Shear stress and the role of high molecular weight von Willebrand factor multimers in thrombus formation.
High molecular weight von Willebrand factor (VWF) multimers have an important role in the formation of platelet thrombi under conditions of high shear stress resulting from rapid blood flow. Laboratory studies conducted using an endothelial cell system have shown that ultra-large VWF multimers (ULVWF) attach to the surface of histamine-stimulated endothelial cells and form large string-like structures to which platelets adhere. Platelet attachment is mediated through the interaction of the glycoprotein (Gp) Ibalpha subunit of the platelet GpIb-IX-V complex with the A1 domain of VWF. These platelet-ULVWF strings are rapidly cleaved by the addition of normal human plasma or the purified plasma metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type I motifs domains). Cleaving activity is absent from the plasma of patients with the congenital or acquired forms of thrombotic thrombocytopenic purpura (TTP) and from mixtures of normal plasma with plasma from patients with acquired TTP. The interaction of VWF with P-selectin is at least partially responsible for the attachment of the VWF strings to the endothelium. Increased tensile stress on ULVWF multimers resulting from the tethering of ULVWF strings to the endothelial surface by P-selectin in flowing blood may expose the cleavage site on the A2 domain of VWF, facilitating multimer degradation by ADAMTS-13. These studies have important implications in bleeding and thrombotic disorders, including von Willebrand disease and TTP.
López
José A
JA
Baylor College of Medicine, Thrombosis Research Section, Houston, TX 77030, USA.
Dong
Jing-fei
JF
D016913:Blood Component Transfusion; D005169:Factor VIII / Q000627:therapeutic use; D006801:Humans; D008970:Molecular Weight; D013314:Stress, Mechanical; D013927:Thrombosis / Q000209:etiology*; D014842:von Willebrand Diseases / Q000150:complications / Q000209:etiology / Q000628:therapy; D014841:von Willebrand Factor / Q000737:chemistry / Q000502:physiology* / Q000627:therapeutic use
D014841:von Willebrand Factor; D005169:Factor VIII