Von Willebrand Disease

Basics

Description

  • Coagulopathy caused by deficiency or dysfunction of von Willebrand factor (vWF)
  • vWF functions:
    • Mediates platelet–endothelial cell adhesion
    • Carrier protein for factor VIII
  • Prevalence as high as 1–2% in the general population
  • Genetics:
    • Most cases inherited – multiple genetic defects identified
    • Type 1 – quantitative defect of vWF:
      • 75% of cases
      • Autosomal dominant
      • vWF deficiency results from decreased synthesis and increased clearance of protein
      • Manifestation ranges from asymptomatic to moderate bleeding
    • Type 2 – qualitative defect of vWF:
      • 10–20% of cases
      • Divided into types 2A, 2B, 2M, 2N
      • 2A(10–15% of cases) and 2M are either autosomal dominant or recessive
      • 2B(5% of cases) is autosomal dominant
      • 2N is autosomal recessive
      • 2A, 2B, and 2M have decreased high molecular-weight multimers and decreased VWF activity
      • 2N – Normal VWF activity, normal multimer electrophoresis, and decreased binding to factor VIII
      • Leads to decreased levels of VIII (5–15%) and thus more serious coagulopathy
    • Type 3 – absent or severe deficiency in amount of vWF:
      • Rare disease – 1 per million cases
      • Autosomal recessive
      • Severe coagulopathy
    • vWD genetically associated with sickle cell disease, hemophilia A, factor XII deficiency, hereditary hemorrhagic telangiectasia, and thrombocytopenia

Etiology

  • In addition to genetic causes, acquired forms exist
  • Multiple mechanisms:
    • vWF antibody production
    • Decreased synthesis
    • Proteolysis
    • Increased clearance from binding to tumor cells
  • Seen in association with the following:
    • Malignancy:
      • Wilms tumor
      • Multiple myeloma
      • Chronic lymphocytic leukemia
      • Non-Hodgkin lymphoma
      • Chronic myelogenous leukemia
      • Waldenstrom macroglobulinemia
      • Monoclonal gammopathy of uncertain significance
    • Immunologic:
      • Systematic lupus erythematosus
      • Rheumatoid arthritis
    • Medication induced:
      • Valproic acid
      • Ciprofloxacin
      • Hetastarch
      • Griseofulvin
    • Miscellaneous:
      • vWF is acute phase reactant with increased levels during adrenergic stimulation, inflammation, and exercise
      • Hypothyroidism reduces plasma level of vWF
      • Uremia
      • Hemoglobinopathies
      • Cirrhosis
      • Congenital heart disease
      • Disseminated intravascular coagulation

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