It is generally assumed that endothelial cell injury is the primary event in the pathogenesis of thrombotic thrombocytopenic purpura (TTP). In this study, we have determined the extent of vascular perturbation during acute episodes of the disease. We performed a prospective, serial study of nine patients with relapsing TTP during hospitalization and treatment, and assessed the degree of endothelial cell involvement at admission, exacerbation and remission by measurement of von Willebrand factor (VWF) and VWF-propeptide levels. Measurement of both VWF and its propeptide enabled discrimination between acute and chronic perturbation of the endothelium. Elevated levels of both VWF and propeptide were found at admission. These levels decreased immediately upon plasma exchange therapy. However, plasma VWF and propeptide concentrations did not change, even at the time of acute exacerbation. These observations suggest that endothelial cell activation is not the primary event leading to TTP. Vascular perturbation seems to be a consequence, rather than a cause, of the disease.