Complement Mediated Endothelial Damage in Thrombotic Microangiopathies

Abstract

Thrombotic microangiopathies (TMA) constitute a group of different disorders that have a common underlying mechanism: the endothelial damage. These disorders may exhibit different mechanisms of endothelial injury depending on the pathological trigger. However, over the last decades, the potential role of the complement system (CS) has gained prominence in their pathogenesis. This is partly due to the great efficacy of complement-inhibitors in atypical hemolytic syndrome (aHUS), a TMA form where the primary defect is an alternative complement pathway dysregulation over endothelial cells (genetic and/or adquired). Complement involvement has also been demonstrated in other forms of TMA, such as thrombotic thrombocytopenic purpura (TTP) and in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), as well as in secondary TMAs, in which complement activation occurs in the context of other diseases. However, at present, there is scarce evidence about the efficacy of complement-targeted therapies in these entities. The relationship between complement dysregulation and endothelial damage as the main causes of TMA will be reviewed here. Moreover, the different clinical trials evaluating the use of complement-inhibitors for the treatment of patients suffering from different TMA-associated disorders are summarized, as a clear example of the entry into a new era of personalized medicine in its management.

Microangiopathy associated with poor outcome of immunoglobulin A nephropathy: a cohort study and meta-analysis

“…It is unknown whether IgAN with MA is a coincidence of two diseases or has an intrinsic relationship. However, there are indications that endothelial cell injury could be a common underlying mechanism of TMA, which consists of a group of different disorders, leading to microvasculature thrombosis [ 18 ]. Dysregulated complement activation has been implicated in TMA disorders such as haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura, leading to endothelial cell injury [ 19 ].…”

“…However, C4d deposits have been associated with renal function decline in IgAN with MA [ 11 , 25 ]. The overwhelming presence of C4d deposits without co-deposition of C1q in IgAN patients with MA suggests a potential role of the lectin pathway in the development of MA in IgAN [ 12 , 18 ].…”

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients

“…Endothelial dysfunction is a common denominator for both HSCT-TMA and GvHD. It is well known that the cornerstone of HSCT-TMA pathogenesis is endothelial dysfunction in combination, which initiates complement activation, leading to the development of thrombi enriched in platelets within the microvasculature [ 37 ]. Recent studies have shown the potential involvement of endothelial dysfunction in the pathogenesis of GvHD, postulating that endothelial dysfunction is a shared characteristic of both diseases.…”

Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

“…It has many causes and associations, and the list of these is growing steadily as new cases are being reported[ 3 - 7 ]. The heterogeneous etiology is reflected in a multitude of pathogenetic pathways leading to the final common pathway of occlusive microvascular injury[ 8 , 9 ]. This review is directed at post-transplant TMA (PT-TMA) in KTRs, which is an important cause of kidney allograft injury and loss if not treated promptly and appropriately.…”