von Willebrand Disease

von Willebrand Disease is a family of bleeding disorders caused by abnormal von Willebrand factor, and classified by cause into:

• Congenital
  Further divided into three subtypes:
  • Type 1
    Quantitative reduction in normal vWF.
    • Mild clinical symptoms
    • Usually autosomal dominant
    • ~75% of patients
  • Type 2
    Primarily qualitative defect.
    • 4 subtypes with varying degrees of severity
    • Autosomal dominant or recessive
  • Type 3
    Absence of vWF.
    • Severe clinical bleeding
    • Autosomal recessive
• Acquired

Epidemiology and Risk Factors

Most common hereditary bleeding disorder:

• Prevalence is ~1% worldwide
  However, only ~1% of these patients will display symptoms.

Pathophysiology

von Willebrand factor is a large glycoprotein that:

• Acts as the carrier protein for factor VIII
• Is required for platelet adhesion
  Provides an adhesive bridge from platelet to damaged subendothelium.

Aetiology

Causes of acquired vWD:

• Malignant
  • Lymphoproliferative disease
  • Myeloproliferative neoplasms
  • Wilms tumour
  • Carcinomas
• Immune
  • SLE
• Vascular flow
  Shear stress on vWF multimers ↑ susceptibility to cleavage by ADAMTS13.
  • AS
  • LVAD/ECMO
  • MV prolapse
  • Congenital heart disease
  • Toxins
    • Valproic acid
    • Ciprofloxacin
  • Other
    • Hypothyroidism

Clinical Features

Bleeding:

• Mucocutaneous bleeding most common
  
  • Dental procedures
• Minor surgery
  • Circumcision
• Menorrhagia
• PPH
  Usually secondary.

Assessment

History:

Exam:

Investigations

Bedside:

Laboratory:

Imaging:

Other:

Diagnostic Approach and DDx

Investigations

Majority of patients will have normal FBE and coagulation studies

Laboratory:

• Blood
  • FBE
    • Thrombocytopaenia
      Mild may be seen in type 2B.
  • Coag
    • Prolonged APTT
      Abnormality depends on degree of factor VIII deficiency.
  • vWF level
  • Factor VIII level
  • Specialised testing
    Distinguish subtypes of type II:
    • Ristocetin co-factor activity
    • VWF collagen binding

Management

• Clot stabilisation
• Replenish vWF and factor VIII levels
• Platelet transfusion

Utility of DDAVP depends on type - if unknown then begin empirically with vWF concentrate.

Specific therapy:

• Pharmacological
  • Clot stabilisation
    
    • Antifibrinolytics (TXA)
      Effective independent of aetiology of defect.
  • Replenish vWF and factor VIII
    • ↑ Native secretion
      • DDAVP
        Causes release of vWF from endothelial storage sites. Therefore:
        • Usually effective in type 1
        • Occasionally effective in type 2
        • Never effective in type 3
    • Exogenous factor replacement
      • vWF/FVIII concentrates
  • Platelet transfusions
  • Refractory bleeding
    • Consider FVIIa
    • Consider IVIG
      May be effective if due to anti-vWF autoantibodies, particularly if immune-acquired disease.
• Procedural
• Physical

DDAVP (desmopressin) is:

• A synthetic vasopressin analogue
• Dosed at 0.3μg/kg
  • Response is variable between patients, but usually consistent for the one patient
  • Tachyphylaxis occurs after 3-5 days
• Used for a variety of pro-coagulant effects:
  • Release of stored vWF
    Effective for mild quantitative and some qualitative von Willebrand disease.
  • Release of factor VIII
    Effective for mild haemophilia A.
  • ↑ Platelet aggregation
    • ↑ Surface GP receptors
    • ↑ Platelet-dependent thrombin generation

Supportive care:

Disposition:

Preventative:

Anaesthetic Considerations

Marginal and Ineffective Therapies

Complications

Prognosis

Key Studies

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References