The Effectiveness of Long-term Use of Low-Molecular-Weight Heparin on Venous Thromboembolism After Sleeve Gastrectomy in Rats

Abstract

Objectives:

The aim of the study was to investigate the effects of bemiparin administration for 15 and 30 days on deep vein thrombosis (DVT) in high-fat diet-induced rats, followed by sleeve gastrectomy (SG) for DVT prophylaxis.

Setting:

The study was conducted at the Kobay Experimental Animals Laboratory.

Materials and Methods:

Forty rats were fed a high-fat diet to induce obesity. They were then equally divided into four groups (n = 10); group 1 (control group); group 2 (nonbemiparin group); and group 3 (15-day bemiparin group) and group 4 (30-day bemiparin group) in which bemiparin therapeutic doses were administered for 15 and 30 days, respectively. Sixteen weeks after feeding, SG was performed on rats from groups 2, 3, and 4. Doppler ultrasonography was performed to investigate thrombosis of the inferior vena cava and iliac veins in all rats before and 1 month after SG. Rat vena cava, iliac veins, and lung tissues were removed to determine venous thrombosis status and investigate microthrombi through histological examination.

Results:

No statistically significant difference was found between groups in terms of the thickness of intima–media (μm), thrombus area (μm²), and erythrocyte, leukocyte, and platelet/fibrin values of the iliac veins (p > 0.05). A statistically significant difference was found between groups in terms of the presence of thrombus and radiological status of the vena cava (p < 0.05). In addition, the measurement percentage was found to be 100% in group 2, 37.5% in group 3, and 12.5% in group 4.

Conclusion:

We believe that administration of bemiparin once a day for 30 days can be a safe and effective treatment method in the prevention of microthrombi, following SG.

Introduction

Obesity is a chronic disease caused by higher energy intake compared with the energy spent, with an increasing prevalence worldwide. Obesity is rapidly increasing particularly among young people due to a sedentary lifestyle and high-calorie fast-food consumption and can cause devastating chronic diseases at an earlier age. Although the low-calorie diet plays a role in the treatment of early obesity (body–mass index [BMI] 30–39), people with advanced obesity (BMI >40) may not achieve weight loss with a diet because changes in feeding habits may be insufficient in many cases. In recent years, surgical approaches have shown great potential as appropriate options in the treatment of morbid obesity. Various methods such as restrictive, absorption reduction or methods that have both effects are performed in surgical procedures. The sleeve gastrectomy (SG) method has been increasingly used in recent years with weight loss rates similar to Roux-en-Y gastric bypass. Following obesity surgery, significant improvements have been seen in comorbidities in addition to weight loss.¹ SG is a surgical weight loss method that consists of removing about 80% of the stomach using the laparoscopic approach.² Improvements have also been observed in patients' complaints, such as high blood pressure, bad cognition and mood status, infertility, and irregular periods, with SG.²

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are serious clinical problems that affect >1 million people and cause 200,000 deaths in the United States each year.^3,4 Autopsy studies have shown that PE accounts for approximately 10%–15% of hospital mortality.⁵ Immobilization, surgery, and obesity are independent risk factors for DVT. The risk of PE and DVT is twofold higher in obese patients when compared with nonobese patients.⁶ An increased risk of DVT can be expected in SG. Low-molecular-weight heparin (LMWH), which is used for chemical thromboprophylaxis, reduces the prevalence of venous thromboembolism (VTE) in hospitalized patients.^7,8 The risk of DVT in surgical patients who received prophylaxis decreases by about 60%.⁷ The reported postoperative incidence of VTE after bariatric surgery, however, varies widely from 0.2% to 5%.⁹ Similarly, the rate of bleeding after surgery varies from 0% to 6%.¹⁰ However, in current practice, there is no exact consensus on the duration of use of LMWH in the prophylaxis of VTE and PE in patients who undergo SG. Inadequate maintenance of LMWH may not prevent DVT and PE, but on the other hand, its overuse can cause the SG incision line related to fatal abdominal bleeding.¹¹

In this present study, we designed a rat model with simulated morbid obese status and SG. We investigated the presence of DVT in the external iliac veins and inferior vena cava of rats that were and were not given bemiparin sodium (LMWH) through Doppler ultrasonography (USG) and histological examination. Histological examination was performed to determine microthrombus formation that could not be visualized with Doppler USG. PE was evaluated with histological examination. The aim of our study was to investigate the adequate administration duration of LMWH to prevent DVT and PE in obese rats after SG.

