Complement biomarkers in the antiphospholipid syndrome – Approaches to quantification and implications for clinical management

Complement is a major driver of antiphospholipid syndrome (APS) and a promising therapeutic target in refractory and catastrophic APS. Complement testing in APS is largely limited to research settings, and reliable, rapid-turnaround biomarkers are needed to predict those at risk for adverse clinical outcomes and most likely to benefit from complement inhibition. We review complement biomarkers and their association with thrombosis and obstetric outcomes, including: (i) complement proteins and activation fragments in the fluid phase; (ii) assays that evaluate complement on cell membranes (e.g. in vivo cell-bound complement fragments, hemolytic assays, and ex vivo ‘functional’ cell-based assays, and (iii) sequencing of complement genes. Current studies highlight the inconsistencies in testing both between studies and various aPL/APS subgroups, suggesting that either cell-based testing or multiplex panels employing a combination of biomarkers simultaneously may be most clinically relevant. Standardization of complement assays is needed to ensure reproducibility and establish clinically relevant applications.