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Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis

Research output: Contribution to journalArticle

  • Sarah N Lauder
  • Keith Allen-Redpath
  • David A Slatter
  • Maceler Aldrovandi
  • Anne O'Connor
  • Daniel Farewell
  • Charles L Percy
  • Jessica E Molhoek
  • Sirpa Rannikko
  • Victoria J Tyrrell
  • Salvatore Ferla
  • Ginger L Milne
  • Alastair W Poolehttp://orcid.org/0000-0002-0868-297X
  • Christopher P Thomas
  • Samya Obaji
  • Philip R Taylor
  • Simon A Jones
  • Phillip G de Groot
  • Rolf T Urbanus
  • Sohvi Hörkkö
  • Stefan Uderhardt
  • Jochen Ackermann
  • P Vince Jenkins
  • Andrea Brancale
  • Gerhard Krönke
  • Peter W Collins
  • Valerie B O'Donnell
Original languageEnglish
Article numbereaan2787
Number of pages19
JournalScience Signaling
Volume10
Issue number507
DOIs
DateAccepted/In press - 10 Nov 2017
DatePublished (current) - 28 Nov 2017

Abstract

Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stopping blood loss (hemostasis). Coagulation involves the external membrane surface of activated platelets and leukocytes. Using lipidomic, genetic, biochemical, and mathematical modeling approaches, we found that enzymatically oxidized phospholipids (eoxPLs) generated by the activity of leukocyte or platelet lipoxygenases (LOXs) were required for normal hemostasis and promoted coagulation factor activities in a Ca2+- and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) enhanced coagulation and restored normal hemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder antiphospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leukocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein β2GP1 (β2-glycoprotein 1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX-derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS.

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via AAAS at http://stke.sciencemag.org/content/10/507/eaan2787. Please refer to any applicable terms of use of the publisher.

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