The Role of Complement in Autoimmune Disease-Associated Thrombotic Microangiopathy and the Potential for Therapeutics

Abstract

The complement system is a tightly regulated, cascading protein network representing a key component linking the innate and humoral immune systems. However, if misdirected or dysregulated, it can be similarly damaging to host-tissue. The role of complement dysregulation on vascular endothelial cells has been well established in atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and target organ injury. Yet a great deal of complexity exists around the role of complement in TMA associated with other diseases. A further complicating factor is the cross-talk between complement, neutrophils, and coagulation pathways in the pathophysiology of TMA. Advancements in the understanding of the etiopathogenesis of aHUS paved the way for the successful development of anti-complement therapies (complement C5 inhibitors), which have revolutionized the treatment of aHUS. Therefore, a clearer understanding of the role of the complement system in TMA associated with other conditions will help to identify patients who would benefit from these therapies. This review aims to provide an assessment of the nature and extent of complement involvement in TMA associated with autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and scleroderma renal crisis. Defining the role of complement in TMA in these conditions will help to guide timely diagnosis and management.

124 A Role for P-selectin and complement in the pathological sequelae of Germinal Matrix Hemorrhage

“…It is clear that P-selectin has both pro-in ammatory and thrombogenic activities, having roles in immune cell in ltration, platelet aggregation and coagulation [29,30], all of which are relevant to GMH and injury progression. And while a 2.12Psel-Crry type construct is obviously not a therapeutic candidate for GMH or other hemorrhagic conditions, it is noteworthy that complement activation is closely associated with multiple thrombotic conditions; for example various rheumatic and autoimmune conditions, transplant related conditions and renal microangiopathies [40][41][42]. Also in this context, we have shown that complement inhibition potentiates thrombolytic therapy with tissue plasminogen activator in a model of ischemic stroke [43].…”