Complement in Secondary Thrombotic Microangiopathy

Abstract

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.

Keywords: HUS; autoimmune disease; complement; drugs; hypertension; thrombotic microangiopathy.

Figure 1

Pathology of thrombotic microangiopathy (TMA). The pathology of TMA on light microscopy includes glomerular and vascular changes. Glomerular changes: thrombi in glomerular capillaries, mesangiolysis, and, in the chronic phase, thickened capillary walls with double contour formation. Vascular changes: thrombi, fragmented red cells, intimal swelling, and fibrous thickening with onion skinning. Representative findings of TMA in a case of aHUS (a,b), antiphospholipid syndrome (c), scleroderma (d), drug (cocaine) (e), and infection (Shiga toxin hemolytic uremic syndrome; STEC-HUS) (f). (f) STEC-HUS shows severe TMA with cortical necrosis. Thin black arrow points to thrombi in glomerular capillaries and arteries; thick black arrow points to myxoid change and onion-skinning of arterial walls. In general, the glomerular and vascular TMA findings are not specific for a particular etiology. (a,b: silver methenamine stain 40×; c, periodic acid–Schiff stain 40×; d, hematoxylin and eosin 20×; e, toluidine blue 10×; and f, hematoxylin and eosin 10×).

Figure 2

Classification of thrombotic microangiopathy. aHUS, atypical hemolytic uremic syndrome; DGKe, diacylglycerol kinase epsilon; INF2, inverted formin 2; STEC-HUS, Shiga toxin hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura. ∗aHUS and TTP can be both hereditary and acquired; aHUS more likely to be hereditary, whereas TTP is more likely to be acquired.

Figure 3

Genetic abnormalities in complement genes in primary and secondary thrombotic microangiopathy. aHUS, atypical hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.

Figure 4

Approach to thrombotic microangiopathy (TMA) management according to evidence of complement involvement. ∗Evidence of complement activation, if available: (i) genetics: pathogenic/likely pathogenic variant or risk haplotype in alternative complement pathway genes; (ii) antibody: autoantibodies to complement factors (mainly anti–factor H and anti–factor B), (iii) functional assays: soluble C5b-9, tissue deposition of C5b-9, others; (iv) biopsy: staining for C4d, C5b-9. aHUS, atypical hemolytic uremic syndrome; STEC-HUS, Shiga toxin hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.