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COMPARISON OF RIVAROXABAN AND DIFFERENT ANTICOAGULANTS ON BONE UNION IN A RAT MODEL

Year 2016, Volume: 2 Issue: 3, 310 - 322, 15.12.2016
https://doi.org/10.30569/adiyamansaglik.438883

Abstract

Objective:
Thromboembolic complications due to
immobilization in the treatment of lower extremity fractures are the leading
problems in treatment.
This
study was undertaken to examine the effect of a number of different
anti-embolic agents, i.e. enoxaparin, fondaparinux, and rivaroxaban, on bone
healing in an experimental rat model.

 

Methods: In
our study, 60 rats of the same number of Sprague-Dawley rats were divided into
4 groups.
Group 1 received 1 cc saline
solution subcutaneously, group 2 fondaparinux 1 mg / kg subcutaneously, group 3
rivaroxaban 3 mg / kg oral gavage and group 4 enoxaparin 100 anti Xa IU / kg
subcutaneously once daily for 2 weeks.All groups were sacrificed at 4 weeks and
biochemical, radiographic and histopathologic evaluations of fractured calluses
in acute and subacute periods were evaluated.

 

Results: A high inter-rater agreement was found for
clinical assessments for the presence of pathological macroscopic mobility in
the fracture line. Complete fusion was significantly lower among rats in Group
4 as compared to Groups, 1, 2, and 3. Group 2 had complete fusion. Radiological
assessment scores in Group 1 were significantly lower as compared to those in
Groups 2 and 3 . Also, Group 4 had significantly lower radiological scores than
Group 2.
Histopathological
assessments showed no statistically significant differences between the study
groups, although scores in Groups 2 and 3 were numerically higher.

 













Conclusion: In
this study,  enoxaparin, rivaroxaban, and
fondaparinux, demonstrated no adverse impacts on bone healing. Rivaroxaban may
represent a viable alternative to other anti-thrombotic agents owing to its
oral administration, no requirement for therapeutic monitoring, and better
patient tolerability.  

