Biopolym. Cell. 2016; 32(2):98-104.
Extracellular annexins in hemostasis system
1Zhernossekov D. D., 1Roka-Moiia Y. M., 1Grinenko T. V.
  1. Palladin Institute of Biochemistry, NAS of Ukraine
    9, Leontovycha Str., Kyiv, Ukraine, 01601


Annexins are calcium-binding proteins that interact with cellular membranes due to their ability to bind phospholipids. The structural and functional peculiarities of these proteins have been described. Being cytosolic proteins, annexins also possess extracellular activities. However, there are some controversial opinions concerning the functional role of extracellular annexins in the human hemostasis system. We have made an attempt to summarize the latest data and consider some ideas of possible annexin application in medical practice.
Keywords: annexins, hemostasis, plasminogen/plasmin system


[1] Bharadwaj A, Bydoun M, Holloway R, Waisman D. Annexin A2 heterotetramer: structure and function. Int J Mol Sci. 2013;14(3):6259-305.
[2] Lizarbe MA, Barrasa JI, Olmo N, Gavilanes F, Turnay J. Annexin-phospholipid interactions. Functional implications. Int J Mol Sci. 2013;14(2):2652-83.
[3] Gerke V, Creutz CE, Moss SE. Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol. 2005;6(6):449-61.
[4] Gerke V, Moss SE. Annexins: from structure to function. Physiol Rev. 2002;82(2):331-71. R
[5] Petrishchev NN, Vasina LV, Lugovaya AV. Content of soluble markers of apoptosis and circulating V annexin-connected apoptosistic cells in the blood of patients with acute coronary syndrome. Vestnik St. Petersburg state university. 2008; Ser 2 (1): 14–23.
[6] Rescher U, Gerke V. Annexins--unique membrane binding proteins with diverse functions. J Cell Sci. 2004;117(Pt 13):2631-9.
[7] Römisch J, Schüler E, Bastian B, Bürger T, Dunkel FG, Schwinn A, Hartmann AA, Pâques EP. Annexins I to VI: quantitative determination in different human cell types and in plasma after myocardial infarction. Blood Coagul Fibrinolysis. 1992;3(1):11-7.
[8] Vergnolle N, Coméra C, Moré J, Alvinerie M, Buéno L. Expression and secretion of lipocortin 1 in gut inflammation are not regulated by pituitary-adrenal axis. Am J Physiol. 1997;273(2 Pt 2):R623-9.
[9] Perretti M, D'Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol. 2009;9(1):62-70.
[10] Revollo JR, Cidlowski JA. Mechanisms generating diversity in glucocorticoid receptor signaling. Ann N Y Acad Sci. 2009;1179:167-78.
[11] Perretti M, Chiang N, La M, Fierro IM, Marullo S, Getting SJ, Solito E, Serhan CN. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat Med. 2002;8(11):1296-302.
[12] Gavins FN, Yona S, Kamal AM, Flower RJ, Perretti M. Leukocyte antiadhesive actions of annexin 1: ALXR- and FPR-related anti-inflammatory mechanisms. Blood. 2003;101(10):4140-7.
[13] Sugimoto MA, Vago JP, Teixeira MM, Sousa LP. Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance. J Immunol Res. 2016;2016:8239258.
[14] Panaro MA, Acquafredda A, Sisto M, Lisi S, Maffione AB, Mitolo V. Biological role of the N-formyl peptide receptors. Immunopharmacol Immunotoxicol. 2006;28(1):103-27.
[15] Menell JS, Cesarman GM, Jacovina AT, McLaughlin MA, Lev EA, Hajjar KA. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999;340(13):994-1004.
[16] Kim J, Hajjar KA. Annexin II: a plasminogen-plasminogen activator co-receptor. Front Biosci. 2002;7:d341-8.
[17] Kato J, Kuwabara Y, Mitani M, Shinoda N, Sato A, Toyama T, Mitsui A, Nishiwaki T, Moriyama S, Kudo J, Fujii Y. Expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy. Int J Cancer. 2001;95(2):92-5.
[18] Lin L, Hu K. Tissue plasminogen activator and inflammation: from phenotype to signaling mechanisms. Am J Clin Exp Immunol. 2014;3(1):30-6.
