AbstractAtypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) that occurs due to defective regulation of the alternative complement pathway (AP). We developed a novel model system using Blood Outgrowth Endothelial Cells (BOEC), whereby the response of these cells to complement challenge could be examined under static and microfluidic conditions, in order to study aHUS pathogenesis. Complete blockade of the membrane-anchored, AP regulator CD46/MCP, associated with disease in patients, was insufficient to cause an ex vivo TMA phenotype. Increasing `complement challenge', mimicking additional genetic `hits' in complement regulation achieved the phenotype. In addition, using BOEC from patients lacking von Willebrand Factor (vWF), a hemostatic protein released from activated endothelial cells, we showed that contrary to current opinion, vWF does not amplify complement, rather regulates it. The paucity of vWF in the glomerular endothelium could explain the vulnerability of the kidney to loss of complement control in aHUS.M.Sc.2016-07-09 00:00:0
