Abstract
Anticoagulant drugs are of crucial importance for the treatment and prophylaxis of thrombotic disorders. The use of traditional anticoagulants like heparin and warfarin is majorly associated with bleeding complications. In the quest for safer anticoagulation therapy, the interest for the isolation of novel anticoagulant compounds has shifted towards natural sources. Peptides can be considered as better alternative due to their therapeutic potential in the treatment of diseases. Peptides from hematophagous (blood-feeding) and venomous organisms have been recognized as potential anticoagulant agents. Of late, peptides derived from the hydrolysis of food proteins, including edible seaweeds, milk and seed proteins, have also shown to possess promising in vitro anticoagulant activity. To overcome the problems associated with regular anticoagulants, peptides targeting vital steps in the clotting cascade have been studied. This review focuses on anticoagulant peptides with known targets, inhibiting crucial factors in the coagulation cascade such as FXa, FXIa, FXIIa and FVIIa/TF complex, as well as peptides with unknown targets.
Similar content being viewed by others
References
Ahmed I, Majeed A, Powell R (2007) Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J 83:575–582. https://doi.org/10.1136/pgmj.2007.059188
Al-horani RA, Desai UR (2016) Factor XIa inhibitors: a review of patent literature. Expert Opin Ther Pat 26:323–345. https://doi.org/10.1517/13543776.2016.1154045
Alquwaizani M, Buckley L, Adams C, Fanikos J (2013) Anticoagulants: a review of the pharmacology, dosing, and complications. Curr Emerg Hosp Med Rep 1:83–97. https://doi.org/10.1007/s40138-013-0014-6
Amorim RCDN., Rodrigues JAG, Holanda ML et al (2011) Anticoagulant properties of a crude sulfated polysaccharide from the red marine alga Halymenia floresia (Clemente) C. Agardh. Acta Sci Biol Sci 33:255–261. https://doi.org/10.4025/actascibiolsci.v33i3.6402
Bane CE Jr, Gailani D (2014) Factor XI as a target for antithrombotic therapy. Drug Discov Today 19:1454–1458. https://doi.org/10.1016/j.drudis.2014.05.018
Bergum PW, Cruikshank A, Maki SL et al (2001) Role of zymogen and activated factor X as scaffolds for the inhibition of the blood coagulation factor VIIa-tissue factor complex by recombinant nematode anticoagulant protein c2. J Biol Chem 276:10063–10071. https://doi.org/10.1074/jbc.M009116200
Binymin KA, Nasher M, Patel D (2014) Warfarin-induced deep vein thrombosis. Int Med Case Rep J 7:123–125. https://doi.org/10.2147/IMCRJ.S62100
Borensztajn K, Spek CA (2011) Blood coagulation factor Xa as an emerging drug target. Expert Opin Ther Targets 15:341–349
Buddai SK, Toulokhonova L, Bergum PW et al (2002) Nematode anticoagulant protein c2 reveals a site on factor Xa that is important for macromolecular substrate binding to human prothrombinase. J Biol Chem 277:26689–26698. https://doi.org/10.1074/jbc.M202507200
Budzynski AZ (2001) Chromogenic substrates in coagulation and fibrinolytic assays. Lab Med 32:365–368
Cao P, Xie P, Wang X et al (2017) Chemical constituents and coagulation activity of Agastache rugosa. BMC Complement Altern Med 17:93. https://doi.org/10.1186/s12906-017-1592-8
Capello M, Vlasuk GP, Bergum PW, Huang S, Hotez PJ (1995) Ancylostoma caninum anticoagulant peptide: a hookworm derived inhibitor of human coagulation factor Xa. Proc Natl Acad Sci USA 92:6152–6156
Cesarman-maus G, Hajjar KA (2005) Molecular mechanisms of fibrinolysis. Br J Hematol 129:307–321. https://doi.org/10.1111/j.1365-2141.2005.05444.x
Charles RS, Padmanabhan K, Arni RV et al (2000) Structure of tick anticoagulant peptide at 1.6 Å resolution complexed with bovine pancreatic trypsin inhibitor. Protein Sci 9:265–272
