Platelets and Lipoxygenases

  • Michael HolinstatEmail author
  • Katrin Niisuke
  • Benjamin E. Tourdot
Part of the Progress in Inflammation Research book series (PIR)


Platelets are a cellular component of blood whose primary function is to maintain hemostasis in response to vessel insult. Beyond their traditional role in hemostasis, platelets are also known to regulate inflammation. These small anucleated cells express a single lipoxygenase, platelet 12(S)-LOX, which is capable of oxidizing a number of fatty acids. Depending on the fatty acid, the metabolite(s) produced by 12(S)-LOX have often been shown to impact platelet and vessel function in distinct ways and therefore are important regulators of platelet reactivity and inflammation. This chapter reviews the roles of 12(S)-LOX and its metabolites on platelet functions in thrombosis, hemostasis and inflammation.


Platelets 12-Lipoxygenase Thrombosis Hemostasis Polyunsaturated fatty acids Oxylipins 12(S)-LOX 


  1. 1.
    Semple JW, Italiano JE Jr, Freedman J (2011) Platelets and the immune continuum. Nat Rev Immunol 11(4):264–274PubMedCrossRefGoogle Scholar
  2. 2.
    Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF (2012) Platelet signaling. Handb Exp Pharmacol 210:59–85PubMedCrossRefGoogle Scholar
  3. 3.
    Morrell CN, Aggrey AA, Chapman LM, Modjeski KL (2014) Emerging roles for platelets as immune and inflammatory cells. Blood 123(18):2759–2767PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11(2):123–134PubMedCrossRefGoogle Scholar
  5. 5.
    Bambace NM, Holmes CE (2011) The platelet contribution to cancer progression. J Thromb Haemost 9(2):237–249PubMedCrossRefGoogle Scholar
  6. 6.
    Huo Y, Ley KF (2004) Role of platelets in the development of atherosclerosis. Trends Cardiovasc Med 14(1):18–22PubMedCrossRefGoogle Scholar
  7. 7.
    Lievens D, von Hundelshausen P (2011) Platelets in atherosclerosis. Thromb Haemost 106(5):827–838PubMedCrossRefGoogle Scholar
  8. 8.
    Boilard E, Nigrovic PA, Larabee K et al (2010) Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327(5965):580–583PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Michou L, Cornelis F, Baron M et al (2013) Association study of the platelet collagen receptor glycoprotein VI gene with rheumatoid arthritis. Clin Exp Rheumatol 31(5):770–772PubMedGoogle Scholar
  10. 10.
    Aslam R, Speck ER, Kim M et al (2006) Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 107(2):637–641PubMedCrossRefGoogle Scholar
  11. 11.
    Hamberg M, Samuelsson B (1974) Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci USA 71(9):3400–3404PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Nugteren DH (1975) Arachidonate lipoxygenase in blood platelets. Biochim Biophys Acta 380(2):299–307PubMedCrossRefGoogle Scholar
  13. 13.
    Burger F, Krieg P, Marks F, Furstenberger G (2000) Positional- and stereo-selectivity of fatty acid oxygenation catalysed by mouse (12S)-lipoxygenase isoenzymes. Biochem J 348(Pt 2):329–335PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Chen X, Kurre U, Jenkins N, Copeland N, Funk C (1994) cDNA cloning, expression, mutagenesis of C-terminal isoleucine, genomic structure, and chromosomal localizations of murine 12-lipoxygenases. J Biol Chem 269(19):13979–13987PubMedGoogle Scholar
  15. 15.
    Michibayashi T (2005) Platelet aggregation and vasoconstriction related to platelet cyclooxygenase and 12-lipoxygenase pathways. J Atheroscler Thromb 12(3):154–162PubMedCrossRefGoogle Scholar
  16. 16.
    Yu JY, Lee JJ, Jung JK et al (2012) Anti-platelet activity of diacetylated obovatol through regulating cyclooxygenase and lipoxygenase activities. Arch Pharm Res 35(12):2191–2198PubMedCrossRefGoogle Scholar
  17. 17.
