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2012 | 59 | 2 | 185-194
Article title

The disturbance of hemostasis induced by hyperhomocysteinemia; the role of antioxidants

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Elevated concentration of homocysteine (Hcy) in human tissues, definied as hyperhomocysteinemia has been correlated with some diseases, such as cardiovascular, neurodegenerative, and kidney disorders. Homocysteine occurs in human blood plasma in several forms, including the most reactive one, the homocysteine thiolactone (HTL) - a cyclic thioester, which represents up to 0.29% of total plasma Hcy. In the article, the effects of hyperhomocysteinemia on the complex process of hemostasis, which regulates the flowing properties of blood, are described. Possible interactions of homocysteine and its different derivatives, including homocysteine thiolactone, with the major components of hemostasis such as endothelial cells, blood platelets, plasmatic fibrinogen and plasminogen, are also discussed. Modifications of hemostatic proteins (N-homocysteinylation or S-homocysteinylation) induced by Hcy or its thiolactone seem to be the main cause of homocysteine biotoxicity in hemostatic abnormalities. It is suggested that Hcy and HTL may also act as oxidants, but various polyphenolic antioxidants are able to inhibit the oxidative damage induced by Hcy or HTL. We also discuss the role of phenolic antioxidants in hyperhomocysteinemia -induced changes in hemostasis.

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  • Department of General Biochemistry, University of Łódź, Łódź, Poland
  • Department of General Biochemistry, University of Łódź, Łódź, Poland
  • Department of General Biochemistry, University of Łódź, Łódź, Poland
  • Acevedo M, Pearce GL, Kottke-Marchant K, Sprecher DL (2002) Elevated fibrinogen and homocysteine levels enhance the risk of mortality in patients from a high-risk preventive cardiology clinic. Arterioscler Thromb Vasc Biol 22: 1042-1045.
  • Alexandru N, Jardin I, Popov D, Simionescu M, Garcia-Estan J, Salido GM, Rosado JA (2007) Effect of homocysteine on calcium mobilization and platelet function in type 2 diabetes mellitus. J Cell Mol Med 14: 111-117.
  • Bednarek-Tupikowska G, Tupikowski K (2004) Homocysteine- an underestimated atheromatosis risk factor. Do sex hormones influence homocysteine concentrations. Postepy Hig Med Dosw 58: 381-389.
  • Bełtowski J (2005) Protein homocysteinylation: a new mechanism of atherogenesis? Postepy Hig Med Dosw 59: 392-404 (in Polish).
  • Blom HJ, Smulders Y (2011) Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 34: 75-81.
  • Bogers RP, Dagnelie PC, Bast A, van Leeuwen M, van Klaveren JD, van den Brandt PA (2007) Effect of increased vegetable and fruit consumption on plasma folate and homocysteine concentrations. Nutrition 23: 97-102.
  • Booth NA (2000) Regulation of fibrinolytic activity by localization of inhibitors to fibrin(ogen). Fibrinolysis & Proteolysis 14: 206-213.
  • Boysen G, Brander T, Christensen H, Gideon R, Truelsen T (2003) Homocysteine and risk of recurrent stroke. Stroke 34: 1258-1261.
  • Brattstörm L, Wilcken DE, Ohrvik J, Brudin L (1998) Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a metaanalysis. Circulation 98: 2520-2526.
  • Cacciapuoti F (2011) Hyper-homocysteinemia: a novel risk factor or a powerful marker for cardiovascular diseases? Pathogenetic and therapeutical uncertainties. J Thromb Thrombolysis 32: 82-88.
  • Carluccio MA, Ancora MA, Massaro M, Carluccio M, Scoditti E, Distante A, Storelli C, De Caterina R (2007) Homocysteine induces VCAM-1 gene expression through NF-kappaB and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants. Am J Physiol Heart Circ Physiol 293: H2344-H2354.
