Deficiency of vWF, cause mixed platelet and coagulation disorders

Epidemiology

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Most common congenital bleeding disorder.

Etiology

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Acquired von Willebrand disease (aVWD)

• Lymphoproliferative and myeloproliferative diseases (e.g., multiple myeloma, monoclonal gammopathies, lymphoma, essential thrombocythemia)
• Autoimmune diseases (e.g., SLE)
• Cardiovascular defects (e.g., ventricular septal defect, aortic stenosis)
  • These conditions lead to increased shear stress in blood vessel which can result in increased degradation of vWF.
• Hypothyroidism
• Side effects of certain drugs (e.g., valproic acid)

Pathophysiology

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• Von Willebrand factor (vWF): plasma protein that is synthesized by and stored in endothelial cells (in Weibel-Palade bodies) and platelets (in α-granules)
  • Mediates platelet adhesion and aggregation
  • Binds factor VIII (and thereby prevents its degradation)

Deficiency or dysfunction of vWF leads to:

• Dysfunctional platelet adhesion → impaired primary hemostasis
• Reduced binding of factor VIII → increased degradation → ↓ factor VIII activity → impaired intrinsic pathway of secondary hemostasis

Clinical features

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• Often asymptomatic
• Symptomatic individuals may develop the following symptoms:
  • Mucocutaneous bleeding
    • Ecchymoses, easy bruising
    • Epistaxis
    • Bleeding of gingiva and gums
    • Petechiae
    • Prolonged bleeding from minor injuries
  • Bleeding after surgical procedures or tooth extraction
  • GI bleeding (can be caused by angiodysplasia)
  • Menorrhagia (affects up to 92% of women with vWD)
  • Postpartum hemorrhage

Diagnostics

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• ↑ Bleeding time
• Normal or ↑ aPTT (may be prolonged as a result of factor VIII deficiency)
• Ristocetin cofactor assay: measures the ability of von Willebrand factor (vWF) to agglutinate platelets.
  • Ristocetin is an antibiotic that activates vWF to bind glycoprotein Ib, thereby inducing platelet aggregation.
  • Interpretation: If ristocetin is added to blood lacking vWF (or the vWF receptor), platelets will not aggregate.

Treatment

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• Desmopressin (DDAVP): stimulates vWF release from endothelial cells
  • Best initial treatment for mild or moderate symptoms (typically type 1 and, sometimes, type 2)
  • Not effective for type 3
  • Has a minimal effect on the V1 vasopressin receptor. Therefore won’t cause vasoconstriction.
• Concentrates containing vWF and factor VIII: indicated for severe bleeding, as prophylaxis for surgical procedures and if DDAVP treatment is ineffective