References

  • 1. Shackford SR, Davis JW, Hollingsworth-Fridlund P, Brewer NS, Hoyt DB, Mackersie RC. Venous thromboembolism in major trauma. Am J Surg 1990;159:365–9.
  • 2. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of deep vein thrombosis after major knee surgery – a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo. Thromb Haemost 1992;67: 417–23.
  • 3. Erli H, Melchert M, Rüger M. The effect of low-dosed unfractioned and low-molecular-weight heparins on bone healing in vivo. Internet J Orthop Surg 2006;3(Number 2)
  • 4. Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin HL, Raschke R, et al. Heparin and low-molecular-weightheparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 2001;119(S1):64–94.
  • 5. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Prog Hemost Thromb 1991;10:1–34.
  • 6. Monreal M, Olive A, Lafoz E, Del Rio L. Heparins, coumarin, and bone density. Lancet 1991;338(8768):706.
  • 7. Lindner T, Cockbain AJ, El Masry MA, et al. The effect of anticoagulant pharmacotherapy on fracture healing. Expert Opin Pharmacother 2008;9(7):1169–87.
  • 8. Palmer AJ, Koppenhagen K, Kirchhof B, Weber U, Bergemann R. Efficacy and safety of low molecular weight heparin, unfractionated heparin and warfarin for thromboembolism prophylaxis in orthopedic surgery: A meta-analysis of randomized clinical trials. Haemostasis 1997;27:75–84.
  • 9. Turpie AG. Fondaparinux: a factor Xa inhibitor for antithrombotic therapy. Expert Opin Pharmacother 2004;5(6):1373–84.
  • 10. Yen SH, Lin PC, Kuo FC, Wang JW. Thromboprophylaxis after minimally invasive total knee arthroplasty: A comparison of rivaroxaban and enoxaparin. Biomed J. 2014;37(4):199-204.
  • 11. Kearon C. Duration of venous thromboembolism prophylaxis after surgery. Chest 2003;124(Suppl.):386–92.
  • 12. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: american college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6_suppl):381–453.
  • 13. Aurégan JC, Coyle RM, Danoff JR, Burky RE, Akelina Y, Rosenwasser MP. The rat model of femur fracture for bone and mineral research: An improved description of expected comminution, quantity of soft callus and incidence of complications. Bone Joint Res. 2013;2(8):149-54.
  • 14. Akman S, Gögüs A, Şener N, Bilgiç B, Aksoy B, Seçkin F. Effect of diclofenac sodium on union of tibial fractures in rats. Adv Ther 2002;19(3):119–25.
  • 15. Goldberg VM, Powell A, Shaffer JW, Zika J, Bos GD, Heiple KG. Bone grafting: role of histocompatibility in transplantation. J Orthop Res. 1985;3(4):389-404.
  • 16. Huo MH, Troiano NW. The influence of ibuprofen on fracture repair: biomechanical, biochemical, histologic and histomorphometric parameters in rats. J Orthop Res. 1991;9(3):383-90.
  • 17. Demirtaş A, Azboy I, Bulut M, Uçar BY, Alabalik U, Necmioğlu NS. Investigation of the effects of Enoxaparin, Fondaparinux, and Rivaroxaban used in thromboembolism prophylaxis on fracture healing in rats: Eur Rev Med Pharmacol Sci. 2013;17:1850-6.
  • 18. Matzsch T, Bergqvist D, Hedner U, Nilsson B, Ostergaard P. Heparininduced osteoporosis in rats. Thromb Haemost. 1986;56(3):293-4.
  • 19. Say F, İltar S, Alemdaroğlu KB, Özel İ, Aydoğan NH, Gönültaş M. The effect of various types low molecular weight heparins on fracture healing; Thromb Res. 2013;131(3):114-9
  • 20. Street JT, McGrath M, O'Regan K, Wakai A, McGuinness A, Redmond HP. Thromboprophylaxis using a low molecular weight heparin delays fracture repair. Clin Orthop Relat Res 2000;381:278–89
  • 21. Shaughnessy SG, Young E, Deschamps P, Hirsh J. The effectss of low molecular weight and Standard heparin on calcium loss from fetal rat calvariae. Blood 1995;86:1368-73.
  • 22. Muir JM, Andrew M, Hirsh J, Weitz JI, Young E, Deschamps P, Shaughnessy SG. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood 1996;88:1314-20.
  • 23. Petilla V, Leinonen P, Markkola A, Hiilesmaa V, Kaaja R. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost 2002;87:182-6.
  • 24. Street J, Wang JH, Redmond HP. Vascular endothelial growth factor in human fracture hematoma does not confer angiogenic capability in vitro. Surg Forum 1999;50:527–9.
  • 25. Walenga MJ, Jeske PW, Bara L, Samama MM, Fareed J. Biochemical and pharmacologic rationale for the development of a synthetic heparin pentasaccharide. Thromb Res 1997;86:1-36.
  • 26. Hawkins D, Evans J. Minimising the risk of heparininduced osteoporosis during pregnancy. Expert Opin Drug Saf 2005;4:583-90.
  • 27. Fusaro M, Crepaldi G, Maggis , D’angelo A, Calo L, Miozzo D, Fornasieri A, Gallieni M. Bleeding, vertebral fractures and vascular calcifications in patients treated with warfarin: hope for lower risks with alternative therapies. Curr Vasc Pharmacol 2011;9:763-9.
  • 28. Borris LC. Rivaroxaban and dabigatran etexilate: two new oral anticoagulants for extended postoperative prevention of venous thromboembolism after elective total hip arthroplasty. Arch Orthop Trauma Surg 2010;130:583-9.
  • 29. Turun S, Banghua L, Yuan Y, Zhenhui L, Ying N, Jin C. A systematic review of Rivaroxaban versus Enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thromb Res 2011;127:525-34.

RİVAROKSABAN VE FARKLI ANTİKOAGÜLANLARIN KIRIK KAYNAMASI ÜZERİNE ETKİLERİNİN BİR RAT MODELİNDE KARŞILAŞTIRILMASI

Year 2016, Volume: 2 Issue: 3, 310 - 322, 15.12.2016
https://doi.org/10.30569/adiyamansaglik.438883

Abstract

Amaç: Alt ekstremite kırıklarının tedavisinde immobilizasyona bağlı
tromboembolik olayları önlemek için antikoagulan profiklasisi kullanmak
gerekmektedir.  Biz bu çalışmada;
deneysel bir sıçan kırık modelinde, faktör Xa’nın seçici olarak inhibisyon
yapan  rivaroksabanın ile kırık iyileşme
süreci üzerine etkilerini,enoksaparin ve fondaparinuks ile kıyaslamayı
amaçladık.