    Baba A, Sakuma S, Okamoto H, Inoue T, Iwata H (1989) Calcium induces membrane translocation of 12-lipoxygenase in rat platelets. J Biol Chem 264(27):15790–15795PubMedGoogle Scholar
  18. 18.
    Stern N, Kisch ES, Knoll E (1996) Platelet lipoxygenase in spontaneously hypertensive rats. Hypertension 27(5):1149–1152PubMedCrossRefGoogle Scholar
  19. 19.
    Katoh A, Ikeda H, Murohara T, Haramaki N, Ito H, Imaizumi T (1998) Platelet-derived 12-hydroxyeicosatetraenoic acid plays an important role in mediating canine coronary thrombosis by regulating platelet glycoprotein IIb/IIIa activation. Circulation 98(25):2891–2898PubMedCrossRefGoogle Scholar
  20. 20.
    Ikei KN, Yeung J, Apopa PL et al (2012) Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation. J Lipid Res 53(12):2546–2559PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ivanov I, Heydeck D, Hofheinz K et al (2010) Molecular enzymology of lipoxygenases. Arch Biochem Biophys 503(2):161–174PubMedCrossRefGoogle Scholar
  22. 22.
    Sutherland M, Shankaranarayanan P, Schewe T, Nigam S (2001) Evidence for the presence of phospholipid hydroperoxide glutathione peroxidase in human platelets: implications for its involvement in the regulatory network of the 12-lipoxygenase pathway of arachidonic acid metabolism. Biochem J 353(Pt 1):91–100PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ozeki Y, Nagamura Y, Ito H et al (1999) An anti-platelet agent, OPC-29030, inhibits translocation of 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid production in human platelets. Br J Pharmacol 128(8):1699–1704PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Coffey MJ, Jarvis GE, Gibbins JM et al (2004) Platelet 12-lipoxygenase activation via glycoprotein VI: involvement of multiple signaling pathways in agonist control of H(P)ETE synthesis. Circ Res 94(12):1598–1605PubMedCrossRefGoogle Scholar
  25. 25.
    Morgan LT, Thomas CP, Kuhn H, O'Donnell VB (2010) Thrombin-activated human platelets acutely generate oxidized docosahexaenoic-acid-containing phospholipids via 12-lipoxygenase. Biochem J 431(1):141–148PubMedCrossRefGoogle Scholar
  26. 26.
    Reed K, Tucker D, Aloulou A et al (2011) Functional characterization of mutations in inherited human cPLA‚ÇÇ deficiency. Biochemistry 50(10):1731–1738PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Adler DH, Cogan JD, Phillips JA 3rd et al (2008) Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J Clin Invest 118(6):2121–2131PubMedPubMedCentralGoogle Scholar
  28. 28.
    Wong DA, Kita Y, Uozumi N, Shimizu T (2002) Discrete role for cytosolic phospholipase A(2)alpha in platelets: studies using single and double mutant mice of cytosolic and group IIA secretory phospholipase A(2). J Exp Med 196(3):349–357PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Schafer A (1982) Deficiency of platelet lipoxygenase activity in myeloproliferative disorders. N Engl J Med 306(7):381–386PubMedCrossRefGoogle Scholar
  30. 30.
    Okuma M, Kanaji K, Ushikubi F et al (1989) Reduced 12-lipoxygenase activity in platelets of patients with myeloproliferative disorders. Adv Prostaglandin Thromboxane Leukot Res 19:148–151PubMedGoogle Scholar
  31. 31.
    Matsuda S, Murakami J, Yamamoto Y et al (1993) Decreased messenger RNA of arachidonate 12-lipoxygenase in platelets of patients with myeloproliferative disorders. Biochim Biophys Acta 1180(3):243–249PubMedCrossRefGoogle Scholar
  32. 32.
