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M118, a novel low-molecular weight heparin with decreased polydispersity leads to enhanced anticoagulant activity and thrombotic occlusion in ApoE knockout mice

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Abstract

Heparin and low-molecular weight heparin (LMWH) are complex, heterogeneous polysaccharides used in the treatment of arterial and venous thrombosis. M118 is a novel LMWH with low polydispersity and pronounced anti-Xa and anti-thrombin (IIa) activity as compared to current LMWHs. To determine if M118 is effective in preventing thrombosis in the setting of a vascular plaque, apolipoprotein E knockout mice fed a high fat diet were injected with M118, enoxaparin, unfractionated heparin, or saline control and examined for arterial thrombosis using a rose bengal laser induced carotid artery injury model. M118 significantly increased the time to occlusion as compared to control and unfractionated heparin but not compared to enoxaparin although fewer M118 treated animals had any vascular occlusion present at the time of protocol completion. Platelet-neutrophil aggregates were studied by flow cytometry and were found to be decreased with M118 as compared to enoxaparin. This is the first published report examining M118, a novel LMWH designed to have low polydispersity and enhanced anticoagulant activity. In an animal model of vascular plaque, M118 is a potent inhibitor of arterial thrombosis and, despite lower in vivo anti-Xa and anti-IIa activity levels, M118 was superior to UFH in the prevention of arterial thrombosis.

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References

  1. Freedman JE (2005) Molecular regulation of platelet-dependent thrombosis. Circulation 112:2725–2734. doi:10.1161/CIRCULATIONAHA.104.494468

    Article  PubMed  Google Scholar 

  2. Bates SM, Weitz JI (2005) New anticoagulants: beyond heparin, low-molecular-weight heparin and warfarin. Br J Pharmacol 144:1017–1028. doi:10.1038/sj.bjp.0706153

    Article  CAS  PubMed  Google Scholar 

  3. Bates SM, Weitz JI (2005) Coagulation assays. Circulation 112:e53–e60. doi:10.1161/CIRCULATIONAHA.104.478222

    Article  PubMed  Google Scholar 

  4. Gross PL, Weitz JI (2008) New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol 28:380–386. doi:10.1161/ATVBAHA.108.162677

    Article  CAS  PubMed  Google Scholar 

  5. Rau JC, Beaulieu LM, Huntington JA et al (2007) Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost 5:102–115. doi:10.1111/j.1538-7836.2007.02516.x

    Article  CAS  PubMed  Google Scholar 

  6. Jin L, Abrahams JP, Skinner R et al (1997) The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci USA 94:14683–14688. doi:10.1073/pnas.94.26.14683

    Article  CAS  PubMed  Google Scholar 

  7. Shriver Z, Sundaram M, Venkataraman G et al (2000) Cleavage of the antithrombin III binding site in heparin by heparinases and its implication in the generation of low molecular weight heparin. Proc Natl Acad Sci USA 97:10365–10370. doi:10.1073/pnas.97.19.10365

    Article  CAS  PubMed  Google Scholar 

  8. Petitou M, Imberty A, Duchaussoy P et al (2001) Experimental proof for the structure of a thrombin-inhibiting heparin molecule. Chemistry (Easton) 7:858–873

    CAS  Google Scholar 

  9. Sundaram M, Qi Y, Shriver Z et al (2003) Rational design of low-molecular weight heparins with improved in vivo activity. Proc Natl Acad Sci USA 100:651–656. doi:10.1073/pnas.252643299

    Article  CAS  PubMed  Google Scholar 

  10. Naoum JJ, Woodside KJ, Zhang S et al (2005) Effects of rapamycin on the arterial inflammatory response in atherosclerotic plaques in Apo-E knockout mice. Transplant Proc 37:1880–1884. doi:10.1016/j.transproceed.2005.02.080

    Article  CAS  PubMed  Google Scholar 

  11. Naoum JJ, Zhang S, Woodside KJ et al (2004) Aortic eNOS expression and phosphorylation in Apo-E knockout mice: differing effects of rapamycin and simvastatin. Surgery 136:323–328. doi:10.1016/j.surg.2004.05.007

    Article  PubMed  Google Scholar 

  12. Wilson KM, Lynch CM, Faraci FM et al (2003) Effect of mechanical ventilation on carotid artery thrombosis induced by photochemical injury in mice. J Thromb Haemost 1:2669–2674. doi:10.1111/j.1538-7836.2003.00482.x

