The effect of postoperative administration of low-molecular-weight-heparin (tinzaparin) on arterial thrombosis in an experimental rat model
Yıl 2024,
Cilt: 5 Sayı: 2, 53 - 59, 29.07.2024
Yıldırım Gültekin
,
Ali Bolat
,
Merih Özbayburt
,
Hatice Aktaş
,
Atike Tekeli Kunt
Öz
Introduction: : Low molecular weight heparins are licensed in the prophylaxis of venous thromboembolism but not of arterial thrombosis. This study aimed to evaluate the effect of postoperative administration of low molecular weight heparin, tinzaparin, on the rate of arterial thrombosis in a rat model.
Method: The right femoral arteries of sixteen male Wistar Albino rats were incised transversely and then were repaired with a continuous suture. Eight rats were given 175 IU/kg/day tinzaparin postoperatively for three days, while the remaining eight rats were kept free of tinzaparin. All rats were controlled daily for vascular circulation, bleeding, and hematoma until the reoperation on the fourth postoperative day. Reoperation was performed to explore vascular patency and excise a sample of vascular tissue from the repaired femoral artery for histopathological examination. A blood sample was also withdrawn for the detection of anti-factor Xa activity to show the efficacy of tinzaparin.
Results: During the postoperative three-day follow-up period, while vascular circulation disorder was detected in none of the tinzaparin-treated rats, it was detected in two rats not treated with tinzaparin (25%). None of the rats in either group developed bleeding or hematoma at the surgical site. Anti-factor Xa activity in the rats treated with tinzaparin postoperatively was found to be significantly higher than in the rats not treated with tinzaparin (p<0.001). Histopathological examination revealed thrombus and fibrin formation at the femoral artery incision line in only one rat (12.5%) treated with tinzaparin, and in seven rats (87.5%) not treated with tinzaparin (p˂0.001). Intimal hyperplasia was not detected in any group, but mixed-type inflammatory cell infiltration and endothelial and fibroblastic activity around the sutures were noted in both.
Conclusion: The postoperative subcutaneous administration of 175 IU/kg/day tinzaparin effectively attenuates the rate of arterial thrombosis in arterial surgical interventions in a rat model.
Kaynakça
- 1. Salemark L. International survey of current microvascular practices in free tissue transfer and replantation surgery. Microsurgery 1991;12:308-11.
- 2. Kaya Çİ, Bulut H, Özbayburtlu M, Kocaoğlu AS. Endovascular Revascularization of Lower Extremity Arteries: A Single-center Retrospective Report on Long Lesions (>100 mm). Int J Cardiovasc Acad 2023;9.3:60-5.
- 3. Kayaalp SO. Antitrombotik ilaçlar. In: Kayaalp SO, editor. Tıbbi Farmakoloji. Ankara; Feryal Matbaa; 1988. p. 1323-70.
- 4. Brace LD, Fareed J. Heparin-induced platelet aggregation: dose/response relationships for a Iow molecular weight heparin derivative (PK 10169) and its subfractions. Thromb Res 1986;42:769-82.
- 5. Kaya İC, Bulut HI. Endovascular Revascularization Outcomes In Peripheral Arterial Disease Patients With Type-Ii Diabetes Mellitus. Eskisehir Med J 2023;4:232-6.
- 6. Gültekin Y, Bolat A, Gemalmaz H. Comparison of sympathectomy and cilostazol treatment results in non-revascularized critical leg ischemia. J Health Sci Med 2021;4:366-71
- 7. Hao C, Sun M, Wang H, Zhang L, Wang W. Low molecular weight heparins and their clinical applications. Prog Mol Biol Transl Sci 2019;163:21-39.
- 8. Levine MN, Planes A, Hirsh J, et al. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 1989;62:940-4.
- 9. Forbes CD. Prevention of deep vein thrombosis--use of the low molecular weight heparin enoxaparin. Br J Gen Pract 1989;43:211-6.
- 10. Crowther MA, Berry LR, Monague PT, Chan AK. Mechanism responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 2002;116:178-86.
