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PNH is a rare but severe hematological disorder characterized by complement\u2010mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement\u2010mediated pathophysiology ultimately led to regulatory approval of the first\u2010in\u2010class complement inhibitor, eculizumab, in 2007. This anti\u2010complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant\u2010resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti\u2010C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low\u2010level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.<\/jats:p>","DOI":"10.1002\/eji.202350817","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T05:49:42Z","timestamp":1722836982000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The complement model disease paroxysmal nocturnal hemoglobinuria"],"prefix":"10.1002","volume":"54","author":[{"given":"Christoph Q.","family":"Schmidt","sequence":"first","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products University of Ulm Medical Centre  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"H\u00f6chsmann","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine University of Ulm  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