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Assembly of alternative prothrombinase by extracellular histones initiates and disseminates intravascular coagulation.

细胞外组蛋白组装替代凝血酶原酶引发和传播血管内凝血。

  • 影响因子:0
  • DOI:10.1182/blood.2019002973
  • 作者列表:"Abrams ST","Su D","Sahraoui Y","Lin Z","Cheng Z","Nesbitt K","Alhamdi Y","Harrasser M","Du M","Foley JH","Lillicrap D","Wang G","Toh CH
  • 发表时间:2021-01-07
Abstract

:Thrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated cofactor V (FVa), and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragment 1 (F1) and fragment 2 (F2) specifically to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa, which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin F1 + F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit patients with sepsis (n = 144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in factor VIII (FVIII)- and FIX-deficient plasma, as well as in FVIII-deficient mice. In summary, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation and correcting coagulation factor deficiency.

摘要

: 凝血酶的产生对于生理性血凝块形成和弥散性血管内凝血 (DIC) 的病理发展都是关键的。在危重症中,广泛的细胞损伤可将组蛋白释放到循环中,可使凝血酶生成增加,引起DIC,但分子机制尚不清楚。通常,凝血酶由凝血酶原酶复合物产生,其包含活化因子X (FXa) 、活化辅因子V (FVa) 和磷脂以在钙存在下裂解凝血酶原。在这项研究中,我们发现在存在细胞外组蛋白的情况下,可以在没有FVa和磷脂的情况下形成替代的凝血酶原酶。组蛋白直接与凝血酶原片段1 (F1) 和片段2 (F2) 特异性结合,以促进FXa裂解凝血酶原以释放活性凝血酶,这与FVa不同,FVa需要磷脂表面来锚定经典的凝血酶原酶复合物。在体内,组蛋白输注到小鼠中诱导DIC,当在组蛋白之前输注凝血酶原F1 + F2时,DIC被显著消除,以充当诱饵。在重症监护病房脓毒症患者队列 (n = 144) 中,DIC患者的循环组蛋白水平显著升高。这些数据表明,没有磷脂锚定的组蛋白诱导的替代凝血酶原酶可能弥散性血管内凝血,并揭示了凝血酶生成和DIC发展的新的分子机制。此外,组蛋白显著降低了凝血级联中FXa的需求,以使得因子VIII (FVIII) 和FIX缺陷血浆以及FVIII缺陷小鼠中能够形成凝块。总之,这项研究强调了一种新的凝血机制,在靶向全身凝血激活和纠正凝血因子缺乏方面具有治疗潜力。

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