Studies of the role of complement factor H in hemolytic uremic syndrome

Abstract: Factor H is the main fluid phase regulator of the alternative pathway of complement. Factor H acts as a co-factor for factor I-mediated C3b degradation, inhibits the formation of the C3bBb convertase and accelerates its decay. By discriminating between host and foreign cells, factor H inhibits complement-mediated injury to host cells. Factor H mutations have been associated with atypical hemolytic uremic syndrome (aHUS) a condition characterized by non-immune hemolytic anemia, thrombocytopenia, and acute renal failure. The mechanism by which factor H mutations lead to aHUS is unclear. The purpose of these studies was therefore to examine the interaction of normal and mutated factor H with platelets and endothelial cells as well as the phenotypic expression of factor H in aHUS patients. Factor H bound to washed human platelets in a dose-dependent manner mainly via the C terminal of the protein and the heparin-binding sites. On platelets, factor H bound via the GPIIb/IIIa receptor as well as thrombospondin. Mutated factor H exhibited less binding, a finding that was verified using mutated factor H purified from the serum of a patient with aHUS. The same patient was found to have activation of the alternative complement pathway on platelets demonstrated by the presence of C3 and C5b-9 on the cell surface. Using the patient's serum we showed that the mutated factor H had reduced ability to protect normal platelets from complement activation. The phenotypic expression of factor H mutations was studied in two other patients in whom we demonstrated that the protein either accumulated in cells or exhibited reduced binding to host cells. Both these mechanisms could result in complement activation on host cells (endothelium and platelets), which would in turn promote endothelial cell injury as well as platelet activation and consumption in thrombi.