Research ArticleBiochemistry

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

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Science Signaling  28 Nov 2017:
Vol. 10, Issue 507, eaan2787
DOI: 10.1126/scisignal.aan2787

Lipid networks and blood clotting

Blood coagulation is important for preventing blood loss (hemostasis) and bacterial invasion. Coagulation depends on factors presented on the plasma membranes of activated platelets and leukocytes. Through biochemical and lipidomic analyses, Lauder et al. showed that the exposure of enzymatically oxidized phospholipids (eoxPLs) derived from lipoxygenases in platelets and leukocytes was required for hemostasis. Compared to platelet eoxPLs from healthy controls, eoxPLs were increased in abundance in platelets from patients with the thrombotic disorder antiphospholipid syndrome (APS). The addition of hydroxyeicosatetraenoic acid–phospholipids (HETE-PLs) to mice deficient in lipoxygenases promoted blood coagulation and restored hemostasis. Together, these data suggest that platelets and leukocytes generate networks of eoxPL molecules, which enhance blood coagulation and contribute to the excessive clotting observed in patients with APS.


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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