    Nyby MD, Sasaki M, Ideguchi Y et al (1996) Platelet lipoxygenase inhibitors attenuate thrombin- and thromboxane mimetic-induced intracellular calcium mobilization and platelet aggregation. J Pharmacol Exp Ther 278(2):503–509PubMedGoogle Scholar
  33. 33.
    Yeung J, Apopa PL, Vesci J et al (2013) 12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity. Thromb Haemost 110(3):569–581PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Svensson Holm AC, Grenegard M, Ollinger K, Lindstrom EG (2014) Inhibition of 12-lipoxygenase reduces platelet activation and prevents their mitogenic function. Platelets 25(2):111–117PubMedCrossRefGoogle Scholar
  35. 35.
    Yeung J, Tourdot BE, Fernandez-Perez P et al (2014) Platelet 12-LOX is essential for FcgammaRIIa-mediated platelet activation. Blood 124:2271–2279PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yeung J, Holinstat M (2011) 12-lipoxygenase: a potential target for novel anti-platelet therapeutics. Cardiovasc Hematol Agents Med Chem 9(3):154–164PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kenyon V, Rai G, Jadhav A et al (2011) Discovery of potent and selective inhibitors of human platelet-type 12-lipoxygenase. J Med Chem 54(15):5485–5497PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Luci DK, Jameson JB 2nd, Yasgar A et al (2014) Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase. J Med Chem 57(2):495–506PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Johnson EN, Brass LF, Funk CD (1998) Increased platelet sensitivity to ADP in mice lacking platelet-type 12-lipoxygenase. Proc Natl Acad Sci USA 95(6):3100–3105PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Yeung J, Apopa P, Vesci J et al (2012) Protein kinase C regulation of 12-lipoxygenase-mediated human platelet activation. Mol Pharmacol 81(3):420–430PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ozeki Y, Ito H, Nagamura Y, Unemi F, Igawa T (1998) 12(S)-HETE plays a role as a mediator of expression of platelet CD62 (P-selectin). Platelets 9(5):297–302PubMedCrossRefGoogle Scholar
  42. 42.
    Holinstat M, Boutaud O, Apopa P et al (2011) Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis. Arterioscler Thromb Vasc Biol 31(2):435–442PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Burzaco J, Conde M, Parada LA, Zugaza JL, Dehaye JP, Marino A (2013) ATP antagonizes thrombin-induced signal transduction through 12(S)-HETE and cAMP. PLoS One 8(6):e67117PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Sekiya F, Takagi J, Usui T et al (1991) 12S-hydroxyeicosatetraenoic acid plays a central role in the regulation of platelet activation. Biochem Biophys Res Commun 179(1):345–351PubMedCrossRefGoogle Scholar
  45. 45.
    Calzada C, Vericel E, Lagarde M (1997) Low concentrations of lipid hydroperoxides prime human platelet aggregation specifically via cyclo-oxygenase activation. Biochem J 325(Pt 2):495–500PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Takenaga M, Hirai A, Terano T, Tamura Y, Kitagawa H, Yoshida S (1986) Comparison of the in vitro effect of eicosapentaenoic acid (EPA)-derived lipoxygenase metabolites on human platelet function with those of arachidonic acid. Thromb Res 41(3):373–384PubMedCrossRefGoogle Scholar
  47. 47.
    Aharony D, Smith JB, Silver MJ (1982) Regulation of arachidonate-induced platelet aggregation by the lipoxygenase product, 12-hydroperoxyeicosatetraenoic acid. Biochim Biophys Acta 718(2):193–200PubMedCrossRefGoogle Scholar
  48. 48.
    Sekiya F, Takagi J, Sasaki K et al (1990) Feedback regulation of platelet function by 12S-hydroxyeicosatetraenoic acid: inhibition of arachidonic acid liberation from phospholipids. Biochim Biophys Acta 1044(1):165–168PubMedCrossRefGoogle Scholar
  49. 49.