Materials and Methods

In this study, we used 40 adult, male, albino Wistar rats (120 g). Animals were obtained from the Kobay Animal Breeding and Experimental Research Laboratory. The experimental protocol was approved by the animal ethics committee of Kobay Company, Turkey (Approved No.: 289). All animal experimentation procedures described were conducted in accordance with accepted standards of animal care. Rats were fed a high-fat diet for 16 weeks to induce obesity. Sixteen weeks after feeding, SG was performed on rats from groups 2, 3, and 4 (Fig. 1). The rats were equally divided into four groups (n = 10): group 1 (control group; only obese and no intervention); group 2 (nonbemiparin group; only SG was performed), group 3 (bemiparin 15 group; SG +250 U/kg bemiparin was subcutaneously administered once a day for 15 days), and group 4 (bemiparin 30 group; SG +250 U/kg bemiparin was subcutaneously administered once a day for 30 days). LMWH (bemiparin) was administered just before the SG.

FIG. 1.

Sleeve gastrectomy technique.

SG technique

The abdomen was shaved using surgical clippers (Andis AG, Shelton, CT). A 4-cm midline epigastric incision was made, then the terminal esophagus and the lesser and greater curvatures of the stomach were dissected free. A clamp was placed along the greater curvature from the antrum to the fundus across the forestomach and glandular stomach. A scalpel was used to divide the greater curvature along the clamp, removing ∼90% of the forestomach and 70% of the glandular stomach. The divided stomach was then closed with a 3-0 Vicryl suture (Ethicon, Piscataway, NJ) in three layers, creating the gastric sleeve. The wound was irrigated with 30 mL of normal saline. The abdominal wall was closed in two layers, the peritoneum and fascia were closed with a 3-0 Vicryl suture (Ethicon), and the skin was closed with a 3-0 Ethilon nylon suture (Ethicon) in a continuous manner.

Radiological examination

Doppler USG was performed using the GE Logiq E9 USG (General Electric Company, Boston, MA, 2016) device to investigate thrombosis of the inferior vena cava and iliac veins. The GE 11L Linear Probe (GE, General Electric Company, 2016), a high-resolution (3–11 MHz) probe, was used for the Doppler USG procedure (Fig. 2). The presence of thrombus was investigated in rats under anesthesia by performing Doppler USG just before and 1 month after SG. Thus, misdiagnosis of possible thrombi in rats was avoided with Doppler USG at the same time. The Doppler USG probe was placed directly on the veins, thus avoiding artifacts that could be caused by rat's skin before scarification under laparotomy. Iliac vein and vena cava inferior Doppler USG findings were divided into 4 categories. Radiological status was defined as follows:

FIG. 2.

Doppler ultrasonography.

Category 1 (Normal): No clotting on Doppler USG.

Category 2 (Focal partial thrombosis): Occlusion of <50% of the lumen or blood flow in a large portion of the lumen with Doppler USG or ability to create compression in a large portion of the lumen with the probe.

Category 3 (Near-complete thrombosis): Occlusion of >50% of the lumen or blood flow in a small portion of the lumen with Doppler USG or ability to create compression in a small portion of the lumen with the probe.

Category 4 (Total thrombosis): Occlusion of the entire lumen, no blood flow with Doppler USG, and lack of a decrease in the anterior–posterior (AP) diameter of the vein when compressed with the probe.

If there was only one of these findings, the case was included in the category in which the finding was defined, and if there were findings of more categories, the case was included in a higher category. In all experimental animals, Doppler USG was performed by the same radiologist (who had at least 10 years of ultrasound experience) along all traces of both iliac vein and inferior vena cava. To detect blood flow on Doppler USG, the examination was carried out using power Doppler mode and possible slow blood flow was detected by keeping Doppler sensitivity as high as possible in the power mode. If there were scattering artifacts on power mode, spectral Doppler was performed at an angle of 60% and the presence of venous flow trace was investigated. Thus, we tried to detect the presence of possible slow flow in the most correct way.

