Revista Cienﬁca, FCV-LUZ / Vol. XXXV Recibido: 07/24/2025 Aceptado: 09/11/2025 Publicado: 15/10/2025 hps://doi.org/10.52973/rcfcv-e35650 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 1 of 6 Revista Cienﬁca, FCV-LUZ / Vol. XXXV hps://doi.org/10.52973/rcfcv-e35757 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Eﬀect of systemic ancoagulants on fracture healing in rats bia Efecto de los ancoagulantes sistémicos en la consolidación de fracturas en la bia de ratas Murat Tanrisever 1* , Umit Koray Can 2 , Ozmen Istek 3 , Erhan Cahit Ozcan 4 , Hatice Eroksuz 5 , Burak Karabulut 5 , Muge Bereket Altintas 6 , Merve Guney 6 , Serkan Dundar 6α ¹Firat University, Faculty of Veterinary Medicine, Department of Surgery, Elazig, Turkiye ²Turkish Jockey Club Elazig Racecourse Horse Hospital, Elazig, Turkiye ³Mus Alparslan University, Faculty of Health Sciences, Department of Nursing, Mus, Turkiye ⁴Firat University, Faculty of Medicine, Department of Esthec, Plasc, Reconstrucve and Esthec Surgery, Elazig, Turkiye ⁵Firat University, Faculty of Veterinary Medicine, Department of Pathology, Elazig, Turkiye ⁶Firat University, Faculty of Denstry, Department of Peridontology, Elazig, Turkiye α Firat University, Instute of Sciences, Department of Stascs, Doctorate Student *Corresponding Author: mtanrisever@ﬁrat.edu.tr ABSTRACT This study aimed to evaluate the eﬀects of the systemic ancoagulants Apixaban, Rivaroxaban, Edoxaban, and Dabigatran on fracture healing. 48 female Spraque Dawley rats were divided into 6 groups with 8 rats in each group. Healthy Control group (n=8): no procedure was applied during the four-week experimental setup. Sham group (n=8): fractures were created in the right bias of the subjects by surgical methods and the fractures were ﬁxed with Kirshner wires in this group and all ancoagulant groups. No addional procedure was applied during the four (4) week to yhe sham group experimental setup. Throughout the 4-week experimental period, the animals were administered the following treatments via oral gavage three mes per week: the Apixaban Group (n=8) received 5 mg/kg of apixaban; the Rivaroxaban Group (n=8) received 3 mg/kg of rivaroxaban; the Edoxaban Group (n=8) received 3 mg/kg of edoxaban; and the Dabigatran Group (n=8) received 10 mg/kg of dabigatran. At the end of the four-week experimental period, all rats were euthanized. Bone ssues were harvested, decalciﬁed, and processed for histological analysis. A stascally signiﬁcant diﬀerence was observed among the groups (P < 0.05). Post hoc analysis revealed that the Apixaban group (M = 55.75, SD = 3.41) and the Rivaroxaban group (M = 55.38, SD = 3.89) had signiﬁcantly higher mean values compared to the Control group (M = 41.75, SD = 5.57) (P < 0.05). Addionally, the Dabigatran group (M = 44.00, SD = 4.66) and the Edoxaban group (M = 48.63, SD = 5.55) also diﬀered signiﬁcantly from the Control, with Edoxaban showing a stascally signiﬁcant diﬀerence compared to Dabigatran (P < 0.05). No signiﬁcant diﬀerence was observed between Apixaban and Rivaroxaban.The histopathological evaluaons revealed that the administraon of these ancoagulants had stascally signiﬁcant eﬀects on new bone formaon compared to the control group. Key words: Apixaban; rivaroxaban; edoxaban; dabigatran; bone healing RESUMEN Este estudio tuvo como objevo evaluar los efectos de los ancoagulantes sistémicos Apixabán, Rivaroxabán, Edoxabán y Dabigatrán en la consolidación de fracturas. Se conformaron 6 grupos de ratas hembra Spraque Dawley de 8 ejemplares cada uno. Grupo control sano (n=8): no se aplicó ningún procedimiento durante las cuatro semanas de duración del experimento. En el resto de los grupos, se crearon fracturas en las bias derechas mediante métodos quirúrgicos y se ﬁjaron con agujas de Kirshner. Grupo simulado (n=8): no recibió tratamiento con ancoagulantes. El resto de los grupos recibieron las siguientes dosis de los farmacos correspondientes mediante sonda oral tres veces por semana: grupo apixabán (n=8) recibió 5 mg/ kg; grupo rivaroxabán (n=8) recibió 3 mg/kg; grupo edoxabán (n=8) recibió 3 mg/kg; y el grupo dabigatrán (n=8) recibió 10 mg/kg. Al ﬁnal del período experimental de cuatro semanas, todas las ratas fueron eutanacia. Se extrajo tejido óseo, se descalciﬁcó