Von willebrand disease

Summary

Von Willebrand Disease (vWD) is the most common inherited bleeding disorder, caused by a quantitative or qualitative defect in von Willebrand factor (vWF).

• Inheritance: Autosomal dominant (most types).
• vWF roles: (1) binds platelets to subendothelial collagen, (2) carries and protects Factor VIII.
• Bleeding pattern: Mucocutaneous → epistaxis, gum bleeding, menorrhagia, easy bruising.
• Classic labs: Normal platelet count, ↑ bleeding time / ↑ PFA-100, ↑ aPTT (due to ↓ Factor VIII), normal PT.
• Confirmatory test: ↓ Ristocetin cofactor activity.
• Treatment: Desmopressin (DDAVP) for type 1; vWF concentrate for severe types.

Definition and Epidemiology

Von Willebrand Disease is a bleeding disorder due to a deficiency or dysfunction of von Willebrand factor (vWF), a glycoprotein synthesized by endothelial cells and megakaryocytes and stored in Weibel-Palade bodies (endothelium) and platelet α-granules.

Key facts

• Most common inherited bleeding disorder (prevalence ~1%).
• Inheritance: Autosomal dominant in types 1 and 2; autosomal recessive in type 3.
• Sex distribution: Affects males and females equally — but women present more often (menorrhagia, postpartum bleeding).
• Onset: Usually mild; often diagnosed in adolescence/adulthood after surgery, dental work, or heavy menses.

Pathophysiology

What vWF does

1. Platelet adhesion (primary hemostasis): At a site of vascular injury, vWF binds exposed subendothelial collagen and then binds platelet GPIb receptor → anchors platelets to the vessel wall.
2. Factor VIII carrier: vWF circulates bound to Factor VIII, protecting it from proteolysis. Without vWF, FVIII half-life drops sharply → functional FVIII deficiency.

Consequences of vWF defect

• Impaired platelet plug → mucocutaneous bleeding (skin, mucous membranes).
• Low Factor VIII → mildly prolonged aPTT (intrinsic pathway).
• Platelet number is normal — only platelet function is impaired.

Think of primary hemostasis as three steps — vWD blocks step 1 (adhesion), while Bernard-Soulier also blocks step 1 (GPIb defect) and Glanzmann blocks step 3 (GPIIb/IIIa defect).

Classification (Types of vWD)

Three main types — distinguished by whether vWF is reduced in quantity or defective in quality.

Clinical Features

The bleeding pattern is mucocutaneous — typical of platelet-type bleeding — not deep tissue bleeding.

Common presentations

• Epistaxis (recurrent nosebleeds) — often the earliest sign in children.
• Gum bleeding, especially after brushing or dental procedures.
• Easy bruising and prolonged bleeding from small cuts.
• Menorrhagia — heavy menstrual bleeding is the most common presentation in women.
• Postpartum hemorrhage.
• GI bleeding — in older patients, may be associated with angiodysplasia.
• Excessive bleeding after surgery, tonsillectomy, or tooth extraction.

What you do NOT typically see

• Hemarthrosis or deep muscle hematoma → these suggest hemophilia, not vWD (exception: severe type 3 vWD).
• Petechiae are uncommon (platelet count is normal).

Diagnosis

Initial labs

• CBC: Normal platelet count (low only in type 2B).
• PT: Normal.
• aPTT: Normal or mildly prolonged (because of low FVIII). Corrects on mixing study — confirms a factor deficiency, not an inhibitor.
• Bleeding time / PFA-100 closure time: Prolonged → reflects defective platelet adhesion.

Confirmatory testing (vWD panel)

• vWF antigen (vWF:Ag) → quantitative level of vWF (low in types 1 and 3).
• Ristocetin cofactor activity (vWF:RCo) → best functional test; ristocetin induces vWF-mediated platelet agglutination. Low in all symptomatic types.
• Factor VIII activity → low (most marked in types 2N and 3).
• vWF multimer analysis → used to subclassify type 2.
• Ristocetin-induced platelet aggregation (RIPA): Increased in type 2B (platelets agglutinate even at low ristocetin doses).

The mixing study is a key step: the prolonged aPTT in vWD corrects because it reflects a factor deficiency (low FVIII), not an inhibitor.

Differential Diagnosis

Compare vWD with the two most common mimics on the exam — hemophilia A (deep bleeding, X-linked, normal platelets) and ITP (low platelets, mucocutaneous bleeding).

Other conditions to consider

• Hemophilia A and B — deep bleeding, hemarthrosis, prolonged aPTT, low FVIII or FIX.
• ITP — isolated low platelets, normal coagulation.
• Bernard-Soulier syndrome: GPIb receptor defect → cannot bind vWF; giant platelets, mild thrombocytopenia.
• Glanzmann thrombasthenia: GPIIb/IIIa defect → impaired platelet aggregation.
• Uremic platelet dysfunction: Acquired, in CKD; also responds to DDAVP.

Management

General principles

• Avoid antiplatelet drugs — no aspirin or NSAIDs.
• Treat minor bleeding with local measures (pressure, packing, tranexamic acid).
• Plan ahead for surgery and dental procedures with prophylactic treatment.

Specific therapies

1. Desmopressin (DDAVP): First-line for type 1 (and mild type 2A). Releases stored vWF and FVIII from endothelium. Given IV or intranasally.
2. vWF-containing concentrates (e.g., Humate-P, plasma-derived or recombinant vWF/FVIII concentrate): Used for types 2 and 3, major surgery, or severe bleeding.
3. Antifibrinolytics: Tranexamic acid or aminocaproic acid — helpful for menorrhagia, dental, and mucosal bleeding.
4. Combined oral contraceptives: Reduce menorrhagia by stabilizing the endometrium and slightly raising vWF/FVIII.
5. Cryoprecipitate: Contains vWF, FVIII, fibrinogen — used only when concentrates are unavailable.

For surgical patients, see the perioperative vWD management protocol and bleeding-risk stratification by procedure.

Complications

• Iron deficiency anemia from chronic mucosal blood loss (menorrhagia, GI bleeding).
• Postpartum hemorrhage — vWF rises during pregnancy but falls rapidly after delivery.
• Excessive surgical / dental bleeding if undiagnosed before procedure.
• GI bleeding from angiodysplasia — particularly in older patients with type 2A.
• Acquired vWD: A rare secondary form — seen with aortic stenosis (Heyde syndrome: aortic stenosis + GI angiodysplasia bleeding due to shear-induced destruction of large vWF multimers), lymphoproliferative disorders, hypothyroidism, and left ventricular assist devices.

Mnemonics

Key Points for Exams