Chen M, Ye X, Ming X et al (2015) A novel direct factor Xa inhibitory peptide with anti-platelet aggregation activity from Agkistrodon acutus venom hydrolysates. Sci Rep 5:10846. https://doi.org/10.1038/srep10846
Cheung RCF, Ng TB, Wong JH (2015) Marine peptides: bioactivities and applications. Mar Drugs 13:4006–4043
Craik DJ, Fairlie DP, Liras S, Price D (2013) The future of peptide-based drugs. Chem Biol Drug Des 81:136–147. https://doi.org/10.1111/cbdd.12055
Dahlback B (2000) Blood coagulation. Lancet 355:1627–1632
Deng L, He Q, Kang T et al (2010) Biochemical and biophysical research communications identification of an anticoagulant peptide that inhibits both fXIa and fVIIa/tissue factor from the blood-feeding nematode Ancylostoma caninum. Biochem Biophys Res Commun 392:155–159. https://doi.org/10.1016/j.bbrc.2009.12.177
Emsley J, McEwan PA, Gailani D (2010) Structure and function of factor XI. Blood 115:2569–2578. https://doi.org/10.1182/blood-2009-09-199182
Franchini M, Mannucci PM (2016) Direct oral anticoagulants and venous thromboembolism. Eur Respir Rev 25:295–302. https://doi.org/10.1183/16000617.0025-2016
Gale AJ (2011) Current understanding of hemostasis. Toxicol Pathol 39:273–280. https://doi.org/10.1177/0192623310389474
Gan W, Deng L, Yang C et al (2009) An anticoagulant peptide from the human hookworm, Ancylostoma duodenale that inhibits coagulation factors Xa and XIa. FEBS Lett 583:1976–1980. https://doi.org/10.1016/j.febslet.2009.05.009
Gou M, Wang L, Liu X (2017) Anticoagulant activity of a natural protein purified from Hypomesus olidus. Nat Prod Res 31:1168–1171. https://doi.org/10.1080/14786419.2016.1222382
Graetz TJ, Tellor BR, Smith JR, Avidan MS (2011) Desirudin: a review of the pharmacology and clinical application for the prevention of deep vein thrombosis. Expert Rev Cardiovasc Ther 9:1101–1109
Greinacher A, Warkentin TE (2008) The direct thrombin inhibitor hirudin. Thromb Haemost 99:819–829. https://doi.org/10.1160/TH07-11-0693
Harrison LM, Nerlinger A, Bungiro RD et al (2002) Molecular characterization of Ancylostoma inhibitors of coagulation factor Xa. J Biol Chem 277:6223–6229. https://doi.org/10.1074/jbc.M109908200
Harter K, Levine M, Henderson SO (2015) Anticoagulation drug therapy: a review. West J Emerg Med 16:11–17. https://doi.org/10.5811/westjem.2014.12.22933
Hawkins D (2004) Limitations of traditional anticoagulants. Pharmacother 24:62–65
Hirsh J, Anand SS, Halperin JL, Fuster V (2001) Mechanism of action and pharmacology of unfractionated heparin. Asterioscler Thromb Vasc Biol 21:1094–1097
Indumathi P, Mehta A (2016) A novel anticoagulant peptide from the Nori hydrolysate. J Funct Foods 20:606–617. https://doi.org/10.1016/j.jff.2015.11.016
Jiang D, Zhan B, Mayor RS et al (2011) Molecular & biochemical parasitology Ac -AP-12, a novel factor Xa anticoagulant peptide from the esophageal glands of adult Ancylostoma caninum. Mol Biochem Parasitol 177:42–48. https://doi.org/10.1016/j.molbiopara.2011.01.008
Jo H, Jung W, Kim S (2008) Purification and characterization of a novel anticoagulant peptide from marine echiuroid worm, Urechis unicinctus. Process Biochem 43:179–184. https://doi.org/10.1016/j.procbio.2007.11.011
Jung W, Kim S (2009) Isolation and characterisation of an anticoagulant oligopeptide from blue mussel, Mytilus edulis. Food Chem 117:687–692. https://doi.org/10.1016/j.foodchem.2009.04.077
Karasudani I, Koyama T, Nakandakari S, Aniya Y (1996) Purification of anticoagulant factor from the spine venom of the crown-of-thorns starfish, Acanthaster Planci. Toxicon 34:871–879. https://doi.org/10.1016/0041-0101(96)00042-6
