Figure 1.

Scheme on the pathophysiologic understanding of extra-renal complement-mediated TMA manifestations. Endothelial dysfunction and injury represent the center of TMA pathogenesis. Different endothelial harming factors can lead to endothelial dysfunction. Especially on the basis of inherited or acquired defects of complement regulation and activation, those factors can lead to severe complement activation inducing widespread endothelial injury with the consequence of local and systemic activation of inflammation and coagulation. All these complex complement concerted and maintained processes may finally lead to vasculopathy of microvessels including vasa-vasorum with large artery stenosis and organ ischemia followed by multiple renal and extra-renal symptoms. C3a, complement component 3a; C5a, complement component 5a; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CNS, central nerve system; EBV, Epstein–Barr virus; e.g., exempli gratia; EHEC, enterohemorrhagic Escherichia coli; H1N1, influence A virus subtype; m-TOR, mammalian target of rapamycin; TCC, terminal complement complex; TMA, thrombotic microangiopathy.