Hypocomplementemia Discloses Genetic Predisposition to Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: Role of Factor H Abnormalities

Familial hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) carry a very poor outcome and have been reported in association with decreased serum levels of the third complement component (C3). Uncontrolled consumption in the microcirculation, possibly related to genetically determined deficiency in factor H—a modulator of the alternative pathway of complement activation—may account for decreased C3 serum levels even during disease remission and may predispose to intravascular thrombosis. In a case-control study by multivariate analysis, we correlated putative predisposing conditions, including low C3 serum levels, with history of disease in 15 cases reporting one or more episodes of familial HUS and TTP, in 25 ageand gendermatched healthy controls and in 63 case-relatives and 56 control-relatives, respectively. The relationship between history of disease, low C3, and factor H abnormalities was investigated in all affected families and in 17 controls. Seventy-three percent of cases compared with 16% of controls (P , 0.001), and 24% of case-relatives compared with 5% of control-relatives (P 5 0.005) had decreased C3 serum levels. At multivariate analysis, C3 serum level was the only parameter associated with the disease within affected families (P 5 0.02) and in the overall study population (P 5 0.01). Thus, subjects with decreased C3 serum levels had a relative risk of HUS or TTP of 16.56 (95% confidence interval [CI], 1.66 to 162.39) within families and of 27.77 (95% CI, 2.44 to 314.19) in the overall population, compared to subjects with normal serum levels. Factor H abnormalities were found in four of the cases, compared with three of the healthy family members (P 5 0.02) and none of the controls (P 5 0.04) and, within families, factor H abnormalities were correlated with C3 reduction (P , 0.05). Reduced C3 clusters in familial HUS and TTP is likely related to a genetically determined deficiency in factor H and may predispose to the disease. Its demonstration may help identify subjects at risk in affected families. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are syndromes of microangiopathic hemolytic anemia and thrombocytopenia, which have in common thrombotic occlusion of the microvasculature of various organs (1). The term HUS is usually preferred to describe the disease in children with renal insufficiency (2), whereas TTP is the most used term to describe adult cases with predominant neurologic symptoms (3). However, it is now recognized that the two syndromes may have different clinical manifestations because of the different distribution of the microvascular lesions, but share the same histologic lesion—widening of the subendothelial space and intravascular platelet thrombi—and reflect a similar pathophysiologic process, leading to thrombocytopenia and anemia through platelet consumption and erythrocyte disruption in the injured microvasculature (4). In their typical presentation, HUS and TTP manifest as an acute disease that recovers without sequelae in 80 to 90% of cases, either spontaneously (as in most cases of childhood HUS) or following a course of plasma infusion or exchange (as in adult or severe forms of HUS and in TTP) (1–3). These forms may be triggered by environmental factors (as the verotoxins produced by some strains of Escherichia coli), drugs, or other diseases and may subside when the underlying condition has been treated or removed. Other forms, however, fail to recover or may relapse after complete recovery of the presenting epiReceived April 20, 1998. Accepted September 4, 1998. a See Appendix for participating investigators and affiliated organizations. Dr. Richard J. Johnson served as Guest Editor and supervised the review and final disposition of this manuscript. Correspondence to Dr. Piero Ruggenenti, Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” “Mario Negri” Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy. Phone: 390 35 319888; Fax: 390 35 319331; E-mail: [email protected] 1046-6673/1002-0281$03.00/0 Journal of the American Society of Nephrology Copyright © 1999 by the American Society of Nephrology J Am Soc Nephrol 10: 281–293, 1999