|Year : 2020 | Volume
| Issue : 1 | Page : 1-8
Effect of fondaparinux on viability and ischemia reperfusion injury in the abdominal perforator flap
Guler Gamze Eren Ozcan1, Hakan Agir2, Murat Sahin Alagoz3, Tugba Kum4, Levent Trabzonlu5
1 Department of Plastic Reconstructive and Aesthetic Surgery, Sultan Abdulhamit Han Training and Research Hospital, Istanbul, Turkey
2 Department of Plastic Reconstructive and Aesthetic Surgery, Acibadem Altunizade Hospital, Istanbul, Turkey
3 Department of Plastic Reconstructive and Aesthetic Surgery, Medicine, Kocaeli University, Kocaeli, Turkey
4 Department of Biochemistry, Artvin State Hospital, Artvin, Turkey
5 Department of Pathology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
|Date of Submission||02-Jan-2019|
|Date of Acceptance||02-Mar-2019|
|Date of Web Publication||31-Dec-2019|
Dr. Guler Gamze Eren Ozcan
Bostanci Mah, Dar Yol Sk, No: 29 D: 4, Kadikoy, Istanbul
Source of Support: None, Conflict of Interest: None
Objective: The epigastric artery perforator flap is commonly used in the breast reconstruction. Ischemia during surgery results in the necrosis of the flap. We aimed to study the effect of fondaparinux in reperfusion injury in perforator flap model and determined its effects on the flap viability. Materials and Methods: Twenty-eight female Wistar Albino rats were included in this study. Rats were separated into three groups: A control (n = 9), B ischemia (n = 9), and C ischemia + drug (n = 10). Superior epigastric artery perforator flap on the single perforator was elevated in all groups. In Group A, flap was sutured back. In Group B, ischemia was applied for 4 h to the pedicle. In Group C, fondaparinux was administered 30 min before the reperfusion of the flap. Serum malondialdehyde (MDA), myeloperoxidase (MPO) levels, and histopathological examination of the flaps were studied. Results: The mean survival areas of flaps were 92.5%, 50.1%, and 91.1% in Group A, Group B, and Group C, respectively. Statistical differences were observed between these values (P < 0.05). The means of MPO and MDA were 22.3 ng/ml and 4.5 nmol/ml; 31.1 ng/ml and 4.7 nmol/ml; 27.1 ng/ml and 4.5 nmol/ml, respectively, for Group A, Group B, and Group C, and no statistically significant difference was found between groups (P > 0.05). Histopathologically, statistically significant difference was found between Group A, Group B, and Group C in terms of the infiltration of the leukocytes with polymorph nuclei (PMNL) for 24 h (P < 0.05). In the histopathological examinations done at the 7th day, statistically significant difference was found between groups in terms of edema, necrosis, increase in connective tissue, and leukocytes with polymorph nuclei (PMNL) (P < 0.05). Conclusion: Administration of fondaparinux after ischemia increased the flap viability in the epigastric artery perforator flap model.
Keywords: Fondaparinux, inflammation, ischemia reperfusion injury, superior epigastric artery perforator flap
|How to cite this article:|
Eren Ozcan GG, Agir H, Alagoz MS, Kum T, Trabzonlu L. Effect of fondaparinux on viability and ischemia reperfusion injury in the abdominal perforator flap. Turk J Plast Surg 2020;28:1-8
|How to cite this URL:|
Eren Ozcan GG, Agir H, Alagoz MS, Kum T, Trabzonlu L. Effect of fondaparinux on viability and ischemia reperfusion injury in the abdominal perforator flap. Turk J Plast Surg [serial online] 2020 [cited 2020 Jul 15];28:1-8. Available from: http://www.turkjplastsurg.org/text.asp?2020/28/1/1/274442
| Introduction|| |
Perforator flaps represent one of the important milestones in the history of plastic surgery. Deep inferior epigastric artery (DIEA) perforator being the first defined perforator flap is one of the methods used commonly for the autogenous breast reconstruction following the breast surgery treatment and giving the best reconstructive result.,
There is an obligatory period of ischemia in microvascular surgical procedures including free tissue transplantation. The ischemia-reperfusion (I/R) injury emerged with the prolongation of the obligatory period of ischemia during surgery may lead partial or complete loss in flaps. Circulation impairments occurring in the flap after the I/R injury still remains a challenge for reconstructive surgeons. In the publications of several centers, different solutions have been recommended, but these solutions require surgical skills and experience in advanced level, and they include an additional procedure.
