title: Factor XII activation is essential to sustain the procoagulant effects of particulate matter.
abstract: BACKGROUND
  Particulate matter (PM) is a key component of ambient air pollution and has been associated with an increased risk of thrombotic events and mortality. The underlying mechanisms remain unclear.
  
  
  OBJECTIVE
  To study the mechanisms of PM-driven procoagulant activity in human plasma and to investigate mainly, the coagulation driven by ultrafine particles (UFPs; < 0.1 μm) in genetically modified mice.
  
  
  METHODS
  Thrombin generation in response to PM of different sizes was assessed in normal human platelet-poor plasma, as well as in plasmas deficient in the intrinsic pathway proteases factors XII (FXII) or XI (FXI). In addition, UFPs were intratracheally instilled in wild-type (WT) and FXII-deficient (FXII(-/-) ) mice and plasma thrombin generation was analyzed in plasma from treated mice at 4 and 20 h post-exposure.
  
  
  RESULTS
  In normal human plasma, thrombin generation was enhanced in the presence of PM, whereas PM-driven thrombin formation was completely abolished in FXII- and FXI-deficient plasma. UFPs induced a transient increase in tissue factor (TF)-driven thrombin formation at 4 h post-instillation in WT mice compared with saline instillation. Intratracheal instillation of UFPs resulted in a procoagulant response in WT mice plasma at 20 h, whereas it was entirely suppressed in FXII(-/-) mice.
  
  
  CONCLUSIONS
  Overall, the data suggest that PM promotes its early procoagulant actions mostly through the TF-driven extrinsic pathway of coagulation, whereas PM-driven long lasting thrombogenic effects are predominantly mediated via formation of activated FXII. Hence, FXII-driven thrombin formation may be relevant to an enhanced thrombotic susceptibility upon chronic exposure to PM in humans.
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands. e.kilinc@maastrichtuniversity.nl
authors.forename: E
authors.initials: E
authors.lastname: Kilinç
authors.forename: R
authors.initials: R
authors.lastname: Van Oerle
authors.forename: J I
authors.initials: JI
authors.lastname: Borissoff
authors.forename: C
authors.initials: C
authors.lastname: Oschatz
authors.forename: M E
authors.initials: ME
authors.lastname: Gerlofs-Nijland
authors.forename: N A
authors.initials: NA
authors.lastname: Janssen
authors.forename: F R
authors.initials: FR
authors.lastname: Cassee
authors.forename: T
authors.initials: T
authors.lastname: Sandström
authors.forename: T
authors.initials: T
authors.lastname: Renné
authors.forename: H
authors.initials: H
authors.lastname: Ten Cate
authors.forename: H M H
authors.initials: HM
authors.lastname: Spronk
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D004789:Enzyme Activation; D005172:Factor XI; D005174:Factor XII / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010316:Particle Size; D052638:Particulate Matter / Q000009:adverse effects*; D013917:Thrombin / Q000096:biosynthesis; D013927:Thrombosis / Q000209:etiology
chemical_list: D052638:Particulate Matter; D005174:Factor XII; D005172:Factor XI; D013917:Thrombin