Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing

Fidalgo, Teresa; Martinho, Patrícia; Pinto, Carla; Oliveira, Ana Catarina Lima de; Salvado, Ramón; Borràs, Nina; Coucelo, Margarida; Manco, Licínio; Maia, Tabita; Mendes, M. João; Barreto, Roberta; Corrales, Irene; Vidal, Francisco; Ribeiro, M. Letícia

doi:10.1002/rth2.12016

Cited by 22 publications

(15 citation statements)

References 59 publications

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“…In association to the above-discussed triggers, our patient had several missense variants in the factor H gene that codifies a key complement alternate pathway regulatory protein. One of the variants after in silico analysis was considered to be likely pathogenic; the other two, although considered benign and not having a marked pathogenic effect on their own, may contribute to an increased risk for a thrombotic microangiopathy when together 4 5. This genetic background made our patient more susceptible to environmental triggers like the ones stated beforehand.…”

Section: Discussionmentioning

confidence: 86%

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Atypical haemolytic uremic syndrome from multiple missenses to a full-blown disease

Mira¹,

Nunes

Elvas

et al. 2019

BMJ Case Rep

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A 72-year-old woman was admitted to the hospital because of dorsal, lumbar and lower abdomen pain that had started 4 days before. She had a history of age-related macular degeneration (treated with intraocular bevacizumab). Blood tests showed anaemia, thrombocytopaenia, acute kidney injury, elevated liver enzymes and total bilirubin (mainly because of the indirect fraction). Viral serologies and ADAMTS13 activity levels were normal, and stool testing was negative for Escherichia coli-producing Shiga toxins. E. coli was isolated in urine. Atypical haemolytic uremic syndrome triggered by a urinary tract infection or by the vascular endothelial growth factor-inhibitor bevacizumab were the most likely hypothesis. The patient started urgent plasmapheresis and dialysis that lasted for a total of 18 days. There was complete remission and recovery of kidney function allowing for treatment discontinuation, and she was discharged home. After 6 months of follow-up, she shows no signs of relapse.

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Section: Discussionmentioning

confidence: 86%

“…Two heterozygous benign missense variants were identified in the CFH gene (c.3172 T>C, p.Tyr1058His and c.3178 G>C, p.Val1060Leu). Another rare heterozygous missense variant was also found in CFH (c.3226 C>G, p.Gln1076Glu) that was analysed with five in silico algorithms and had a score >=3 and thus considered to be likely pathogenic 4 5…”

Section: Investigationsmentioning

confidence: 99%

Atypical haemolytic uremic syndrome from multiple missenses to a full-blown disease

Mira¹,

Nunes

Elvas

et al. 2019

BMJ Case Rep

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“…1). Meanwhile, the negative search for mutations in the genes encoding the complement regulating proteins by next generation sequencing and multiplex ligation-dependent probe amplification of CFH, CFHR1, CFHR3, CFHR4, CFI, CFB, C3, THBD, and DGKE (as previously described [3]) allowed for a cautious eculizumab suspension; we saw no relapse in hemolysis parameters thereafter. After almost 12 months of effective targeted therapy, despite full neurological and hematological recovery, the patient remains dialysis dependent, and is now being considered for renal transplantation.…”

Section: Case Reportmentioning

confidence: 82%

Atypical adult-onset methylmalonic acidemia and homocystinuria presenting as hemolytic uremic syndrome

et al. 2018

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Thrombotic microangiopathy (TMA) syndromes can be secondary to a multitude of different diseases. Most can be identified with a systematic approach and, when excluded, TMA is generally attributed to a dysregulation in the activity of the complement alternative pathways-atypical hemolytic uremic syndrome (aHUS). We present a challenging case of a 19-year-old woman who presented with thrombotic microangiopathy, which was found to be caused by methylmalonic acidemia and homocystinuria, a rare vitamin B12 metabolism deficiency. To our knowledge, this is the first time that an adult-onset methylmalonic acidemia and homocystinuria presents as TMA preceding CNS involvement.

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“…An international World Health Organization standard plasma method for the measurement of ADAMTS13 has recently become available [61]. DNA testing for ADAMTS13 genes has also been developed [62].…”

Section: Diagnostic Testsmentioning

confidence: 99%

Diagnostic testing for differential diagnosis in Thrombotic Microangiopathies

Zini¹,

Cristofaro²

2019

Tjh

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Thrombotic microangiopathies (TMAs) are multiple disease entities with different etiopathogeneses, characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytosis, variable symptoms including fever, and multi-organ failure such as mild renal impairment and neurological deficits. The two paradigms of TMAs are represented on one hand by acquired thrombotic thrombocytopenic purpura (TTP) and on the other by hemolytic uremic syndrome (HUS). The differential diagnosis between these two paradigmatic forms of TMA is based on the presence of either frank renal failure in HUS or a severe deficiency (<10%) of the zincprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in TTP. ADAMTS13 is an enzyme involved in the proteolytic processing of von Willebrand factor (vWF), and its deficiency results in formation of highmolecular-weight vWF-rich microthrombi in the environment of the microvasculature. The presence of these ultra-large vWF multimers in the microcirculation can recruit platelets, promoting multi-organ ischemic lesions. The presence of ADAMTS13 activity at >10% could rule out the presence of a TTP form. However, it is often difficult to differentiate either a TTP or HUS clinical scenario presenting with typical symptoms of TMA. There are in fact several additional diagnoses that should be considered in patients with ADAMTS13 activity of >10%. Widespread inflammation with endothelial damage and adverse reactions to drugs play a central role in the pathogenesis of several forms of TMA, and in these cases, the differential diagnosis should be directed at the underlying disease. Hence, a correct etiologic diagnosis of TMA should involve a critical illness, cancer-associated TMA, drug-induced TMA, and hematopoietic transplant-associated TMA. A complete assessment of all the possible etiologies for TMA symptoms, including acquired or congenital TTP, will allow for a more accurate diagnosis and application of a more appropriate treatment.

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Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing

Cited by 22 publications

References 59 publications

Atypical haemolytic uremic syndrome from multiple missenses to a full-blown disease

Atypical haemolytic uremic syndrome from multiple missenses to a full-blown disease

Atypical adult-onset methylmalonic acidemia and homocystinuria presenting as hemolytic uremic syndrome

Diagnostic testing for differential diagnosis in Thrombotic Microangiopathies

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