P1579: GENOTYPE-PHENOTYPE CORRELATION IN THREE CASES OF PREGNANCY ONSET CONGENITAL THROMBOTIC THROMBOCYTOPENIC PURPURA (CTTP): A SINGLE CENTRE STUDY (2023)

Topic: 31. Transfusion medicine Background: cTTP is an ultra-rare thrombotic microangiopathy, with two presentation peaks: in childhood and adulthood, in the latter typically presenting in pregnancy and puerperium. Although there are limited data on genotype-phenotype correlation in cTTP, some mutations are more likely associated with the pregnancy onset. Aims: Aim of this study was to evaluate the genotype-phenotype correlation in our cohort of pregnancy-related cTTP patients. Methods: Three pregnant women with cTTP were enrolled into the study. ADAMTS-13 activity (chromogenic assay), inhibitors (mixing studies), and anti-ADAMTS-13 antibodies (ELISA) were measured in plasma. The genetic analysis was performed by Sanger method. Results: Patient (P) 1 was a 30 y.o. Italian healthy blood donor. After delivery of her first child in a peripheral Hospital, she became severely anaemic and thrombocytopenic. She received RBC transfusion and steroids, meanwhile, blood samples sent to our Centre revealed ADAMTS13 of 5% and no auto-antibodies. Platelet count recovered after delivery. Genetic analysis revealed homozygosity for the c.3178C>T variant (p.R1060W). The familiar study showed a moderate reduction in the levels of ADAMTS13 activity in the mother (47%) and father (43%), both carrying the same variant in heterozygosity. Prophylactic plasma infusions were provided during her second pregnancy, that was carried through the 38th week without complications pre- and post-partum. P2 was a 21 y.o. Pakistani woman, who developed TTP during her first pregnancy (15th week). ADAMTS13 activity was 0% and no anti-ADAMTS13 antibodies were detected. Admitted to our hospital, from the 15th to 20th weeks of gestation, she received 9 PEX plus steroids. For persistence of severely reduced ADAMTS13 activity, molecular analysis was performed, revealing homozygosity for two rare missense mutations: c.2351G>A in exon 19 (R784S) and c.2746C>T (R916C) in exon 22 of ADAMTS13 gene. After the diagnosis of cTTP, she received treatment with plasma infusion. The pregnancy was continued throughout the 40th week, when she delivered a healthy baby. Plasma was also infused from day 1 to day 4 postpartum. Two years later, pregnant for the second time, she received prophylactic plasma infusions from the 13th week through the 38th, and delivered a healthy baby without problems. P3 was a 28 y.o. Italian woman with a previous diagnosis of HELLP syndrome in her first pregnancy. She was diagnosed with TTP in the 3rd trimester of her second pregnancy. PEX treatment was started, however, she underwent a caesarean section at 32 weeks due to clinical worsening, with a successful outcome. She had persistent low ADAMTS13 activity levels (10%) with no auto-antibodies, and at molecular analysis, compound heterozygosity for two novel ADAMTS13 mutations was found: a frameshift mutation in exon 6 (Gly149ArgfsX54) and a missense in exon 11 (Arg421Cys). Summary/Conclusion: In our series of pregnancy-onset cTTP, the genotype-phenotype correlation was confirmed in two out of three cases. Indeed, the first patient carried the p.R1060W, which is commonly associated with first presentation in pregnancy. The second patient was homozygous for the complex allele c.2351G>A; c.2746C>T (of which the variant c.2746C>T is probably pathogenic, while the c.2351G>A benign), described only in an adult-onset cTTP case. Finally, two new variants in compound heterozygosity, involving exons 6 and 11, were found in the third patient, classifiable as prespacer mutations, which are usually described in childhood-onset cases. The molecular study allowed to diagnose congenital cases, improving the management and outcome of subsequent pregnancies. Keywords: Pregnancy, Thrombotic thrombocytopenic purpura (TTP), Mutation analysis, ADAMTS13