Histological analysis

Rats were sacrificed and the vena cava, iliac veins, and lung tissues were removed for histological examination. Vena cava, iliac vein, and lung tissues were fixed with 10% formalin for 48 h and embedded in paraffin wax. The tissues were then cut into 4-μm-thick sections and the sections were dewaxed in xylene twice at 37°C for 15 min each, rehydrated through decreasing concentrations of ethanol, and washed in distilled water at room temperature for 5 min each. They were finally stained with hematoxylin and eosin (H&E). For H&E staining, the slides were dipped into the jar containing hematoxylin for 5 min and stained with eosin for 30 s at room temperature. After staining, specimens were observed under a light microscope to evaluate the histomorphology of the thrombus in venous walls and lung tissues.

The concept of the presence of thrombus and measured percentages were as follows:

The thrombus predominantly consists of three components: fibrin/platelet accumulations, red blood cells (RBCs), and white blood cells (WBCs). Data were normalized to the square meter thrombus area. The percentage of fibrinogen, erythrocytes, and platelet area in relation to the whole thrombus area was investigated in overview images of the thrombi that were taken with a camera and analyzed using Cap-Image 7.1 software (Dr Zeintl, Heidelberg, Germany) and Adobe Photoshop. The specimens were examined for histologic changes in the vein wall and the presence of associated thrombus stained with H&E. In all segments, venous wall thickness was measured using real-time high-definition zoom with a high-resolution linear array transducer. For each venous segment, three measurements were obtained and the average value was used. Additionally, after staining the lung samples, specimens were observed under a light microscope to evaluate the histomorphology of the lung tissue.

Statistical analysis

Data were statistically analyzed using IBM SPSS Statistics 23.0 software. Numerical variables were expressed as descriptive statistics (mean and standard deviation) and categorical variables were also expressed as descriptive statistics (frequency and percentage). Differences between two groups were examined with an independent sample t test, and differences between more than two groups were examined with one-way ANOVA. As the result of ANOVA, first the Levene test was used for variance homogeneity, and then the group or groups that caused the difference were analyzed with a multiple comparison test (Bonferroni or Tamhane's T2). Differences between groups were examined with the Bonferroni test for variables that met variance homogeneity and Tamhane's T2 test for variables that did not meet variance homogeneity. In addition, correlations between categorical variables were analyzed with the chi-square test.

Results

The median initial weights of the rats were 120.5 g (min–max: 119–123) in group 1; 120 g (min–max: 119–122) in group 2; 120.5 g (min–max: 119–123) in group 3; and 120 g (min–max: 119–123) in group 4. After 16 weeks of feeding with a high-fat diet, the median weights of rats were determined as follows: 548.5 g (min–max: 500–600) in group 1; 566.5 g (min–max: 500–600) in group 2; 566.5 g (min–max: 500–600) in group 3; and 554 g (min–max: 510–600) in group 4. DVT was not observed in Doppler USG performed before SG in all rats of all groups. The radiological and histological features of iliac veins and the inferior vena cava after SG are presented below. Table 1 summarizes the findings of Doppler USG.

Table 1.

Doppler Ultrasonography Findings of the Study

		Category 1, n (%)	Category 2, n (%)	Category 3, n (%)	Category 4, n (%)	p^*
Iliac V	Nonbemiparin group	4 (50)	3 (37.5)	1 (12.5)	None	>0.05
	Bemiparin 15 group	5 (62.5)	3 (37.5)	None	None
	Bemiparin 30 group	7 (87.5)	1 (12.5)	None	None
IVC	Nonbemiparin group	None	1 (12.5)	3 (37.5)	4 (50)	<0.05 ^*
	Bemiparin 15 group	5 (62.5)	3 (37.5)	None	None
	Bemiparin 30 group	7 (87.5)	1 (12.5)	None	None

Statistically significant is indicated by bold characters, p < 0.05.

Iliac V, iliac veins; IVC, inferior vena cava.

Radiological and histological findings of iliac veins

Doppler USG findings of iliac veins

In the nonbemiparin group, Category 1 (no vein thrombosis) was found in 50%, Category 2 was found in 37.5%, Category 3 was found in 12.5%, and Category 4 was not observed. In the bemiparin 15 group, Category 1 was found in 62.5% and Category 2 was found in 37.5%. In the bemiparin 30 group, Category 1 was found in 87.5% and Category 2 was found in 12.5%. Category 3 and Category 4, indicating more severe thrombosis, were not observed in any of the rats of the bemiparin 15 group and bemiparin 30 group.

