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Complement and the prothrombotic state

Lookup NU author(s): Professor David KavanaghORCiD


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In 2007 and 2009 the regulatory approval of the first-in-class complement inhibitor Eculizumab has revolutionized the clinical management of two rare, life-threatening clinical conditions: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). While being completely distinct diseases affecting blood cells and the glomerulus, PNH and aHUS remarkably share several features in their etiology and clinical presentation. An imbalance between complement activation and regulation at host surfaces underlies both diseases precipitating in severe thrombotic events that are largely resistant to anti-coagulant and/or anti-platelet therapies. Inhibition of the common terminal complement pathway by Eculizumab prevents the frequently occurring thrombotic events responsible for the high mortality and morbidity observed in patients not treated with anti-complement therapy. While many in vitro and ex vivo studies elaborate numerous different molecular interactions between complement activation products and hemostasis, this review focuses on the clinical evidence that links these two fields in humans. Several non-infectious conditions with known complement involvement are scrutinized for common patterns concerning a prothrombotic statues and the occurrence of certain complement activation levels. Next to PNH and aHUS, germline encoded CD59 or CD55 deficiency (the latter causing the disease Complement Hyperactivation, Angiopathic thrombosis, and Protein-Losing Enteropathy; CHAPLE), autoimmune hemolytic anemia (AIHA), (catastrophic) anti-phospholipid syndrome (APS, CAPS) and C3 glomerulopathy are considered. Parallels and distinct features among these conditions are discussed against the background of thrombosis, complement activation, and potential complement diagnostic and therapeutic avenues.

Publication metadata

Author(s): Schmidt CQ, Schrezenmeier H, Kavanagh D

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2022

Volume: 139

Issue: 13

Pages: 1954-1972

Print publication date: 31/03/2022

Online publication date: 20/08/2021

Acceptance date: 08/06/2021

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology


DOI: 10.1182/blood.2020007206


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