  • Chango A, Boisson F, Barbe F, Quilliot D, Droesch S, Pfister M, Fillon-Emery N, Lambert D, Frémont S, Rosenblatt DS, Nicolas JP (2000) The effect of 677 C→T and 1298 A→C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr 83: 593-596.
  • Chwatko G, Jakubowski H (2005a) The determination of homocysteine-thiolactone in human plasma. Anal Biochem 337: 271-277.
  • Chwatko G, Jakubowski H (2005b) Urinary excretion of homocysteine thiolactone in humans. Clin Chem 51: 408-415.
  • Colucci M, Cattaneo M, Martinelli I, Semeraro F, Binetti BM, Semeraro N (2008) Mild hyperhomocysteinemia is associated with increased TAFI levels and reduced plasma fibrinolytic potential. Journal of Thrombosis and Haemostasis 6: 1571-1577.
  • D'Angelo A, Selhub J (1997) Homocysteine and thrombotic disease. Blood 90: 1-11.
  • Dassah M, Deora AB, He K, Hajjar KA (2009) The endothelial cell annexin A2 system and vascular fibrinolysis. Gen Physiol Biophys 28: F20-F28.
  • Di Minno MND, Tremoli E, Coppola, Lupoli R, Di Minno G (2010) Homocysteine and arterial thrombosis: Challenge and opportunity. Thromb Haemost 103: 942-961.
  • Durand P, Prost M, Blache D (1996) Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis 121: 231-243.
  • Essex DW, Li M, Feinman RD, Miller A (2004) Platelet surface glutathione reductase-like activity. Blood 104: 1383-1385.
  • Essex DW, Li M (2003) Redox control of platelet aggregation. Biochemistry 42: 129-136.
  • Franconi F, Miceli M, Alberti L, Seghieri G, De Montis MG, Tagliamonte A (1998) Further insights into the anti-aggregating activity of NMDA in human platelets. Br J Pharmacol 124: 35-40.
  • Franken DG, Boers GHJ, Blom HJ, and Trijbels JMF (1994) Effect of various regimens of vitamin B6 and folic acid on mild hyperhomocysteinaemia in vascular patients. J Inherited Metab Dis 17: 159-162.
  • Freyburger G, Labrouche S, Sassoust G, Rouanet K, Javorschi S, Parrot F (1997) Mild hyperhomocysteinemia and hemostatic factors in patients with arterial vascular diseases. Thromb Haemost 77: 466-471.
  • Fu W, Conklin BS, Lin PH, Lumsden AB, Yao Q, Chen C (2003) Red wine prevents homocysteine-induced endothelial dysfunction in porcine coronary arteries. J Surg Res 115: 82-91.
  • Glowacki R, Jakubowski H (2004) Cross-talk between Cys34 and lysine residues in human serum albumin revealed by N-homocysteinylation. J Biol Chem 279: 10864-10871.
  • Hajjar KA, Mauri L, Jacovina AT, Zhong F, Mirzai UA, Padovani JC, Chait BT (1998) Tissue plasminogen activator binding to the annexin II tail domain. J Biol Chem 273: 9987-9993.
  • Harpel PC, Chang VT, Borth W (1992) Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 89: 10193-10197.
  • Harpel PC, Zhang X, Borth W (1996) Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr 126: 1285S-1289S.
  • Hop CE, Bakhtiar R (2002) Homocysteine thiolactone and protein homocysteinylation: mechanistic studies with model peptides and proteins. Rapid Commun Mass Spectrom 16: 1049-1053.
  • Inayama T, Oka J, Kashiba M, Saito M, Higuchi M, Umegaki K, Yamamoto Y, Matsuda M (2002) Moderate physical exercise induces the oxidation of human blood protein thiols. Life Sci 70: 2039-2046.
  • Jacobsen DW (1998) Homocysteine and vitamins in cardiovascular disease. Clin Chem 44: 1833-1843.
  • Jakubowski H (1990) Proofreading in vivo: editing of homocysteine by methionyl-tRNA synthetase in Escherichia coli. Proc Natl Acad Sci USA 87: 4504-4508.