- 11. Friedel HA, Balfour JA. Tinzaparin. A review of its pharmacology and clinical potential in the prevention and treatment of thromboembolic disorders. Drugs 1994;48:638-60.
- 12. Lapidus L, Börretzen J, Fahlén M, et al. Home treatment of deep vein thrombosis. An out-patient treatment model with once-daily injection of low-molecular-weight heparin (tinzaparin) in 555 patients. Pathophysiol Haemost Thromb 2002;32:59-66.
- 13. Wolff CT, Ritschl LM, Düring MV, Fichter AM, Mücke T. Alterations in surgically created intimal lesions: an observation study in the aortic rat model. J Reconstr Microsurg 2020;36:339-45.
- 14. Guven C, Kafadar H. Evaluation of extremity vascular injuries and treatment approaches. Niger J Clin Pract 2020;23:1221-8.
- 15. Habib A, Petrucci G, Rocca B. Pathophysiology of thrombosis in peripheral artery disease. Curr Vasc Pharmacol 2020;18:204-14.
- 16. Atalan N. Hemostaz. GKDA Derg 2013;19:109-12.
- 17. Jackson SP. Arterial thrombosis--insidious, unpredictable and deadly. Nat Med 2011;17:1423-36.
- 18. Bochenek ML, Katrin Schäfer K. Role of endothelial cells in acute and chronic thrombosis. Hamostaseologie 2019;39:128-39.
- 19. Hirsh J. Heparin. N Engl J Med 1991;324:1565-74.
- 20. Alsov SA, Osipov DE, Akchurin RS, et al. Mikrokhirurgiia koronarnykh arteriĭ s ispol'zovaniem operatsionnogo mikroskopa [Microsurgery of coronary arteries using an operating microscope]. Khirurgiia (Mosk). 2019;1:60-4.
- 21. Hogan M, Berger JS. Heparin-induced thrombocytopenia (HIT): Review of incidence, diagnosis, and management. Vasc Med 2020;25:160-73.
- 22. Toya SP, Malik AB. Role of endothelial injury in disease mechanisms and contribution of progenitor cells in mediating endothelial repair. Immunobiology 2012;217:569-80.
- 23. Samama CM, Barre E, Combe S, et al. A pilot study on the use of a low molecular weight heparin (Enoxaparin) in arterial reconstructive surgery. Semin Thromb Hemost 1991;17:367-70.
- 24. Tamai S. History of microsurgery. Plast Reconstr Surg 2009;124:e282-94.
- 25. Roqué M, Rauch U, Reis ED, et al. Comparative study of antithrombotic effect of a low molecular weight heparin and unfractionated heparin in an ex vivo model of deep arterial injury. Thromb Res 2000;98:499-505.
- 26. Forbes CD. Prevention of deep vein thrombosis--use of the low molecular weight heparin enoxaparin. Br J Clin Pract 1989;43:396-400.
- 27. Quader MA, Stump LS, Sumpio BE. Low molecular weight heparins: current use and indications. J Am Coll Surg 1998;187:641-58.
- 28. Ageno W, Huisman MV. Arterial indications for the low molecular weight heparins. Curr Control Trials Cardiovasc Med 2001;2:233-39.
- 29. Daskalopoulos ME, Daskalopoulou SS, Liapis CD. Tinzaparin in long-term treatment of deep venous thrombosis. Eur J Vasc Endovasc Surg 2007;34:353-4.
- 30. Leizorovicz A, Bara L, Samama MM, Haugh MC. Factor Xa inhibition: correlation between the plasma levels of anti-Xa activity and occurrence of thrombosis and haemorrhage. Haemostasis 1993;23:89-98.
- 31. Holst J, Lindblad B, Bergqvist D, et al. Protamine neutralization of intravenous and subcutaneous low-molecular-weight heparin (tinzaparin, Logiparin). An experimental investigation in healthy volunteers. Blood Coagul Fibrinolysis 1994;5:795-803.