    Setty BN, Werner MH, Hannun YA, Stuart MJ (1992) 15-hydroxyeicosatetraenoic acid-mediated potentiation of thrombin-induced platelet functions occurs via enhanced production of phosphoinositide-derived second messengers—sn-1,2-diacylglycerol and inositol-1,4,5-trisphosphate. Blood 80(11):2765–2773PubMedGoogle Scholar
  50. 50.
    Chang J, Blazek E, Kreft AF, Lewis AJ (1985) Inhibition of platelet and neutrophil phospholipase A2 by hydroxyeicosatetraenoic acids (HETES). A novel pharmacological mechanism for regulating free fatty acid release. Biochem Pharmacol 34(9):1571–1575PubMedCrossRefGoogle Scholar
  51. 51.
    Fonlupt P, Croset M, Lagarde M (1991) 12-HETE inhibits the binding of PGH2/TXA2 receptor ligands in human platelets. Thromb Res 63(2):239–248PubMedCrossRefGoogle Scholar
  52. 52.
    Siegel MI, McConnell RT, Abrahams SL, Porter NA, Cuatrecasas P (1979) Regulation of arachidonate metabolism via lipoxygenase and cyclo-oxygenase by 12-HPETE, the product of human platelet lipoxygenase. Biochem Biophys Res Commun 89(4):1273–1280PubMedCrossRefGoogle Scholar
  53. 53.
    Morita I, Takahashi R, Saito Y, Murota S (1983) Stimulation of eicosapentaenoic acid metabolism in washed human platelets by 12-hydroperoxyeicosatetraenoic acid. J Biol Chem 258(17):10197–10199PubMedGoogle Scholar
  54. 54.
    Calzada C, Vericel E, Mitel B, Coulon L, Lagarde M (2001) 12(S)-hydroperoxy-eicosatetraenoic acid increases arachidonic acid availability in collagen-primed platelets. J Lipid Res 42(9):1467–1473PubMedGoogle Scholar
  55. 55.
    Guo Y, Zhang W, Giroux C et al (2011) Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid. J Biol Chem 286(39):33832–33840PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Hampson AJ, Grimaldi M (2002) 12-hydroxyeicosatetrenoate (12-HETE) attenuates AMPA receptor-mediated neurotoxicity: evidence for a G-protein-coupled HETE receptor. J Neurosci 22(1):257–264PubMedGoogle Scholar
  57. 57.
    Thomas CP, Morgan LT, Maskrey BH et al (2010) Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation. J Biol Chem 285(10):6891–6903PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Morgan A, Dioszeghy V, Maskrey B et al (2009) Phosphatidylethanolamine-esterified eicosanoids in the mouse: tissue localization and inflammation-dependent formation in Th-2 disease. J Biol Chem 284(32):21185–21191PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Faraci FM, Sobey CG, Chrissobolis S, Lund DD, Heistad DD, Weintraub NL (2001) Arachidonate dilates basilar artery by lipoxygenase-dependent mechanism and activation of K(+) channels. Am J Physiol Regul Integr Comp Physiol 281(1):R246–253PubMedGoogle Scholar
  60. 60.
    Turner SR, Tainer JA, Lynn WS (1975) Biogenesis of chemotactic molecules by the arachidonate lipoxygenase system of platelets. Nature 257(5528):680–681PubMedCrossRefGoogle Scholar
  61. 61.
    Palmer RM, Stepney RJ, Higgs GA, Eakins KE (1980) Chemokinetic activity of arachidonic and lipoxygenase products on leuocyctes of different species. Prostaglandins 20(2):411–418PubMedCrossRefGoogle Scholar
  62. 62.
    Sultana C, Shen Y, Rattan V, Kalra VK (1996) Lipoxygenase metabolites induced expression of adhesion molecules and transendothelial migration of monocyte-like HL-60 cells is linked to protein kinase C activation. J Cell Physiol 167(3):477–487PubMedCrossRefGoogle Scholar
  63. 63.
