Congenital thrombotic thrombocytopenic purpura with novel mutations in three unrelated turkish children

Metìn, Ayşe; Ünal, Şule; Gümrük, Fatma; Palla, Roberta; Cairo, Andrea; Underwood, Mary; Gürgey, Aytemiz

doi:10.1002/pbc.24764

Cited by 4 publications

(8 citation statements)

References 16 publications

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“…hemorrhagic unexplained diathesis in childhood). Similar to our case, another cTTP patient carrying a homozygous missense mutation at the same exon (p.Ile143Thr, c.428T>C) leading to low residual ADAMTS13 activity showed an early onset (at 7 years) but a detailed medical history revealed easy bruising and anemia since birth .…”

Section: Discussionsupporting

confidence: 84%

Risk of diagnostic delay in congenital thrombotic thrombocytopenic purpura

Ferrari

Cairo

Pagliari

et al. 2019

Journal of Thrombosis and Haemostasis

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Congenital thrombotic thrombocytopenic purpura (cTTP) is a very rare thrombotic microangiopathy. Its rarity and great phenotype heterogeneity may account for misdiagnosis. We report the history of a middle‐aged woman with cTTP, misdiagnosed until adulthood. Accurate clinical history is crucial for early diagnosis to prevent long‐term sequelae. Summary Thrombotic thrombocytopenic purpura (TTP) is an acute life‐threatening disorder characterized by multiple organ ischemia due to disseminated thrombus formation in the microvasculature. The congenital form of the disease (Upshaw‐Schulman syndrome) is related to ADAMTS13 mutations. Adulthood‐onset of TTP does not exclude the congenital form of the disease and a diagnostic delay may account for a great morbidity burden in these patients. We describe the case of a middle‐aged woman who presented to our attention with a clinical diagnosis of a chronic relapsing form of TTP. The medical history of the patient raised the suspicion of a congenital form of TTP. Phenotype and genotype tests were performed, and clinical diagnosis was confirmed. Upshaw‐Schulman syndrome is a rare congenital disease with a great phenotype heterogeneity that can be diagnosed also in adulthood. Accurate clinical history is crucial. Early diagnosis can prevent recurrences and long‐term organ damage with long‐term sequelae.

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Section: Discussionsupporting

confidence: 84%

Risk of diagnostic delay in congenital thrombotic thrombocytopenic purpura

Ferrari

Cairo

Pagliari

et al. 2019

Journal of Thrombosis and Haemostasis

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“…Of 18 patients, 10 had previously been screened for ADAMTS13 mutations by our groups (Table 1) (16,17,19,20,25,26). Here we identified the genetic ADAMTS13 defect in the other 8 patients (R002, F1518#728, F1519#728, F1627#873, F1628#873, F769#239, F1116#239, and R564).…”

Section: Mutation Screeningmentioning

confidence: 68%

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

Rurali

Banterla

Donadelli

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Acute renal impairment is observed in 11%-23% of patients with congenital thrombotic thrombocytopenic purpura (TTP) and deficiency of a disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13, a metalloprotease that cleaves von Willebrand factor [VWF] multimers), a substantial percentage of whom develop CKD during follow-up.Design, setting, participants, & measurements Here we investigated whether, in 18 patients with congenital recruited from 1996 to 2013 who fulfilled inclusion criteria, acute renal involvement occurred during bouts segregated with lower secretion and activity levels of ADAMTS13 mutants. We performed expression studies and a sensitive recombinant VWF (rVWF) A1-A2-A3 cleavage test (detection limit, 0.78% of normal ADAMTS13 activity).Results A higher risk of acute renal impairment during bouts was observed in patients with childhood (,18 years) onset (odds ratio [OR], 24.6 [95% confidence interval (CI), 1.11 to 542.44]) or a relapsing ($1 episode per year) disease (OR, 54.6 [95% CI, 2.25 to 1326.28]) than in patients with adulthood onset or long-lasting remission, respectively. Whatever the age at onset, patients with acute renal impairment had mutations different from those in patients without renal involvement. Moreover, mutations in patients with acute renal impairment compared with those in patients without renal involvement caused lower in vitro rADAMTS13 secretion (1.33% versus 12.5%; P,0.001) and residual activity (0.11% versus 3.47%; P=0.003). rADAMTS13 secretion #3.75% and residual activity #0.4% best discriminated patients with renal impairment (receiveroperating characteristic curve sensitivity, 100% and 100%; specificity, 100% and 83.3%, respectively; logistic regression OR, 325 [95% CI, 6 to 18339] and 91.7 [95% CI, 3.2 to 2623.5], respectively). All mutations found in patients with childhood onset or relapsing disease were associated with acute renal impairment during bouts, confirming the link between acute renal impairment and early onset or a relapsing course. ADAMTS13 activity levels in vivo, measured in patients' serum by rVWF A1-A2-A3 cleavage test, correlated with in vitro rADAMTS13 mutant activity (r=0.95; P,0.001).Conclusions In congenital TTP, renal impairment and relapsing disease might be predicted by measurements of in vitro rADAMTS13 secretion and activity levels and in vivo serum ADAMTS13 activity.

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“…Over 150 mutations have been identified throughout the ADAMTS13 gene in patients with congenital TTP [1,[6][7][8][9][10][11][12][13][14][15][16][17][18][19] and relationships appear to exist between ADAMTS13 genotype, age of disease onset [20] and residual ADAMTS13 activity [11]. Residual ADAMTS13 activity in turn appears to be associated with the annual rate of TTP episodes and with the requirements for fresh frozen plasma prophylaxis [11].…”

Section: Introductionmentioning

confidence: 99%

“…With this in mind we studied two novel previously uncharacterised mutations (p.I143T, p.Y570C) present in a homozygous form in two different congenital TTP patients [17,23].…”

Section: Introductionmentioning

confidence: 99%

“…The p.Y570C mutation localises within the spacer domain which is important for VWF binding [25][26][27]. The clinical history of both patients has been described previously [17], but in brief both presented with acute TTP during adolescence with undetectable ADAMTS13 activity and antigen and both receive prophylactic plasma infusion every three to four weeks. The effect of these mutations on ADAMTS13 secretion was assessed along with their effect on the intracellular localization of ADAMTS13.…”

Section: Introductionmentioning

confidence: 99%

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