Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome

Abstract

BACKGROUND The hemolytic–uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin–producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic–uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic–uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic–uremic syndrome. METHODS We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic–uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic–uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells. RESULTS Of 152 patients with atypical hemolytic–uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I–mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic–uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement. CONCLUSIONS Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic–uremic syndrome.

Síndrome hemolítico urémico atípico, revisión de la literatura y documento de consenso. Enfoque diagnóstico y tratamiento

“…En casos de mutación, su capacidad de descomponer C3b se encuentra disminuida. Los niveles de C3 están bajos en la mitad de los pacientes y no se ha determinado el riesgo de recurrencia postrasplante 34,41 .…”

Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

“…Among the reported cases, approximately 50% had mutations of the complement regulatory proteins factor H (CFH) (7)(8)(9)(10)(11)(12), membrane cofactor protein (13)(14)(15), or factor I (16)(17)(18); mutations occurred less frequently in factor B (19), C3 (20), and thrombomodulin (21).…”

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

“…Gain-of-function mutations in key proteins of the alternative pathway, complement factor B (CFB), and C3 have also been reported (7)(8)(9). More recently, mutations in THBD encoding thrombomodulin, a membrane-bound glycoprotein with anticoagulant properties that modulates complement activation on cell surfaces, have also been associated with aHUS (10). Finally, anti-CFH autoantibodies have been described in sporadic forms (11).…”