  • Jakubowski H (1999) Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels. Faseb J 13: 2277-2283.
  • Jakubowski H (2000) Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J Biol Chem 275: 3957-3362.
  • Jakubowski H (2002) Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease. J Biol Chem 277: 30425-30428.
  • Jakubowski H (2003) Homocysteine-thiolactone and S-nitroso-homocysteine mediate incorporation of homocysteine into protein in humans. Clin Chem Lab Med 41: 1462-1466.
  • Jakubowski H (2004) Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci 61: 470-487.
  • Jakubowski H (2005) Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease. Clin Chem Lab Med 43: 1011-1014.
  • Jakubowski H (2006) Pathophysiological consequences of homocysteine excess. J Nutr 136: 1741S-1749S.
  • Jakubowski H (2010) The role of paraoxonase 1 in the detoxification of homocysteine thiolactone. Adv Exp Med Biol 660: 113-127.
  • Jakubowski H, Głowacki R (2011) Chemical biology of homocysteine thiolactone and related metabolites. Adv Clin Chem 55: 81-103.
  • Jakubowski H, Zhang L, Bardeguez A, Aviv A (2000) Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res 87: 45-51.
  • Kamat GV, Metgud SC, Pattanshetti VM, Godhi AS (2010) A cross-sectional study to detect the prevalence of hyperhomocysteinemia in cases of deep vein thrombosis. Indian J Surg 72(4): 323-326.
  • Kang SS, Wong PW, Malinow MR (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12: 279-289.
  • Karolczak K, Olas B (2009) Mechanism of action of homocysteine and its thiolactone in haemostasis system. Physiol Res 58: 623-633.
  • Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, MTHFR Studies Collaboration Group (2002) MTHFR 677C→T polymorphism and risk of coronary heart disease: meta-analysis. JAMA 288: 2023-2031.
  • Kolling J, Scherer EB, da Cunha AA, da Cunha MJ, Wyse AT (2011) Homocysteine induces oxidative-nitrative stress in heart of rats: prevention by folic acid. Cardiovasc Toxicol 11: 67-73.
  • Kolodziejczyk J, Malinowska J, Nowak P, Olas B (2010) Comparison of the effect of homocysteine and its thiolactone on the fibrinolytic system using human plasma and purified plasminogen. Mol Cell Biochem 344: 217-220.
  • Kolodziejczyk J, Malinowska J, Olas B, Stochmal A, Oleszek W, Erler J (2011) The polyphenol-rich extract from grape seeds suppresses toxicity of homocysteine and its thiolactone on the fibrinolytic system. Thromb Res 127: 489-491.
  • Lee J, Ku Y, Rhyu I, Chung Ch, Park Y (2010) Effects of fibrin-binding oligopeptide on osteopromotion in rabbit calvarial defects. J Periodontal Implant Sci 40: 211-219.
  • Lentz SR, Erger RA, Dayal S, Maeda N, Malinow MR, Heistad DD, Faraci FM (2000) Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta-synthase-deficient mice. Am J Physiol 279: H970-H975.
  • Lentz SR, Haynes WG (2004) Homocysteine: is it a clinically important cardiovascular risk factor? Cleve Clin J Med 71: 729-734.
  • Leoncini G, Bruzzese D, Signorello MG (2006) Activation of p38 MAPKinase/cPLA2 pathway in homocysteine treated platelets. J Thromb Haemost 4: 209-216.
  • Leoncini G, Bruzzese D, Signorello MG (2007) A role for PLCgamma2 in platelet activation by homocysteine. J Cell Biochem 100: 1255-1265.
  • Levy-Toledano S (1999) Platelet signal transduction pathways: Could we organize them into a 'hierarchy'? Haemostasis 29: 4-15.
  • Li Z, Sun L, Zhang H, Liao Y, Wang D, Zhao B, Zhu Z, Zhao J, Ma A, Han Y (2003) Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: a Multicenter Case-Control Study in China. Stroke 34: 2085-2090.
