Identification of 8 Rare Deleterious Variants in ADAMTS13 by Next-generation Sequencing in a Chinese Population with Thrombotic Thrombocytopenic Purpura

Objective Thrombotic thrombocytopenic purpura(TTP)is a rare and fatal disease caused by a severe deficiency in the metalloprotease ADAMTS13 and is characterized by thrombotic microangiopathy.The present study aimed to investigate the genes and variants associated with TTP in a Chinese population.Methods Target sequencing was performed on 220 genes related to complements,coagulation factors,platelets,fibrinolytic,endothelial,inflammatory,and anticoagulation systems in 207 TTP patients and 574 controls.Subsequently,logistic regression analysis was carried out to identify the TTP-associated genes based on the counts of rare deleterious variants in the region of a certain gene.Moreover,the associations between common variants and TTP were also investigated.Results ADAMTS13 was the only TTP-associated gene(OR=3.77;95%CI:1.82–7.81;P=3.6×10^(-4))containing rare deleterious variants in TTP patients.Among these 8 variants,5 novel rare variants that might contribute to TTP were identified,including rs200594025,rs782492477,c.T1928G(p.I643S),c.3336_3361del(p.Q1114Afs*20),and c.3469_3470del(p.A1158Sfs*17).No common variants associated with TTP were identified under the stringent criteria of correction for multiple testing.Conclusion ADAMTS13 is the primary gene related to TTP.The genetic variants associated with the occurrence of TTP were slightly different between the Chinese and European populations.

Acquired immune thrombotic thrombocytopenic purpura(TTP)associated with inactivated COVID-19 vaccine CoronaVac

Corona virus disease 2019(COVID-19)due to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has affected the whole world.Acquired thrombotic thrombocytopenic purpura(TTP)has been reported after administration of mRNA-or adenoviral vector-based COVID-19 vaccines,including Ad26.COV2-S,BNT162b2,mRNA-1273,and ChAdOx1 nCov-19.However,whether inactivated vaccines,such as CoronaVac,could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are unknown.In this study,two cases were reported.Both cases developed TTP after the second CoronaVac vaccination shot,but not the first.They demonstrated symptoms of fever,neurological abnormalities,renal dysfunction,thrombocytopenia,and hemolysis.Both patients achieved complete remission through several sessions of plasma exchanges and immune suppression.The incidence of TTP in Nanjing area was analyzed.The number of patients with TTP was 12 in 2019,6 in 2020,16 in 2021,and 19 in 2022.To the authors’knowledge,this report is the first report of TTP associated with inactivated COVID-19 vaccine(CoronaVac).The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based ones.Timely plasma exchange is a vital treatment for CoronaVac-related TTP,similar to activated vaccine-related TTP.