In previously conducted studies, many drugs have been tested to prevent or to treat the thrombosis causing I/R injury, but most of them failed to enter into the clinical practice. Fondaparinux being selective factor Xa inhibitor used in the treatment and prophylaxis of the postoperative thrombosis and acute coronary syndrome, may have a potential role in flap surgery.,
Although studies have been conducted on fondaparinux and I/R injury, there is no conducted research on the perforator flap model. In our study, we aimed to investigate the I/R injury in the model of perforator flap model of fondaparinux and its effects on the flap viability.
| Materials and Methods|| |
The study was approved by the Local Ethical Committee of Animal Experiences of the Faculty of Medicine of Kocaeli University (KOU HADYEK). Twenty-eight female Wistar Albino rats weighing between 180 and 319 g were used.
Surgery was performed under the anesthesia obtained after the intraperitoneal injection of the combination of ketamine (0.9 g/kg) (Ketalar®, Pfizer, Turkey) and xylazine (10 mg/kg) (Xylazin® Bio, Bioveta, Czech Republic).
Flaps were drawn with the xiphoid located cranially and the spina iliaca in an anterosuperior direction caudally and at the level of the axillary line on both sides. The mean flap dimensions were 5.6 cm × 4.8 cm. In a clean but nonsterile environment, surgery was performed under loupe magnification and microscope.
The flaps were elevated with the preservation of the perforator vessels. We defined the first or the second perforator vessel of the rectus abdominis (RA) muscle as the dominant vessel of the flap [Figure 1] and cauterized the other perforators. DIEA was ligated within the rectus muscle just caudal to the selected perforator by protecting the point where the vessel was emerged from deep superior epigastric artery [Figure 2]. Following flap creation, rats were further divided into 3 groups.
|Figure 1: (a) Flap is elevated on the perforators, arrows indicate perforators. (b) Flap is elevated on a single perforator|
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|Figure 2: (a) Perforators of the epigastric artery within the right rectus muscle. (b) Application of ischemia to the dominant vascular perforator through the vascular clamp. (c) Deep inferior epigastric artery is tied with suture in the muscle. (d) Deep inferior epigastric artery is magnified under microscope|
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Group A (n = 9) formed the control group. The elevated flap on the selected perforator was again sutured back to its place with 5.0 monofilament nonabsorbable suture.
Group B (n = 9) formed the ischemia group. The pedicle was clipped for 4 h through BV1 vascular clamp (Trimed, Turkey) with the observation of ischemia under the microscope that there was no blood flow in the vessels. The restoration of blood flow to the flap after declamping of the pedicle was ensured under the microscope by visual control of the vessels.
In Group C (n = 10), ischemia was applied as in Group B. Rats received 0.02 mg/kg fondaparinux (Arixtra®, GlaxoSmithKline, Canada) subcutaneously 30 min before ensuring reperfusion to the flap. The dose and route of administration of fondaparinux were selected on the basis of dose–response data provided by Novo Nordisk from previous studies on rats. The flap was returned to its bed after reperfusion.
On the 24th h of surgery, 5-mm width biopsies were harvested along the inferior boundary of the flap [Figure 3] which is the less-perfused area of the flap, and also, 1-cc blood sample was collected from the distal of the tail.
|Figure 3: In the 24th h of surgery, biopsies were taken from the inferior border of the flap|
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Rats in the Group C were given daily dorsal subcutaneous injection of 0.02 mg/kg fondaparinux for 7 days.
At the end of the 7th day, photography was taken in standard height and under standard light from all animals under ether euthanasia of the flaps in the abdomen.
Microangiography was done with barium solution by applying cardiac perfusion to one randomly selected animal from each group.
