- Von Willebrand factor (vWF) is a large multimeric glycoprotein that plays a central role in hemostasis, the process that stops bleeding after vascular injury.
- It is produced mainly by endothelial cells, which line the interior surface of blood vessels, and by megakaryocytes, the precursor cells of platelets. Once synthesized, vWF is stored in specialized intracellular granules—Weibel–Palade bodies in endothelial cells and α-granules in platelets—or secreted directly into the blood plasma. Its structure is composed of repeating subunits that can assemble into very large multimers, and these multimers are critical for the protein’s biological activity.
- The primary function of vWF is to mediate platelet adhesion at sites of vascular injury. When a blood vessel is damaged, the subendothelial matrix is exposed, revealing collagen fibers. vWF binds to this exposed collagen and simultaneously binds to the glycoprotein Ib (GPIb) receptor on platelets. This dual interaction tethers platelets to the site of injury, even under high shear stress in the circulation. The bound platelets then become activated, releasing their own mediators and recruiting additional platelets to form the initial platelet plug. This step is essential for the rapid arrest of bleeding before the coagulation cascade consolidates the clot.
- In addition to its adhesive function, vWF serves as a carrier protein for coagulation factor VIII, protecting it from rapid degradation in the bloodstream. This carrier role is critical because factor VIII is a key component of the intrinsic pathway of the coagulation cascade. Without sufficient vWF, circulating factor VIII levels drop, leading to impaired clot formation. This is why deficiencies or defects in vWF, as seen in von Willebrand disease, can result in both platelet dysfunction and reduced coagulation factor activity, producing a spectrum of bleeding symptoms ranging from mild to severe.
- The size and activity of vWF multimers are regulated by a specific protease called ADAMTS13. Under normal conditions, ADAMTS13 cleaves ultra-large vWF multimers into smaller, less adhesive forms, preventing excessive platelet aggregation. In thrombotic thrombocytopenic purpura (TTP), ADAMTS13 activity is severely reduced or absent, allowing ultra-large vWF multimers to persist in circulation. This leads to widespread platelet-rich thrombus formation in small vessels, which can cause multiorgan ischemia. Understanding the biology of vWF has therefore been critical not only for diagnosing and managing bleeding disorders like von Willebrand disease but also for developing targeted treatments for thrombotic conditions such as TTP.
