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 Ca 2+ -and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) † Corresponding author. o-donnellvb@cardiff.ac.uk (V.B.O'D.); collinspw@cardiff.ac.uk (P.W.C.). * These authors contributed jointly to the work. Author contributions:Experiments were conducted by SNL, DAS, GM, RU, AOC, DF, JM, SR, VJT, AB, SF, MA, MH, KAR, CPT, JA and GK, and designed by SNL, DAS, PDG, SH, VBO, SAJ, PRT, PWC, PVJ. CLP and SO provided clinical samples. AP provided supervision and training. SNL, DAS, VBO and PWC wrote the paper. All authors edited the manuscript. Competing interests:The authors have declared that they have no competing interests. Europe PMC Funders GroupAuthor Manuscript Sci Signal. Author manuscript; available in PMC 2017 December 07. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts 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 β2GPI (β2-glycoprotein I), 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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Lupus anticoagulant (LA) represents the most enigmatic antibody population in patients with antiphospholipid syndrome and represents a paradox that is still unsolved. This class of antiphospholipid antibody causes a phospholipid-dependent prolongation of the clotting time but is associated with an increased risk of thrombosis and pregnancy morbidity. In this review, we will provide an overview of the different antibodies that have been associated with LA activity, their importance based on clinical studies, and address the question why this prolongation of the clotting time is associated with thrombosis rather than a bleeding tendency.