Identification of the live area of flap
On the 7th day, a digital photograph was taken from the excised flaps [Figure 4]. Digital images were uploaded into the computer, and they were transferred into SketchUp (Version 8, Google) program. The survival rate was assessed in two separate times and was expressed as a percentage of the total flap area [Figure 5]. Live surface area was proportioned to the total surface of the flap by recording unit square area of the drawn surface given in the computer program after each drawing. In the statistical assessments, the mean of these two measurements was used for the percentage of live area of a flap.
|Figure 4: Photography of the excised flaps. (a) Control group (b) ischemia group (c) drug group|
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|Figure 5: Drawing the flap survival area with SketchUp program. (a) Gray area indicates the viable flap area, white area indicates the necrotic area. (b) Drawing the total area of the flap. (c) Drawing the necrotic area of the flap|
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Serum specimens separated from the blood taken from the individuals were studied by Alisei Quality System SEAC (Rome, Italy) by enzyme-linked immunosorbent assay method with malondialdehyde (MDA) and myeloperoxidase (MPO) reagents (Eastbiopharm, Hangzhou Co LTD, China) appropriate for rats.
The biopsies and the excised flaps were inserted into the 10% formaldehyde from those by putting a marking suture to the necrosis boundary (zone IV) at the contralateral after photographing. It was ensured to stay at least 24 h in 10% formaldehyde.
Paraffin blocks were prepared by taking into the routine follow-up, and 5-μm sections were taken from these blocks. Sections were stained through hematoxylin eosin. The sections were examined by a blind researcher under the light microscope (Olympus BX 51, Japan). Each biopsy was taken under the investigation that it will contain whole of the horizontal length of the flap. Necrosis, edema, thrombus, and infiltration of leukocytes with polymorphic nuclei (PMNL) in extravascular area were assessed. Each parameter was score between 0 and 5.
Increase in connective tissue was studied in samples taken at the 7th day in addition to other parameters. Sections were stained with Masson Trichrome. The procedure was repeated in two different sections belonging to the same biopsy [Figure 6].
|Figure 6: Examples of the histopathological biopsies (a) control group (24th hour), (b) ischemia group (24th hour), (c) drug group (24th hour), (d) control group (7th day), (e) ischemia group (7th day), (f) drug group (7th day) larger images are with x40 magnification, smaller images are with x400 magnification|
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At the end of the 7th day, anesthesia was applied to one randomly selected rat from each group. Left ventricle cannulation was ensured by opening the left side of the ribcage, and perfusion was initiated with warmed heparinized (prepared with Nevparin® 5000 IU/ml, Mustafa Nevzat, in 25 IU/ml) 0.9% NaCl solution. All vascular bed of the experiment animal was washed with approximately 500-ml perfusion solution following the incision done to the right atrium. Following the washing procedure, approximately warmed 60 ml NaCl solution with 25% barium sulfate was administrated by injector slowly through the same cannula. Then, dead rat was kept at 4°C for 24 h, and afterward, mammography was done to the flaps.
While assessing the findings obtained in the study, Number Cruncher Statistical System 2007 and PASS 2008 Statistical Software (Utah, USA) program were used for the statistical analyses. While assessing the study data, in addition to statistical methods (mean, Standard deviation, median), in comparing the quantitative data, Kruskal–Wallis test was used in the comparisons of the parameters that do not demonstrate normal distribution between groups, and Mann–Whitney U and independent sample t-test were used in the detection of the group causing difference and the assessment of two groups. ANOVA test was used in the comparisons between triple groups. Significance was assessed in the level of P < 0.05.
| Results|| |
In terms of general characteristics (weight, flap areas, and number of perforator), there was no statistical significant differences between groups and that they demonstrated homogeneous distribution [Table 1].
Flap survival area measurements
In Group A (control) (n = 9), the flap viability ratios varied between 85.51% and 99.08%, and the mean flap viability was 92.5% ± 4.9. The mean viable flap area was 22.6 ± 3.3 cm2 in the control group.
