Current prophylactic plasma infusion protocols do not adequately prevent long‐term cumulative organ damage in the Japanese congenital thrombotic thrombocytopenic purpura cohort

2021 ◽  
Author(s):  
Kazuya Sakai ◽  
Yoshihiro Fujimura ◽  
Toshiyuki Miyata ◽  
Ayami Isonishi ◽  
Koichi Kokame ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Organ Damage ◽  
Thrombocytopenic Purpura ◽  
Plasma Infusion ◽  
Congenital Thrombotic Thrombocytopenic Purpura

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 Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 440-448 ◽  
Author(s):  
Luca A. Lotta ◽  
Haifeng M. Wu ◽  
Ian J. Mackie ◽  
Marina Noris ◽  
Agnes Veyradier ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Limit Of Detection ◽  
Clinical Phenotype ◽  
Characteristic Curve ◽  
Activity Levels ◽  
Dependent Manner ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Plasma Infusion ◽  
Congenital Thrombotic Thrombocytopenic Purpura

Abstract The quantification of residual plasmatic ADAMTS13 activity in congenital thrombotic thrombocytopenic purpura (TTP) patients is constrained by limitations in sensitivity and reproducibility of commonly used assays at low levels of ADAMTS13 activity, blunting efforts to establish genotype-phenotype correlations. In the present study, the residual plasmatic activity of ADAMTS13 was measured centrally by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (limit of detection = 0.5%) in 29 congenital TTP patients. The results were used to study correlations among ADAMTS13 genotype, residual plasmatic activity, and clinical phenotype severity. An ADAMTS13 activity above 0.5% was measured in 26 (90%) patients and lower levels of activity were associated with earlier age at first TTP episode requiring plasma infusion, more frequent recurrences, and prescription of fresh-frozen plasma prophylaxis. Receiver operating characteristic curve analysis showed that activity levels of less than 2.74% and 1.61% were discriminative of age at first TTP episode requiring plasma infusion < 18 years, annual rate of TTP episodes > 1, and use of prophylaxis. Mutations affecting the highly conserved N-terminal domains of the protein were associated with lower residual ADAMTS13 activity and a more severe phenotype in an allelic-dose dependent manner. The results of the present study show that residual ADAMTS13 activity is associated with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations.

scholarly journals Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura

Blood ◽  
2017 ◽  
Vol 130 (19) ◽  
pp. 2055-2063 ◽  
Author(s):  
Marie Scully ◽  
Paul Knöbl ◽  
Karim Kentouche ◽  
Lawrence Rice ◽  
Jerzy Windyga ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Phase 1 ◽  
Pharmacokinetic Profile ◽  
Human Pharmacokinetics ◽  
Phase 1 Study ◽  
Thrombocytopenic Purpura ◽  
Plasma Infusion ◽  
Key Points ◽  
Congenital Thrombotic Thrombocytopenic Purpura

Key PointsFirst-in-human, phase 1 study, recombinant ADAMTS-13 was safe, nonimmunogenic, and tolerated in congenital thrombotic thrombocytopenic purpura. Recombinant ADAMTS-13 pharmacokinetic profile was comparable to plasma infusion studies, with evidence of pharmacodynamic activity.

scholarly journals Long-term Kidney Outcomes in Patients With Acquired Thrombotic Thrombocytopenic Purpura

2017 ◽  
Vol 2 (6) ◽  
pp. 1088-1095 ◽  
Author(s):  
Dustin J. Little ◽  
Lauren M. Mathias ◽  
Evaren E. Page ◽  
Johanna A. Kremer Hovinga ◽  
Sara K. Vesely ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura
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