In all groups, there was no statistically significant difference in terms of the radiological findings of iliac veins (p > 0.05). However, the measured percentage, which was an indicator of iliac vein thrombosis, was higher in nonbemiparin and bemiparin 15 groups than in the bemiparin 30 group (50% vs. 12.5%).

Findings of iliac veins on histological examination

In all groups, the thickness of intima–media (μm) (Fig. 3); thrombus area (μm²); erythrocyte, leukocyte, and platelet/fibrin values; and presence of thrombus were similar (p > 0.05) (Table 2).

FIG. 3.

Photomicrographs of the iliac vein sections. Organized thrombus consists of platelets, large amount of red blood cells, and variably interspersed white blood cells in iliac vein lumen sections of rats from the nonbemiparin group (A, B). Small thrombus was present in the vascular lumen of rats from the bemiparin 15 group (C, D). No thrombus was observed in the lumen of iliac veins of rats from the bemiparin 30 group (E, F) (H&E stained; scale bars of the pictures on the left, 500 μm; scale bars of the pictures on the right, 20 μm). H&E, hematoxylin and eosin.

Table 2.

Examining the Relationship Between Values and Groups

Iliac vein	Nonbemiparin		Bemiparin 15		Bemiparin 30		Test	p
Iliac vein	N	%	N	%	N	%	Test	p
Intima–media measurement (μm)	81.72 ± 15.49		76.15 ± 9.12		76.80 ± 16.34		0.377^a	0.690
Thrombus area (μm²)	341178.68 ± 483808.85		133072.03 ± 18432.22		33108.57 ± —		0.720^b	0.490
Thrombus measurement status
No	0	0.0	5	62.5	7	87.5	13.000^c	0.002
Yes	8	100.0	3	37.5	1	12.5	13.000^c	0.002
Radiology
No	0	0.0	5	62.5	7	87.5	18.500^c	0.005
<50	1	12.5	0	0.0	1	12.5
50–99	3	37.5	3	37.5	0	0.0
100	4	50.0	0	0.0	0	0.0
Erythrocytes	337212.19 ± 316770.06		18689.83 ± 3507.97		16947.54 ± —		2.844^b	0.025
Leukocytes	109238.80 ± 74298.79		42493.16 ± 30309.21		13573.03 ± —		2.115^b	0.065
Platelets/fibrin	258723.04 ± 348993.44		19152.35 ± 2809.49		4088.00 ± —		1.941^b	0.093

Statistically significant is indicated by bold characters, p < 0.05.

One-way ANOVA test.

Independent sample t test.

Chi-square test.

Radiological and histological findings of the inferior vena cava

Doppler USG findings of the inferior vena cava

In the nonbemiparin group, all rats had a clot in the inferior vena cava, Category 1 was not observed, Category 2 was found in 12.5%, Category 3 was found in 37.5%, and Category 4 was found in 50%. In the bemiparin 15 group, Category 1 was found in 62.5% and Category 3 was found in 37.5%. In the bemiparin 30 group, Category 1 was found in 87.5% and Category 2 was found in 12.5%. Category 3 and Category 4, indicating more severe thrombosis, were not observed in the bemiparin 30 group. The rate of Category 4 was statistically significantly higher in the nonbemiparin group compared with the bemiparin 15 and bemiparin 30 groups.

A statistically significant difference was found between all groups in terms of Doppler USG findings of the inferior vena cava (p < 0.05). The rate of thrombi in the inferior vena cava was less frequent in the bemiparin 30 group than in other groups.

In addition, the measurement percentage, which is an indicator of inferior vena cava thrombosis, was found to be 100% in the nonbemiparin group, 37.5% in the bemiparin 15 group, and 12.5% in the bemiparin 30 group. The measurement percentage was statistically significantly higher in the nonbemiparin group compared with the bemiparin 30 group (p < 0.05).

Findings of inferior vena cava on histological examination

The thickness of intima–media (μm), thrombus area (μm²), and leukocyte and platelet/fibrin values of the inferior vena cava were similar (p > 0.05) in all groups (Table 3).

Table 3.

