Atypical — I’ll Say!

Hematologists encounter patients with atypical hemolytic-uremic syndrome (aHUS) when they are asked to evaluate a patient (often a child) with the triad of severe thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. Although the differential is broad, the most common etiology is HUS. Approximately 90 percent of HUS is caused by infection with shiga toxin and shiga-like toxin- (verotoxin) producing bacteria, particularly enterohemorrhagic E. coli. With supportive care, patients who develop this typical, diarrhea-positive variant of HUS have a favorable prognosis, with spontaneous resolution of the classic disease triad in approximately 90 percent of cases (although temporary dialysis may be required). However, for patients who present with the diarrhea-negative form, aHUS, the prognosis is bleak, with 50 percent developing end-stage renal failure and 25 percent dying from complications of the disease.

Over the past five years, exciting new insights into the etiology of aHUS have emerged, with studies from a number of laboratories demonstrating that mutations in genes that regulate the alternative pathway of complement (Figure) underlie the pathophysiology of the disease in approximately 50 percent of cases. Specifically, complement factor H (CFH) is mutated in approximately 30 percent of cases, membrane co-factor protein (MCP, CD46) in approximately 10 percent, and complement factor I (CFI) in approximately 10 percent. In another 10 percent, autoantibodies against CFH have been identified. Now, an international group of investigations, led by Edward Conway of the University of British Columbia, have reported mutation of the thrombomodulin gene in about 5 percent of patients with aHUS, identifying six missense mutations in seven patients. All of the mutations were heterozygous, and extended family studies demonstrated variable penetrance. These findings are remarkable (atypical) because thrombomodulin is not usually regarded as a complement regulatory protein. Rather, this transmembrane protein, expressed on endothelial cells, is best known for the important role that it plays in hemostasis as an obligate constituent of the protein C anticoagulant pathway. Nonetheless, based on a series of in vitro experiments, Delvaeye and colleagues concluded that thrombomodulin, in concert with CFH, interacts with complement C3b, thereby enhancing the degradation of C3b by CFI (Figure). They also demonstrated that the mutant forms of thrombomodulin functioned aberrantly in their experimental models.

To declare thrombomodulin a physiologically relevant alternative complement pathway regulator, however, seems premature. Structurally, thrombomodulin differs from well-characterized C3b binding proteins, such as CFH and MCP, that are composed of a series of short consensus repeats that mediate interaction with C3b, and thrombomodulin appears to have no independent CFI co-factor activity (i.e., CFI co-factor activity is observed only in the presence of an established co-factor such as CFH). And, although the experiments of Delvaeye et al. were exhaustive and rigorously performed, the in vitro models are artificial, and differences between controls and wild-type and between wild-type and mutant forms, while statistically significant, were, in general, modest in magnitude. Still, the finding of mutant thrombomodulin in 5 percent of cases of aHUS could not occur by chance. Therefore, it seems plausible to suggest that the aHUS phenotype can arise as a consequence of dysregulation of biological systems other than the APC (e.g., those that regulate hemostasis). This hypothesis is supported by the observation that, in ~50 percent of cases of aHUS, inherited or acquired abnormalities of complement regulatory proteins are not observed.