What are the primary roles of von Willebrand factor (VWF)?

Primary Roles of von Willebrand Factor (VWF)

The primary roles of von Willebrand factor (VWF) are to mediate platelet adhesion at sites of vascular injury and to serve as a carrier molecule for factor VIII in the circulation. 1

Key Functions of VWF

1. Platelet Adhesion and Aggregation

• VWF is a multimeric plasma glycoprotein that mediates platelet adhesion and accumulation at sites of blood vessel injury 1
• Under high shear stress conditions, VWF unfolds from its globular conformation, allowing it to bind to platelets and subendothelial matrix 1
• VWF serves as a "bridge" between:
  • Platelet membrane glycoproteins (GP Ib and GP IIb/IIIa)
  • Subendothelial components such as collagen 2
• The primary function of VWF is the promotion of platelet adhesion by anchoring platelets to the subendothelial matrix 1

2. Factor VIII Carrier Function

• VWF carries and stabilizes coagulation factor VIII (FVIII) in the circulation 1
• This carrier function protects FVIII from premature clearance and degradation 3
• The binding site for FVIII has been mapped to a region spanning amino acids 78-96 of the mature VWF protein 4

Structural Characteristics Related to Function

• VWF is composed of multimers of different sizes:

  • Low-molecular-weight (2500-3000 kDa)
  • Intermediate-molecular-weight (3000-5000 kDa)
  • High-molecular-weight (HMW, 5500-10,000 kDa) 1

• The HMW multimers are the most effective in promoting platelet adhesion under high shear rates at sites of vascular injury 1

• VWF has a domain structure consisting of repeated A, B, C, and D domains:

  • A1 domain: binds to platelet receptor glycoprotein Ib
  • A2 domain: contains the cleavage site for ADAMTS13 (between Tyr842 and Met843)
  • A3 domain: has a binding site for collagen 5, 6

Regulation of VWF Activity

• ADAMTS13 is the metalloprotease responsible for cleaving ultra-large/large high molecular weight VWF multimers 6
• This cleavage occurs at the proteolytically sensitive bond between Tyr842 and Met843 in the A2 domain when VWF unfolds under high shear stress 6
• Proper regulation of VWF by ADAMTS13 is crucial for normal hemostasis 6

Clinical Significance

• Deficiency or dysfunction of VWF leads to von Willebrand Disease (VWD), the most common inherited bleeding disorder 1
• Acquired von Willebrand syndrome (AVWS) can occur in various clinical settings, including during extracorporeal membrane oxygenation (ECMO) support 1
• Conversely, excessive VWF activity (due to ADAMTS13 deficiency) can contribute to thrombotic disorders like thrombotic thrombocytopenic purpura (TTP) 7

Answer to Multiple Choice Question

Based on the evidence presented, the correct answer is: C. mediate platelet adhesion; carrier molecule for factor VIII

This answer accurately reflects the two primary roles of VWF as established in the literature: mediating platelet adhesion at sites of vascular injury and serving as a carrier molecule for factor VIII in the circulation.