Factor XII activation is essential to sustain the procoagulant effects of particulate matter

E. Kilinc*, R. Van Oerle, J. I. Borissoff, C. Oschatz, M.E. Gerlofs Nijland, N. A. Janssen, Flemming R. Cassee, T. Sandstrom, Thomas Renne, H. Ten Cate, H. M. H. Spronk

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

33 Citations (Web of Science)

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. Objectives: 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 mu m) 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, where as 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.
Original languageEnglish
Pages (from-to)1359-1367
JournalJournal of Thrombosis and Haemostasis
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 2011

Keywords

  • air pollution
  • blood coagulation
  • factor XII
  • intrinsic coagulation pathway
  • particulate matter
  • thrombin generation

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