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Abstract
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.
Highlights
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy which manifests as an acute episode of thrombocytopenia, microangiopathic hemolytic anemia and disseminated microvascular thrombosis with variable and multiple organ involvement [1]
Between January 2002 and March 2018, 252 patients were referred to the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center for ADAMTS13 testing for a first episode of Immune-mediated thrombotic thrombocytopenic purpura (iTTP)
In a large population of 161 Italian Caucasian incident cases of iTTP, we found that the high-risk rs6903608 genotype was associated with both the first and the second episode of acute iTTP, conferring a 4.7-fold and a 2.1-fold higher risk than the reference genotype, respectively
Summary
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy which manifests as an acute episode of thrombocytopenia, microangiopathic hemolytic anemia and disseminated microvascular thrombosis with variable and multiple organ involvement [1]. TTP is caused by a severe deficiency of the von Willebrand factor cleaving protease ADAMTS13 (a disintegrin metalloproteinase with thrombospondin type 1 motif 13) and exists in two forms: congenital TTP, an autosomal recessive disease due to mutations in the ADAMTS13 gene on chromosome 9, and acquired immune-mediated TTP (iTTP), an autoimmune disease caused by immunological tolerance loss in ADAMTS13. With an estimated annual incidence of 2–6 cases per million people [2,3], iTTP affects mostly women in the forth to fifth decade of life [4,5], and may arise idiopathically or secondary to other conditions, such as concomitant autoimmune diseases and pregnancy [1]. Severe ADAMTS13 deficiency and the presence of anti-ADAMTS13 autoantibodies during disease remission are known risk factors for iTTP relapse [10,11], which, remains largely unpredictable
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