  • Lijnen HR (2002) Non-haemostatic role of blood coagulation proteases and their receptors. Biochemical Society Transactions 30: 163-167.
  • Lippi G, Franchini M, Favaloro EJ, Targher G (2010) Moderate red wine consumption and cardiovascular disease risk: beyond the 'French paradox'. Semin Thromb Hemost 36: 59-70.
  • Machado FR, Ferreira AG, da Cuncha AA, Tagliari B, Mussulini BH, Wofchuk S, Wyse AT (2011) Homocysteine alters glutamate uptake and Na+,K+-ATPase activity and oxidative status in rats hippocampus: protection by vitamin C. Metab Brain Dis 26: 61-67.
  • Majors AK, Sengupta S, Willard B, Kinter MT, Pyeritz RD, Jacobsen DW (2002) Homocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin. Arterioscler Thromb Vasc Biol 22: 1354-1359.
  • Malinowska J, Babicz K, Olas B, Stochmal A, Oleszek W (2011) Aronia melanocarpa extract suppresses biotoxicity of homocysteine and its metabolite on hemostatic activity of fibrinogen and plasma. Nutrition 28 793-798.
  • Malinowska J, Kolodziejczyk J, Olas B (2010) Prophylaxis and treatment of hyperhomocysteinemia. Progress in Medicine 23: 571-576.
  • Malinowska J, Nowak P, Olas B (2011) Comparison of the effect of homocysteine in the reduced form, its thiolactone and protein homocysteinylation on hemostatic properties of plasma. Thromb Res 127: 214-219.
  • Malinowska J, Olas B (2010) Effect of resveratrol on hemostatic properties of human fibrinogen and plasma during model of hyperhomocysteinemia. Thromb Res 126: e379-e382.
  • Malinowska J, Olas B (2011) Response of blood platelets to resveratrol during model of hyperhomocysteinemia. Platelets 22: 277-283.
  • Manolescu BN, Oprea E, Farcasanu IC, Berteanu M, Cercasov C (2010) Homocysteine and vitamin therapy in stroke prevention and treatment: a review. Acta Biochim Pol 57: 467-477.???? 4
  • Mansoor MA, Svardal AM, Ueland PM (1992) Determination of the in vivo redox status of cysteine, cysteinylglycine, homocysteine, and glutathione in human plasma. Anal Biochem 200: 218-229.
  • Marczak L, Sikora M, Stobiecki M, Jakubowski H (2011) Analysis of site-specific N-homocysteinylation of human serum albumin in vitro and in vivo using MALDI-ToF and LC-MS/MS mass spectrometry. J Proteomics 74: 967-974.
  • Martin C, Martinez R, Navarro R, Ruiz-Sanz JI, Lacort M, Ruiz-Larrea MB (2001) tert-Butyl hydroperoxide-induced lipid signalling in hepatocytes: involvement of glutathione and free radicals. Biochem Pharmacol 62: 705-712.
  • Mc Donald L, Bray C, Field C, Love F, Davies B (1964) Homocystinuria, thrombosis and the blood platelets. Lancet 1: 745-746.
  • Morrell CN, Sun H, Ikeda M, Beique JC, Swaim AM, Mason E, Martin TV, Thompson LE, Gozen O, Ampagoomian D, Sprengel R, Rothstein J, Faraday N, Huganir R, Lowenstein CJ (2008) Glutamate mediates platelet activation through the AMPA receptor. J Exp Med 205: 575-584.
  • Mutus B, Rabini RA, Staffolani R, Ricciotti R, Fumelli P, Moretti N, Martarelli D, Mazzanti L (2001) Homocysteine-induced inhibition of nitric oxide production in platelets: A study on healthy and diabetic subjects. Diabetologia 44: 979-982.
  • Nardulli M, Durlach V, Pepe G, Anglés-Cano E (2005) Mechanism for the homocysteine-enhanced antifibrinolytic potential of lipoprotein(a) in human plasma. Thromb Haemost 94: 75-81.
