Von Willebrand Disease

Risk factors

• Family history of bleeding (autosomal dominant in types 1 and most 2)
• Type 3 is autosomal recessive — consanguinity
• Acquired vWD: lymphoproliferative disorders (MGUS, Waldenström), severe aortic stenosis (Heyde syndrome), LVAD support, hypothyroidism, Wilms tumor
• Pregnancy raises vWF (worsening type 2B, masking type 1)

Pathophysiology

vWF, synthesized by endothelial cells and megakaryocytes, has two key roles: (1) mediates platelet adhesion to exposed subendothelial collagen at sites of vascular injury via the platelet GPIb receptor, and (2) circulates as a chaperone protein that protects factor VIII from proteolysis. Deficient or dysfunctional vWF impairs platelet adhesion (mucocutaneous bleeding) and can lower factor VIII (deep tissue bleeding in severe disease). vWF circulates as multimers; the largest (high-molecular-weight) multimers are the most hemostatically active.

Clinical presentation

Differential diagnosis

• Hemophilia A — Joint and deep tissue bleeding (not mucocutaneous), normal vWF, low factor VIII, X-linked; severe forms differ clinically
• Platelet function disorders (Glanzmann, Bernard-Soulier, storage pool) — Mucocutaneous bleeding similar to vWD; platelet aggregation studies abnormal in specific patterns
• Immune thrombocytopenia (ITP) — Low platelet count (vWD has normal platelets unless type 2B), petechiae prominent
• Acquired vWD — New-onset bleeding in older adult or with underlying condition (severe AS, lymphoproliferative disorder, hypothyroidism)
• Ehlers-Danlos / vascular fragility — Easy bruising, joint hypermobility, skin findings; normal coagulation studies
• Antiplatelet drug effect — Recent aspirin, clopidogrel, NSAID use

Diagnostic workup

Diagnostic algorithm

Treatment

Complications

• Heavy menstrual bleeding with iron deficiency anemia
• Postpartum hemorrhage — vWF drops within days of delivery
• Bleeding with dental procedures and surgery
• Joint and CNS bleeding in type 3 (resembling hemophilia)
• Heyde syndrome — acquired vWD from severe AS plus GI angiodysplasia
• Iron deficiency anemia from chronic mucosal blood loss
• Tachyphylaxis to DDAVP with repeated doses; hyponatremia from fluid retention with DDAVP — limit fluid intake and check sodium

PANCE pearls

• vWD is the most common inherited bleeding disorder — consider in any patient with mucocutaneous bleeding or heavy menses.
• Normal vWF levels vary by blood type — type O has ~25% lower levels than non-O. ABO group must be considered in interpretation.
• DDAVP is the treatment of choice for type 1 vWD but is CONTRAINDICATED in type 2B (worsens thrombocytopenia through increased platelet binding) and INEFFECTIVE in type 3 (no vWF to release).
• Heyde syndrome = severe aortic stenosis + acquired vWD + GI angiodysplasia bleeding. Aortic valve replacement corrects the acquired vWD and the bleeding.
• Type 2N vWD mimics hemophilia A (low factor VIII) — vWF antigen normal but cannot bind/stabilize VIII. Suspect when 'mild hemophilia A' is autosomal in inheritance or in a female.
• Pregnancy raises vWF/factor VIII in normal women and in mild type 1 vWD — bleeding risk often improves during pregnancy but returns rapidly postpartum.
• DDAVP-induced hyponatremia: limit free water intake during therapy; can cause seizures, especially in children and elderly.
• PFA-100 has largely replaced bleeding time but is not sufficiently sensitive to rule out vWD — perform specific vWF assays if clinical suspicion is high.

References

• ASH/ISTH/NHF/WFH 2021 — ASH/ISTH/NHF/WFH 2021 guidelines on the diagnosis of von Willebrand disease (James et al., Blood Adv 2021)
• ASH/ISTH/NHF/WFH 2021 — ASH/ISTH/NHF/WFH 2021 guidelines on the management of von Willebrand disease (Connell et al., Blood Adv 2021)
• Heyde — Gastrointestinal bleeding in aortic stenosis (Heyde, NEJM 1958)
• Mannucci — Treatment of von Willebrand's Disease (Mannucci, NEJM 2004)