Von Willebrand Disease: Pathophysiology and Clinical Characteristics
Von Willebrand disease (VWD) is characterized by mucosal bleeding due to deficiency or dysfunction of von Willebrand factor (VWF), does not result in prolonged prothrombin time, typically presents with abnormal bleeding time, is synthesized by endothelial cells and megakaryocytes (not the liver), and rarely presents with joint bleeding. 1
Pathophysiology of VWD
VWD is the most common inherited bleeding disorder, affecting males and females equally with a prevalence of up to 1% of the population. The disease stems from:
- Deficiency or dysfunction of VWF: A multimeric plasma glycoprotein that mediates platelet adhesion and aggregation at sites of vascular injury 1
- VWF's dual role: It facilitates platelet adhesion to damaged endothelium and carries/stabilizes factor VIII in circulation 1, 2
- Production site: VWF is produced by endothelial cells and megakaryocytes, not by the liver (unlike most other coagulation factors) 2
Classification of VWD
VWD is classified into three main types:
- Type 1 (75% of cases): Partial quantitative deficiency of VWF
- Type 2: Qualitative deficiency with four subtypes (2A, 2B, 2M, 2N)
- Type 3: Virtually complete quantitative deficiency (rare, affecting ~1 in 1,000) 1
VWD can also occur as an acquired disorder (acquired von Willebrand syndrome) associated with various medical conditions 1, 3.
Laboratory Findings in VWD
Key laboratory findings in VWD include:
- Bleeding time: Typically prolonged (abnormal) due to impaired platelet adhesion 2
- Prothrombin time (PT): Normal in VWD, as PT measures the extrinsic pathway which is not directly affected by VWF deficiency 2
- Factor VIII levels: May be reduced (especially in Type 3) due to decreased stabilization by VWF 1
- VWF antigen and activity tests: Reduced in varying degrees depending on VWD type 4
Clinical Presentation
The clinical presentation of VWD typically includes:
- Mucosal bleeding: Most characteristic finding, including epistaxis, gingival bleeding, and gastrointestinal bleeding 1, 2
- Menorrhagia: Heavy menstrual bleeding in women 1
- Easy bruising and prolonged bleeding from minor wounds 1
- Bleeding after surgery or invasive procedures 1
Important distinction:
- Joint bleeding (hemarthrosis): Rarely seen in VWD except in severe Type 3 disease with very low factor VIII levels. Hemarthrosis is more characteristic of hemophilia A and B 1, 2
Diagnostic Approach
Diagnosis requires:
- Comprehensive bleeding history
- Laboratory testing including VWF antigen (VWF:Ag), VWF activity (VWF:RCo), factor VIII levels, and multimer analysis 1, 5
- Bleeding time assessment (typically prolonged)
- Normal PT (distinguishing it from disorders affecting the extrinsic pathway)
Treatment Considerations
Treatment options include:
- Desmopressin (DDAVP): First-line for Type 1 VWD, stimulates release of endogenous VWF 2, 6
- VWF-containing concentrates: For Type 3 and severe forms of Type 1 and 2 where DDAVP is ineffective 2
- Hormone therapy: May be beneficial for women with menorrhagia 7
Remember that VWD is often misdiagnosed or underdiagnosed, particularly in women where heavy menstrual bleeding may be attributed to gynecological rather than hematological causes 5.