[19] MacLeod TJ, Kwon M, Filipenko NR, Waisman DM. Phospholipid-associated annexin A2-S100A10 heterotetramer and its subunits: characterization of the interaction with tissue plasminogen activator, plasminogen, and plasmin. J Biol Chem. 2003;278(28):25577-84.
[20] Zhernosekov DD, Iusova EI, Grinenko TV. [Role of plasminogen/plasmin in functional activity of blood cells]. Ukr Biokhim Zh (1999). 2012;84(4):5-19.
[21] Fitzpatrick SL, Kassam G, Choi KS, Kang HM, Fogg DK, Waisman DM. Regulation of plasmin activity by annexin II tetramer. Biochemistry. 2000;39(5):1021-8.
[22] Lin L, Wu C, Hu K. Tissue plasminogen activator activates NF-κB through a pathway involving annexin A2/CD11b and integrin-linked kinase. J Am Soc Nephrol. 2012;23(8):1329-38.
[23] Tzima E, Walker JH. Platelet annexin V: the ins and outs. Platelets. 2000;11(5):245-51.
[24] Simák J, Holada K, Vostal JG. Release of annexin V-binding membrane microparticles from cultured human umbilical vein endothelial cells after treatment with camptothecin. BMC Cell Biol. 2002;3:11.
[25] Heemskerk JW, Bevers EM, Lindhout T. Platelet activation and blood coagulation. Thromb Haemost. 2002;88(2):186-93.
[26] Ueki H, Mizushina T, Laoharatchatathanin T, Terashima R, Nishimura Y, Rieanrakwong D, Yonezawa T, Kurusu S, Hasegawa Y, Brachvogel B, Pöschl E, Kawaminami M. Loss of maternal annexin A5 increases the likelihood of placental platelet thrombosis and foetal loss. Sci Rep. 2012;2:827.
[27] Bouter A, Carmeille R, Gounou C, Bouvet F, Degrelle SA, Evain-Brion D, Brisson AR. Review: Annexin-A5 and cell membrane repair. Placenta. 2015;36 Suppl 1:S43–9.
[28] Ramstrom S, O'Neill S, Dunne E, Kenny D. Annexin V binding to platelets is agonist, time and temperature dependent. Platelets. 2010;21(4):289-96.
[29] Tait JF, Gibson D. Phospholipid binding of annexin V: effects of calcium and membrane phosphatidylserine content. Arch Biochem Biophys. 1992;298(1):187-91.
[30] Sun J, Bird P, Salem HH. Interaction of annexin V and platelets: effects on platelet function and protein S binding. Thromb Res. 1993;69(3):289-96.
[31] van Heerde WL, Robert-Offerman S, Dumont E, Hofstra L, Doevendans PA, Smits JF, Daemen MJ, Reutelingsperger CP. Markers of apoptosis in cardiovascular tissues: focus on Annexin V. Cardiovasc Res. 2000;45(3):549-59.
[32] Jackson SP, Schoenwaelder SM. Procoagulant platelets: are they necrotic? Blood. 2010;116(12):2011-8.
[33] Albanyan AM, Harrison P, Murphy MF. Markers of platelet activation and apoptosis during storage of apheresis- and buffy coat-derived platelet concentrates for 7 days. Transfusion. 2009;49(1):108-17.
[34] Gyulkhandanyan AV, Mutlu A, Freedman J, Leytin V. Selective triggering of platelet apoptosis, platelet activation or both. Br J Haematol. 2013;161(2):245-54.
[35] Hiddink L, de Visser MC, van Heerde WL. Polymorphisms in the Annexin A5 gene influence circulating Annexin A5 levels in healthy controls. Thromb Res. 2012;129(6):815-7.
[36] Das R, Plow EF. Phosphatidylserine as an anchor for plasminogen and its plasminogen receptor, histone H2B, to the macrophage surface. J Thromb Haemost. 2011;9(2):339-49.
[37] Whyte CS, Swieringa F, Mastenbroek TG, Lionikiene AS, Lancé MD, van der Meijden PE, Heemskerk JW, Mutch NJ. Plasminogen associates with phosphatidyl serine-exposing platelets and contributes to thrombus lysis under flow. Blood. 2015;125(16):2568–78.
