Too Much of a Good Thing at the Site of Tissue Injury: The Instructive Example of the Complement System Predisposing to Thrombotic Microangiopathy

Abstract

The interplay between the complement and coagulation systems is just beginning to be explored and characterized. This interaction, however, is ancient. For example, if endotoxin is added to the hemolymph of the horseshoe crab, a protease is activated that triggers both the coagulation and complement systems. However, in extant mammals, these 2 cascades have diverged. These infamous "terrible C's" are the scourge of many a medical student (and possibly even a few hematologists). They also are intimately involved in the pathophysiology of thrombomicroangiopathies (TMAs). The complement system generates a procoagulant microenvironment and the coagulation system forms a clot in the renal microvasculature, and thus the 2 systems are partners in mediating multiple pathophysiological conditions.

Genetic variants in the complement system predisposing to age-related macular degeneration: A review

“…First, FH must bind to a damaged surface via exposed GAGs and/or C3b/iC3b/C3d fragments. Second, FI variants teach us that cofactor activity is the critical regulatory activity as it is in aHUS (Liszewski and Atkinson, 2011). Cofactor deficiency can be achieved in multiple ways: low FI levels or activity, low FH levels or activity, or mislocalization of FH not at critical sites.…”

Preeclampsia: a gestational cardiorenal syndrome

“…The endothelium can be considered as a distinct organ within the cardiovascular system with widespread, but very specific functions (Galley & Webster, ). Endothelial dysfunction triggers a chronic endovascular inflammatory response via activation of the complement system (Liszewski & Atkinson, ), with increased serum concentration of the highly sensitive C‐reactive protein being a characteristic feature of preeclampsia (Kwiatkowski et al . ).…”

“…). Furthermore, in severe end‐stage preeclampsia regardless of gestation, active intravascular inflammation stimulates the coagulation cascade with formation of intravascular microthrombi and eventually micro‐angiopathy (Liszewski & Atkinson, ). The latter is associated with acute kidney injury and consistent with acute (type I) cardiorenal dysfunction.…”

“…The endothelium can be considered as a distinct organ within the cardiovascular system with widespread, but very specific functions (Galley & Webster, 2004). Endothelial dysfunction triggers a chronic endovascular J Physiol 597.18 inflammatory response via activation of the complement system (Liszewski & Atkinson, 2011), with increased serum concentration of the highly sensitive C-reactive protein being a characteristic feature of preeclampsia (Kwiatkowski et al 2017). Furthermore, in severe end-stage preeclampsia regardless of gestation, active intravascular inflammation stimulates the coagulation cascade with formation of intravascular microthrombi and eventually micro-angiopathy (Liszewski & Atkinson, 2011).…”

Overactivation of Complement Alternative Pathway in Postpartum Atypical Hemolytic Uremic Syndrome Patients with Renal Involvement

“…Recently, several studies have revealed that aHUS, even diarrhea‐associated HUS, TTP, and other types of TMA, is associated with defective regulation of complement alternative pathway activation on microvascular endothelial cells . Abnormal control of the complement alternative pathway usually results from genetic deficiencies or autoantibodies to complement regulatory proteins .…”