Complement inhibitors in thrombotic microangiopathies and nephropathies: from bench to bedside

Eleni Gavriilaki

Hematology Department – BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece


Thrombotic microangiopathies (TMAs) consist a heterogeneous group of entities characterized by similar phenotypes: microangiopathic hemolytic anemia, thrombocytopenia and organ damage. Two major syndromes with distinct pathophysiology have been recognized: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Except for them, differential diagnosis also includes TMAs associated with underlying conditions. Since these entities share a common phenotype, pathophysiological features are warranted for early diagnosis and appropriate treatment.

Atypical HUS has served as a disease model of excessive complement activation. Over the last decade, the terminal complement inhibitor, eculizumab, has revolutionized treatment of HUS showing safety and efficacy. Although experience with eculizumab raised confidence in the approach, its clinical use revealed certain limitations. First, treatment is often delayed or not administered due to the lack of a confirmatory diagnostic assay and high cost. Second, clinical application of criteria for plasma exchange failure is not always straightforward. Diagnostic difficulties in the disease are highlighted by the fact that response to eculizumab is often used to confirm diagnosis. Third, vaccination is required at least 2 weeks before initiation of treatment in patients with a need of urgent treatment. Fourth, eculizumab is approved for life-long intravenous treatment, although cessation of treatment might be feasible in most of patients. In an effort to overcome eculizumab’s limitations, numerous novel complement inhibitors are on the horizon, with some studied under phase 3 clinical trials.

In light of genetic and functional data of complement dysregulation in several nephropathies, a number of clinical studies have also investigated the role of complement inhibition in C3 glomerulopathy, membranous and IgA nephropathy. Inhibitors of proximal complement pathways targeting C3, complement factor B or factor D and MASP-2 (Mannan-binding lectin serine protease 2) are expected to provide safety and efficacy in the ongoing phase 2 and 3 studies.

Keywords: thrombotic microangiopathy, complement inhibitors, hemolytic uremic syndrome, nephropathies