Surgery Today

, Volume 37, Issue 5, pp 406–411 | Cite as

Effect of a Low Molecular Weight Heparin Molecule, Dalteparin, on Cellular Apoptosis and Inflammatory Process in an Incisional Wound-Healing Model

  • Ali Civelek
  • Koray Ak
  • Ozlem Kurtkaya
  • Atike Tekeli
  • Selim Isbir
  • Erol Nargileci
  • Sinan Arsan
  • Aydin Sav
Original Articles



In this study we aimed to test the effect of a low molecular weight heparin molecule, namely dalteparin, on the inflammation and cellular apoptosis in an incisional wound-healing model in rats.


Eighteen male Sprague–Dawley rats were randomly assigned to three groups (n = 6 for each group). Two full-thickness skin incisions were made over cervical and lumbar regions of all rats. Group 1 (sham group) received no treatment, group 2 (control group) received 0.01 ml/g saline subcutaneously 12 h two times daily from 0 to 10th postoperative day, and group 3 (dalteparin group): received 1 IU/g dalteparin subcutaneously two times daily from 0 to 10th postoperative day. A histological evaluation was done by light microscopy. Apoptosis was detected immunohistochemically by anti-poly (ADP-ribose) polymerase p85 fragment pAb.


The early inflammatory response and related tissue edema were depressed on day 3 in the dalteparin group when compared with those in the other groups (P < 0.05). Fibroblast proliferation was also depressed on day 10 in the dalteparin group compared to the others (P < 0.05). Furthermore, increased apoptosis was detected in the dalteparin group both on day 3 and day 10.


Our results showed that dalteparin may adversely affect the incisional wound healing by suppressing the early inflammatory process and increasing cellular apoptosis; however, further studies are warranted to confirm the results.

Key words

Low molecular weight heparin Wound healing Inflammatory process Apoptosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Boneu, B 2000Low molecular weight heparins: are they superior to unfractionated heparins to prevent and to treat deep vein thrombosis?Thromb Res10011320CrossRefGoogle Scholar
  2. 2.
    Levine, M, Gent, M, Hirsh, J, Leclerc, J, Anderson, D, Weitz, J,  et al. 1996A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosisN Engl J Med33467781PubMedCrossRefGoogle Scholar
  3. 3.
    Hirsh, J, Warkentin, TE, Raschke, R, Granger, C, Ohman, EM, Dalen, JE 1998Heparin and low molecular weight heparin: Mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safetyChest114489S510SPubMedGoogle Scholar
  4. 4.
    Itoh, K, Nakao, A, Kishimoto, W, Takagi, H 1995Heparin effects on superoxide production by neutrophilsEur Surg Res271848PubMedGoogle Scholar
  5. 5.
    Norrby, K 2006Low-molecular-weight heparins and angiogenesisAPMIS11479102PubMedCrossRefGoogle Scholar
  6. 6.
    Hunt, TK, Hussain, Z 1992