- 32. Hadlock TA, Kim J, Deschler DG. The effect of subcutaneously administered low-molecular-weight heparin on microarterial thrombosis in the rat. Arch Facial Plast Surg 2003;5:36-9.
- 33. Emerick KS, Deschler DG. The effect of low-molecular-weight heparin on microvenous thrombosis in a rat model. Arch Facial Plast Surg 2007;9:19-21.
- 34. Chen LE, Seaber AV, Korompilias AV, Urbaniak JR. Effects of enoxaparin, standard heparin, and streptokinase on the patency of anastomoses in severely crushed arteries. Microsurgery. 1995;16:661-5.
- 35. Korompilias AV, Chen LE, Seaber AV, Urbaniak JR. Antithrombotic potencies of enoxaparin in microvascular surgery: influence of dose and administration methods on patency rate of crushed arterial anastomoses. J Hand Surg Am 1997;22:540-6.
- 36. Gurbuz H, Kocabey Y, Sarikaya A, Candan L. The effects of low molecular weight heparin (enoxaparin) on the microsurgical vessel repair. Acta Orthop Traumatol Turc 2006;32:29-33.
- 37. Cheer SM, Dunn CJ, Foster R. Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease. Drugs 2004;64:1479-502.
- 38. Jorgensen M, Nielsen JD. The low molecular weight heparin, tinzaparin, is effective and safe as thromboembolic prophylaxis during pregnancy. Blood 2004;04:1774.
0
Deneysel rat modelinde postoperatif düşük molekül ağırlıklı heparin (tinzaparin) uygulamasının arteriyel tromboz üzerine etkisi
Yıl 2024,
Cilt: 5 Sayı: 2, 53 - 59, 29.07.2024
Yıldırım Gültekin
,
Ali Bolat
,
Merih Özbayburt
,
Hatice Aktaş
,
Atike Tekeli Kunt
Öz
Giriş: : Düşük molekül ağırlıklı heparinler, venöz tromboemboli profilaksisinde ruhsatlıdır ancak arteriyel tromboz profilaksisinde ruhsatlı değildir. Bu çalışmada sıçan modelinde postoperatif düşük molekül ağırlıklı heparin tinzaparin uygulamasının arteriyel tromboz oranına etkisinin değerlendirilmesi amaçlandı.
Yöntem: On altı erkek Wistar Albino sıçanın sağ femoral arterleri transvers olarak kesildi ve daha sonra sürekli dikişle onarıldı. Sekiz sıçana postoperatif üç gün boyunca 175 IU/kg/gün tinzaparin verilirken, geri kalan sekiz sıçana tinzaparin verilmedi. Tüm sıçanlar ameliyat sonrası dördüncü günde tekrar ameliyata alınana kadar damar dolaşımı, kanama ve hematom açısından günlük olarak kontrol edildi. Vasküler açıklığı araştırmak ve histopatolojik inceleme için onarılan femoral arterden bir vasküler doku örneğini çıkarmak için yeniden ameliyat yapıldı. Tinzaparinin etkinliğini göstermek amacıyla anti-faktör Xa aktivitesinin saptanması için de bir kan örneği alındı.
Bulgular: Ameliyat sonrası üç günlük takipte tinzaparin uygulanan sıçanların hiçbirinde damar dolaşım bozukluğu saptanmazken, tinzaparin tedavisi uygulanmayan iki sıçanda (%25) damar dolaşım bozukluğu tespit edildi. Her iki gruptaki sıçanların hiçbirinde cerrahi bölgede kanama veya hematom gelişmedi. Postoperatif dönemde tinzaparin uygulanan sıçanlarda anti-faktör Xa aktivitesinin, tinzaparin uygulanmayan sıçanlara göre anlamlı derecede yüksek olduğu görüldü (p<0,001). Histopatolojik incelemede tinzaparin tedavisi gören yalnızca bir sıçanda (%12,5) ve tinzaparin tedavisi görmeyen yedi sıçanda (%87,5) femoral arter insizyon hattında trombüs ve fibrin oluşumu saptandı (p˂0,001). Hiçbir grupta intimal hiperplazi saptanmadı ancak her iki grupta da karışık tipte inflamatuar hücre infiltrasyonu ve sütür çevresinde endotelyal ve fibroblastik aktivite dikkat çekti.
