Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry

Abstract

SummaryHereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is a rare recessively inherited disease. Underlying is a severe constitutional deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, due to compound heterozygous or homozygous mutations in the ADAMTS13 gene. The clinical picture is variable and more and more patients with an adult-onset are diagnosed.In the majority of countries the only available treatment is plasma, which when administered regularly can efficiently prevent acute disease bouts. The decision to initiate regular prophylaxis is often not easy, as evidence based guidelines and long term outcome data are lacking. Through the hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier: NCT01257269), which was initiated in 2006 and is open to all patients diagnosed with Upshaw-Schulman syndrome and their family members, we aim to gain further information and insights into this rare disease, which eventually will help to improve clinical management of affected patients.

Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency

“…From two congenital TTP cohorts, that of the Hemostasis Research Laboratory in Bern, Switzerland [10,11] and the Japanese congenital TTP study [4], confirmed congenital TTP patients were selected based on the following two criteria: a) the patient had not been extensively studied by other groups and b) whole blood for DNA extraction was available. A total of 32 congenital TTP patients (30 from Europe and 2 from Japan) were included in this study, of which thirteen had severe renal insufficiency up to end-stage renal disease ( Table 1).…”

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

“…33,34 Analysis of VWF multimers was performed using sodium dodecyl sulfate-agarose gel electrophoresis followed by western blotting and sensitive luminescence detection. 4,35 VWF degradation products generated by ADAMTS-13-mediated cleavage were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions followed by western blotting and immunostaining with a horseradish peroxidase-labeled polyclonal rabbit antihuman VWF antibody with enhanced chemiluminescence detection. 4,35,36 …”

“…3 The congenital form of TTP (cTTP, previously termed hereditary TTP or Upshaw-Schulman syndrome) is an ultrarare, although likely underestimated, condition with a prevalence of approximately 1 case per million. 4,5 It exhibits an autosomal recessive mode of inheritance caused by homozygous or compound heterozygous mutations in both ADAMTS-13 alleles on chromosome 9. 6 The nature of the mutations is diverse and includes single amino acid missense substitution (approximately 60%), as well as nonsense, frame-shift, splice site mutations and deletions and insertions (collectively, approximately 40%).…”

Long-Term Prevention of Congenital Thrombotic Thrombocytopenic Purpura in ADAMTS13 Knockout Mice by Sleeping Beauty Transposon-Mediated Gene Therapy

“…Indeed, regular plasma infusions-of which the number depends on the patient's phenotype-may prevent acute TTP episodes. [11][12][13] Lifelong treatment with plasma, however, is inconvenient, and administration of plasma may result in fluid overload or elicit allergic reactions to plasma proteins. The risk of viral/prion transmission also remains a major concern.…”