    Wound microenvironment

    Cohen, IKDiegelmann, RFLindblad, WJ eds. Wound healing: biochemical and clinical aspectsSaundersPhiladelphia27481
    Google Scholar
  7. 7.
    Hayward, P, Hokanson, J, Heggers, J, Fiddes, J, Klingbeil, C, Goeger, M,  et al. 1992Fibroblast growth factor reverses the bacterial retardation of wound contractionAm J Surg16328893PubMedCrossRefGoogle Scholar
  8. 8.
    Hunt, TK 1980Disorders of wound healingWorld J Surg42717PubMedCrossRefGoogle Scholar
  9. 9.
    Dingfelder, JR 1982Prostaglandin inhibitors: new treatment for an old nemesisN Engl J Med3077467PubMedCrossRefGoogle Scholar
  10. 10.
    Graves, G, Cunningham, P, Raaf, J 1980Effect of Chemotherapy on healing of surgical woundsClin Bull101449PubMedGoogle Scholar
  11. 11.
    Stadelmann, WK, Didenis, AG, Tobin, GR 1998Impediments to wound healingAm J Surg1763947CrossRefGoogle Scholar
  12. 12.
    Laing, P 1998The development and complications of diabetic foot ulcersAm J Surg176119CrossRefGoogle Scholar
  13. 13.
    Fareed, J, Leong, WL, Hoppensteadt, DA, Jeske, WP, Walenga, J, Wahi, R,  et al. 2004Generic low-molecular-weight heparins: some practical considerationsSemin Thromb Hemost3070313PubMedCrossRefGoogle Scholar
  14. 14.
    Deepa, PR, Varalakshmi, P 2003The cytoprotective role of a low-molecular-weight heparin fragment studied in an experimental model of glomerulotoxicityEur J Pharmacol478199205PubMedCrossRefGoogle Scholar
  15. 15.
    Rumelt, S, Stolovich, C, Segal, ZI, Rehany, U 2006Intraoperative enoxaparin minimizes inflammatory reaction after pediatric cataract surgeryAm J Ophthalmol1414337PubMedCrossRefGoogle Scholar
  16. 16.
    Lever, R, Hoult, JR, Page, CP 2000The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitroBr J Pharmacol12953340PubMedCrossRefGoogle Scholar
  17. 17.
    Manduteanu, I, Voinea, M, Capraru, M, Dragomir, E, Simionescu, M 2002A novel attribute of enoxaparin: inhibition of monocyte adhesion to endothelial cells by a mechanism involving cell adhesion moleculesPharmacology65327PubMedCrossRefGoogle Scholar
  18. 18.
    Nelson, RM, Cecconi, O, Roberts, WG, Aruffo, A, Linhardt, RJ, Bevilacqua, MP 1993Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammationBlood8232538PubMedGoogle Scholar
  19. 19.
    Deepa, PR, Varalakshmi, P 2005Atheroprotective effect of exogenous heparin-derivative treatment on the aortic disturbances and lipoprotein oxidation in hypercholesterolemic diet fed ratsClin Chim Acta35511930PubMedCrossRefGoogle Scholar
  20. 20.
    Deepa, PR, Varalakshmi, P 2005Biochemical evaluation of the inflammatory changes in cardiac, hepatic and renal tissues of adriamycin-administered rats and the modulatory role of exogenous heparin-derivative treatmentChem Biol Interact15693100PubMedCrossRefGoogle Scholar
  21. 21.
    Greenhalgh, DG 1998The role of apoptosis in wound healingInt J Biochem Cell Biol30101930PubMedCrossRefGoogle Scholar
  22. 22.
    Desmouliere, A, Redard, M, Darby, I, Gabbiani, G 1995Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scarAm J Pathol1465666PubMedGoogle Scholar
  23. 23.
    Edwards, MJ, Jones, DW 2001Programmed cell death in human acute cutaneous woundsJ Cutan Pathol281515PubMedCrossRefGoogle Scholar
  24. 24.
    Darby, IA, Bisucci, T, Hewitson, TD, MacLellan, DG 1997Apoptosis is increased in a diabetes-impaired wound healing in genetically diabetic miceInt J Biochem Cell Biol29191200PubMedCrossRefGoogle Scholar
  25. 25.
    Brown, DL, Kao, WW, Greenhalgh, DG 1997Apoptosis down-regulates inflammation under the advancing epithelial wound edge: delayed patterns in diabetes and improvement with topical growth factorsSurgery12137280PubMedCrossRefGoogle Scholar
  26. 26.
    Nishimura, F, Terranova, V, Foo, H, Kurihara, M, Kurihara, H, Murayama, Y 1996Glucose-mediated alteration of cellular function in human periodontal ligament cellsJ Dent Res75166471PubMedCrossRefGoogle Scholar
  27. 27.
    Kane, CD, Greenhalgh, DG 2000Expression and localization of p53 and bcl-2 in healing wounds in diabetic and nondiabetic miceWound Repair Regen84558PubMedCrossRefGoogle Scholar
  28. 28.
    Deepa, PR, Varalakshmi, P 2006Influence of a low-molecular-weight heparin derivative on the nitric oxide levels and apoptotic DNA damage in adriamycin-induced cardiac and renal toxicityToxicology21717683PubMedCrossRefGoogle Scholar
  29. 29.
    Koller, M, Kutscha-Lissberg, F, Brom, J, Weidinger, G, Muhr, G 2001Influence of low molecular weight heparin (certoparin) and unfractionated heparin on the release of cytokines from human leukocytesInflammation253317PubMedCrossRefGoogle Scholar
  30. 30.
    Siragusa, S, Cosmi, B, Piovella, F, Hirsh, J, Ginsberg, JS 1996Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysisAm J Med10026977PubMedCrossRefGoogle Scholar
  31. 31.
    Collen, A, Smorenburg, SM, Peters, E, Lupu, F, Koolwijk, P, Van Noorden, C,  et al. 2000Unfractionated and low molecular weight heparins affect fibrin structure and angiogenesis in vitroCancer Res606196200PubMedGoogle Scholar
  32. 32.
    Jorneskog, G, Brismar, K, Fagrell, B 1993Low molecular weight heparin seems to improve local capillary circulation and healing of chronic foot ulcers in diabetic patientsVasa2213742PubMedGoogle Scholar
  33. 33.
    Kalani, M, Apelqvist, J, Blomback, M, Brismar, K, Eliasson, B, Eriksson, JW,  et al. 2003Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-blind, placebo-controlled studyDiabetes Care26257580PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Ali Civelek
    • 1
  • Koray Ak
    • 1
  • Ozlem Kurtkaya
    • 2
  • Atike Tekeli
    • 1
  • Selim Isbir
    • 1
  • Erol Nargileci
    • 1
  • Sinan Arsan
    • 1
  • Aydin Sav
    • 2
  1. 1.Department of Cardiovascular SurgeryMarmara University School of Medicine, Kalp Damar Cerrahisi ADIstanbulTurkey
  2. 2.Department of PathologyMarmara University School of MedicineIstanbulTurkey

Personalised recommendations