Thromb Haemost 2001; 85(03): 482-487
DOI: 10.1055/s-0037-1615609
Review Article
Schattauer GmbH

Novel Design of Peptides to Reverse the Anticoagulant Activities of Heparin and other Glycosaminoglycans

Barbara P. Schick
1   Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA
,
Joel F. Gradowski
1   Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA
,
James D. San Antonio
1   Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA
,
Jose Martinez
1   Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA
› Author Affiliations
Further Information

Publication History

Received 28 August 2000

Accepted after revision 13 October 2000

Publication Date:
08 December 2017 (online)

Summary

Patients undergoing anticoagulation with unfractionated heparin, low molecular weight heparin, or danaparoid may experience excess bleeding which requires reversal of the anticoagulant agent. Protamine is at present the only agent available for reversal of unfractionated heparin. Protamine is not effective in patients who have received low molecular weight heparin or danaparoid. We have developed a series of peptides based on consensus heparin binding sequences (Verrecchio et al., J Biol Chem 2000; 275: 7701-7707) that are capable of neutralizing the anti-thrombin activity of unfractionated heparin in vitro, the antifactor Xa activity of unfractionated heparin, Enoxaparin (Lovenox) and danaparoid (Orgaran) in vitro and the anti-Factor Xa activity of Enoxaparin in vivo in rats. These peptides may serve as alternatives for Protamine reversal of UFH and may be useful for neutralization of enoxaparin and danaparoid in humans.