Sonuç: Sıçan modelinde postoperatif subkutan 175 IU/kg/gün tinzaparin uygulamasının arteriyel cerrahi girişimlerde arteriyel tromboz oranını etkili bir şekilde azalttığı görüldü.
Destekleyen Kurum
KIRIKKALE ÜNİVERSİTESİ BİLİMSEL ARAŞTIRMA PROJE (BAP) BİRİMİ
Kaynakça
- 1. Salemark L. International survey of current microvascular practices in free tissue transfer and replantation surgery. Microsurgery 1991;12:308-11.
- 2. Kaya Çİ, Bulut H, Özbayburtlu M, Kocaoğlu AS. Endovascular Revascularization of Lower Extremity Arteries: A Single-center Retrospective Report on Long Lesions (>100 mm). Int J Cardiovasc Acad 2023;9.3:60-5.
- 3. Kayaalp SO. Antitrombotik ilaçlar. In: Kayaalp SO, editor. Tıbbi Farmakoloji. Ankara; Feryal Matbaa; 1988. p. 1323-70.
- 4. Brace LD, Fareed J. Heparin-induced platelet aggregation: dose/response relationships for a Iow molecular weight heparin derivative (PK 10169) and its subfractions. Thromb Res 1986;42:769-82.
- 5. Kaya İC, Bulut HI. Endovascular Revascularization Outcomes In Peripheral Arterial Disease Patients With Type-Ii Diabetes Mellitus. Eskisehir Med J 2023;4:232-6.
- 6. Gültekin Y, Bolat A, Gemalmaz H. Comparison of sympathectomy and cilostazol treatment results in non-revascularized critical leg ischemia. J Health Sci Med 2021;4:366-71
- 7. Hao C, Sun M, Wang H, Zhang L, Wang W. Low molecular weight heparins and their clinical applications. Prog Mol Biol Transl Sci 2019;163:21-39.
- 8. Levine MN, Planes A, Hirsh J, et al. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 1989;62:940-4.
- 9. Forbes CD. Prevention of deep vein thrombosis--use of the low molecular weight heparin enoxaparin. Br J Gen Pract 1989;43:211-6.
- 10. Crowther MA, Berry LR, Monague PT, Chan AK. Mechanism responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 2002;116:178-86.
- 11. Friedel HA, Balfour JA. Tinzaparin. A review of its pharmacology and clinical potential in the prevention and treatment of thromboembolic disorders. Drugs 1994;48:638-60.
- 12. Lapidus L, Börretzen J, Fahlén M, et al. Home treatment of deep vein thrombosis. An out-patient treatment model with once-daily injection of low-molecular-weight heparin (tinzaparin) in 555 patients. Pathophysiol Haemost Thromb 2002;32:59-66.
- 13. Wolff CT, Ritschl LM, Düring MV, Fichter AM, Mücke T. Alterations in surgically created intimal lesions: an observation study in the aortic rat model. J Reconstr Microsurg 2020;36:339-45.
- 14. Guven C, Kafadar H. Evaluation of extremity vascular injuries and treatment approaches. Niger J Clin Pract 2020;23:1221-8.
- 15. Habib A, Petrucci G, Rocca B. Pathophysiology of thrombosis in peripheral artery disease. Curr Vasc Pharmacol 2020;18:204-14.
- 16. Atalan N. Hemostaz. GKDA Derg 2013;19:109-12.
- 17. Jackson SP. Arterial thrombosis--insidious, unpredictable and deadly. Nat Med 2011;17:1423-36.
- 18. Bochenek ML, Katrin Schäfer K. Role of endothelial cells in acute and chronic thrombosis. Hamostaseologie 2019;39:128-39.
