Linking von Willebrand factor (VWF) and the alternative complement pathway. Activation and amplification of the alternative complement pathway (AP) can occur on ultra-large (UL) VWF strings. The image depicts assembly of C3 convertase (C3bBb) and C5 convertase (C3bBbC3b) on endothelial cell (EC) secreted/anchored ULVWF multimeric strings, leading to the formation of copies of the membrane attack complex (MAC; C5b-9) that are potentially injurious to target (and host) cells. In individuals with ≥1 mutation/polymorphism promoting amplification of the AP (eg, by impairing the negative regulatory activity on C3 convertase by factor H, factor I, or CD46), acute aHUS episodes are likely. Normally, the VWF-cleaving protease ADAMTS13, released from EC cytoplasm, diminishes the brief time available for AP activation by the EC-secreted/anchored ULVWF strings. This proteolytic control mechanism is likely to be less effective if functional ADAMTS13 production is reduced even moderately (∼50% of normal ADAMTS13 activity is shown as cleavage of 1 of 2 ULVWF strings) and will be compromised further if the rate of ULVWF secretion/anchorage is increased by cytokines during inflammation or infection. Not shown are complement components regulating C3 convertase positively (properdin or factor P) or negatively (factors H and I and CD46) and platelet adherence to the ULVWF strings. C3b, Bb, C5b, activated C3, factor B, or C5, respectively; C3a, C5a, small cleavage products of C3 or C5; C5b-9, MAC complex composed of C5b, C6, C7, C8, and C9; WPB, Weibel-Palade body. Original figure prepared by Nancy A. Turner, Rice University. Professional illustration by Somersault18:24.