[38] Abaeva AA, Canault M, Kotova YN, Obydennyy SI, Yakimenko AO, Podoplelova NA, Kolyadko VN, Chambost H, Mazurov AV, Ataullakhanov FI, Nurden AT, Alessi MC, Panteleev MA. Procoagulant platelets form an α-granule protein-covered "cap" on their surface that promotes their attachment to aggregates. J Biol Chem. 2013;288(41):29621-32.
[39] Mitchell JL, Lionikiene AS, Fraser SR, Whyte CS, Booth NA, Mutch NJ. Functional factor XIII-A is exposed on the stimulated platelet surface. Blood. 2014;124(26):3982-90.
[40] Roka-Moiia YM, Korsa VV, Guzyk MM, Tykhomyrov AO, Zhernossekov DD. Plasminogen modulates exogenic annexin V binding to human platelets. In “Modern aspects of Biochemistry and Biotechnology” Kyiv, Sanchenko, 2016:40.
[41] Ishitsuka R, Kojima K, Utsumi H, Ogawa H, Matsumoto I. Glycosaminoglycan binding properties of annexin IV, V, and VI. J Biol Chem. 1998;273(16):9935-41.
[42] Kassam G, Manro A, Braat CE, Louie P, Fitzpatrick SL, Waisman DM. Characterization of the heparin binding properties of annexin II tetramer. J Biol Chem. 1997;272(24):15093-100.
[43] Rand ML, Wang H, Pluthero FG, Stafford AR, Ni R, Vaezzadeh N, Allison AC, Kahr WH, Weitz JI, Gross PL. Diannexin, an annexin A5 homodimer, binds phosphatidyl serine with high affinity and is a potent inhibitor of platelet-mediated events during thrombus formation. J Thromb Haemost. 2012;10(6):1109–19.
[44] Lu C, Jiang Q, Hu M, Tan C, Yu H, Hua Z. Preliminary biological evaluation of ¹⁸F-FBEM-Cys-Annexin V a novel apoptosis imaging agent. Molecules. 2015;20(3):4902-14.
[45] Montón H, Parolo C, Aranda-Ramos A, Merkoçi A, Nogués C. Annexin-V/quantum dot probes for multimodal apoptosis monitoring in living cells: improving bioanalysis using electrochemistry. Nanoscale. 2015;7(9):4097-104.
[46] Wang J, He L, Chen D, Pi Y, Zhou W, Xiong X, Ren Y, Lai Y, Hua Z. Quantitative analysis of annexin V-membrane interaction by flow cytometry. Eur Biophys J. 2015;44(5):325-36.
[47] Jakubowska A, Kiliś-Pstrusińska K. [Importance of annexin V in kidney diseases]. Postepy Hig Med Dosw (Online). 2015;69:153-7.
[48] Schurgers LJ, Burgmaier M, Ueland T, Schutters K, Aakhus S, Hofstra L, Gullestad L, Aukrust P, Hellmich M, Narula J, Reutelingsperger CP. Circulating annexin A5 predicts mortality in patients with heart failure. J Intern Med. 2016;279(1):89-97.
[49] Kennedy JR. Attenuating a sickle cell crisis with annexin V. Med Hypotheses. 2015;84(5):434-6.
[50] Peng B, Guo C, Guan H, Liu S, Sun MZ. Annexin A5 as a potential marker in tumors. Clin Chim Acta. 2014;427:42-8.
[51] Linke B, Abeler-Dörner L, Jahndel V, Kurz A, Mahr A, Pfrang S, Linke L, Krammer PH, Weyd H. The tolerogenic function of annexins on apoptotic cells is mediated by the annexin core domain. J Immunol. 2015;194(11):5233-42.
[52] Wang J, Zhang Y, Liu X, Ma J, Liu P, Hu C, Zhang G. Annexin A5 inhibits diffuse large B-cell lymphoma cell invasion and chemoresistance through phosphatidylinositol 3-kinase signaling. Oncol Rep. 2014;32(6):2557-63.