Characterizing the United Kingdom Congenital Thrombotic Thrombocytopenic Purpura Population

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare thrombomicroangiopathy in which there is an inherited deficiency of ADAMTS13. The prevalence of cTTP has been estimated at one per million per year and accounts for 5-10% of all TTP cases in international registries. Two main peaks of presentation are seen, in childhood and in pregnancy. The ADAMTS13 gene consists of 29 exons whilst the ADAMTS13 protein consists of 16 domains. Over 150 mutations spanning the entire length of ADAMTS13 have been discovered, but there is little evidence on their respective impact on the disease phenotype and evidence is lacking on the optimal management of patients.

Since January 2009, the United Kingdom TTP registry has been collecting information on all acute presentations of TTP across the country. Whilst patients were primarily taken from the registry, additional cases from before its formation were also identified from the major TTP treating centers in the UK. Using this combined cohort we undertook a review of all suspected cases of congenital TTP to evaluate the potential impact of the genotype on disease outcomes.

Method:

Congenital TTP was considered in patients who presented with thrombocytopenia and microangiopathic hemolytic anemia with ADAMTS13 protease activity below 10IU/dL (NR: 60-146IU/dL) and no evidence of anti-ADAMTS13 IgG antibodies. Prior to Sanger sequencing, DNA was extracted from whole blood samples and the 29 ADAMTS13 exons amplified using a polymerase chain reaction method and custom oligonucleotide primers. NCBI NG_011934.2 was used as the reference sequence.

Results:

69 patients from across the United Kingdom were confirmed to have congenital TTP by genetic analysis. Of those diagnosed in childhood 68% were male whilst 93% diagnosed in adulthood were female. 36% of patients had symptom onset in the neonatal or childhood period and 41% first experienced symptoms in pregnancy. 32% had homozygous mutations, 43% were compound heterozygotes and the remaining patients had insertion or deletion mutations. The most common mutation seen was the exon 24 R1060W missense mutation (rs142572218).

Over two thirds of pre-spacer mutations were seen in patients who first presented with TTP symptoms in childhood. Those seen in adult presentations were all heterozygote mutations and in all but three cases, the accompanying mutation was the rs142572218 (R1060W) mutation presenting in pregnant women. 95% of patients with first presentation in adult life had a mutation in post spacer exons.

62% of all patients received regular prophylactic therapy with the intermediate purity Factor VIII concentrate, BPL 8Y, the most common choice for children and solvent/detergent fresh frozen plasma (SD-FFP) for adults. 72% of patients had treatment during their pregnancy with 41% continuing with regular prophylactic SD-FFP treatment postpartum. Half of these patients needed treatment for persistent thrombocytopenia whilst the other half were symptomatic patients with normal platelet counts. The most common symptoms were persistent headaches and lethargy with considerable symptom improvement seen in all patients. Additionally, five patients were not diagnosed with cTTP until presenting with strokes; one aged 26, 2 in the 5^th decade and 2 in the 6^th decade who had both also had prior strokes when younger. All six gave clear histories of pregnancy loss with thrombocytopenia that were not linked to a cTTP diagnosis at the time. One patient died and the remaining four receive regular prophylactic therapy.

Conclusion:

Pre-spacer mutations are more common in childhood presentations of congenital TTP and post-spacer mutations more common in adult presentations. Prophylactic treatment should be considered for symptomatic patients despite a normal platelet count. The cohort of cases presenting later in life with cerebrovascular events suggests prophylaxis in cases presenting in adulthood should be considered to prevent early morbidity. The data also suggests that routine laboratory parameters, including platelet count are not sensitive in identifying symptoms related to cTTP.