Complement Factor H Mutation in Familial Thrombotic Thrombocytopenic Purpura with ADAMTS13 Deficiency and Renal Involvement

Abstract

Thrombotic thrombocytopenic purpura is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease ADAMTS13, which favors platelet adhesion and aggregation in the microcirculation. The disease manifests mainly with central nervous system symptoms, but cases of renal insufficiency have been reported. Presented are findings of the genetic basis of phenotype heterogeneity in thrombotic thrombocytopenic purpura in two sisters within one family. The patients had ADAMTS13 deficiency as a result of two heterozygous mutations (causing V88M and G1239V changes). In addition, a heterozygous mutation (causing an S890I change) in factor H of complement was found in the patient who developed chronic renal failure but not in her sister, who presented with exclusive neurologic symptoms. 16: 117716: -118316: , 200516: . doi: 10.1681 T hrombotic thrombocytopenic purpura (TTP) is a disease of small vessels characterized by anemia that is caused by erythrocyte fragmentation in the microcirculation and thrombocytopenia that is caused by intravascular thrombi of aggregated platelets (1). Recent studies provided substantial evidence that 70 to 80% of cases of TTP are triggered by a deficiency of ADAMTS13 (2-4), a plasma metalloprotease that cleaves von Willebrand factor multimers soon after their secretion by endothelial cells (1,5-7). ADAMTS13 deficiency can be constitutive, as a result of homozygous or double heterozygous mutations in the corresponding gene (8 -13), or acquired, as a result of the presence of circulating inhibitory antibodies (1,3,4,14 -20). J Am Soc NephrolTTP manifests mainly with central nervous system symptoms, but cases of renal insufficiency have been reported (1). In rare cases, renal involvement is severe enough to cause endstage renal failure (1,21-25). Those patients' clinical manifestations are difficult to distinguish from those of hemolytic uremic syndrome (HUS), a form of thrombotic microangiopathy characterized by predominant renal involvement, often with renal failure (1,20,26). This difficulty has given rise to a heated debate on whether a severe deficiency of ADAMTS13 activity is enough to distinguish TTP from HUS (27,28).Here we present findings of the genetic basis of phenotype heterogeneity in patients with congenital ADAMTS13 deficiency. We studied a family with two affected sisters, one who presented with exclusive neurologic symptoms and the other one with severe renal involvement that required chronic dialysis. These diverse clinical manifestations suggested to us that the genetic background could be different. Materials and Methods PatientsA woman, now 60 yr old (F48), and her younger sister (F45, died in 2002 at the age of 55 yr) were referred to our International Registry of Recurrent and Familial HUS/TTP in 1996 because of history of recurrent and familial thrombotic microangiopathy. The youngest brother died at the age of 15 yr of leukemia. The other four siblings (three male and one female) all seem to be healthy and have no sig...

ADAMTS13 Secretion and Residual Activity among Patients with Congenital Thrombotic Thrombocytopenic Purpura with and without Renal Impairment

“…ADAMTS13, CFH, MCP and CFI were directly sequenced (17,18). rADAMTS13 mutants were expressed in HEK293 cells (19,20).…”

“…Clinical histories of patients included in the study are provided in the Supplemental Material. Among them, patients manifesting acute renal impairment during bouts were screened for CFH, MCP, and CFI; one of these (F45#002), who carried the heterozygous missense p.S890I CFH variant (17), was excluded from further analyses.…”

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

“…Acute renal failure may be severe but is reversible if plasma therapy is instituted promptly. Chronic renal failure is uncommon, but may occur if the patients are not treated with plasma therapy or have a concurrent mutation of atypical HUS [105].…”

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

“…El SHUa es una enfermedad ultra-rara, con una prevalencia de 3.3 pacientes por millón de habitantes, con comportamiento devastador, progresivo y potencialmente fatal debido a la activación sistémica no controlada del complemento [1][2][3][4][5][6] . Nueve a quince por ciento de los pacientes mueren después del primer año de presentar la manifestación de MAT y hasta 33% de los pacientes con SHUa progresan a enfermedad renal crónica (ERC) estadio 5 (en la era pre-eculizumab) 2,7 .…”