 
  • References

  • 1 Makris M, Hough RE, Kitchen S. Poor reversal of low molecular weight heparin by protamine. Brit J, Haematology 2000; 108: 884-5.
  • 2 Gikakis N, Rao AK, Miyamoto S, Gorman JHr, Khan MM, Anderson HL, Hack CE, Sun L, Niewiarowski S, Colman RW. and others. Enoxaparin suppresses thrombin formation and activity during cardiopulmonary bypass in baboons. J Thorac Cardiovasc Surg 1998; 116: 1043-51.
  • 3 Holst J, Lindblad B, Bergqvist D, Hedner U, Nordfang O, Ostergaard P. The effect of protamine sulfate on plasma tissue factor pathway inhibitor release by intravenous and subcutaneous unfractionated and low molecular weight heparin in man. Thrombos Res 1997; 86: 343-8.
  • 4 Wolzt M, Weltermann A, Nieszpaur-Los M, Schneider B, Fassolt A, Lechner K, Eichler HG, Kyrle PA. Studies on the neutralizing effects of prota-mine on unfractionated and low molecular weight heparin (Fragmin) at the site of activation of the coagulation system in man. Thromb Haemost 1995; 73: 439-43.
  • 5 Zmuda K, Neofotistos D, Ts’ao CH. Effects of unfractionated heparin, low-molecular-weight heparin, and heparinoid on thromboelastographic assay of blood coagulation. Am J Clin Pathol 2000; 113: 725-31.
  • 6 Mochizuki T, Olson PJ, Szlam F, Ramsay JG, Levy JH. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analgesia 1998; 87: 781-5.
  • 7 Wakefield TW, Bouffard JA, Spaulding SA, Petry NA, Gross MD, Lind-blad B, Stanley JC. Sequestration of platelets in the pulmonary circulation as a consequence of protamine reversal of the anticoagulant effects of heparin. J Vasc Surg 1987; 5: 187-93.
  • 8 Monrad ES. Role of low-molecular-weight heparins in the management of patients with unstable angina pectoris and non-Q-wave acute myocardial infarction. Amer J Cardiol 2000; 85: 2C-9C.
  • 9 Dix D, Andrew M, Marzinotto V, Charpentier K, Bridge S, Monagle P, de Veber G, Leaker M, Chan AKC, Massicotte MP. The use of low molecular weight heparin in pediatric patients: A prospective cohort study. J Pediatrics 2000; 136: 439-45.
  • 10 Younis JS, Ohel G, Brenner B, Haddad S, Lanir N, Ben-Ami M. The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with Factor V Leiden mutation. Brit J, Obstetr and Gynaec 2000; 107: 415-9.
  • 11 Ginsberg JS, Genr M, Turkstra F, Buller HR, MacKinnon B, Magier D, Hirsh J. Postthrombotic syndrome after hip or knee arthroplasty – a cross-sectional study. Archives of Internal Med 2000; 160: 669-72.
  • 12 Deutsch E. The emerging role of low-molecular-weight heparin and anti-platelet therapies in the cardiac catheterization laboratory. Amer Heart J 1999; 138: S577-S85.
  • 13 Della Valle CJ, Jazrawi LM, Idjadi J, Hiebert RN, Stuchin SA, Steiger DJ, DiCesare PE. Anticoagulant treatment of thromboembolism with intravenous heparin therapy in the early postoperative period following total joint arthroplasty. J, Bone and Joint Surg-American 2000; 82A: 207-12.
  • 14 Hulin MS, Wakefield TW, Andrews PC, Wroblewski SK, Stoneham MD, Doyle AR, Zelenock GB, Jacobs LA, Shanley CJ, TenCate VM. and others. A novel protamine variant reversal of heparin anticoagulation in human blood in vitro. J Vasc Surg 1997; 26: 1043-8.
  • 15 Hulin MS, Wakefield TW, Andrews PC, Wrobleski SK, Kadell AM, Downing LJ, Stanley JC. Comparison of the hemodynamic and hematologic toxicity of a protamine variant after reversal of low-molecular-weight heparin anticoagulation in a canine model. Lab Animal Sci 1997; 47: 153-60.
  • 16 Wakefield TW, Andrews PC, Wrobleski SK, Kadell AM, Tejwani S, Hulin MS, Stanley JC. A [+18RGD]protamine variant for nontoxic and effective reversal of conventional heparin and low molecular weight heparin anticoagulation. J Surg Res 1996; 63: 280-6.
  • 17 Wakefield TW, Andrews PC, Wrobleski SK, Kadell AM, Schmidt R, Tejwani S, Stanley JC. Effective and less toxic reversal of low-molecular weight heparin anticoagulation by a designer variant of protamine. J Vasc Surgery 1995; 21: 839-49.
  • 18 Wakefield TW, Andrews PC, Wrobleski SK, Kadell AM, Fazzalari A, Nichol BJ, Vanderkooi T, Stanley JC. Reversal of low-molecular-weight heparin anticoagulation by synthetic protamine analogs. J Surg Res 1994; 56: 586-93.
  • 19 Ferran DS, Sobel M, Harris RB. Design and synthesis of a helix heparin-binding peptide. Biochemistry 1992; 31: 5010-6.
  • 20 Tyler-Cross R, Sobel M, McAdory LE, Harris RB. Structure-function relations of antithrombin III-heparin interactions as assayed by biophysical and biological assays and molecular modeling of peptide-pentasaccharide-docked complexes. Arch Bioch Biophys 1996; 334: 206-13.
  • 21 Shenoy S, Sobel M, Harris RB. Development of heparin antagonists with focused biological activity. Curr Pharm Design 1999; 5: 965-86.
  • 22 Liu S, Zhou F, Hook M, Carson DD. A heparin-binding synthetic peptide of heparin/heparan sulfate-interacting protein modulates blood coagulation activities. Proc Natl Acad Sci USA 1997; 94: 1739-44.
  • 23 Cardin AD, Weintraub HJ. Molecular modeling of protein-glycosaminoglycan interactions. Arterioscler 1989; 9: 21-32.
  • 24 Verrecchio A, Germann MW, Schick BP, Kung B, Twardowski T, San Antonio JD. Design of peptides with high affinities for heparin and endothelial cell proteoglycans. J Biol Chem 2000; 275: 7701-7.
  • 25 Meuleman DG. Orgaran (Org 10172): its pharmacologic profile in experimental models. Haemostasis 1992; 22: 58-65.
  • 26 Ofusu FA. Anticoagulant mechanisms of Orgaran (Org 10172) and its fraction with high affinity to antithrombin III. Haemostasis 1992; 22: 66-72.
  • 27 Zammit A, Dawes J. Low-affinity material does not contribute to the anti-thrombotic activity of Orgaran in human plasma. Thromb Haemost 1994; 71: 759-67.