Yöntem: Çalışmamızda 60 adet Sprague
-Dawley cinsi
eşit sayıda rat 4 guruba ayrıldı ve



Grup 1’e (kontrol grubu) 1
cc salin solüsyonu subkutan,
grup 2’ye fondaparinuks 1 mg/kg dozunda subkutan, grup 3’e
rivaroksaban 3 mg/kg dozunda oral gavaj yoluyla ve
grup 4’e enoxaparin 100 anti Xa IU/kg dozunda subkutan olarak, 2 hafta
boyunca günde tek doz uygulandı
. Tüm gruplar 4. haftada sakrifiye edilerek kırık kallusları akut
ve subakut dönemlerde biyomekanik, radyografik ve histopatolojik olarak
değerlendirildi.



Bulgular: Makroskopik patolojik hareket varlığı
incelendiğinde, gözlemciler arasındaki uyum istatistiksel olarak anlamlı
bulundu
. Grup 4’ün tam füzyon istatistiksel olarak anlamlı derecede düşük
bulundu ve grup 2’deki tüm sıçanlarda tam füzyon gözlendi.  Radyolojik incelemede; Grup 1’in radyolojik
değerlendirme skorları grup 2 ve grup 3’den istatistiksel olarak anlamlı
derecede düşük bulundu, grup 4’ün radyolojik değerlendirme skorları grup 2’den
istatistiksel olarak anlamlı derecede düşük bulundu.
Histopatolojik sonuçlar değerlendirildiğinde,
grup 2 ve grup 3’te skorlar daha yüksek olsa da,
tüm
grupların histopatolojik skorları arasında istatistiksel olarak anlamlı farklılık
gözlenmedi.



Sonuç: Çalışmamızda enoksaparin,
rivaroksaban ve fondaparinuksun kırık iyileşmesi üzerine herhangi bir olumsuz
etkisi görülmemiş olup aksine fondaparinuks ve rivaroksabanın bir miktar olumlu
etkilesi olabileceği düşünülmüştür. Rivaroksaban; oral yolla kullanılabilmesi
ve monitörizasyon gerektirmemesi nedeniyle, hastalar tarafından daha kolay
tolere edilebileceği ve diğer antikoagulan ajanlara iyi bir alternatif olacağı
kanaatindeyiz.

