reduced factor VIII levels
      • May be misdiagnosed as mild hemophilia A (factor VIII deficiency)
  • Inheritance: Usually autosomal dominant

• Type 3 vWD: (Rare)

  • Severe quantitative deficiency of vWF (vWF is virtually absent)
  • Very low or undetectable levels of vWF and factor VIII
  • Severe bleeding symptoms
  • Inheritance: Autosomal recessive

Clinical Features

• Variable bleeding symptoms:

  • Severity of bleeding depends on the type and severity of vWD
  • Bleeding symptoms may be mild and only become apparent after surgery or trauma

• Common Manifestations:

  • Nosebleeds (epistaxis)
  • Easy bruising
  • Prolonged bleeding after cuts or dental procedures
  • Menorrhagia (heavy menstrual bleeding) in women
  • Postpartum hemorrhage
  • Gastrointestinal bleeding (less common)
  • Joint bleeds (hemarthrosis) are rare, unlike in hemophilia

• Symptoms by vWD Type:

  • Type 1 vWD: Mild to moderate bleeding symptoms
  • Type 2 vWD: Variable bleeding symptoms, depending on the subtype
    • Type 2A: Moderate bleeding symptoms
    • Type 2B: Moderate bleeding symptoms; may also have thrombocytopenia
    • Type 2M: Mild to moderate bleeding symptoms
    • Type 2N: Moderate to severe bleeding symptoms; may be misdiagnosed as hemophilia A
  • Type 3 vWD: Severe bleeding symptoms

Laboratory Diagnosis

• Screening Tests:

  • Complete Blood Count (CBC):
    • Platelet count is usually normal, but may be decreased in some cases (e.g., type 2B vWD)
  • Prothrombin Time (PT): Usually normal
  • Activated Partial Thromboplastin Time (aPTT): May be prolonged if factor VIII is significantly reduced (especially in type 2N and type 3 vWD)

• Specific vWD Assays:

  • von Willebrand Factor Antigen (vWF:Ag):
    • Measures the amount of vWF protein in the plasma
    • Decreased in type 1 and type 3 vWD
    • May be normal in type 2 vWD
  • von Willebrand Factor Activity (vWF:RCo):
    • Measures the ability of vWF to bind to platelets using ristocetin as a cofactor
    • Ristocetin-induced platelet aggregation (RIPA)
    • Decreased in most types of vWD (except for type 2B, where it is increased)
  • Factor VIII Activity (FVIII:C):
    • Measures the activity of factor VIII
    • May be decreased in vWD, especially in type 2N and type 3
  • vWF Multimer Analysis:
    • Evaluates the distribution of vWF multimers
    • Decreased high molecular weight multimers in type 2A vWD
  • Platelet Function Analyzer (PFA-100):
    • Measures platelet function under high shear stress
    • Prolonged closure time in most types of vWD

• Diagnostic Approach:

  1. Perform Initial Screening Tests (CBC, PT, aPTT)
  2. Measure vWF:Ag and vWF:RCo:
     • If both are decreased -> Consider type 1 or type 3 vWD
     • If vWF:Ag is normal but vWF:RCo is decreased -> Consider type 2 vWD
  3. Perform FVIII:C Assay:
     • If FVIII:C is decreased -> Consider type 2N vWD
  4. Perform vWF Multimer Analysis:
     • To differentiate type 2A from other subtypes
  5. Perform RIPA at low concentrations of ristocetin:
     • To identify type 2B vWD (RIPA is enhanced)
  6. Genetic Testing: May be considered in some cases to confirm the diagnosis or classify the subtype of vWD

Treatment

• Desmopressin (DDAVP):

  • A synthetic analog of vasopressin that stimulates the release of vWF and factor VIII from endothelial cells
  • Effective in treating type 1 vWD and some subtypes of type 2 vWD
  • Administered intravenously, subcutaneously, or intranasally
  • Side effects: Flushing, headache, hyponatremia (low sodium)

• vWF/Factor VIII Concentrates:

  • Plasma-derived concentrates that contain both vWF and factor VIII
  • Used to treat bleeding episodes or for prophylaxis in patients with severe vWD or those who do not respond to DDAVP
  • Examples: Humate-P, Alphanate SDH, Wilate

• Antifibrinolytic Agents:

  • Tranexamic acid or aminocaproic acid
  • Inhibit fibrinolysis (the breakdown of blood clots)
  • Used to prevent or treat bleeding, especially mucosal bleeding (e.g., menorrhagia, dental procedures)

• Topical Hemostatic Agents:

  • Thrombin-soaked gauze or fibrin sealants
  • Used to control local bleeding

• Other Considerations:

  • Avoid Aspirin and NSAIDs: These medications can impair platelet function and increase the risk of bleeding
  • Hormonal Therapy: Oral contraceptives or other hormonal treatments may be used to manage menorrhagia

Key Terms

• von Willebrand Factor (vWF): A protein that mediates platelet adhesion and carries factor VIII
• vWF Antigen (vWF:Ag): Measures the amount of vWF protein
• vWF Activity (vWF:RCo): Measures the ability of vWF to bind to platelets
• Factor VIII (FVIII:C): A coagulation protein that is carried by vWF
• Ristocetin-Induced Platelet Aggregation (RIPA): A test used to assess vWF function
• Desmopressin (DDAVP): A synthetic analog of vasopressin that stimulates the release of vWF and factor VIII
• Multimers: Polymers of vWF subunits
• Platelet Function Analyzer (PFA): A test that measures platelet function under high shear stress