Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies
Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies
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DOI：
10.1182/blood-2012-02-412197
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发表时间：
2012-08-09
期刊：
影响因子：
20.3
通讯作者：
Laemmle, Bernhard
中科院分区：
文献类型：
--
作者：
Fuchs, Tobias A.;Hovinga, Johanna A. Kremer;Laemmle, Bernhard
血栓性微血管病 (TMA) 是一组危及生命的疾病，其特征为血小板减少、红细胞破碎和缺血性器官损伤。遗传性疾病、自身免疫性疾病和癌症是 TMA 的危险因素，但需要额外的未知触发因素才能引发急性疾病。最近的研究表明，DNA 和组蛋白在炎症或感染期间释放，并刺激小鼠的凝血、血栓形成、血小板减少和器官损伤。我们发现急性 TMA 中存在细胞外 DNA 和组蛋白以及中性粒细胞标记。对不同临床类别的 TMA 患者血浆的分析显示，DNA-组蛋白复合物和中性粒细胞颗粒中的髓过氧化物酶 (MPO) 以及中性粒细胞胞质中富含的异质复合物 S100A8/A9 的水平升高。在血栓性血小板减少性紫癜（一种 TMA 亚型，通常与严重 ADAMTS13（一种具有血小板反应蛋白 1 型基序的解整合素和金属蛋白酶，成员 13）缺陷相关）的治疗过程中，血浆 DNA 和 MPO 与血小板计数呈负相关，它们的水平表明疾病的改善或恶化。 ADAMTS13 缺乏以及血浆 DNA 和 MPO 水平升高是急性血栓性血小板减少性紫癜的特征。轻微感染通常发生在急性 TMA 之前，炎症反应期间释放的细胞外 DNA 和组蛋白可能会造成第二次打击，从而在已有危险因素的患者中引发急性 TMA。 （血。2012；120（6）：1157-1164）
Thrombotic microangiopathies (TMAs) are a group of life-threatening disorders characterized by thrombocytopenia, fragmentation of erythrocytes, and ischemic organ damage. Genetic disorders, autoimmune disease, and cancer are risk factors for TMAs, but an additional, unknown trigger is needed to bring about acute disease. Recent studies suggest that DNA and histones are released during inflammation or infection and stimulate coagulation, thrombosis, thrombocytopenia, and organ damage in mice. We show that extracellular DNA and histones as well as markers of neutrophils are present in acute TMAs. Analysis of plasma from TMA patients of different clinical categories revealed elevated levels of DNA-histone complexes and myeloperoxidase (MPO) from neutrophil granules as well as S100A8/A9, a heterocomplex abundant in neutrophil cytosol. During therapy of thrombotic thrombocytopenic purpura, a subtype of TMAs often associated with severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) deficiency, plasma DNA and MPO were inversely correlated with platelet counts, and their levels indicated amelioration or exacerbation of the disease. ADAMTS13 deficiency together with increased levels of plasma DNA and MPO were characteristic for acute thrombotic thrombocytopenic purpura. A minor infection often precedes acute TMA and extracellular DNA and histones released during the inflammatory response could provide the second hit, which precipitates acute TMA in patients with pre-existing risk factors. (Blood. 2012; 120(6):1157-1164)