  • Noll C, Hamelet J, Ducros V, Belin N, Paul JL, Delabar JM, Janel N (2009) Resveratrol supplementation worsen the dysregulation of genes involved in hepatic lipid homeostasis observed in hyperhomocysteinemic mice. Food Chem Toxicol 47: 230-236.
  • Noll C, Hamelet J, Matulewicz E, Paul JL, Delabar JM, Janel N (2009) Effects of red wine polyphenolic compounds on paraoxonase-1 and lectin-like oxidized low-density lipoprotein receptor-1 in hyperhomocysteinemic mice. J Nutr Biochem 20: 586-596.
  • Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE (1997) Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337: 230-236.
  • Olas B, Kedzierska M, Wachowicz B (2008) Comparative studies on homocysteine and its metabolite - homocysteine thiolactone action in blood platelets in vitro. Platelets 19: 520-527.
  • Olas B, Kolodziejczyk J, Kedzierska M, Rywaniak J, Wachowicz B (2009) Modification of human blood platelet induced by homocysteine and its thiolactone in vitro. Thromb Res 124: 689-94.
  • Olas B, Kolodziejczyk J, Malinowska J (2010) May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of haemostatic function of plasma in vitro? Gen Physiol Biophys 29: 186-193.
  • Olas B, Malinowska J, Rywaniak J (2010) Homocysteine and its thiolactone may promote apoptotic events in blood platelets in vitro. Platelets 21: 533-540.
  • Olas B, Wachowicz B (2005) Resveratrol, a phenolic antioxidant with effects on blood platelet functions. Platelets 16: 251-260.
  • Olas B, Wachowicz B (2007) Role of reactive nitrogen species in blood platelet functions. Platelets 18: 555-565.
  • Perla-Kaján J, Jakubowski H (2010) Paraoxonase 1 protects against protein N-homocysteinylation in humans. FASEB J 24: 931-936.
  • Perła-Kajan J, Twardowski T, Jakubowski H (2007) Mechanisms of homocysteine toxicity in humans. Amino Acids 32: 561-572.
  • Pietrzik K, Bronstrup A (1998) Vitamins B12, B6 and folate as determinants of homocysteine concentration in the healthy population. Eur J Pediatr 157: S135-S138.
  • Rajkumar V, Ragatzki P, Sima A, Levy J (1999) Enhanced platelet aggregation, high homocysteine level, and microvascular disease in diabetic muscle infarctions: Implications for therapy. Endocrine 11: 57-60.
  • Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R, Angayarkanni K (2006) Biochemistry of homocysteine in health and diseases. Indian J Biochem Biophys 43: 275-283.
  • Raposo B, Rodriguez C, Martinez-Gonzales J, Badimon L (2004) High levels of homocysteine inhibit lysyl oxidase (LOX) and downregulate LOX expression in vascular endothelial cells. Atherosclerosis 177: 1-8.
  • Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F (2005) Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 82: 636-664.
  • Riba R, Nicolaou A, Troxler M, Homer-Vaniasinkam S, Naseem KM (2004) Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels. Atherosclerosis 175: 69-75.
  • Rodgers GM, Kane WH (1986) Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77: 1909-1916.
  • Romberger DJ (1997) Fibronectin. Int J Biochem Cell Biol 29: 939-943.
  • Ryningen A, Holmsen H (1999) In Platelet Physiology and Pharmacology. Gundu H, Rao R, red, pp 1-22. Kluwer Academic Publishers Norwell.
  • Sauls DL, Arnold EK, Bell CW, Allen JC, Hoffman M (2007) Pro-thrombotic and pro-oxidant effects of diet-induced hyperhomocysteinemia. Thromb Res 120: 117-126.
  • Sauls DL, Lockhart E, Warren ME, Lenkowski A, Wilhelm S, Hoffman M (2006) Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry 45: 2480-2487.
  • Sauls DL, Wolberg AS, Hoffman M (2003) Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: Implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost 1: 300-306.
