Platelets adhere to sites of vascular injury to form an initial platelet plug, and this process requires von Willebrand factor (VWF) to bridge platelet membrane glycoprotein Ib (GPIb) and ligands in exposed connective tissue. The GPIb binding site is known to reside in VWF domain A1, which is 1 of 3 tandemly repeated 24 kd A domains in the VWF subunit. But the nature of the VWF–connective tissue interaction remains controversial. VWF binds several types of fibrillar collagen in vitro, and the major collagen binding site is within VWF domain A3. A second site may be present in domain A1, but domain A1 cannot sustain normal platelet adhesion to collagen if domain A3 is deleted. Sites other than A3 may bind connective tissue, and connective tissue ligands other than fibrillar collagens may bind VWF. For example, nonfibrillar collagen type VI binds domain A1 rather than domain A3, and monoclonal antibodies have been prepared that prevent VWF binding to fibrillar collagen or subendothelial connective tissue, but not both. Therefore, the contribution of VWF-collagen binding to the initial stages of platelet plug formation remains poorly defined.
Wu and colleagues (page 3623) now have shown that a monoclonal antibody to VWF domain A3 that inhibits VWF-collagen binding in vitro can prevent platelet-rich thrombi from forming in damaged femoral arteries in vivo. At higher doses, the antibody also prolongs the skin bleeding time of baboons. These findings demonstrate the physiologic importance of VWF domain A3 in platelet adhesion and suggest that the relevant connective tissue ligand is a fibrillar collagen. The data do not exclude a role for other VWF binding sites or other connective tissue ligands, but they do suggest that VWF sites other than domain A3 may be insignificant for connective tissue interactions. Furthermore, the antithrombotic effect of the anti-VWF antibody persisted for several hours after a single injection, raising the possibility that interference with the VWF domain A3-collagen interaction could be a feasible antithrombotic strategy.
