Von Willebrand disease

Von Willebrand disease (vWD) is a bleeding disorder characterized by a deficiency or dysfunction of von Willebrand factor (vWF). In the vast majority of cases, vWD is an inherited disorder caused by mutations in the vWF gene. vWF is involved in platelet adhesion and prevents degradation of factor VIII. Therefore, vWF deficiency or dysfunction impairs primary hemostasis as well as the intrinsic pathway of secondary hemostasis. vWD is often asymptomatic, but mucocutaneous bleeding, GI bleeding, and menorrhagia may occur. Diagnosis is based on patient history and laboratory studies such as quantitative measurement of vWF and ristocetin cofactor assay. Treatment is indicated for symptomatic patients; prophylaxis is indicated for surgical candidates and involves desmopressin and concentrates containing vWF and factor VIII.

• Most common congenital bleeding disorder ^[1]
• Prevalence: estimated to affect approx. 1% of the US population ^[1]

Epidemiological data refers to the US, unless otherwise specified.

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

The severity of symptoms varies between the different types of vWD. Type 1 and avWD usually manifest more mildly; type 3 is the most severe form. ^[2][4]

• 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) ^[5]
  • Postpartum hemorrhage
  • Severe cases: large hematomas, hemarthrosis, life-threatening bleeding (e.g., during childbirth)

History

• Recurrent episodes of bleeding since childhood
• Often positive family history

Laboratory studies ^[2]

• ↑ Bleeding time
• Normal or ↑ aPTT (may be prolonged as a result of factor VIII deficiency)
• Normal PT and platelet count
• ↓ Factor VIII
• ↓ vWF antigen levels
• Ristocetin cofactor assay: failure of platelet aggregation or a ristocetin cofactor level < 30 IU/dL
• Further qualitative assessment by collagen binding assay

Treatment is only indicated if symptoms occur or as prophylaxis before surgical procedures. ^[2]

Inherited von Willebrand disease

• 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
• Concentrates containing vWF and factor VIII: indicated for severe bleeding, as prophylaxis for surgical procedures and if DDAVP treatment is ineffective
• Other treatment options: antifibrinolytic drugs (i.e., aminocaproic acid, tranexamic acid), oral contraceptives for menorrhagia

Acquired von Willebrand syndrome

• Desmopressin and vWF/VIII concentrates are often less effective than in inherited vWD.
• Patients may benefit from intravenous immune globulin (IVIG) treatment.
• Treatment of the underlying cause.

Platelet aggregation inhibitors (e.g., aspirin, NSAIDs, clopidogrel) and intramuscular injections are contraindicated in von Willebrand disease because they further increase the risk of bleeding!