Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation.
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.
Kannemeier
Christian
C
Research Laboratories, Aventis Behring, D-35392 Marburg, Germany.
Shibamiya
Aya
A
Nakazawa
Fumie
F
Trusheim
Heidi
H
Ruppert
Clemens
C
Markart
Philipp
P
Song
Yutong
Y
Tzima
Eleni
E
Kennerknecht
Elisabeth
E
Niepmann
Michael
M
von Bruehl
Marie-Luise
ML
Sedding
Daniel
D
Massberg
Steffen
S
Günther
Andreas
A
Engelmann
Bernd
B
Preissner
Klaus T
KT
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
D001779:Blood Coagulation Factors; D012313:RNA; D012697:Serine Endopeptidases