  • Sawula W, Banecka-Majkutewicz Z, Kadziński L, Jakobkiewicz-Banecka J, Wegrzyn G, Nyka W, Banecki B (2009) Homocysteine level and metabolism in ischemic stroke in the population of Northern Poland. Clinical Biochemistry 42: 442-447.
  • Schoecksnadel K, Winkler C, Wirleitner B, Schennach H, Weiss G, Fuchs D (2005) Anti-inflammatory compound resveratrol suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells in vitro. Clin Chem Lab Med 43: 1084-1088.
  • Sengupta S, Chen H, Togawa T, Dibello PM, Majors K, Budy B, Ketterer ME, Jacobsen DW (2001) Albumin thiolate anion is an intermediate in the formation of albumin-S-S-homocysteine. J Biol Chem 276: 30111-30117.
  • Seo H, Oh H, Park H, Jang Y, Lee M (2010) Contribution of dietary intakes of antioxidants to homocysteine-induced low density lipoprotein (LDL) oxidation in atherosclerotic patients. Yonsei Med J 51: 526-533.
  • Sibrian-Vazquez M, Escobedo JO, Lim S, Samoei GK, Strongin RM (2010) Homocystamides promote free-radical and oxidative damage to proteins. Proc Natl Acad Sci USA 107: 551-554.
  • Signorello MG, Pascale R, Leoncini G (2002) Effect of homocysteine on arachidonic acid release in human platelets. Eur J Clin Invest 32: 279-284.
  • Signorello MG, Viviani GL, Armani U, Cerone R, Minniti G, Piana A, Leoncini G (2007) Homocysteine, reactive oxygen species and nitric oxide in type 2 diabetes mellitus. Thromb Res 120: 607-613.
  • Sikora M, Marczak L, Twardowski T, Stobiecki M, Jakubowski H (2010) Direct monitoring of albumin lysine-525 N-homocysteinylation in human serum by liquid chromatography/mass spectrometry. Anal Biochem 405: 132-134.
  • Speidl WS, Nikfardjam M, Niessner A, Zeiner A, Jordanova N, Zorn G, Maurer G, Schreiber W, Wojta J, Huber K (2007) Mild hyperhomocysteinemia is associated with a decreased fibrinolytic activity in patients after ST-elevation myocardial infarction. Thromb Res 119: 331-336.
  • Suwala W, Banecka-Majkutewicz Z, Kadziński L, Jakóbkiewicz-Banecka J, Wegrzyn G, Nyka W, Banecki B (2008) Improved HPLC method for total plasma homocysteine detection and quantification. Acta Biochim Pol 55: 119-125.
  • Undas A, Brozek J, Jankowski M, Siudak Z, Szczeklik A, Jakubowski H (2006) Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol 26: 1397-1404.
  • Undas A, Stepien E, Plicner D, Zielinski L, Tracz W (2007) Elevated total homocysteine is associated with increased platelet activation at the site of microvascular injury. Effects of folic acid administration. J Thromb Haemost 5: 1070-1072.
  • Undas A, Williams EB, Butenas S, Orfeo T, Mann KG (2001) Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem 276: 4389-4397.
  • Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JFJ, Loscalzo J (1997) Homocyst(e)ine decreases biovailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 272: 17012-17017.
  • Wu K (1996) Platelet activation mechanisms and marker in arterial thrombosis. J Intern Med 239: 17-34.
  • Xue S, Green MA, LoGrasso PV, Boettcher BR, Madison EL, Curtiss LK, Miles LA (1999) Comparison of the effects of Apo(a) kringle IV-10 and plasminogen kringles on the interactions of lipoprotein(a) with regulatory molecules. Thromb Haemost 81: 428-435.
  • Zimny J (2008) Mechanisms that protect against homocysteine toxicity. Postepy Biochem 54: 91-96.
  • Zou CG, Banerjee R (2005) Homocysteine and redox signaling. Antioxid Redox Signal 7: 547-559.
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