Complement activation and TMA. The scheme highlights some of the mechanisms by which unregulated complement activation provokes the development of microvascular thrombi via unrelenting activation/damage to the endothelium and platelet. With excess complement activation, the abundant anaphylatoxins C3a and C5a bind to their widely expressed cognate receptors. Endothelial cells and platelets can thus be activated, whereupon intracellular proinflammatory and procoagulant signaling cascades are recruited (eg, nuclear factor κB [NFκB], phospho-ERK 1/2 [pERK1/2]). In endothelial cells, these upregulate expression of adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule [VCAM-1], E-selectin), the release of proinflammatory cytokines (eg, monocyte chemotactic protein 1 [MCP-1], interleukin-6 [IL-6]), exposure of TF, suppressed expression of the anticoagulant/anticomplement thrombomodulin (TM), and reduced release of nitric oxide (NO). P-selectin, FH, and ULVWF multimers are secreted from endothelial cell Weibel-Palade bodies, and they are released from α-granules and/or the cytoplasm (for FH) of platelets. P-selectin and ULVWF facilitate platelet adhesion/aggregation, but also are receptors for C3b binding, allowing assembly of the AP C3 and C5 convertases (C3bBb and C3bBbC3b, respectively). These further amplify complement activation, with release of more C3a and C5a. Downstream, complement activation yields terminal pathway complexes (C5b-7, sC5b-9) which induce TF exposure, endothelial membrane “flipping” to support prothrombinase assembly, and the transformation of prothrombin (II) to the procoagulant, platelet activating and proinflammatory protease, thrombin (IIa). Thrombin and other procoagulant enzymes (eg, factor Xa) also feed back to cleave C5, fueling further activation of complement. C3a, C5a, and cell-released chemokines also recruit inflammatory cells, which in turn exacerbate endothelial damage via the release of reactive oxygen species and cytokines (eg, tumor necrosis factor α [TNFα], high-mobility group box 1 [HMGB1]). Activated platelets also release their granule contents which are primarily procoagulant and proinflammatory. Platelet and endothelial microparticles, released in response to exposure to C3a and C5a, carry complement factors and express TF to further promote coagulation and complement. ULVWF multimers support platelet adhesion/aggregation and the formation of thrombi, as well as further activation of complement. In aHUS, eculizumab interferes with cleavage of C5 to C5b and C5a, and effectively reverses the unrelenting, self-propelling activation of the cascades that otherwise result in the TMA.