The role of ADAMTS‐13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies

Abstract

Essentials Molecular diagnostics has improved the differentiation of acute thrombotic microangiopathys (TMAs). Atypical hemolytic uremic syndrome may have features mimicking thrombotic thrombocytopenic purpura. We identified novel complement mutations and a high incidence of CD46, with favorable long term outcomes. Complement mutation analysis in TMA where the diagnosis is unclear and ADAMTS‐13 activity is >10%. SummaryBackgroundDifferentiation of acute thrombotic microangiopathy (TMA) at presentation has historically been dependent on clinical parameters. Confirmation of thrombotic thrombocytopenic purpura (TTP) is increasingly reliant on demonstrating deficient ADAMTS‐13 activity. The identification of alternative complement pathway abnormalities in atypical hemolytic uremic syndrome (aHUS), along with the proven efficacy of terminal complement inhibitors in treatment, has increased the need for rapid differentiation of TTP from aHUS.ObjectivesWe describe the clinical phenotype and nature of complement mutations in a cohort of aHUS patients referred as acute TMAs.Patients/methodsFourteen consecutive aHUS patients were screened for mutations in C3,CD46,CFH,CFI, and CFB, as well as factor H (FH) antibodies. All aHUS patients had ADAMTS‐13 activity > 10%.ResultsOf 14 aHUS patients, 11 (79%) had platelet counts < 30 × 109/L during the acute phase. Median presenting creatinine level was 295 μmol L−1, while five (36%) of 14 presented with a serum creatinine level < 200 μmol L−1. Alternative complement pathway mutations were detected in 9 (64%) of 14 patients, including CD46 mutations in five (36%) of 14 patients. Patients were identified with novel mutations in CFB and C3 that have not been previously reported.ConclusionsWe demonstrate that diagnostic differentiation based on platelet count and renal function is insufficient to predict an underlying complement mutation in some aHUS cases. Specifically, we demonstrate a high frequency of functionally significant CD46 mutations which may mimic TTP. ADAMTS‐13 activity > 10% in a patient with a TMA should necessitate genetic screening for complement abnormalities.

Complement in disease: a defence system turning offensive

“…Thus far, complement-targeted therapies have only been explored in one case study of TTP with favourable outcome 114,127 . Of note, however, the clinical distinction between aHUS and TTP remains challenging in some cases, and individual patients may have clinical signs of both TTP and aHUS 128,129 ; more research is needed to elucidate the effect of complement on TMA beyond aHUS.…”

Thrombotic Microangiopathy and the Kidney

“…1ve, positive; AAV, ANCA-associated vasculitis; Ab, antibody; ACA, anticentromere antibody; ACEI, angiotensin-converting enzyme inhibitor; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; Ag, antigen; aHUS, atypical hemolytic uremic syndrome; ANA antinuclear antibody; anti-ds DNA, antidouble-stranded DNA; anti-Scl70, anti-topoisomerase I antibody; BMT; bone marrow transplant; C3G, C3 glomerulopathy; CAPS, catastrophic antiphospholipid syndrome; DGKE, gene encoding diacylglycerol kinase «; DIC, disseminated intravascular coagulation; FH, factor H; FI, factor I; Hb, hemoglobin; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; MN, membranous nephropathy; MPGN,membranoproliferative GN; PE, plasma exchange; SRC,scleroderma renalcrisis; STEC, shiga toxin-producing Escherichia coli;Stx, shiga toxin; T-Ag, Thomsen-Friedenreich antigen; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura. reportedly more severe thrombocytopenia (,30310 9 /L) and less severe AKI (serum creatinine, 1.7-2.3 mg/dl) (45), but these are not absolute and should not be relied upon in clinical practice (10), where the diagnosis is confirmed by ADAMTS13 activity ,10% (5). TTP was historically almost universally fatal, but after the introduction of PE treatment, mortality decreased to ,10% (46).…”

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

“…delirium, seizures). It has been suggested that more severe thrombocytopenia (platelet count <30 × 10 9 /L) and milder renal impairment (serum creatinine <200 μmol/L) may help to distinguish TTP from aHUS but these criteria are neither sensitive nor specific . Rather, TTP is defined by severely reduced (<10%) activity of the von Willebrand factor (vWF)‐cleaving protease, ADAMTS13.…”