In Group B (ischemia) (n = 9), the viability ratios varied between 3.63% and 84.95%, and the mean survival ratio was 50.1% ± 30.4. The mean viable flap area was 11.8 ± 2.3 cm2 in the ischemia group.
In Group C (ischemia + drug) (n = 10), the viability ratios varied between 68.49% and 97.17%, and the mean value was 91.1% ± 9.9. The mean viable flap area was 21.2 ± 2.9 cm2 in the ischemia + drug group.
The viability ratios of the control group (A) and the drug group (C) which were 92.5% and 91.1%, respectively, were observed higher than the ischemia group (50.1%). There was a statistically significant difference between the control group and the ischemia group and between the drug and the ischemia group in viability ratios (P < 0.001). It was observed that the drug administration after the ischemia has increased the flap survival area ratios than the control group [Table 2].
MPO and MDA values were examined from the serum sample taken from rats of all groups, at the 24th h.
In MPO measurement, the mean values were 22.3 ± 9.6 ng/ml in control group, 31.1 ± 9.1 ng/ml in ischemia group, and 27.1 ± 5.2 ng/ml in drug group, and no statistically significant differences were observed between three groups (P = 0.09). It was observed that the mean MPO value of the ischemia group (31.1 ng/ml) was higher than that of the control group (22.3 ng/ml) and higher than that of the drug group (27.1 ng/ml), but this was not statistically significant (P = 0.24) [Table 3].
In MPO measurement, the mean values were 4.5 ± 0.2 nmol/ml in control group, 4.7 ± 0.4 nmol/ml in ischemia group, and 4.5 ± 0.3 nmol/ml in drug administrated group, and no statistically significant differences were observed between the three groups (P = 0.25) [Table 3].
The mean MDA value in the ischemia group (4.7 nmol/ml) was found to be slightly higher than control group (4.5 nmol/ml) and higher than that of the drug group (4.5 nmol/ml), but no statistically significant differences were observed between both groups (P = 0.29) [Table 4].
The histopathological assessment of biopsies harvested at 24th h
The mean value of edema was 1.55 ± 0.5 and the mean value of the infiltration of PMNL was 1 ± 0.7 in control group. In ischemia group, the mean value of edema was 2.3 ± 0.7 and the mean value of PMNL was 1.6 ± 0.5. In drug group, the mean value of edema was 2 ± 1 and the mean value of PMNL was 0.7 ± 0.5.
Necrosis and thrombus scoring were assessed as 0 in all groups. There was no statistically significant difference in edema between three groups (P = 0.16), and no significant difference in edema was found between ischemia group and drug-administrated group after ischemia (P = 0.49) [Table 5].
When three groups were compared in PMNL infiltration, statistically significant differences were observed (P < 0.001). When the drug group was compared with control group and ischemia group, the reduction between them was statistically significant. It was revealed that fondaparinux administration reduced leukocyte infiltration in the extravascular area after the ischemia [Figure 6] and [Table 5].
The histopathological examination done at the 7th day
In control group, the mean value of the necrosis was 0.35 ± 0.1, the mean of the edema was 2.5 ± 0.75, the mean value of the infiltration of PMNL was 2.37 ± 1.18, and the mean value of the connective tissue increase was 2.12 ± 1.55.
In ischemia group, the mean value of the necrosis was 3.33 ± 1.93, the mean of the edema was 3.9 ± 0.6, the mean value of the thrombus was computed as 1.22 ± 0.24, the mean value of PMNL infiltration was 4.33 ± 0.86, and the mean value of the connective tissue increase was 1.67 ± 1.55.
In the drug-administrated group after ischemia, the mean value of the necrosis was 0.55 ± 0.2, the mean of the edema was 2.5 ± 0.75, the mean value of infiltration of PMNL was 2.41 ± 0.75, and the mean value of the connective tissue increase was 2.97 ± 1.25.
No thrombus was observed in the control and drug groups.
Between three groups and between ischemia and drug groups, it was seen that there was a statistically significant difference in terms of necrosis, edema, and PMNL (P < 0.001). It was found that connective tissue increase was higher in drug group than other groups (P = 0.05) [Table 6].