Katritsis DG, Gersh BJ, Camm AJ (2015) Anticoagulation in atrial fibrillation—current concepts. Arrhythm Electrophysiol Rev 4:100–107. https://doi.org/10.15420/aer.2015.04.02.100
Kenne E, Renné T (2014) Factor XII: a drug target for safe interference with thrombosis and inflammation. Drug Discov Today 19:1459–1464. https://doi.org/10.1016/j.drudis.2014.06.024
Kenne E, Nickel KF, Long AT et al (2015) Factor XII: a novel target for safe prevention of thrombosis and inflammation. J Intern Med 278:571–585. https://doi.org/10.1111/joim.12430
Koh CY, Kini RM (2008) Anticoagulants from hematophagous animals. Expert Rev Hematol 1:135–139
Kong Y, Shao Y, Chen H et al (2013a) A novel factor Xa-inhibiting peptide from centipedes venom. Int J Pept Res Ther 19:303–311. https://doi.org/10.1007/s10989-013-9353-0
Kong Y, Huang SL, Shao Y et al (2013b) Purification and characterization of a novel antithrombotic peptide from Scolopendra subspinipes Mutilans. J Ethnopharmacol 145:182–186. https://doi.org/10.1016/j.jep.2012.10.048
Kovalenko TA, Panteleev MA, Sveshnikova AN (2017) The mechanisms and kinetics of initiation of blood coagulation by the extrinsic tenase complex. Bio Phys 62:291–300. https://doi.org/10.1134/S0006350917020105
Koyama T, Noguchi K, Aniya Y, Sakanashi M (1998) Analysis for sites of anticoagulant action of plancinin, a new anticoagulant peptide isolated from the starfish Acanthaster planci, in the blood coagulation cascade. Gen Pharmacol 31:277–282
Leadley RJ Jr, Chi L, Porcari AR (2001) Non-hemostatic activity of coagulation factor Xa: potential implications for various diseases. Curr Opin Pharmacol 1:169–175
Lee AY, Agnelli G, Büller H et al (2001) Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 104:74–78. https://doi.org/10.1161/hc2601.091386
Lee S, Qian Z, Kim S (2010) A novel angiotensin I converting enzyme inhibitory peptide from tuna frame protein hydrolysate and its antihypertensive effect in spontaneously hypertensive rats. Food Chem 118:96–102. https://doi.org/10.1016/j.foodchem.2009.04.086
Li X, Chi C, Li L, Wang B (2017) Purification and identification of antioxidant peptides from protein hydrolysate of scalloped hammerhead (Sphyrna lewini) cartilage. Mar Drugs 15:61. https://doi.org/10.3390/md15030061
Lim-Wilby MSL, Hallenga K, Maeyer MD, Lasters I, Vlasuk GP, Brunck TK (1995) NMR structure determination of tick anticoagulant peptide (TAP). Protein Sci 4:178–186
Lopez-Exposito I, Minervini F, Amigo L, Recio I (2006) Identification of antibacterial peptides from bovine κ-Casein. J Food Prot 69:2992–2997
Lowenberg EC, Meijers JCM, Monia BP, Levi M (2010) Coagulation factor XI as a novel target for antithrombotic treatment. J Thromb Haemost 8:2349–2357
Mackman N (2009) The role of tissue factor and factor VIIa in hemostasis. Anesth Analg 108:1447–1452
Mackman N (2012) New insights into the mechanisms of venous thrombosis. J Clin Investig 122:2331–2336. https://doi.org/10.1172/JCI60229.paralysis
Mega JL, Simon T, Paris P, De et al (2015) Novel antithrombotic agents 1 pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet 386:281–291. https://doi.org/10.1016/S0140-6736(15)60243-4
Mieszczanek J, Harrison LM, Vlasuk GP, Cappello M (2004a) Anticoagulant peptides from Ancylostoma caninum are immunologically distinct and localize to separate structures within the adult hookworm. Mol Biochem Parasitol 133:319–323. https://doi.org/10.1016/j.molbiopara.2003.10.015
Mieszczanek J, Harrison LM, Cappello M (2004b) Ancylostoma ceylanicum anticoagulant peptide-1: role of the predicted reactive site amino acid in mediating inhibition of coagulation factors Xa and VIIa. Mol Biochem Parasitol 137:151–159. https://doi.org/10.1016/j.molbiopara.2004.05.011
