Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura

2014 ◽  
Vol 34 (03) ◽  
pp. 244-248 ◽  
Author(s):  
J. A. Hovinga ◽  
K. Lackner ◽  
H.-G. Füllemann ◽  
B. Lämmle ◽  
I. Scharrer ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Late Onset ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Compound Heterozygous ◽  
Thrombocytopenic Purpura ◽  
Exon 2 ◽  
Acid Therapy ◽  
Gestational Week ◽  
Adamts13 Deficiency

SummaryWe report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. Diagnosis: In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. Conclusion: Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

scholarly journals TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency

2004 ◽  
pp. 463-465 ◽  
Author(s):  
LA Metherell ◽  
MO Savage ◽  
M Dattani ◽  
J Walker ◽  
PE Clayton ◽  
...  
Keyword(s):  
Dna Binding ◽  
Early Onset ◽  
Late Onset ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Nucleotide Polymorphisms ◽  
Exon 2 ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency ◽  
T Box

OBJECTIVE: Congenital isolated ACTH deficiency (IAD) is a rare inherited disorder that is clinically and genetically heterogeneous. Patients are characterised by low or absent cortisol production secondary to low plasma ACTH despite normal secretion of other pituitary hormones and the absence of structural pituitary defects. Onset may occur in the neonatal period, but may first be observed in later childhood. Recently, mutations in the TPIT gene, a T-box factor selectively expressed in developing corticotroph cells, have been found in cases of early-onset IAD. DESIGN: Here we report the screening of the TPIT gene in seven patients with IAD, four of whom had neonatal onset. METHODS: Genomic DNA was extracted and the sequences of the 8 TPIT exons and their intron/exon junctions were determined by automated sequencing. RESULTS: Two siblings with early-onset IAD were both compound heterozygotes for mutations in exons 2 and 6. The missense mutation (Met86Arg) in exon 2 within the T-box (or DNA binding domain) is predicted to disrupt DNA binding. A frameshift mutation in exon 6 (782delA) introduces a premature stop codon and is likely to lead to a non-functional truncated protein. No nucleotide changes were observed in exonic sequences in the other two early- or the three later-onset cases. Fifteen single nucleotide polymorphisms that were not predicted to change the TPIT transcript were also detected. CONCLUSIONS: These findings provide a further illustration of the genetic heterogeneity of IAD and are highly suggestive of one or more other genes being implicated in this disorder.

scholarly journals Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 610-616 ◽  
Author(s):  
Johanna A. Kremer Hovinga ◽  
Bernhard Lämmle
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Gene Mutations ◽  
Immunologic Tolerance ◽  
Diagnosis And Treatment ◽  
Compound Heterozygous ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Circulating Autoantibodies

Abstract The regulation of VWF multimer size is essential in preventing spontaneous microvascular platelet clumping, a central pathophysiologic finding in thrombotic thrombocytopenic purpura (TTP). In the majority of TTP patients, ADAMTS13, the principal regulator of VWF size, is severely deficient. Today, 2 forms of severe ADAMTS13 deficiency are recognized. The acquired form is caused by circulating autoantibodies inhibiting ADAMTS13 activity or increasing ADAMTS13 clearance. Pathogenic anti-ADAMTS13 Abs are mainly of the IgG class, predominantly of subclass IgG4, and inhibitory Abs recognize a defined epitope in the ADAMTS13 spacer domain. The reasons underlying the failure to maintain immunologic tolerance to ADAMTS13, however, are still poorly understood. Constitutional ADAMTS13 deficiency leading to hereditary TTP, also known as Upshaw-Schulman syndrome, is the result of homozygous or compound heterozygous ADAMTS13 gene mutations.

scholarly journals Characterization and treatment of congenital thrombotic thrombocytopenic purpura

Blood ◽  
2019 ◽  
Vol 133 (15) ◽  
pp. 1644-1651 ◽  
Author(s):  
Ferras Alwan ◽  
Chiara Vendramin ◽  
Ri Liesner ◽  
Amanda Clark ◽  
William Lester ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Age Of Onset ◽  
Organ Damage ◽  
Compound Heterozygous ◽  
Prophylactic Therapy ◽  
Thrombocytopenic Purpura ◽  
Stroke Incidence ◽  
End Organ Damage ◽  
Congenital Thrombotic Thrombocytopenic Purpura ◽  
Diagnosis Age

Abstract Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

scholarly journals Annual Incidence and Severity of Acute Episodes in Hereditary Thrombotic Thrombocytopenic Purpura