y se procesó para análisis histológico. Se observó una diferencia estadíscamente signiﬁcava entre los grupos (P < 0,05). El análisis post hoc reveló que el grupo Apixabán (M = 55,75, DE = 3,41) y el grupo Rivaroxabán (M = 55,38, DE = 3,89) tuvieron valores medios signiﬁcavamente más altos en comparación con el grupo Control (M = 41,75, DE = 5,57) (P < 0,05). Además, el grupo Dabigatrán (M = 44,00, DE = 4,66) y el grupo Edoxabán (M = 48,63, DE = 5,55) también diﬁrieron signiﬁcavamente del Control, con Edoxabán mostrando una diferencia estadíscamente signiﬁcava en comparación con Dabigatrán (P < 0,05). No se observó una diferencia signiﬁcava entre Apixabán y Rivaroxabán. Las evaluaciones histopatológicas revelaron que la administración de estos ancoagulantes tuvo efectos estadíscamente signiﬁcavos en la formación de hueso nuevo en comparación con el grupo control. Palabras clave: Apixabán, rivaroxabán, edoxabán, dabigatrán, consolidación ósea

Systemic ancoagulants on fracture healing / Tanrisever et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico INTRODUCTION Unlike muscle and skin ssues, which typically heal through the formaon of scar ssue, bone possesses a unique regenerave capacity whereby fracture healing restores both the original structure and funcon of the ssue. Eﬀecve fracture repair requires accurate reducon and adequate immobilizaon to facilitate opmal bone healing. These objecves are achieved through the applicaon of surgical instruments, orthopedic implants and specialized reducon techniques [1]. Accurate alignment of fracture fragments is crucial to enable the connuous progression of secondary osteons across the fracture interface. Although minor bone defects oﬅen undergo spontaneous healing without the need for supplementary bone regeneraon strategies, larger defects—especially those idenﬁed as crical-sized—represent a substanal challenge in both human and veterinary orthopaedics due to their limited intrinsic regenerave capacity, necessitang addional therapeuc intervenons to achieve bone union [2 ,[3]. Bone healing proceeds through a series of sequenal and overlapping regenerave stages, beginning with the hematoma and inﬂammatory phase, followed by callus formaon and the development of woven bone, ulmately culminang in the remodeling phase that restores the bone’s original structure and funcon [4 , 5]. However, this depicon of fracture healing serves as a simpliﬁed overview of a mulfaceted physiological process. The inﬂammatory phase, for instance, is acvated by a pro- inﬂammatory signaling cascade that is crical for the iniaon of the ssue repair process The inial pro-inﬂammatory reacon shares a phylogenec connecon with the coagulaon cascade iniated in the course of hematoma development. Subsequent suppression of the inﬂammatory response is essenal to facilitate revascularizaon, which is vital for re-establishing blood ﬂow to the injury site [5 , 6 , 7]. The process of bone ssue formaon and destrucon, also known as remodeling, connues throughout life. Certain medicaons used for various diseases can directly aﬀect the quality of bone ssue and the process of formaon and destrucon. For example, bisphosphonates, used in the treatment of some types of cancer that cause bone metastases and metabolic bone diseases, are examples of such drugs. Bisphosphonates exert a relave osteoblasc eﬀect on bone ssue while suppressing the osteoclastogenesis step of the bone formaon and destrucon process [8]. Various medicaons used for systemic condions and diseases can aﬀect bone healing. Ancoagulant therapies are commonly employed in the management of coronary artery disease (CAD) and related condions, including stroke, ischemia, and myocardial infarcon. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor, approved for both the prevenon and treatment of thromboembolic condions [9]. Rivaroxaban has more recently gained approval in select countries for prophylacc use against venous thromboembolism in paents undergoing elecve hip or knee arthroplasty [9]. Rivaroxaban exerts selecve inhibion not only on free Factor Xa (Ki = 0.4 nM), but also on Factor Xa associated with the prothrombinase complex and ﬁbrin-bound forms. In vitro studies have shown that rivaroxaban inhibits thrombin generaon and prolongs clong mes, while in vivo experiments demonstrate its potent anthromboc eﬃcacy in mulple animal models of arterial and venous thrombosis [9]. Apixaban is a potent, orally administered, and highly selecve direct Factor Xa inhibitor indicated for the treatment and prevenon of venous and arterial thromboembolic disorders. Apixaban reversibly inhibits the acvity of Factor Xa in both its free form and when bound within the prothrombinase complex. In addion, apixaban is indicated for both the prophylaxis and management of venous thrombosis in clinical sengs [10 , 11]. As a reversible, selecve thrombin inhibitor with oral bioavailability, Dabigatran is experiencing growing ulizaon in complex clinical scenarios [12 , 13]. Edoxaban, a recently developed oral Factor Xa inhibitor, demonstrates reversible acvity and has an eliminaon half-life of approximately 10 to 14 hours. Clinical studies have shown that it is non-inferior to warfarin for the prevenon of stroke and systemic embolism in individuals with atrial ﬁbrillaon [14 , 15]. The purpose of this invesgaon was to evaluate how systemic ancoagulants, including rivaroxaban, apixaban, dabigatran and edoxaban , inﬂuence the fracture healing process. MATERIAL AND METHODS Study design and animals This study was approved by the Fırat University Animal Experiments Local Ethics Commiee (Approval No: 21318, Date: 12 January 2024) and was conducted at the Fırat University Experimental Research Center. The principles outlined in the Declaraon of Helsinki were rigorously adhered to throughout the experimental procedures. For the standardizaon of this animal study, 48 female Spraque Dawley rats (Raus norvegicus) that were determined to be in the same estrus period aﬅer vaginal swabs were included in the study due to the possibility that female hormones could aﬀect bone healing. The rats were obtained from the Firat University Experimental Research Center. The rats were housed in plasc cages, with the room temperature consistently maintained at 22 °C each day. Throughout the experimental period, the rats were housed under a 12-hour light/12-hour dark cycle and provided with ad libitum access to food and water. The subjects were divided into 6 groups with 8 rats in each group. Healthy Control group (n=8): no procedure was applied during the four-week experimental setup. Sham group (n=8): fractures were created in the right bias of the subjects by surgical methods and the fractures were ﬁxed with Kirshner wires. No addional procedure was applied during the four (4) week experimental setup. Apixaban Group (n=8): fractures were created in the right bias of the subjects by surgical methods and the fractures were ﬁxed with Kirshner wires. 5 mg/kg Apixaban (Eliquis 2,5 2 of 6

Revista Cienﬁca, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico mg, Pﬁzer, Germany) was administered to the subjects by oral gavage 3 mes a week during the 4-week experimental setup. Rivaroxaban Group (n=8): fractures were created in the right bias of the subjects by surgical methods and the fractures were ﬁxed with Kirshner wires. 3 mg/kg rivaroxaban (Xarelto 10 mg, Bayer, Germany) was administered to the subjects by oral gavage 3 mes a week during the 4-week experimental setup. Edoxaban Group (n=8): fractures were surgically created in the right bias of the subjects, and the fractures were ﬁxed with Kirshner wires. 3 mg/kg edoxaban (Lixiana 30 mg, Daiichi Sankyo, Germany) was administered to the subjects via oral gavage, 3 mes a week, for a 4-week experimental setup. Dabigatran Group (n=8): fractures were surgically created in the right bias of the subjects, and the fractures were ﬁxed with Kirshner wires. 