Effects of Clopidogrel and Low-Molecular-Weight Heparin on Viability of Random Skin Flaps in Rats

Abstract

Background The viability of skin flaps is critical and greatly affects patient's quality of life. Effects of anticoagulant use on focal skin flap necrosis were explored, administering clopidogrel or low-molecular-weight heparin (LMWH) singly and in combination.

Methods Adult male rats (N = 40) were randomly assigned to one of four equally divided groups, raising a random dorsal flap (10 × 4 cm) on each animal and delivering either no drug (control group) or daily applications of LMWH (4 mg/kg), clopidogrel (20 mg/kg), or both agents (LMWH–Clop) for a 7-day period. Thereafter, area and the percentage of flap necrosis (NP) were individually determined.

Results Average NP values were as follows: controls, 51.61%; LMWH, 49.50%; clopidogrel, 27.70%; and LMWH–Clop, 29.71%.

Conclusion Clopidogrel significantly enhanced the viability of random skin flap in rats, whereas single-agent LMWH or its combined usage conferred no significant benefits in this setting.

Keywords

anticoagulants - flap viability - clopidogrel - heparin

• References

• 1 Abla LEF, Gomes HC, Percario S, Ferreira LM. Acetylcysteine in random skin flap in rats. Acta Cir Bras 2005; 20 (2) 121-123
• 2 Duarte IdS, Gomes HFdC, Ferreira LM. Effect of dimethyl sulphoxide on necrosis of skin flaps in rats. Can J Plast Surg 1998; 6 (2) 93-97
• 3 Sasaki GH, Pang CY. Hemodynamics and viability of acute neurovascular island skin flaps in rats. Plast Reconstr Surg 1980; 65 (2) 152-158
• 4 Kerrigan CL, Stotland MA. Ischemia reperfusion injury: a review. Microsurgery 1993; 14 (3) 165-175
• 5 Russell RC, Roth AC, Kucan JO, Zook EG. Reperfusion injury and oxygen free radicals: a review. J Reconstr Microsurg 1989; 5 (1) 79-84
• 6 Miyawaki T, Jackson IT, Elmazar H , et al. The effect of low-molecular-weight heparin in the survival of a rabbit congested skin flap. Plast Reconstr Surg 2002; 109 (6) 1994-1999
• 7 Sawhney CP. The role of heparin in restoring the blood supply in ischaemic skin flaps: an experimental study in rabbits. Br J Plast Surg 1980; 33 (4) 430-433
• 8 Törkvist L, Löfberg R, Raud J, Thorlacius H. Heparin protects against skin flap necrosis: relationship to neutrophil recruitment and anti-coagulant activity. Inflamm Res 2004; 53 (1) 1-3
• 9 Wray Jr RC, Young VL. Drug treatment and flap survival. Plast Reconstr Surg 1984; 73 (6) 939-942
• 10 Shalom A, Friedman T, Westreich M. Effect of aspirin and heparin on random skin flap survival in rats. Dermatol Surg 2008; 34 (6) 785-790 , discussion 790
• 11 Bielecki M, Karpik M, Skowroński J. The effect of prophylactic doses of nadroparin and therapeutic doses of betamethasone on skin flap survival in rats. Folia Histochem Cytobiol 2009; 47: 673-677
• 12 Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 2007; 115 (16) 2196-2207
• 13 Roden DM, Shuldiner AR. Responding to the clopidogrel warning by the US food and drug administration: real life is complicated. Circulation 2010; 122 (5) 445-448
• 14 Gurbel PA, Tantry US. Combination antithrombotic therapies. Circulation 2010; 121 (4) 569-583
• 15 McFarlane RM, Deyoung G, Henry RA. The design of pedicle flap in the rat to study necrosis and its preventions. Plast Reconstr Surg 1965; 35: 177-182
• 16 Gomes HC, Bueno PCS, Scardoeli CAC, Percario S, Landman MRL, Ferreira LM. Effect of n-acetylcysteine in a random skin flap after administration of nicotine in the rat. FMED 1998; 117: 209-211
• 17 Körlof B, Ugland O. Flaps and flap necrosis. Improving the circulation in skin flaps with Complamin and with Dicoumarol: animal experiments. Acta Chir Scand 1966; 131 (5) 408-412
• 18 Sano K, Hallock GG, Wasser TE, Robson PA, Rice DC. Comparison of a new method for computer analysis with standard techniques for measuring survival rates in the rat transverse rectus abdominis musculocutaneous flap. Ann Plast Surg 2001; 47 (6) 647-651
• 19 Liebano RE, Ferreira LM, Sabino Neto M. Transcutaneous electrical nerve stimulation on viability of random skin flap in rats. Can J Plast Surg 2002; 10: 151-154
• 20 Kaufman T, Angel MF, Eichenlaub EH, Levin M, Hurwitz DJ, Futrell JW. The salutary effects of the bed on the survival of experimental flaps. Ann Plast Surg 1985; 14 (1) 64-73
• 21 Ertas NM, Goldman C, Deitcher S, Siemionow M. Dose response of enoxaparin at the cremaster muscle flap microcirculation. Microsurgery 2005; 25 (2) 147-151
• 22 O'Donoghue M, Wiviott SD. Clopidogrel response variability and future therapies: clopidogrel: does one size fit all?. Circulation 2006; 114 (22) e600-e606
• 23 Atalay C, Koçkaya EA, Çetin B, Kismet K, Akay MT. Efficacy of topical nitroglycerin and transcutaneous electrical nerve stimulation on survival of random-pattern skin flaps in rats. Scand J Plast Reconstr Surg Hand Surg 2003; 37 (1) 10-13
• 24 Aral M, Tuncer S, Şencan A, Elmas Ç, Ayhan S. The Effect of Thrombolytic, Anticoagulant, and Vasodilator Agents on the Survival of Random Pattern Skin Flap. J Reconstr Microsurg 2015; 31 (7) 487-492
• 25 Akan M, Cakir B, Misirlioğlu A, Yildirim S, Taylan G, Aköz T. Effects of clopidogrel and high dose aspirin on survival of skin flaps in rats. Scand J Plast Reconstr Surg Hand Surg 2005; 39 (1) 7-10
• 26 Ersoy A, Sevin K, Sevin A, Serel S. Effects of clopidogrel on survival of rat skin flaps. J Plast Reconstr Aesthet Surg 2007; 60 (8) 861-863
• 27 Khouri RK, Cooley BC, Kunselman AR , et al. A prospective study of microvascular free-flap surgery and outcome. Plast Reconstr Surg 1998; 102 (3) 711-721
• 28 Savoie FH, Cooley BC, Gould JS. Evaluation of the effect of pharmacologic agents on crush-avulsion arterial injuries: a scanning electron microscopy study. Microsurgery 1991; 12 (4) 292-300
• 29 Fatemi MJ, S. Forootan K, S. Jalali SZ, Mousavi SJ, Pedram MS. The effect of enoxaparin and clopidogrel on survival of random skin flap in rat animal model. World J Plast Surg 2012; 1 (2) 64-70
• 30 Chung TL, Holton III LH, Silverman RP. The effect of fondaparinux versus enoxaparin in the survival of a congested skin flap in a rabbit model. Ann Plast Surg 2006; 56 (3) 312-315