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.

Background and Purpose-The burden of stroke is high in sub-Saharan Africa, and improved knowledge of risk factors is needed. Antiphospholipid antibodies are a common acquired stroke risk factor in young individuals. Antiphospholipid antibodies may be induced by infectious diseases. Sub-Saharan Africa has a high infectious burden, and we analyzed the contribution of antiphospholipid antibodies to the risk of stroke in an incident population from rural and urban Tanzania. Methods-Stroke cases and age-and sex-matched community-acquired controls from the rural Hai district and urban Dares-Salaam areas of Tanzania were recruited in a wider study of stroke incidence between June 2003 and June 2006. Lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I, and antiphosphatidylserine/prothrombin antibodies were determined in stored plasma, as well as IgG antibodies against Treponema pallidum. Results-Data from 158 stroke cases and 369 controls were analyzed. Thirty cases (19%) and 4 controls (1%) had a lupus anticoagulant (odds ratio, 20.8; 95% confidence interval, 7.2-60.5). Anticardiolipin IgG was the only other antiphospholipid antibody subtype associated with increased stroke risk (odds ratio, 2.1; 95% confidence interval, 1.0-4.3), but this association disappeared when corrected for IgG antibodies against Treponema pallidum results. The prevalence of anti-β2-glycoprotein I IgG antibodies in the Tanzanian healthy population was high when Dutch cutoff values were applied (67%), whereas presence of anti-β2-glycoprotein I IgM was associated with a reduced stroke risk (odds ratio 0.3; 95% confidence interval, 0.1-1.1). Conclusions-The presence of lupus anticoagulant is a strong, and to date unrecognized, risk factor for stroke in Tanzania, especially in young and middle-aged individuals.