10 mg/kg dabigatran (Pradaxa 110 mg, Boehringer, Germany) was administered to the subjects via oral gavage, 3 mes a week, for a 4-week experimental setup. Surgical Procedures All surgical procedures were performed under sterile condions. General anesthesia was induced by intramuscular administraon of Xylazine (10 mg/kg; Rompun, Bayer, Germany) and Ketamine (40 mg/kg; Ketasol, Richter Pharma, Wels, Austria). Prior to the incision, the surgical site was shaved and disinfected with a povidone–iodine soluon. In accordance with standard asepc and ansepc protocols, an approximately 5 mm longitudinal incision was made along the bial crest using a no. 22 scalpel blade. Aﬅer elevaon of the soﬅ ssues and periosteum, the diaphyseal region of the bia was exposed. A bicorcal osteotomy was then performed using a rotary disk under connuous saline irrigaon (FIG. 1). The resulng bone fragments were stabilized with Kirschner wires (FIG. 2), and the surrounding soﬅ ssues were anatomically reposioned and sutured. No intraoperave or postoperave complicaons, either fatal or non-fatal, were observed. Postoperavely, rats were administered intramuscular anbiocs 40 mg/kg Cefazolin sodium (Iespor, I.E. Ulagay, Turkiye) and analgesics Tramadol hydrochloride, 0.1 mg/kg (Contramal, Mefar, Turkiye). At the conclusion of the four-week experimental period, all rats were euthanized. Bone specimens were harvested, decalciﬁed, and processed for histological analysis. FIGURE 1. Rats Tibia bone undergoing bicorcal osteotomy using a rotang disc FIGURE 2. Fixaon of Rats bone fragments with Kirschner wire 3 of 6

Systemic ancoagulants on fracture healing / Tanrisever et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Histopathological analysis Tibias obtained from euthanasia procedures were stored in a 10% neutral formalin soluon for 3 days (d). They were then cleared of surrounding soﬅ ssues such as muscle, tendon, and fascia and decalciﬁed in a 10% formic acid soluon for approximately one week. They were then processed through ascending alcohol, xylene, and paraﬃn series using an automac ssue processing device (Leica TP 1020, Germany) and embedded longitudinally in paraﬃn (Leica EG1150 H-C, Germany). 3-micron-thick secons were cut using a rotary microtome (Leica RM2125 RTS, Germany) and stained with hematoxylin and eosin (H&E) (Leica Autostainer XL). The examinaon was performed under a standard light microscope (Olympus BX42, Japan). New bone formaon was used to assess healing. For this purpose, the enre healing ssue area at the fracture site was measured. The area of new bone formaon was then measured and compared to the total area. This gave the rate of new bone formaon at the healing site for each sample. Stascal analysis Stascal analyses were performed using IBM SPSS Stascs version 23. Data normality was evaluated with the Shapiro–Wilk and Kolmogorov–Smirnov tests. Given that the data sasﬁed the normality assumpons, group diﬀerences were assessed using one-way analysis of variance (ANOVA), followed by Tukey’s Honestly Signiﬁcant Diﬀerence (HSD) post hoc test for pairwise comparisons. Results are expressed as mean ± standard deviaon, with stascal signiﬁcance deﬁned as P < 0.05. All analyses were conducted by a blinded invesgator, who was unaware of the group assignments. RESULTS AND DISCUSSION In both the control and experimental groups, callus ssue was observed at the fracture site, covering the defect in most samples. New bone formaon (NBF) within the healing callus was more pronounced in the A, D, E, and R experimental groups. In contrast, some animals in the control group exhibited incomplete ﬁlling of the fracture area with healing ssue, and one animal showed a notably irregular and excessive healing ssue. Addionally, the control group displayed a higher density of ﬁbrous connecve ssue (F) in the healing region, with most samples being at the stage of ﬁbrous callus formaon. In groups A and R, the areas of new bone and carlage formaon (CF) within the healing region were more prominent, whereas groups D and E demonstrated a greater extent of ﬁbrous ssue (FIGS. 3 and 4). FIGURE 3. General view of the healing area at the fracture site in the Control (C) and treatment groups (A, D, E, and R), excluding the Healthy Control (HC). Magniﬁcaon 4×, H&E staining FIGURE 4. Normal bone ssue (BT) in the Healthy Control (HC) group, and areas of new bone formaon (NBF), ﬁbrosis or ﬁbrous callus (F), and carlage formaon (CF) in the experimental groups. Magniﬁcaon 10×, H&E staining 4 of 6