Mohanty DP, Mohapatra S, Misra S, Sahu PS (2016) Milk derived bioactive peptides and their impact on human health—a review. Saudi J Biol Sci 23:577–583. https://doi.org/10.1016/j.sjbs.2015.06.005
Moons AHM, Peters RJG, Bijsterveld NR, Piek JJ, Prins MH, Vlasuk GP, Rote WE, Buller HR (2003) Recombinant nematode anticoagulant protein c2, an inhibitor of the tissue factor/factor VIIa complex, in patients undergoing elective coronary angioplasty. J Am Coll Cardiol 41:2147–2153. https://doi.org/10.1016/S0735-1097(03)00478-9
Mukherjee AK, Mackessy SP, Dutta S (2014) Characterization of a Kunitz-type protease inhibitor peptide (Rusvikunin) purified from Daboia russelii russelii venom. Int J Biol Macromol 67:154–162. https://doi.org/10.1016/j.ijbiomac.2014.02.058
Murakami MT, Weaver SE, Tulinsky A et al (2007) Intermolecular interactions and characterization of the novel factor Xa exosite involved in macromolecular recognition and inhibition: crystal structure of human Gla-domainless factor Xa complexed with the anticoagulant protein NAPc2 from the hematophagous nematode Ancylostoma caninum. J Mol Biol 366:602–610. https://doi.org/10.1016/j.jmb.2006.11.040
Nasri R, Nasri M (2013) Marine-derived bioactive peptides as new anticoagulant agents: a review. Curr Protein Pept Sci 14:199–204. https://doi.org/10.2174/13892037113149990042
Palta S, Sarao R, Palta A (2014) Overview of the coagulation system. Indian J Anaesth 58:515–523. https://doi.org/10.4103/0019-5049.144643
Patterson SL, LaMonte MP, Mikdashi JA et al (2006) Anticoagulation strategies for treatment of ischemic stroke and antiphospholipid syndrome: case report and review of the literature. Pharmacotherapy 26:1518–1525. https://doi.org/10.1592/phco.26.10.1518
Rajapakse N, Jung W, Mendis E et al (2005) A novel anticoagulant purified from fish protein hydrolysate inhibits factor XIIa and platelet aggregation. Life Sci 76:2607–2619. https://doi.org/10.1016/j.lfs.2004.12.010
Raskob GE, Angchaisuksiri P, Bianco AN, Buller H et al (2014) Thrombosis: a major contributor to the global disease burden. J Thromb Haemost 12:1580–1590. https://doi.org/10.1111/jth.12698
Rebello SAMS., Blank HS, Rote WE et al (1997) Antithrombotic efficacy of a recombinant nematode anticoagulant peptide (rNAP5) in canine models of thrombosis after single subcutaneous administration. J Pharmacol Exp Ther 283:91–99
Rebello SS, Blank HS, Lucchesi BR (2000) Antithrombotic efficacy of single subcutaneous administration of a recombinant nematode anticoagulant peptide (rNAP5) in a canine model of coronary artery. Thromb Res 98:531–540
Ren Y, Wu H, Lai F et al (2014) Isolation and identification of a novel anticoagulant peptide from enzymatic hydrolysates of scorpion (Buthus martensii Karsch) protein. Food Res Int 64:931–938. https://doi.org/10.1016/j.foodres.2014.08.031
Ren Y, Yang Y, Wu W et al (2016) Identification and characterization of novel anticoagulant peptide with thrombolytic effect and nutrient oligopeptides with high branched chain amino acid from Whitmania pigra protein. Amino Acids 48:2657–2670. https://doi.org/10.1007/s00726-016-2299-8
Renné T, Pozgajová M, Grüner S et al (2005) Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 202:271–281. https://doi.org/10.1084/jem.20050664
Rios-steiner JL, Murakami MT, Tulinsky A, Arni RK (2007) Active and exo-site inhibition of human factor Xa: structure of des-Gla factor Xa inhibited by NAP5, a potent nematode anticoagulant protein from Ancylostoma caninum. J Mol Biol 371:774–786. https://doi.org/10.1016/j.jmb.2007.05.042
Rojas-Ronquillo R, Cruz-Guerrero A, Flores-Nájera A et al (2012) Antithrombotic and angiotensin-converting enzyme inhibitory properties of peptides released from bovine casein by Lactobacillus casei Shirota. Int Dairy J 26:147–154. https://doi.org/10.1016/j.idairyj.2012.05.002