Examining the Relationship Between Values and Groups

Inferior vena cava	Nonbemiparin		Bemiparin 15		Bemiparin 30		Test	p
Inferior vena cava	N	%	N	%	N	%	Test	p
Intima–media measurement (μm)	24.68 ± 17.38		26.89 ± 15.64		23.20 ± 6.55		0.140^a	0.870
Thrombus area (μm²)	62697.35 ± 29619.46		28518.41 ± 18110.67		17088.33 ± —		1.969^b	0.096
Thrombus measurement status
No	4	50.0	4	50.0	7	87.5	3.200^c	0,202
Yes	4	50.0	4	50.0	1	12.5	3.200^c	0,202
Radiology
No	4	50.0	5	62.5	7	87.5	4.018^c	0.404
<50%	3	37.5	3	37.5	1	12.5
99–50%	1	12.5	0	0.0	0	0.0
Erythrocytes	13858.14 ± 24285.01		1642.12 ± 611.42		1489.75 ± —		1.006^b	0.389
Leukocytes	15552.52 ± 17914.04		4286.14 ± 4214.35		2353.32 ± —		1.224^b	0.267
Platelets/fibrin	6300.33 ± 7121.54		1478.49 ± 776.45		1055.05 ± —		1.346^b	0.269

One-way ANOVA test.

Independent sample t test.

Chi-square test.

In all groups, there was a statistically significant difference in terms of the presence of thrombus or not (p < 0.05). The mean erythrocyte value was significantly higher in the nonbemiparin group compared with the bemiparin 15 group (Fig. 4). The rate of thrombi in the inferior vena cava was more frequent in the nonbemiparin group than in other groups.

FIG. 4.

Photomicrographs of the vena cava sections. Example of a histologically processed well-organized thrombus with red blood cells (red) and fibrin accumulation (pink areas) and white blood cells that are variably interspersed (dark blue) from the nonbemiparin group (A, B). Small thrombus was seen in the lumen of vena cava from bemiparin 15 (C, D) and 30 (E, F) groups (H&E stained, scale bars of the pictures on the left, 500 μm, scale bars of the pictures on the right, 20 μm).

Additionally, we histologically examined the lung tissue of rats. The H&E stain exhibited the mixed thrombus consisting of platelets, a large amount of RBCs, and interspersed WBCs in the lumen of the pulmonary artery, and no statistically significant difference was found between all groups (Fig. 5).

FIG. 5.

Photomicrographs of the lung sections. Mixed thrombus with accumulation of a large amount of red blood cells (red) and white blood cells (dark blue) and fibrin areas (pink) in the lumen of pulmonary artery (A, B: nonbemiparin group; C, D: bemiparin 15 group; E, F: bemiparin 30 group; H&E stained; scale bars of the pictures on the left, 100 μm, scale bars of the pictures on the right, 50 μm).

Discussion

Obesity surgery has been shown to be the most effective treatment method in morbidly obese patients and provides continuous weight loss. Many international surgery and medicine societies such as the International Federation for the Surgery of Obesity (IFSO), European Association for Study of Obesity (EASO), and European Childhood Obesity Group (ECOG) conduct research to provide safe and effective clinical applications in the field of bariatric surgery.^12,13 Especially morbid obesity with a BMI >50 is an important predisposing factor for VTE. Increased intra-abdominal pressure due to sedentary life and truncal obesity significantly affects inferior vena cava blood flow. In addition, other risk factors, including advanced age, a history of VTE, immobilization, venous insufficiency, smoking, oral contraceptives, hormone replacement treatment, and coagulation disorders, also increase this risk.¹⁴

Patients without any complaints for thrombosis and with no clinical, radiological, or pathological findings after the operation can usually be discharged with 10-day LMWH. Since the majority of VTE complications occur after hospital discharge, an extended thromboprophylaxis approach is necessary, especially for high-risk patients.¹⁵ Magee et al. reported that the rate of postoperative VTE and bleeding was 0% for 735 patients who underwent bariatric surgery and received extended-duration (1–3 weeks) thromboprophylaxis with LMWH.¹⁶ Tseng et al., in a retrospective study of 817 patients, reported a 0.5% rate of postoperative VTE in those managed with extended duration (10 days) of tinzaparin.¹⁷ To our knowledge, there are no studies of long-term use of bemiparin after SG and our study is the first to histologically evaluate the occurrence of thrombus in the iliac vein, vena cava, and lung tissue after SG, which is today's most commonly performed bariatric procedure.

