Extra-renal manifestations of complement-mediated thrombotic microangiopathies

Abstract

Thrombotic microangiopathies (TMA) are rare but severe disorders, characterized by endothelial cell activation and thrombus formation leading to hemolytic anemia, thrombocytopenia, and organ failure. Complement over activation in combination with defects in its regulation is described in an increasing number of TMA and if primary for the disease denominated as atypical hemolytic-uremic syndrome. Although TMA predominantly affects the renal microvasculature, extra-renal manifestations are observed in 20% of patients including involvement of the central nerve system, cardiovascular system, lungs, skin, skeletal muscle, and gastrointestinal tract. Prompt diagnosis and treatment initiation are therefore crucial for the prognosis of disease acute phase and the long-term outcome. This review summarizes the available evidence on extra-renal TMA manifestations and discusses the role of acute and chronic complement activation by highlighting its complex interaction with inflammation, coagulation, and endothelial homeostasis.

Keywords: TMA; aHUS; cardiovascular complication; complement; extra-renal TMA; gastrointestinal complications; neurovascular complications.

Figure 1

Scheme on the pathophysiologic understanding of extra-renal complement-mediated TMA manifestations. Endothelial dysfunction and injury represent the center of TMA pathogenesis. Different endothelial harming factors can lead to endothelial dysfunction. Especially on the basis of inherited or acquired defects of complement regulation and activation, those factors can lead to severe complement activation inducing widespread endothelial injury with the consequence of local and systemic activation of inflammation and coagulation. All these complex complement concerted and maintained processes may finally lead to vasculopathy of microvessels including vasa-vasorum with large artery stenosis and organ ischemia followed by multiple renal and extra-renal symptoms. C3a, complement component 3a; C5a, complement component 5a; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CNS, central nerve system; EBV, Epstein–Barr virus; e.g., exempli gratia; EHEC, enterohemorrhagic Escherichia coli; H1N1, influence A virus subtype; m-TOR, mammalian target of rapamycin; TCC, terminal complement complex; TMA, thrombotic microangiopathy.

Figure 2

Recommendation for evaluation and monitoring of extra-renal manifestations in patients with complement-mediated TMA. Depending on the clinical presentation and possible symptoms, the physicians have to be aware of TMA associated, potentially devastating extra-renal TMA manifestations. A high level of suspicion may be needed to diagnose and treat those complications early in disease course. Thus, the initial laboratory and imaging investigations as well as the monitoring procedures have to reflect this knowledge. However, the indications for highly invasive diagnostic procedures like heart catheterization and MRI/A in small children with the need of total anesthesia have to be proven on an individual basis. The recommendation for MRI/A 2 years after onset in all patients with complement-mediated TMA excludes children with the need for total anesthesia, except those with clinical cerebrovascular symptoms. ALAT, Alanin-aminotransferase; AP, alkaline phosphatase; ASAT, aspartat-aminotransferase; CK, creatine kinase; ECG, electrocardiography; ECHO, echocardiography; EEG, electroencephalography; gamma-GT, gamma-glutamyl transpeptidase; MRI/A, magnetic resonance imaging/angiography; nt-pro-BNP, N-terminal pro brain natriuretic peptide.