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Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome Mieke Delvaeye, Ph.D., Marina Noris, Ph.D., Astrid De Vriese, M.Sc., Charles T. Esmon, Ph.D., Naomi L. Esmon, Ph.D., Gary Ferrell, M.Sc., Jurgen Del-Favero, Ph.D., Stephane Plaisance, Ph.D., Bart Claes, M.Sc., Diether Lambrechts, Ph.D., Carla Zoja, Ph.D., Giuseppe Remuzzi, M.D., and Edward M. Conway, M.D., Ph.D. N ENGL J MED 361;4 July 23, 2009 R2 Lee Eun Jung / prof Hwi Joong Yun Introduction • The hemolytic–uremic syndrome - microangiopathic hemolytic anemia - thrombocytopenia - acute renal failure Triad • “typical” HUS : preceded by diarrhea caused by strains of Escherichia coli that produce Shiga like toxins • “atypical” HUS : not linked to Shiga toxin–producing bacteria ; almost always follows an aggressive course - End stage renal failure develops in 50% - 25% of patients die as a result of the syndrome Introduction • Association between atypical HUS and uncontrolled complement activation has been established • Approximately 50% of patients have heterozygous loss-of-function mutations in gene encoding inhibitors of the alternative pathway of the complement system : factor H (CFH), factor I (CFI), CFH-related proteins (CFHR), membrane cofactor protein (MCP), C4b binding protein (C4bBP) • Gain-of-function mutations in genes encoding factor B (CFB), C3 : promote alternative-pathway activation Cell lysis Protecting cell membrane Introduction • Thrombomodulin - ubiquitous transmembrane endothelial-cell glycoprotein - It accelerates thrombin-mediated activation of protein C down-regulates further thrombin generation thereby suppressing clot formation - thrombin mediated activation of plasma procarboxypeptidase B (thrombin activatable fibrinolysis inhibitor [TAFI] , an inhibitor of fibrinolysis ) inactivates complement-derived anaphylatoxins C3a and C5a Introduction • Variants of the gene encoding thrombomodulin (THBD) : predisposition to endothelial injury and microvascular thrombosis which is manifested as the atypical hemolytic–uremic syndrome • Thrombomodulin - negative regulator of the complement system thrombomodulin mutations associated with atypical hemolytic–uremic syndrome cause defective complement regulation Patients and methods • Patients -152 consecutive patients with atypical HUS - diagnosis : one or more episodes of microangiopathic hemolytic anemia and thrombocytopenia associated with acute renal failure - associated with Shiga toxin–producing bacteria excluded • screening for mutations in CFH, MCP, CFI, and THBD • ADAMTS13 have been associated with atypical hemolytic–uremic syndrome measured activity Results Lower percentage of iC3b Interaction is increased in the presence of CFH CFH directly interacts with thrombomodulin Significant increase in binding to variants C3b iC3b By CFI with cofactors < CFI mediated inactivation of C3b > Mutant forms of thrombomodulin : significantly less effective than wild type Conclusion • Thrombomodulin : negative regulator of the complement system • Mutant variants of thrombomodulin may contribute to the development of atypical hemolytic–uremic syndrome