title: Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation.
abstract: Upon vascular injury, locally controlled haemostasis prevents life-threatening blood loss and ensures wound healing. Intracellular material derived from damaged cells at these sites will become exposed to blood components and could contribute to blood coagulation and pathological thrombus formation. So far, the functional and mechanistic consequences of this concept are not understood. Here, we present in vivo and in vitro evidence that different forms of eukaryotic and prokaryotic RNA serve as promoters of blood coagulation. Extracellular RNA was found to augment (auto-)activation of proteases of the contact phase pathway of blood coagulation such as factors XII and XI, both exhibiting strong RNA binding. Moreover, administration of exogenous RNA provoked a significant procoagulant response in rabbits. In mice that underwent an arterial thrombosis model, extracellular RNA was found associated with fibrin-rich thrombi, and pretreatment with RNase (but not DNase) significantly delayed occlusive thrombus formation. Thus, extracellular RNA derived from damaged or necrotic cells particularly under pathological conditions or severe tissue damage represents the long sought natural "foreign surface" and provides a procoagulant cofactor template for the factors XII/XI-induced contact activation/amplification of blood coagulation. Extracellular RNA thereby reveals a yet unrecognized target for antithrombotic intervention, using RNase or related therapeutic strategies.
authors.affiliation: Research Laboratories, Aventis Behring, D-35392 Marburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kannemeier
authors.forename: Aya
authors.initials: A
authors.lastname: Shibamiya
authors.forename: Fumie
authors.initials: F
authors.lastname: Nakazawa
authors.forename: Heidi
authors.initials: H
authors.lastname: Trusheim
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
authors.forename: Yutong
authors.initials: Y
authors.lastname: Song
authors.forename: Eleni
authors.initials: E
authors.lastname: Tzima
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kennerknecht
authors.forename: Michael
authors.initials: M
authors.lastname: Niepmann
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: von Bruehl
authors.forename: Daniel
authors.initials: D
authors.lastname: Sedding
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.forename: Bernd
authors.initials: B
authors.lastname: Engelmann
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004926:Escherichia coli; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000378:metabolism*; D011817:Rabbits; D012697:Serine Endopeptidases / Q000097:blood; D015003:Yeasts
chemical_list: D001779:Blood Coagulation Factors; D012313:RNA; D012697:Serine Endopeptidases