It was revealed that fondaparinux reduced necrosis, edema, thrombus, and leukocyte infiltration after the ischemia.
In the drug-administrated group, it was seen that vessels were macroscopically more and larger [Figure 7].
|Figure 7: Microangiographic results of the flaps. (a) control group (b) ischemia group (c) drug group|
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| Discussion|| |
The main findings of our study were administration of fondaparinux in the I/R model of the deep superior epigastric artery perforator flap increased flap viability, histopathologically decreased infiltration of leukocyte with polymorphic nuclei at the 1st day, and was associated with reduction in edema, thrombus, PMNL, necrosis, and increase in the connective tissue at 7th day.
Ischemia is one of the primary factors affecting flap viability. Kerrigan et al. have identified three probable causes of the global flap ischemia as a flap being designed greater than the intrinsic blood flow, arterial thrombosis, and venous thrombosis.
Thrombosis in flaps with axial and random pattern occurs secondarily to the lower flow emerging usually at the microcirculation level, and its causes are systemic factors such as inappropriate flap design, I/R injury, hypotension, smoking, sepsis or compression of the pedicle or flap. In free flaps, arterial or venous thrombosis causing to the total flap loss yields from the anastomosis line. This is usually a result of the poor technique, the exposition of the adventitia or media tending to thrombosis instead of smooth endothelium at the anastomosis line leads to the accumulation of fibrin and thrombocyte during blood flow. Therefore, flap surgery should be combined with antiplatelet and antithrombocyte treatment.
The ideal agent used in the flap surgery should reduce the thrombus formation which will increase blood flow to the flap and can be clinically applicable with a low rate of bleeding complications.
I/R injury is associated with the free oxygen radicals and inflammatory mediators which increase cellular damage in addition to injury caused by the ischemia. Due to the fact that thrombosis and free oxygen radicals are two main causes in the I/R injury, drugs such as Vitamin A and Vitamin E among antioxidants, heparin, dextran, aspirin, and pentoxifylline, have been tested to prevent thrombosis and to reduce the inflammation initiated by thrombosis.
It has been observed that the use of Vitamin A and Vitamin E in the venous ischemia increases flap viability, but their effects are synergistic and these agents do not demonstrate this effect alone.
In 2014, Pan et al. have evaluated aspirin, low-molecular weight heparin, and the use of heparin in free flaps in the thrombus prophylaxis. They found that the flap loss ratios of either heparin or aspirin were similar, but they observed that the use of heparin and low molecular weight heparin in higher dose was associated with greater flap loss. The ideal anticoagulant treatment in free flap surgery should decrease thrombosis effectively in the pedicle and it should have minimal side effects (especially hematoma).
Unal et al. observed in their ischemia model in rat muscle tissue that pentoxifylline decreases leukocyte–endothelium interaction in the examination of intravital fluorescent microscopy and that pentoxifylline may have therapeutic effect by reducing the I/R injury. Moreover, Isken et al. observed that pentoxifylline increases the flap viability by reducing the unfavorable effects of the diabetes in diabetic rats.
Aǧir et al. demonstrated that hyperbaric oxygen treatment increased the flap viability in axial abdominal skin flap of rat, and they have demonstrated that it reduced the effects of the I/R injury.
In our study, we aimed to study the efficacy of fondaparinux which is one of the new generation anticoagulants in ischemia perfusion injury and in the flap viability.
Fondaparinux is a synthetic indirect inhibitor of active Factor Xa, and it binds to antithrombin III selectively and it increases the neutralization of AT III of Factor Xa approximately 300 folds and decrease formation of thrombin, the development of thrombus are prevented. Unlike other anticoagulants, it does not bind more than one factor in the coagulation cascade.
Fondaparinux does not cause thrombocytopenia which can be observed during heparin and low molecular weight heparin treatment. It has advantages such as the administration of daily single dose (2.5 mg, subcutaneously), having a half-life of 17–21 h, having an stable anticoagulant dose response, and requiring no laboratory monitoring; on the other hand, it does not have a specific antidote.
