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Mario Negri Institute for Pharmacological Research, Clinical Research
Center for Rare Diseases "Aldo e Cele
Daccò," Villa Camozzi, Ranica,
Italy
Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di
Bergamo, Italy
Bernhard Noch Institute for Tropical Medicine, Hamburg,
Germany.
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: noris{at}irfmn.mnegri.it
Abstract. 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 age- and gender-matched 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 = 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 = 0.02) and in the overall study population (P = 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 = 0.02) and none of the controls (P = 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.
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