- 19. Hirsh J. Heparin. N Engl J Med 1991;324:1565-74.
- 20. Alsov SA, Osipov DE, Akchurin RS, et al. Mikrokhirurgiia koronarnykh arteriĭ s ispol'zovaniem operatsionnogo mikroskopa [Microsurgery of coronary arteries using an operating microscope]. Khirurgiia (Mosk). 2019;1:60-4.
- 21. Hogan M, Berger JS. Heparin-induced thrombocytopenia (HIT): Review of incidence, diagnosis, and management. Vasc Med 2020;25:160-73.
- 22. Toya SP, Malik AB. Role of endothelial injury in disease mechanisms and contribution of progenitor cells in mediating endothelial repair. Immunobiology 2012;217:569-80.
- 23. Samama CM, Barre E, Combe S, et al. A pilot study on the use of a low molecular weight heparin (Enoxaparin) in arterial reconstructive surgery. Semin Thromb Hemost 1991;17:367-70.
- 24. Tamai S. History of microsurgery. Plast Reconstr Surg 2009;124:e282-94.
- 25. Roqué M, Rauch U, Reis ED, et al. Comparative study of antithrombotic effect of a low molecular weight heparin and unfractionated heparin in an ex vivo model of deep arterial injury. Thromb Res 2000;98:499-505.
- 26. Forbes CD. Prevention of deep vein thrombosis--use of the low molecular weight heparin enoxaparin. Br J Clin Pract 1989;43:396-400.
- 27. Quader MA, Stump LS, Sumpio BE. Low molecular weight heparins: current use and indications. J Am Coll Surg 1998;187:641-58.
- 28. Ageno W, Huisman MV. Arterial indications for the low molecular weight heparins. Curr Control Trials Cardiovasc Med 2001;2:233-39.
- 29. Daskalopoulos ME, Daskalopoulou SS, Liapis CD. Tinzaparin in long-term treatment of deep venous thrombosis. Eur J Vasc Endovasc Surg 2007;34:353-4.
- 30. Leizorovicz A, Bara L, Samama MM, Haugh MC. Factor Xa inhibition: correlation between the plasma levels of anti-Xa activity and occurrence of thrombosis and haemorrhage. Haemostasis 1993;23:89-98.
- 31. Holst J, Lindblad B, Bergqvist D, et al. Protamine neutralization of intravenous and subcutaneous low-molecular-weight heparin (tinzaparin, Logiparin). An experimental investigation in healthy volunteers. Blood Coagul Fibrinolysis 1994;5:795-803.
- 32. Hadlock TA, Kim J, Deschler DG. The effect of subcutaneously administered low-molecular-weight heparin on microarterial thrombosis in the rat. Arch Facial Plast Surg 2003;5:36-9.
- 33. Emerick KS, Deschler DG. The effect of low-molecular-weight heparin on microvenous thrombosis in a rat model. Arch Facial Plast Surg 2007;9:19-21.
- 34. Chen LE, Seaber AV, Korompilias AV, Urbaniak JR. Effects of enoxaparin, standard heparin, and streptokinase on the patency of anastomoses in severely crushed arteries. Microsurgery. 1995;16:661-5.
- 35. Korompilias AV, Chen LE, Seaber AV, Urbaniak JR. Antithrombotic potencies of enoxaparin in microvascular surgery: influence of dose and administration methods on patency rate of crushed arterial anastomoses. J Hand Surg Am 1997;22:540-6.
- 36. Gurbuz H, Kocabey Y, Sarikaya A, Candan L. The effects of low molecular weight heparin (enoxaparin) on the microsurgical vessel repair. Acta Orthop Traumatol Turc 2006;32:29-33.
- 37. Cheer SM, Dunn CJ, Foster R. Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease. Drugs 2004;64:1479-502.
- 38. Jorgensen M, Nielsen JD. The low molecular weight heparin, tinzaparin, is effective and safe as thromboembolic prophylaxis during pregnancy. Blood 2004;04:1774.
0