Revista Cienﬁca, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Fracture healing in the apixaban, edoxaban, and rivaroxaban groups was signiﬁcantly greater compared to the control group. Moreover, healing in the apixaban group was signiﬁcantly greater than that observed in both the dabigatran and edoxaban groups. Fracture healing in the rivaroxaban group was also signiﬁcantly greater than in the dabigatran group (TABLE I). Although not stascally signiﬁcant, there was a trend toward signiﬁcance in the comparison between the edoxaban and rivaroxaban groups (P = 0.05). TABLE I New Bone Formaon (NBF) Raos Across Experimental Groups Groups N Mean Std. Deviaon P* Control 8 41,75 5,57 0,000 (P<0,05) Apixaban a1 8 55,75 3,41 Dabigatran b1 8 44,00 4,66 Edoxaban a2, b2 8 48,63 5,55 Rivoraxaban a3,c 8 55,38 3,89 One Way Anova. P=0,000. a1 : 0,000 , a2 :0,044 , a3 :0,000. a1,2,3 : Diﬀerent compared with the controls. b1 0,000 , b2 :0,034, b1,b2 : Diﬀerent compared with the apixaban. c Diﬀerent compared with the dabigatran. c :=0,000. a1,2,3, b1,2, c : Tukey HSD. The mechanism of how ancoagulant medicaon interfere with bone healing was sll unclear. In this study, it was invesgated whether apixaban, edoxaban, rivaroxaban and dabigatran used as ancoagulants have any eﬀects on fracture bone healing. Prodinger et al. [16] invesgated the eﬀects of rivaroxaban on fracture healing and evaluated it biomechanically. They also examined callus formaon and found that more callus formaon occurred compared to the control group. In a study conducted by Klüter et al. [17], aﬅer creang fractures in the femurs of rats and ﬁxing them with Krishner wires, they reported a larger callus and a marginal increase in ssue mineral density in the rivaroxaban group compared to the control group. Histopathological evaluaon of rivaroxaban, one of the ancoagulant agents used in this study, revealed signiﬁcantly higher new bone (callus) formaon compared to the control group. The studies appear to be parallel. Namba et al. [18] reported that transioning paents with atrial ﬁbrillaon from warfarin to rivaroxaban was associated with increased markers of bone formaon and decreased markers of bone resorpon. These ﬁndings are consistent with the results of the present study, which demonstrated improved bone healing parameters in rats treated with rivaroxaban. Lau et al. [19] reported a lower risk of hip and vertebral fractures in dabigatran users compared to warfarin. In a similar study, Norby et al. [20] demonstrated a lower risk of hip and pelvic fractures in rivaroxaban users compared to warfarin. In this study, bone healing data in the rivoraxaban and dabigatran group were found to be higher compared to controls. Kyriakaki et al. [21] reported in a study that dabigatran did not produce a signiﬁcant diﬀerence in early bone defect healing compared to controls. A literature review did not reveal suﬃcient studies on the subject. However, this study observed a slight diﬀerence in callus formaon compared to the control group. Consequently, this study is not consistent with the current study. This diﬀerence may be due to the two studies being evaluated at diﬀerent stages of healing. Butler et al. [22] noted in a review that some limited studies suggested that ancoagulants may be eﬀecve in enhancing bone healing. Gómez-Outes et al. [23] evaluated apixaban, dabigatran, and rivaroxaban for thromboprophylaxis aﬅer total hip or knee arthroplasty and reported no signiﬁcant diﬀerence in eﬃcacy or safety among these new ancoagulants. In this study, no lesions were encountered in terms of thromboprophylaxis aﬅer the use of these new ancoagulants. Fusaro et al. [24] invesgated the eﬀects of dabigatran and warfarin on bone volume and architecture, suggesng that treatment with dabigatran may be associated with a reduced incidence of fractures. CONCLUSION There is very lile literature demonstrang the eﬀects of the new ancoagulant apixaban, edoxaban, rivaroxaban, and dabigatran on fracture healing. In this study, histopathological analyses demonstrated stascally signiﬁcant eﬀects of these ancoagulants on new bone formaon compared to the control group. Conﬂicts of interest The authors declare that there are no known conﬂicts of interest. BIBLIOGRAPHIC REFERENCES [1] Brinker WO, Piermaei DL, Flo GL. Small Animal Orthopedics & Fracture Treatment. 2nd ed. Philadelphia: WB Saunders Company; 1990. [2] Gartner LP, Hia JL. Color textbook of histology, 2nd ed. Philadelphia: WB Saunders Company; 2001. [3] Vertenten G, Gasthuys F, Cornelissen M, Schacht E, Vlaminck L. 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