Blood ◽  
2021 ◽  
Author(s):  
Erika Tarasco ◽  
Lukas Bütikofer ◽  
Kenneth D. Friedman ◽  
James N George ◽  
Ingrid V Hrachovinova ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Premature Death ◽  
Annual Incidence ◽  
Prospective Data ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Survival Frequency ◽  
Overt Disease ◽  
Plasma Infusions

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in hTTP patients is largely lacking. This study reports prospective data of 87 patients from the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) for survival, frequency and severity of acute episodes from enrollment until December 2019. The 87 patients, followed for median 4.2 years (range 0.01-15), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and of 18 years (range 0.0-70 for both), respectively. Forty-three patients received regular plasma prophylaxis, while 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes of which 91 (69%) occurred in patients on regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95%CI 0.29-0.44) with and of 0.41 (95%CI 0.30-0.56) without regular plasma treatment. More than one third of acute episodes (n=51) were documented in children &lt;10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients &gt;40 years of age (1.18 [95% CI 0.88-1.55] vs. 0.14 [95% CI 0.08-0.23]). Prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, caregivers, patients and their guardians are reluctant to start regular plasma infusions, from which particularly children would benefit.

Systemic Lupus Erythematosus with Secondary Thrombotic Thrombocytopenic Purpura and Acute Parkinsonism: A Case Report

2022 ◽  
Vol 71 (12) ◽  
Author(s):  
Pooja Deepak ◽  
Roha Saeed Memon ◽  
Fizza Tariq ◽  
Hassan Ahmed ◽  
Shaheen Bhatti
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Lupus Erythematosus ◽  
Late Onset ◽  
Case Reports ◽  
Gastrointestinal Symptoms ◽  
Signs And Symptoms ◽  
Urgent Care ◽  
Systemic Lupus ◽  
Thrombocytopenic Purpura

Systemic lupus erythematosus (SLE) is an autoimmune disease that has certain characteristic features but can also present with misleading signs and symptoms especially when it is of late-onset. Various case reports address its association with thrombotic thrombocytopenic purpura (TTP), however, its association with parkinsonism remains unclear. We present the case of a 58-year-old male who reported with acute-onset parkinsonism along with some gastrointestinal symptoms. Detailed laboratory investigations unmasked the underlying SLE with an overlapping picture of TTP. This unusual presentation in a resource-constrained setting created challenges and subsequent delays in the diagnosis and management of the patient. Despite urgent care, the patient’s age, presence of overlapping conditions, and multi-organ involvement were some of the factors due to which the treatment failed and he could not survive. We report the association of SLE with secondary TTP and parkinsonism.

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children

2009 ◽  
Vol 24 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Chantal Loirat ◽  
Jean-Pierre Girma ◽  
Céline Desconclois ◽  
Paul Coppo ◽  
Agnès Veyradier
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

scholarly journals Beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 539-547 ◽  
Author(s):  
Kathryn Dane ◽  
Shruti Chaturvedi
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Relapse Prevention ◽  
Tissue Injury ◽  
Novel Therapies ◽  
Thrombocytopenic Purpura ◽  
Platelet Recovery ◽  
Adamts13 Deficiency ◽  
Prophylactic Use ◽  
Von Willebrand

Abstract The advent of plasma exchange has dramatically changed the prognosis of acute thrombotic thrombocytopenic purpura (TTP). Recent insights into TTP pathogenesis have led to the development of novel therapies targeting pathogenic anti-ADAMTS13 antibody production, von Willebrand factor (VWF)–platelet interactions, and ADAMTS13 replacement. Retrospective and prospective studies have established the efficacy of rituximab as an adjunct to plasma exchange for patients with acute TTP, either upfront or for refractory disease. Relapse prevention is a major concern for survivors of acute TTP, and emerging data support the prophylactic use of rituximab in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. Capalcizumab, a nanobody directed against domain A1 of VWF that prevents the formation of VWF–platelet aggregates, recently completed phase 2 (TITAN) and 3 (HERCULES) trials with encouraging results. Compared with placebo, caplacizumab shortened the time to platelet recovery and may protect against microthrombotic tissue injury in the acute phase of TTP, though it does not modify the underlying immune response. Other promising therapies including plasma cell inhibitors (bortezomib), recombinant ADAMTS13, N-acetyl cysteine, and inhibitors of the VWF–glycoprotein Ib/IX interaction (anfibatide) are in development, and several of these agents are in prospective clinical studies to evaluate their efficacy and role in TTP. In the coming years, we are optimistic that novel therapies and international collaborative efforts will usher in even more effective, evidence-based approaches to address refractory acute TTP and relapse prevention.

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