A patient undergoing bariatric surgery is at low–moderate risk of VTE.¹⁸ In addition, many obesity-related conditions such as chronic venous insufficiency, sleep apnea, obesity hypoventilation syndrome, painful degenerative arthropathy (decreasing mobility), or chronic hypoxemia may increase the risk of VTE in obese patients.¹⁶ Many obese patients may have three or four of these additional risk factors.¹⁹

It is thought that placing the patient in the reverse Trendelenburg position with pneumoperitoneum will increase venous stasis in lower extremities and decrease the flow to the iliac veins and inferior vena cava, posing a risk for VTE during laparoscopic SG. In bariatric surgery, VTE prophylaxis can be administered mechanically with graduated compression stockings, intermittent pneumatic compression (IPC) devices, and venous food pumps and pharmacologically using a vena cava filter.²⁰

Today, LMWH is widely recommended for acute and long-term treatment of VTE.²¹ In addition, randomized controlled studies have shown that LMWH is more reliable and effective than vitamin K antagonists.²² Bemiparin is an LMWH that has been used for thromboprophylaxis and treatment of VTE for 20 years. Bemiparin is named as a second-generation LMWH because it has a lower average molecular weight than other LMWHs at 3.6 kDa and narrow distribution of saccharide chain lengths and most of them are <6 kDa. It is used as a single daily dose.²³

Meyer et al. prospectively used long-term bemiparin for the first time for VTE in 89 active cancer patients. The patients were followed up for 9 months and received bemiparin once a day. VTE recurrence was observed at 2.4% in the sixth month and at 5.9% in the ninth month. Major bleeding was found at 1.3% and minor bleeding at 8% at the 6-month follow-up. Bleeding rates in that study were interpreted as less than the other studies. The authors argued that bemiparin is effective and reliable in long-term treatment of cancer-related VTE.²⁴ Revilla-Penaloza et al. compared the use of bemiparin and enoxaparin in DVT prophylaxis in patients undergoing plastic and reconstructive surgical procedures, with a moderate–high thrombogenic risk, and argued that bemiparin can be considered as a good alternative drug because it is more cost-effective and has no hemorrhage and adverse effects; however, as far as we know, there are very few studies on the use of bemiparin in bariatric surgery.²⁵

Unfortunately, there is still no exact consensus on prevention of VTE in bariatric surgery patients. Some authors administer dosage based on body weight, while others suggest that body weight is not important.²⁰ The American College of Chest Physicians recommends LMWH, unfractionated heparin, fondaparinux, or a combination of one of these drugs with IPC three times a day. The American Society for Metabolic and Bariatric Surgery recommends the use of both mechanical and pharmacological prophylaxis in bariatric patients. Data of bariatric surgeons on adherence to the mentioned instructions are controversial.⁷ Wu and Barba reported that 95% of bariatric surgeons follow the VTE prophylaxis rules, while in another study, it was demonstrated that only 58.5% of surgical patients under VTE risk received prophylaxis.²⁶

In a prospective study by Vavken et al., investigating the effectiveness of 3500 IU versus 5000 IU bemiparin for the prophylaxis of postoperative thrombotic events in obese patients undergoing orthopedic surgery, it was argued that administration of higher than usual doses of LMWH can decrease the incidence of thrombotic events without affecting safety or provoking adverse events in obese patients undergoing orthopedic surgery. As a result of that study, no significant difference was observed between patients who received 3500 and 5000 IU in terms of the incidence rate, while higher bemiparin doses may be potentially helpful in more severe patients.²⁷ There are many studies about the thrombosis model created with the mesenteric vein, femoral vein, and IVC in rats in the literature.²⁸ Establishment of the experimental DVT/VTE in rats by methods such as genetic changes and surgical ligation is well known.²⁹ Surgical procedures such as SG not only increase DVT/VTE by causing limitation of movement but also increase the secretion of mediators that allow a thrombogenic environment.³⁰ Obesity is a risk factor that increases DVT/VTE in rats as well as in humans.³¹ For these reasons, we believe that SG and obesity may cause DVT/VTE in rats as well as in humans.

