Anti-endothelial cell antibodies from patients with thrombotic thrombocytopenic purpura specifically activate small vessel endothelial cells

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disease of an unkn own etiology, characterized by consumptive thrombocytopenia, microangiopath ic hemolytic anemia, fever and acute thrombotic complications, especially w ithin the cerebral circulation. Although anti-endothelial cell antibodies ( AECA) have occasionally been shown to be present in TTP, their role in the pathogenesis of the disease has never been ascertained. In the current stud y we demonstrated the pathogenic activity of affinity-purified anti-endothe lial cell F(ab)(2) antibodies (AECA/TTP) from four consecutive patients wit h active TTP, These AECA/TTP bound to and activated only microvascular endo thelial cells (EC) and not large vessel EC, The specificity of AECA/TTP bin ding to microvascular EC was confirmed by competition assay employing membr anes derived from small and large vessels EC, Activation included enhanced IL-6 and von Willebrand factor release from the EC followed by increased ex pression of adhesion molecules P-selectin, E-selectin and vascular cell adh esion molecule-1 on the EC, as evaluated by ELISA, Increased expression of adhesion molecules was followed by an increase in monocyte adhesion to EC, The level of soluble thrombomodulin (TM) also increased in the culture medi um of activated microvascular EC upon exposure to AECA/TTP antibodies and w as directly correlated to a decrease in cell-associated TM. Our data sugges t that AECA/TTP directed against microvascular EC could play a pathogenic r ole in the development of endothelial injury in TTP that leads to thrombosi s.