    Dobrian AD, Lieb DC, Cole BK, Taylor-Fishwick DA, Chakrabarti SK, Nadler JL (2011) Functional and pathological roles of the 12- and 15-lipoxygenases. Prog Lipid Res 50(1):115–131PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Bunce PE, High SM, Nadjafi M, Stanley K, Liles WC, Christian MD (2011) Pandemic H1N1 influenza infection and vascular thrombosis. Clin Infect Dis 52(2):e14–17PubMedCrossRefGoogle Scholar
  65. 65.
    Boilard E, Pare G, Rousseau M et al (2014) Influenza virus H1N1 activates platelets through FcgammaRIIA signaling and thrombin generation. Blood 123(18):2854–2863PubMedCrossRefGoogle Scholar
  66. 66.
    Manolakis A, Kapsoritakis AN, Potamianos SP (2007) A review of the postulated mechanisms concerning the association of Helicobacter pylori with ischemic heart disease. Helicobacter 12(4):287–297PubMedCrossRefGoogle Scholar
  67. 67.
    Corcoran PA, Atherton JC, Kerrigan SW et al (2007) The effect of different strains of Helicobacter pylori on platelet aggregation. Can J Gastroenterol 21(6):367–370PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Wassermann GE, Olivera-Severo D, Uberti AF, Carlini CR (2010) Helicobacter pylori urease activates blood platelets through a lipoxygenase-mediated pathway. J Cell Mol Med 14(7):2025–2034PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340(2):115–126PubMedCrossRefGoogle Scholar
  70. 70.
    Nakao J, Ito H, Chang WC, Koshihara Y, Murota S (1983) Aortic smooth muscle cell migration caused by platelet-derived growth factor is mediated by lipoxygenase product(s) of arachidonic acid. Biochem Biophys Res Commun 112(3):866–871PubMedCrossRefGoogle Scholar
  71. 71.
    Nakao J, Ooyama T, Ito H, Chang WC, Murota S (1982) Comparative effect of lipoxygenase products of arachidonic acid on rat aortic smooth muscle cell migration. Atherosclerosis 44(3):339–342PubMedCrossRefGoogle Scholar
  72. 72.
    Preston IR, Hill NS, Warburton RR, Fanburg BL (2006) Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 290(2):L367–374PubMedCrossRefGoogle Scholar
  73. 73.
    Nieves D, Moreno JJ (2008) Enantioselective effect of 12(S)-hydroxyeicosatetraenoic acid on 3T6 fibroblast growth through ERK 1/2 and p38 MAPK pathways and cyclin D1 activation. Biochem Pharmacol 76(5):654–661PubMedCrossRefGoogle Scholar
  74. 74.
    Walenga RW, Boone S, Stuart MJ (1987) Analysis of blood HETE levels by selected ion monitoring with ricinoleic acid as the internal standard. Prostaglandins 34(5):733–748PubMedCrossRefGoogle Scholar
  75. 75.
    Vijil C, Hermansson C, Jeppsson A, Bergstrom G, Hulten LM (2014) Arachidonate 15-lipoxygenase enzyme products increase platelet aggregation and thrombin generation. PLoS One 9(2):e88546PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Maclouf J (1993) Transcellular biosynthesis of arachidonic acid metabolites: from in vitro investigations to in vivo reality. Baillieres Clin Haematol 6(3):593–608PubMedCrossRefGoogle Scholar
  77. 77.
    Marcus AJ, Hajjar DP (1993) Vascular transcellular signaling. J Lipid Res 34(12):2017–2031PubMedGoogle Scholar
  78. 78.
    Brady HR, Papayianni A, Serhan CN (1994) Leukocyte adhesion promotes biosynthesis of lipoxygenase products by transcellular routes. Kidney Int Suppl 45:S90–97PubMedCrossRefGoogle Scholar
  79. 79.
    Lindgren JA, Edenius C (1993) Transcellular biosynthesis of leukotrienes and lipoxins via leukotriene A4 transfer. Trends Pharmacol Sci 14(10):351–354PubMedCrossRefGoogle Scholar
  80. 80.
