The Syndromes of Thrombotic Microangiopathy: A Critical Appraisal on Complement Dysregulation

Abstract

Thrombotic microangiopathy (TMA) is a rare and potentially life-threatening condition that can be caused by a heterogeneous group of diseases, often affecting the brain and kidneys. TMAs should be classified according to etiology to indicate targets for treatment. Complement dysregulation is an important cause of TMA that defines cases not related to coexisting conditions, that is, primary atypical hemolytic uremic syndrome (HUS). Ever since the approval of therapeutic complement inhibition, the approach of TMA has focused on the recognition of primary atypical HUS. Recent advances, however, demonstrated the pivotal role of complement dysregulation in specific subtypes of patients considered to have secondary atypical HUS. This is particularly the case in patients presenting with coexisting hypertensive emergency, pregnancy, and kidney transplantation, shifting the paradigm of disease. In contrast, complement dysregulation is uncommon in patients with other coexisting conditions, such as bacterial infection, drug use, cancer, and autoimmunity, among other disorders. In this review, we performed a critical appraisal on complement dysregulation and the use of therapeutic complement inhibition in TMAs associated with coexisting conditions and outline a pragmatic approach to diagnosis and treatment. For future studies, we advocate the term complement-mediated TMA as opposed to the traditional atypical HUS-type classification.

Keywords: atypical hemolytic uremic syndrome; complement; eculizumab; hypertensive emergency; kidney transplantation; pregnancy; thrombotic microangiopathy.

Figure 1

The atypical HUS-type classification [1,2].

Figure 2

Schematic overview of complement activation and regulation in health and disease. (A) The complement system can be initiated via the classical (C1qrs), lectin (MBL), and alternative pathways (C3), converging to C3. The alternative pathway is a spontaneously and continuously active surveillance system operating in the circulation and on the cell surface. C3 (H₂O) binds factor B (fB) and factor D (fD), and the latter cleaves fB into Bb, the serine esterase that cleaves C3 into C3a and C3b. C3’s thioester domain located in C3b can bind to the cell surface (e.g., microbes), providing a platform to form the C3 convertase of the alternative pathway (i.e., C3Bb) to cleave more C3, activating an amplification loop. Next, additional C3b can shift the C3 convertase to a C5 convertase, cleaving C5 into C5a and C5b, activating the terminal complement pathway. C5a and, to a lesser extent, C3a attract leukocytes to the site of complement activation. C5b can bind C6, C7, C8, and various C9 molecules to form the lytic C5b9 (i.e., membrane attack complex) on cells. Host cells, including the endothelium, are protected from the harmful effects of complement activation by factor I, factor H, and CD46 (also known as membrane cofactor protein); these proteins have decay-accelerating and cofactor activities, leading to factor I-mediated cleavage of C3b into inactivated proteins. (Normal ex vivo C5b9 formation on perturbed human microvascular endothelial cells of dermal origin (HMEC–1) indicates normal complement regulation.). (B) In C-TMA, rare variants in complement genes (i.e., loss of function of factor I, factor H, or CD46 (thin red lines); gain of function of C3 or CFB (green lines)) and/or autoantibodies targeting complement regulatory proteins result in unrestrained complement activation, formation of C5b9 on the endothelium, and a procoagulant environment that triggers thrombosis. (Massive ex vivo C5b9 formation on perturbed HMEC–1 indicates unrestrained C5 activation.) fP, properdin.

Figure 3

Pragmatic approach to diagnosis and treatment of TMA. Patients should be tested for the enzymatic activity of ADAMTS13 (i.e., >10% excludes thrombotic thrombocytopenic purpura (TTP)). Patients with a normal activity of ADAMTS13 should be screened for coexisting conditions. DGKE, diacylglycerol kinase epsilon. HSCT, hematopoietic stem cell transplantation. HUS, hemolytic uremic syndrome. STEC, Shiga toxin–producing E. coli.

Figure 4

Morphologic features of TMA on kidney biopsy cannot define etiology. Representative cases of TMA presenting with coexisting hypertensive emergency: (A) 28-year-old woman with a gain-of-function C3 protein (p.R161W); (B) 47-year-old man with no rare variants in complement genes identified, after surgery; (C) 37-year-old woman with no rare variants in complement genes identified, and coexisting pregnancy; (D) 28-year-old woman with no rare variants in complement genes identified. The arrowheads indicate glomerular thrombosis, often accompanied by mesangiolysis. Jones methenamine silver (A–C) and hematoxylin and eosin (D) staining; original magnification, ×400.