Thrombotic microangiopathy (TMA) is a condition characterized by
thrombocytopenia and
microangiopathic hemolytic anemia (MAHA) with varying degrees of organ damage in the setting of normal international normalized ratio and activated partial thromboplastin time.
Complement has been implicated in the etiology of TMA, which are classified as primary TMA when genetic and acquired defects in
complement proteins are the primary drivers of TMA (
complement-mediated TMA or
atypical hemolytic uremic syndrome, aHUS) or secondary TMA, when complement activation occurs in the context of other disease processes, such as
infection,
malignant hypertension,
autoimmune disease,
malignancy,
transplantation, pregnancy, and drugs. It is important to recognize that this classification is not absolute because genetic variants in
complement genes have been identified in patients with secondary TMA, and distinguishing
complement/genetic-mediated TMA from secondary causes of TMA can be challenging and lead to potentially harmful delays in treatment. In this review, we focus on data supporting the involvement of
complement in aHUS and in secondary forms of TMA associated with
malignant hypertension, drugs,
autoimmune diseases, pregnancy, and
infections. In aHUS, genetic variants in
complement genes are found in up to 60% of patients, whereas in the secondary forms, the finding of genetic defects is variable, ranging from almost 60% in TMA associated with
malignant hypertension to less than 10% in drug-induced TMA. On the basis of these findings, a new approach to management of TMA is proposed.