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


Abrams, Simon T, Su, Dunhao, Sahraoui, Yasmina, Lin, Ziqi, Cheng, Zhenxing, Nesbitt, Kate, Alhamdi, Yasir, Harrasser, Micaela, Du, Min, Foley, Jonathan H et al (show 3 more authors) (2021) Assembly of alternative prothrombinase by extracellular histones initiates and disseminates intravascular coagulation. BLOOD, 137 (1). pp. 103-114.

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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.

Item Type: Article
Uncontrolled Keywords: Animals, Mice, Inbred C57BL, Humans, Mice, Disseminated Intravascular Coagulation, Factor Xa, Factor V, Factor X, Thromboplastin, Histones, Blood Coagulation
Depositing User: Symplectic Admin
Date Deposited: 01 Mar 2021 10:44
Last Modified: 18 Jan 2023 23:00
DOI: 10.1182/blood.2019002973
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3115683

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