    Fiore S, Ryeom SW, Weller PF, Serhan CN (1992) Lipoxin recognition sites. Specific binding of labeled lipoxin A4 with human neutrophils. J Biol Chem 267(23):16168–16176PubMedGoogle Scholar
  81. 81.
    Romano M, Chen XS, Takahashi Y, Yamamoto S, Funk CD, Serhan CN (1993) Lipoxin synthase activity of human platelet 12-lipoxygenase. Biochem J 296(Pt 1):127–133PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Serhan CN, Sheppard KA (1990) Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro. J Clin Invest 85(3):772–780PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Weber PC, Fischer S (1984) Arachidonic acid and eicosapentaenoic acid metabolism in platelets and vessel walls. Med Biol 62(2):129PubMedGoogle Scholar
  84. 84.
    Serhan CN, Romano M (1995) Lipoxin biosynthesis and actions: role of the human platelet LX-synthase. J Lipid Mediat Cell Signal 12(2–3):293–306PubMedCrossRefGoogle Scholar
  85. 85.
    Freire-Moar J, Alavi-Nassab A, Ng M, Mulkins M, Sigal E (1995) Cloning and characterization of a murine macrophage lipoxygenase. Biochim Biophys Acta 1254(1):112–116PubMedCrossRefGoogle Scholar
  86. 86.
    Berger M, Schwarz K, Thiele H et al (1998) Simultaneous expression of leukocyte-type 12-lipoxygenase and reticulocyte-type 15-lipoxygenase in rabbits. J Mol Biol 278(5):935–948PubMedCrossRefGoogle Scholar
  87. 87.
    Fleming J, Thiele BJ, Chester J et al (1989) The complete sequence of the rabbit erythroid cell-specific 15-lipoxygenase mRNA: comparison of the predicted amino acid sequence of the erythrocyte lipoxygenase with other lipoxygenases. Gene 79(1):181–188PubMedCrossRefGoogle Scholar
  88. 88.
    Dadaian M, Westlund P (1999) Albumin modifies the metabolism of hydroxyeicosatetraenoic acids via 12-lipoxygenase in human platelets. J Lipid Res 40(5):940–947PubMedGoogle Scholar
  89. 89.
    Westlund P, Palmblad J, Falck JR, Lumin S (1991) Synthesis, structural identification and biological activity of 11,12-dihydroxyeicosatetraenoic acids formed in human platelets. Biochim Biophys Acta 1081(3):301–307PubMedCrossRefGoogle Scholar
  90. 90.
    Maclouf J, Kindahl H, Granstrom E, Samuelsson B (1980) Interactions of prostaglandin H2 and thromboxane A2 with human serum albumin. Eur J Biochem 109(2):561–566PubMedCrossRefGoogle Scholar
  91. 91.
    Fitzpatrick FA, Morton DR, Wynalda MA (1982) Albumin stabilizes leukotriene A4. J Biol Chem 257(9):4680–4683PubMedGoogle Scholar
  92. 92.
    Flohé L (1989) Glutathione: chemical, biochemical, and medical aspects (Dolphin, David.; Avramovi, Olga.; Poulson, Rozanne.). Wiley, New YorkGoogle Scholar
  93. 93.
    Marshall PJ, Kulmacz RJ, Lands WE (1987) Constraints on prostaglandin biosynthesis in tissues. J Biol Chem 262(8):3510–3517PubMedGoogle Scholar
  94. 94.
    Ludwig P, Holzhutter HG, Colosimo A, Silvestrini MC, Schewe T, Rapoport SM (1987) A kinetic model for lipoxygenases based on experimental data with the lipoxygenase of reticulocytes. Eur J Biochem 168(2):325–337PubMedCrossRefGoogle Scholar
  95. 95.
    Hecker G, Utz J, Kupferschmidt RJ, Ullrich V (1991) Low levels of hydrogen peroxide enhance platelet aggregation by cyclooxygenase activation. Eicosanoids 4(2):107–113PubMedGoogle Scholar
  96. 96.