    Article  CAS  PubMed  Google Scholar 

  13. Vanichakarn P, Blair P, Wu C et al (2008) Neutrophil CD40 enhances platelet-mediated inflammation. Thromb Res 122:346–358. doi:10.1016/j.thromres.2007.12.019

    Article  CAS  PubMed  Google Scholar 

  14. Chakrabarti S, Varghese S, Vitseva O et al (2005) CD40 ligand influences platelet release of reactive oxygen intermediates. Arterioscler Thromb Vasc Biol 25:2428–2434. doi:10.1161/01.ATV.0000184765.59207.f3

    Article  CAS  PubMed  Google Scholar 

  15. Smyth SS, Reis ED, Vaananen H et al (2001) Variable protection of beta 3-integrin-deficient mice from thrombosis initiated by different mechanisms. Blood 98:1055–1062. doi:10.1182/blood.V98.4.1055

    Article  CAS  PubMed  Google Scholar 

  16. Severin S, Gratacap MP, Lenain N et al (2007) Deficiency of Src homology 2 domain-containing inositol 5-phosphatase 1 affects platelet responses and thrombus growth. J Clin Invest 117:944–952. doi:10.1172/JCI29967

    Article  CAS  PubMed  Google Scholar 

  17. Brey EM, Lalani Z, Johnston C et al (2003) Automated selection of DAB-labeled tissue for immunohistochemical quantification. J Histochem Cytochem 51:575–584

    CAS  PubMed  Google Scholar 

  18. Furman MI, Krueger LA, Linden MD et al (2005) GPIIb-IIIa antagonists reduce thromboinflammatory processes in patients with acute coronary syndromes undergoing percutaneous coronary intervention. J Thromb Haemost 3:312–320. doi:10.1111/j.1538-7836.2005.01124.x

    Article  CAS  PubMed  Google Scholar 

  19. Furman MI, Kereiakes DJ, Krueger LA et al (2001) Leukocyte-platelet aggregation, platelet surface P-selectin, and platelet surface glycoprotein IIIa after percutaneous coronary intervention: effects of dalteparin or unfractionated heparin in combination with abciximab. Am Heart J 142:790–798. doi:10.1067/mhj.2001.119128

    Article  CAS  PubMed  Google Scholar 

  20. Furman MI, Barnard MR, Krueger LA et al (2001) Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 38:1002–1006. doi:10.1016/S0735-1097(01)01485-1

    Article  CAS  PubMed  Google Scholar 

  21. Furman MI, Benoit SE, Barnard MR et al (1998) Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 31:352–358. doi:10.1016/S0735-1097(97)00510-X

    Article  CAS  PubMed  Google Scholar 

  22. Westrick RJ, Eitzman DT (2007) Plasminogen activator inhibitor-1 in vascular thrombosis. Curr Drug Targets 8:966–1002. doi:10.2174/138945007781662328

    Article  PubMed  Google Scholar 

  23. Bates SM, Weitz JI (2000) The mechanism of action of thrombin inhibitors. J Invasive Cardiol 12:27–32

    Google Scholar 

  24. Gallus AS (2003) Preventing venous thromboembolism in general medical inpatients and after an ischaemic stroke. Haemostasis 30:64–71. doi:10.1159/000054166

    Google Scholar 

  25. Michelson AD, Barnard MR, Krueger LA et al (2001) Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 104:1533–1537. doi:10.1161/hc3801.095588

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

These studies were partly supported by a grant from Momenta Pharmaceuticals, Cambridge, MA (JEF). Analysis of plasma samples was performed in a blinded manner by Brian Vozzella and Alison Long (anti-Xa, -IIa), at Momenta Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, 715 Albany Street, W507, Boston, MA, 02118, USA

    Subrata Chakrabarti, Lea M. Beaulieu & Jane E. Freedman

  2. Department of Surgery, Tufts Medical Center, Boston, MA, USA

    Lara A. Reyelt & Mark D. Iafrati

Authors
  1. Subrata Chakrabarti
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  2. Lea M. Beaulieu
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  3. Lara A. Reyelt
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  4. Mark D. Iafrati
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  5. Jane E. Freedman
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Correspondence to Subrata Chakrabarti.

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Chakrabarti, S., Beaulieu, L.M., Reyelt, L.A. et al. M118, a novel low-molecular weight heparin with decreased polydispersity leads to enhanced anticoagulant activity and thrombotic occlusion in ApoE knockout mice. J Thromb Thrombolysis 28, 394–400 (2009). https://doi.org/10.1007/s11239-009-0340-4

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  • DOI: https://doi.org/10.1007/s11239-009-0340-4

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