Mancini Ilaria, Giacomini Elisa, Pontiggia Silvia, Artoni Andrea, Ferrari Barbara, Pappalardo Emanuela, Gualtierotti Roberta, Trisolini Silvia Maria, Capria Saveria, Facchini Luca, Codeluppi Katia, Rinaldi Erminia, Pastore Domenico, Campus Simona, Caria Cinzia, Caddori Aldo, Nicolosi Daniela, Giuffrida Gaetano, Agostini Vanessa, Roncarati Umberto, Mannarella Clara, Fragasso Alberto, Podda Gian Marco, Birocchi Simone, Cerbone Anna Maria, Tufano Antonella, Menna Giuseppe, Pizzuti Michele, Ronchi Michela, De Fanti Alessandro, Amarri Sergio, Defina Marzia, Bocchia Monica, Cerù Silvia, Gattillo Salvatore, Rosendaal Frits R, Peyvandi Flora
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy.
J Clin Med. 2020 Oct 21;9(10):3379. doi: 10.3390/jcm9103379.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.
免疫介导的血栓性血小板减少性紫癜（iTTP）是一种罕见的、危及生命的血栓性微血管病，由严重的ADAMTS13（含血小板反应蛋白基序的解聚素和金属蛋白酶13）缺乏引起，30%-50%的患者会复发。已发现常见的人类白细胞抗原（HLA）变体rs6903608与iTTP的流行有关，但该变体是否与疾病复发有关尚不清楚。为了评估rs6903608对iTTP发病和复发的影响，我们对161例2002年至2018年间首次发作iTTP的意大利患者以及456例意大利对照进行了病例对照和队列研究。rs6903608的变异与iTTP发病密切相关（纯合子优势比（OR）为4.68（95%置信区间（CI）为2.67至8.23）；杂合子OR为1.64（95%CI为0.95至2.83）），每增加一个风险等位基因，发病时间提前三年（β为-3.34，95%CI为-6.69至0.02）。在153名幸存者中（中位随访时间4.9年（95%CI为3.7至6.1）），44例（29%）复发。到第6年时，风险等位基因纯合子的复发绝对风险为46%（95%CI为36%至57%），显著高于杂合子（22%（95%CI为16%至29%））和参考等位基因纯合子（30%（95%CI为23%至39%））。总之，HLA变体rs6903608是iTTP发病和复发的危险因素。这一新发现的生物标志物可能有助于识别复发风险高的患者，这些患者将从密切监测或强化免疫抑制治疗中获益。