    Schewe T, Rapoport SM, Kuhn H (1986) Enzymology and physiology of reticulocyte lipoxygenase: comparison with other lipoxygenases. Adv Enzymol Relat Areas Mol Biol 58:191–272PubMedGoogle Scholar
  97. 97.
    Yamamoto S, Suzuki H, Ueda N (1997) Arachidonate 12-lipoxygenases. Prog Lipid Res 36(1):23–41PubMedCrossRefGoogle Scholar
  98. 98.
    Honn KV, Tang DG, Gao X et al (1994) 12-lipoxygenases and 12(S)-HETE: role in cancer metastasis. Cancer Metastasis Rev 13(3–4):365–396PubMedCrossRefGoogle Scholar
  99. 99.
    Pace-Asciak CR (1994) Hepoxilins: a review on their cellular actions. Biochim Biophys Acta 1215(1–2):1–8PubMedCrossRefGoogle Scholar
  100. 100.
    Lin Z, Laneuville O, Pace-Asciak CR (1991) Hepoxilin A3 induces heat shock protein (HSP72) expression in human neutrophils. Biochem Biophys Res Commun 179(1):52–56PubMedCrossRefGoogle Scholar
  101. 101.
    Jacquier-Sarlin MR, Fuller K, Dinh-Xuan AT, Richard MJ, Polla BS (1994) Protective effects of hsp70 in inflammation. Experientia 50(11–12):1031–1038PubMedCrossRefGoogle Scholar
  102. 102.
    Larson MK, Shearer GC, Ashmore JH et al (2011) Omega-3 fatty acids modulate collagen signaling in human platelets. Prostaglandins Leukot Essent Fatty Acids 84(3–4):93–98PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    von Schacky C, Fischer S, Weber PC (1985) Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J Clin Invest 76(4):1626–1631CrossRefGoogle Scholar
  104. 104.
    Boberg M, Vessby B, Selinus I (1986) Effects of dietary supplementation with n-6 and n-3 long-chain polyunsaturated fatty acids on serum lipoproteins and platelet function in hypertriglyceridaemic patients. Acta Med Scand 220(2):153–160PubMedCrossRefGoogle Scholar
  105. 105.
    Marra F, Riccardi D, Melani L et al (1998) Effects of supplementation with unsaturated fatty acids on plasma and membrane lipid composition and platelet function in patients with cirrhosis and defective aggregation. J Hepatol 28(4):654–661PubMedCrossRefGoogle Scholar
  106. 106.
    Dyerberg J, Bang HO (1979) Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet 2(8140):433–435PubMedCrossRefGoogle Scholar
  107. 107.
    Knauss HJ, Sheffner AL (1967) Effect of unsaturated fatty acid supplements upon mortality and clotting parameters in rats fed thrombogenic diets. J Nutr 93(3):393–400PubMedGoogle Scholar
  108. 108.
    Tamura Y, Hirai A, Terano T et al (1986) Clinical and epidemiological studies of eicosapentaenoic acid (EPA) in Japan. Prog Lipid Res 25(1–4):461–466PubMedCrossRefGoogle Scholar
  109. 109.
    Lorenz R, Spengler U, Fischer S, Duhm J, Weber PC (1983) Platelet function, thromboxane formation and blood pressure control during supplementation of the Western diet with cod liver oil. Circulation 67(3):504–511PubMedCrossRefGoogle Scholar
  110. 110.
    Siess W, Roth P, Scherer B, Kurzmann I, Bohlig B, Weber PC (1980) Platelet-membrane fatty acids, platelet aggregation, and thromboxane formation during a mackerel diet. Lancet 1(8166):441–444PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Michael Holinstat
    • 1
    Email author
  • Katrin Niisuke
    • 1
  • Benjamin E. Tourdot
    • 1
  1. 1.University of Michigan Medical SchoolAnn ArborUSA

Personalised recommendations