Congenital thrombotic thrombocytopenic purpura: genetics and emerging therapies

Congenital thrombotic thrombocytopenic purpura (cTTP), also known as Upshaw-Schulman syndrome, is a rare thrombotic disorder caused by biallelic ADAMTS13 mutations that lead to fatal ischemic organ failure. Although the extremely low prevalence of cTTP has hindered links between genotype and phenotype, long-term comorbidity/complications, and optimal treatment regimens, several national registries from the United Kingdom, Switzerland, France, and Japan have revealed the epidemiology of cTTP in a stepwise manner. However, it is not widely recognized that patients can develop TTP episodes after childhood. Adamts13-knockout mouse studies identified that additional triggers, like von Willebrand factor concentrate or Shiga toxin, can induce severe thrombocytopenia, hemolytic anemia, and ischemic organ damage. A pattern of autosomal recessive inheritance is observed in cTTP with homozygous or compound heterozygous gene mutations. To date, more than 200 causative mutations spread throughout all ADAMTS13 protein domains have been reported globally. Although c.4143_4144dupA (p.E1382Rfs*6) and p.R1060W are the most prevalent mutations in Western cohorts, p.R193W and p.C908Y were dominant among patients with cTTP in Japanese cohorts. Regular plasma infusion is commonly administered to cTTP patients depending on the ADAMTS13 supply to prevent TTP episodes; however, intolerant allergic reactions and time-consuming transfusions are burdens for patients. Identical treatment intervals and amounts of plasma remain unclear, and 5-10 mL/kg of plasma is empirically infused every 2 weeks to most patients in Japan. Recent alarming results have demonstrated that a trough level of ADAMTS13 activity should be maintained as much as possible for successful delivery during pregnancy and preventing from longterm organ damage. The emerging recombinant ADAMTS13 product (TAK-755), which is currently under phase III clinical trials, will overcome the current limitations of plasma therapy in patients. Furthermore, novel gene therapies, such as those for hemophilia, have been explored for cTTP as a curative option. This review on cTTP focused on genetics and emerging therapies based on large-scale cTTP cohorts including our Japanese cohort and discussed the significant advances and controversial issues related to cTTP.