Rupprecht H, Blank R (2010) Clinical pharmacology of direct and indirect factor Xa inhibitors. Drugs 70:2153–2170
Sabbione AC, Scilingo A, Añón MC (2015) Potential antithrombotic activity detected in amaranth proteins and its hydrolysates. LWT Food Sci Technol 60:171–177. https://doi.org/10.1016/j.lwt.2014.07.015
Secemsky EA, Kirtane A, Bangalore S et al (2016) Use and effectiveness of bivalirudin versus unfractionated heparin for percutaneous coronary intervention among patients with ST-segment elevation myocardial infarction in the United States. JACC 9:2376–2386. https://doi.org/10.1016/j.jcin.2016.09.020
Shin SC, Ahn IH, Ahn DH et al (2017) Characterization of two antimicrobial peptides from antarctic fishes (Notothenia coriiceps and Parachaenichthys charcoti). PLoS ONE 1–12. https://doi.org/10.1371/journal.pone.0170821
Snipelisky D, Kusumoto F (2013) Current strategies to minimize the bleeding risk of warfarin. J Blood Med 4:89–99
Stanssens P, Bergumt PW, Gansemanst Y et al (1996) Anticoagulant repertoire of the hookworm Ancylostoma caninum. Proc Natl Acad Sci 93:2149–2154
Thakur R, Kumar A, Bose B et al (2014) A new peptide (Ruviprase) purified from the venom of Daboia russelii russelii shows potent anticoagulant activity via non-enzymatic inhibition of thrombin and factor Xa. Biochimie 105:149–158. https://doi.org/10.1016/j.biochi.2014.07.006
Umayaparvathi S, Meenakshi S, Vimalraj V et al (2014) Antioxidant activity and anticancer effect of bioactive peptide from enzymatic hydrolysate of oyster (Saccostrea cucullata). Biomed Prev Nutr 4:343–353. https://doi.org/10.1016/j.bionut.2014.04.006
Vlasuk GP, Rote WE (2002) Inhibition of factor VIIa/tissue factor with nematode anticoagulant protein C2. Trends Cardiovasc Med 12:325–331
Waxman L, Smith DE, Arcuri KE, Vlasuk GP (1990) Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa. Science 248:593–596. https://doi.org/10.1126/science.2333510
Yang WG, Wang Z, Xu SY (2007) A new method for determination of antithrombotic activity of egg white protein hydrolysate by microplate reader. Chin Chem Lett 18:449–451. https://doi.org/10.1016/j.cclet.2007.02.014
Young G (2015) Anticoagulants in children and adolescents. Hematol Am Soc Hematol Educ Progr 1:111–116. https://doi.org/10.1182/asheducation-2015.1.111
Yu L, Yang L, An W, Su X (2014) Anticancer bioactive peptide-3 inhibits human gastric cancer growth by suppressing gastric cancer stem cells. J Cell Biochem 711:697–711. https://doi.org/10.1002/jcb.24711
Zhang SB (2016) In vitro antithrombotic activities of peanut protein hydrolysates. Food Chem 202:1–8. https://doi.org/10.1016/j.foodchem.2016.01.108
Zhang Z, Zhang Q, Wang J et al (2010) Regioselective syntheses of sulfated porphyrans from Porphyra haitanensis and their antioxidant and anticoagulant activities in vitro. Carbohydr Polym 79:1124–1129. https://doi.org/10.1016/j.carbpol.2009.10.055
Acknowledgements
The authors are grateful to the management of Vellore Institute of Technology for their encouragement and providing financial support to write this review article.
Funding
The author Azeemullah A. Syed gratefully acknowledges the financial support provided by the management of VIT.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Azeemullah A. Syed and Alka Mehta declare that they have no conflict of interest.
Ethical Approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Syed, A.A., Mehta, A. Target Specific Anticoagulant Peptides: A Review. Int J Pept Res Ther 24, 1–12 (2018). https://doi.org/10.1007/s10989-018-9682-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10989-018-9682-0