Fondaparinux was more effective than enoxaparin in patients who underwent orthopedic surgery in preventing venous thromboembolism and that it has similar activity as enoxaparin or unfractionated heparin in patients with deep venous thrombosis and pulmonary embolism., In pilot studies conducted in patients with acute coronary syndrome and primary percutaneous intervention,,, it was observed that fondaparinux was effective as enoxaparin and safer than unfractionated heparin.
In patients with acute coronary syndrome, it was demonstrated that fondaparinux and enoxaparin have similar clinical efficacy in hospital period; fondaparinux was associated with lower bleeding when compared with enoxaparin, and in long-term follow-up, the use of fondaparinux was associated with lower mortality. In patients with ST elevation myocardial infarction who underwent primary percutaneous intervention, it has been demonstrated that fondaparinux was associated with lower mortality and also reduced hemorrhage and stroke.
Demirtas et al. investigated the effect of fondaparinux on fracture healing, and they observed that it has no effect on the fracture healing and that it can be used for the postoperative thromboembolism prophylaxis during surgery.
This is the first study in the literature conducted to investigate the effect of fondaparinux on the flap I/R injury model.
Chung et al. demonstrated that fondaparinux was effective as low molecular weight heparin in increasing flap viability in a venous congestion model of rabbit auricular flaps, and both drugs were superior when compared to controls. Consistent with their study, in our study, we have observed that fondaparinux increases the flap viability when compared to control group. In addition to their study, we have observed that it has a positive effect on I/R injury and improvement in histopathological findings.
An experimental I/R study demonstrated that fondaparinux decreases the expression of interleukin-6 mRNA and MP-2 mRNA, but it does not affect the expression of MCP-1 m-RNA. Fondaparinux decreases the neutrophil accumulation around the tubules, and hence, it has protective effect for the I/R injury. Montaigne et al. demonstrated that fondaparinux reduces the inflammatory response and oxidative stress in the I/R model in the heart, and it was suggested that fondaparinux may have protective activity in myocardial dysfunction.
Frank et al. demonstrated that fondaparinux has a protective effect in the renal I/R injury model and is associated with reduced inflammation.
Based on the above-mentioned studies, fondaparinux was associated with reduced ischemia, prevents I/R injury in experimental studies, and is also associated with a low bleeding rate compared to other anticoagulants in clinical studies. Therefore, we suggested that fondaparinux can be an ideal drug in reducing flap ischemia.
We also have demonstrated that administration of fondaparinux increased the flap viability compared to control group in macroscopic evaluation, and it was also associated with improvement in histopathological findings. Fondaparinux reduced the infiltration of leukocytes with polymorph nuclei (PMNL) in extravascular level. In the evaluation done at the 7th day, fondaparinux reduced thrombus, edema, leukocyte infiltration, and necrosis in the drug-administrated group. These findings may be associated with anti-inflammatory activity of fondaparinux in addition to the anti-ischemic effects.
No significant differences were found between the groups in levels of MPO and MDA among the I/R parameters.
Similar to our study, it was observed that the MDA levels measured after 5-min reperfusion following ischemia in the epigastric island flap in rats exposed to smoking showed an inverse correlation with flap viability and that there were no significant difference between groups in MPO levels.
Fondaparinux pretreatment caused no significant alteration in the MPO level in the intestinal ischemia and reperfusion model. Insufficient response was related to the limited dose-response data in the literature. In our study, we could not find statistically significant differences between MDA and MPO values because the lower number of rats which we included into the groups may affect these results.
| Conclusion|| |
In our study, we found that fondaparinux has increased the flap viability in superior epigastric artery perforator flap of rat after the ischemia. In addition, we have observed improvement in histologic findings consistent with reduced inflammation and I/R injury. Our study is promising for future studies in humans, and fondaparinux may be a potential drug for the improvement of flap viability among other anticoagulant treatment options. If future studies support our findings, it may become alternative drug in clinical practice.
In our study, the number of rats may be considered low to assess the statistical significance for the biochemical parameters. The causal relationship of mechanism of the reduction of I/R injury cannot be clearly elucidated based on our findings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]