title: Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo.
abstract: Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
authors.affiliation: Deutsches Herzzentrum and I. Medizinische Klinik, Technische Universität München (TUM), 80333 Munich, Germany.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: von Brühl
authors.forename: Konstantin
authors.initials: K
authors.lastname: Stark
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinhart
authors.forename: Sue
authors.initials: S
authors.lastname: Chandraratne
authors.forename: Ildiko
authors.initials: I
authors.lastname: Konrad
authors.forename: Michael
authors.initials: M
authors.lastname: Lorenz
authors.forename: Alexander
authors.initials: A
authors.lastname: Khandoga
authors.forename: Anca
authors.initials: A
authors.lastname: Tirniceriu
authors.forename: Raffaele
authors.initials: R
authors.lastname: Coletti
authors.forename: Maria
authors.initials: M
authors.lastname: Köllnberger
authors.forename: Robert A
authors.initials: RA
authors.lastname: Byrne
authors.forename: Iina
authors.initials: I
authors.lastname: Laitinen
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Alexander
authors.initials: A
authors.lastname: Brill
authors.forename: Susanne
authors.initials: S
authors.lastname: Pfeiler
authors.forename: Davit
authors.initials: D
authors.lastname: Manukyan
authors.forename: Siegmund
authors.initials: S
authors.lastname: Braun
authors.forename: Philipp
authors.initials: P
authors.lastname: Lange
authors.forename: Julia
authors.initials: J
authors.lastname: Riegger
authors.forename: Jerry
authors.initials: J
authors.lastname: Ware
authors.forename: Annekathrin
authors.initials: A
authors.lastname: Eckart
authors.forename: Selgai
authors.initials: S
authors.lastname: Haidari
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Katrin
authors.initials: K
authors.lastname: Echtler
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Bernd
authors.initials: B
authors.lastname: Engelmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002450:Cell Communication; D005174:Factor XII / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000502:physiology; D013925:Thromboplastin / Q000502:physiology; D020246:Venous Thrombosis / Q000209:etiology*
chemical_list: D019007:P-Selectin; D005174:Factor XII; D013925:Thromboplastin