Vwd
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Here is a comprehensive overview of von Willebrand Disease (VWD):
Von Willebrand Disease (VWD)
Definition & Epidemiology
VWD is the most common inherited bleeding disorder, caused by quantitative or qualitative reductions in plasma von Willebrand factor (VWF). Clinically significant bleeding occurs in approximately 1 in 1,000 individuals, with a relatively consistent prevalence across races and ethnicities. Overall, roughly 1% of people may have some degree of VWD, though many are asymptomatic.
Pathobiology
VWF is a large multimeric plasma glycoprotein with two essential roles in hemostasis:
- Mediates platelet adhesion to exposed subendothelial tissues at sites of vascular injury (primarily through the GpIb platelet receptor and collagen binding via the A1 and A3 domains).
- Carrier protein for factor VIII — protects it from premature proteolytic degradation in the circulation.
VWF is synthesized by:
- Endothelial cells (stored in Weibel-Palade bodies; primary plasma source)
- Megakaryocytes (stored in platelet α-granules; ~10–20% of platelet-rich plasma VWF)
VWF is secreted as heterogeneous multimers. High-molecular-weight (HMW) multimers are the most functionally active. Circulating multimer composition is regulated by ADAMTS13, a metalloprotease that cleaves VWF.
Normal plasma VWF: 50–150 IU/dL.
Classification (Subtypes)
| Type | Description |
|---|---|
| Type 1 | Most common (~70–80%); partial quantitative deficiency — reduced VWF levels. Autosomal dominant. Mild-moderate bleeding. |
| Type 2A | Qualitative defect; HMW multimers not synthesized → true functional deficiency |
| Type 2B | "Hyperfunctional" HMW multimers synthesized but rapidly cleared → spontaneous platelet aggregation → mild chronic thrombocytopenia |
| Type 2M | Qualitative defect without selective loss of HMW multimers |
| Type 2N | Markedly reduced binding affinity for factor VIII (mimics hemophilia A but is autosomal) |
| Type 3 | Rare; near-complete absence of VWF → severe bleeding resembling hemophilia A (due to concomitant factor VIII deficiency) |
Clinical Features
- Mucocutaneous bleeding: epistaxis, gingival bleeding, easy bruising
- Menorrhagia (often the presenting symptom in females)
- Excessive bleeding after wounds or surgery
- Usually autosomal dominant transmission (Type 1, 2); Type 3 is autosomal recessive
- Often underrecognized due to mild manifestations and need for sophisticated testing
Diagnosis
Key laboratory findings:
- Prolonged bleeding time and prolonged aPTT (due to factor VIII deficiency)
- Reduced VWF antigen (VWF:Ag)
- Reduced VWF activity (ristocetin cofactor assay, VWF:RCo)
- Reduced factor VIII activity (especially in Type 2N and Type 3)
- Multimer analysis to subtype Type 2 variants
Treatment
- Desmopressin (DDAVP): First-line for Type 1; triggers release of VWF from Weibel-Palade bodies. Contraindicated in Type 2B (worsens thrombocytopenia).
- VWF concentrates / factor VIII–VWF concentrates: For Type 2, Type 3, or when DDAVP is ineffective.
- Antifibrinolytics (tranexamic acid, aminocaproic acid): Adjunct for mucosal bleeding and surgical procedures.
- Cryoprecipitate: Contains VWF and factor VIII; used when concentrates unavailable.
Sources: Goldman-Cecil Medicine, p. 1400–1415; Robbins & Kumar Basic Pathology, p. 430
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