References

  • 1. Shackford SR, Davis JW, Hollingsworth-Fridlund P, Brewer NS, Hoyt DB, Mackersie RC. Venous thromboembolism in major trauma. Am J Surg 1990;159:365–9.
  • 2. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of deep vein thrombosis after major knee surgery – a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo. Thromb Haemost 1992;67: 417–23.
  • 3. Erli H, Melchert M, Rüger M. The effect of low-dosed unfractioned and low-molecular-weight heparins on bone healing in vivo. Internet J Orthop Surg 2006;3(Number 2)
  • 4. Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin HL, Raschke R, et al. Heparin and low-molecular-weightheparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 2001;119(S1):64–94.
  • 5. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Prog Hemost Thromb 1991;10:1–34.
  • 6. Monreal M, Olive A, Lafoz E, Del Rio L. Heparins, coumarin, and bone density. Lancet 1991;338(8768):706.
  • 7. Lindner T, Cockbain AJ, El Masry MA, et al. The effect of anticoagulant pharmacotherapy on fracture healing. Expert Opin Pharmacother 2008;9(7):1169–87.
  • 8. Palmer AJ, Koppenhagen K, Kirchhof B, Weber U, Bergemann R. Efficacy and safety of low molecular weight heparin, unfractionated heparin and warfarin for thromboembolism prophylaxis in orthopedic surgery: A meta-analysis of randomized clinical trials. Haemostasis 1997;27:75–84.
  • 9. Turpie AG. Fondaparinux: a factor Xa inhibitor for antithrombotic therapy. Expert Opin Pharmacother 2004;5(6):1373–84.
  • 10. Yen SH, Lin PC, Kuo FC, Wang JW. Thromboprophylaxis after minimally invasive total knee arthroplasty: A comparison of rivaroxaban and enoxaparin. Biomed J. 2014;37(4):199-204.
  • 11. Kearon C. Duration of venous thromboembolism prophylaxis after surgery. Chest 2003;124(Suppl.):386–92.
  • 12. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: american college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6_suppl):381–453.
  • 13. Aurégan JC, Coyle RM, Danoff JR, Burky RE, Akelina Y, Rosenwasser MP. The rat model of femur fracture for bone and mineral research: An improved description of expected comminution, quantity of soft callus and incidence of complications. Bone Joint Res. 2013;2(8):149-54.
  • 14. Akman S, Gögüs A, Şener N, Bilgiç B, Aksoy B, Seçkin F. Effect of diclofenac sodium on union of tibial fractures in rats. Adv Ther 2002;19(3):119–25.
  • 15. Goldberg VM, Powell A, Shaffer JW, Zika J, Bos GD, Heiple KG. Bone grafting: role of histocompatibility in transplantation. J Orthop Res. 1985;3(4):389-404.
  • 16. Huo MH, Troiano NW. The influence of ibuprofen on fracture repair: biomechanical, biochemical, histologic and histomorphometric parameters in rats. J Orthop Res. 1991;9(3):383-90.
  • 17. Demirtaş A, Azboy I, Bulut M, Uçar BY, Alabalik U, Necmioğlu NS. Investigation of the effects of Enoxaparin, Fondaparinux, and Rivaroxaban used in thromboembolism prophylaxis on fracture healing in rats: Eur Rev Med Pharmacol Sci. 2013;17:1850-6.
  • 18. Matzsch T, Bergqvist D, Hedner U, Nilsson B, Ostergaard P. Heparininduced osteoporosis in rats. Thromb Haemost. 1986;56(3):293-4.
  • 19. Say F, İltar S, Alemdaroğlu KB, Özel İ, Aydoğan NH, Gönültaş M. The effect of various types low molecular weight heparins on fracture healing; Thromb Res. 2013;131(3):114-9
  • 20. Street JT, McGrath M, O'Regan K, Wakai A, McGuinness A, Redmond HP. Thromboprophylaxis using a low molecular weight heparin delays fracture repair. Clin Orthop Relat Res 2000;381:278–89
  • 21. Shaughnessy SG, Young E, Deschamps P, Hirsh J. The effectss of low molecular weight and Standard heparin on calcium loss from fetal rat calvariae. Blood 1995;86:1368-73.
  • 22. Muir JM, Andrew M, Hirsh J, Weitz JI, Young E, Deschamps P, Shaughnessy SG. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood 1996;88:1314-20.
  • 23. Petilla V, Leinonen P, Markkola A, Hiilesmaa V, Kaaja R. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost 2002;87:182-6.
  • 24. Street J, Wang JH, Redmond HP. Vascular endothelial growth factor in human fracture hematoma does not confer angiogenic capability in vitro. Surg Forum 1999;50:527–9.
  • 25. Walenga MJ, Jeske PW, Bara L, Samama MM, Fareed J. Biochemical and pharmacologic rationale for the development of a synthetic heparin pentasaccharide. Thromb Res 1997;86:1-36.
  • 26. Hawkins D, Evans J. Minimising the risk of heparininduced osteoporosis during pregnancy. Expert Opin Drug Saf 2005;4:583-90.
  • 27. Fusaro M, Crepaldi G, Maggis , D’angelo A, Calo L, Miozzo D, Fornasieri A, Gallieni M. Bleeding, vertebral fractures and vascular calcifications in patients treated with warfarin: hope for lower risks with alternative therapies. Curr Vasc Pharmacol 2011;9:763-9.
  • 28. Borris LC. Rivaroxaban and dabigatran etexilate: two new oral anticoagulants for extended postoperative prevention of venous thromboembolism after elective total hip arthroplasty. Arch Orthop Trauma Surg 2010;130:583-9.
  • 29. Turun S, Banghua L, Yuan Y, Zhenhui L, Ying N, Jin C. A systematic review of Rivaroxaban versus Enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thromb Res 2011;127:525-34.
There are 29 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Research Article
Authors

Muhammet Zeki Gültekin

Ender Alagöz

Serdar Yüksel

Şule Özsoy This is me

Ali Avcı

Mehmet Akif Güleç This is me

Oğuz Uğur

Publication Date December 15, 2016
Submission Date June 29, 2018
Acceptance Date July 10, 2018
Published in Issue Year 2016 Volume: 2 Issue: 3

Cite

AMA Gültekin MZ, Alagöz E, Yüksel S, Özsoy Ş, Avcı A, Güleç MA, Uğur O. RİVAROKSABAN VE FARKLI ANTİKOAGÜLANLARIN KIRIK KAYNAMASI ÜZERİNE ETKİLERİNİN BİR RAT MODELİNDE KARŞILAŞTIRILMASI. ADYÜ Sağlık Bilimleri Derg. December 2016;2(3):310-322. doi:10.30569/adiyamansaglik.438883