What is the mechanism by which von Willebrand's disease causes bleeding?

Mechanism of Bleeding in von Willebrand Disease

Von Willebrand disease causes bleeding through two primary mechanisms: impaired platelet adhesion at sites of vascular injury and decreased factor VIII levels in circulation. 1

Primary Pathophysiological Mechanisms

• Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that serves two critical hemostatic functions:

  1. Mediates platelet adhesion and aggregation at sites of blood vessel injury 1
  2. Carries and stabilizes coagulation factor VIII (FVIII) in the circulation 1

• When VWF is deficient or defective, these two critical hemostatic functions are compromised, leading to bleeding manifestations 1

Impaired Platelet Function

• VWF normally functions as a bridge between:

  • Exposed subendothelial structures (like collagen) at sites of vascular injury
  • Platelet membrane receptors (particularly glycoprotein Ib) 2

• This bridging action is especially critical under high shear stress conditions found in small vessels 2

• In VWD, this platelet-adhesive function is impaired, preventing the formation of the initial platelet plug at sites of vascular injury 1, 2

• The defect in platelet adhesion primarily manifests as mucosal bleeding (epistaxis, gingival bleeding, menorrhagia) and easy bruising 1, 3

Factor VIII Deficiency

• VWF serves as a carrier protein for factor VIII, protecting it from premature clearance 1

• In VWD, particularly in severe forms like Type 3, reduced VWF leads to secondary deficiency of factor VIII 1, 3

• Low factor VIII levels contribute to impaired secondary hemostasis (coagulation cascade), resulting in prolonged bleeding after surgery, trauma, or childbirth 4, 3

Variability Based on VWD Type

• Type 1 VWD (partial quantitative deficiency): Mild to moderate reduction in functionally normal VWF 1, 5

• Type 2 VWD (qualitative defects): Four subtypes with different functional abnormalities:

  • Type 2A: Decreased high-molecular-weight VWF multimers, which are most effective in platelet adhesion 3
  • Type 2B: Pathologically increased VWF-platelet interactions, leading to clearance of high-molecular-weight multimers and thrombocytopenia 3
  • Type 2M: Decreased VWF-platelet interactions not due to loss of high-molecular-weight multimers 3
  • Type 2N: Reduced binding of VWF to factor VIII, causing a hemophilia A-like phenotype 3

• Type 3 VWD (virtually complete quantitative deficiency): Severe bleeding due to profound deficiency of both VWF functions 1, 3

Clinical Manifestations

• The dual defect in VWD explains the spectrum of bleeding symptoms:
  • Mucosal bleeding (epistaxis, gingival bleeding, menorrhagia) primarily from platelet dysfunction 1, 3
  • Prolonged bleeding after surgery or trauma from factor VIII deficiency 4, 3
  • Severity ranges from mild bleeding in Type 1 to severe, life-threatening bleeding in Type 3 1

Diagnostic Implications

• Diagnosis requires specialized assays that assess both functions of VWF:

  • VWF antigen level (quantitative measurement)
  • Ristocetin cofactor activity (measures platelet-binding function)
  • Factor VIII coagulant activity 6

• Additional tests like collagen binding assay and VWF multimer analysis help differentiate between VWD subtypes 6

Treatment Considerations

• Therapy targets both defects:
  • Desmopressin (DDAVP) increases plasma levels of VWF and factor VIII in responsive patients (mainly Type 1) 5, 3
  • VWF-containing factor concentrates replace both VWF and factor VIII in more severe cases 3