In our study, we performed the histopathological and radiological evaluation of the occurrence of thrombus in the iliac vein, vena cava, and lung tissues of rats without bemiparin administration and in rats given bemiparin (once a day) for 15 and 30 days. We found that the risk of DVT was significantly lower in the rats given bemiparin for 30 days compared with the other rats. Our histological findings were correlated with the radiological findings. We believe that in our study, since we performed Doppler USG directly through the iliac vein and vena cava, we could clearly observe intraoperative thrombi, but in clinical practice, the effectiveness of postoperative Doppler USG in viewing the veins for DVT in obese patients undergoing SG could be lower.

Balibrea et al. compared the effect of 2500 IU versus 3500 IU bemiparin in 197 cancer patients and no difference was found between the two dosages in terms of adverse effects.³² In a multicenter randomized study by Suchkov et al., 312 patients with DVT detected by complete compression ultrasound were administered bemiparin once a day or a combination of enoxaparin twice a day and 5 mg/day warfarin for 7 days. At least one risk factor of DVT was found in 26.1% and 28.7% of patients who received bemiparin and enoxaparin, respectively, and the rate of patients with improved thrombotic load was similar between the two groups. No repeated DVT, symptomatic PE, and major bleeding were seen in both groups, and no difference was found between the groups in terms of the incidence of minor bleeding. In conclusion, the authors argued that the effectiveness of bemiparin administered once a day is not lower than enoxaparin given twice a day with a similar safety profile.³³ In a cohort study by Gould et al., in 122 morbidly obese patients who underwent bariatric surgery, 5000 IU/day bemiparin was administered for 30 days as a thrombophylactic regimen. Postoperative first- and third-day F Xa levels were measured (prophylactic range: 3–5 IU/mL). BMI, comorbidities, prothrombotic risk factors, and thrombotic and hemorrhagic events were recorded. It was argued that after the use of 5000 IU/24 h bemiparin for 30 days, following obesity surgery, the F Xa level was not associated with postoperative thrombotic or hemorrhagic events and the use of 30-day bemiparin does not increase the major hemorrhage risk in VTE after bariatric surgery.³⁴

Due to scarcity of prospective studies in the literature, thromboprophylaxis guidelines do not include recommendations for the types of drugs to be used for thromboembolic prophylaxis in patients undergoing bariatric surgery. In addition, there are no clear guidelines about dose or optimal duration. Current guidelines used for antithrombotic drugs usually differ according to the experience of each team and ease of use. The practicality of measuring factor Xa is yet to be fully clarified.³⁰ In a study by the American College of Chest Physicians in 2012, it was stated that optimal regimen, correct dosage, and ideal time of thromboprophylaxis could not be clearly known in evidence-based studies in bariatric surgery.³⁵

Celik et al. reported a significant correlation between BMI and F Xa in patients who received a constant dose of enoxaparin for 1 month. Studies have shown that symptomatic VTE occurred in patients undergoing bariatric surgery after discharge from hospital and discontinuation of prophylactic treatment.³⁶ In addition, in a study by Hamad and Choban, PE was shown to occur in the long term in patients with discontinued LMWH therapy.³⁷ Steele et al. found at the 12-month follow-up of patients that 74% of VTEs occurred after discharge. According to our current knowledge, there is still no prospective study evaluating the duration of prophylaxis for DVT and PE following bariatric surgery. However, some researchers recommend administration of LMWH after the first intervention and prolonging it for 3 to 4 weeks in obese patients with many risk factors and those undergoing abdominal surgery.³⁸

DVT initiates in deep peripheral veins such as crural or popliteal veins. Moreover, femoral vein and external iliac vein thromboses accompany popliteal vein thrombosis.³⁹ An isolated IVC thrombosis is not frequent in a wide population, except in patients with Budd–Chiari disease, Behcet's disease, and tumor invasion.⁴⁰ In our study, we observed that inferior vena cava thrombosis was more frequent than iliac vein thrombosis in rats with SG. Doppler USG is the most common radiological examination method to investigate the presence of DVT. Imaging of IVC can be difficult in routine clinical practice.⁴¹ Doppler USG is technically more challenging in morbidly obese patients undergoing SG than nonobese patients. Therefore, IVC thrombosis may be overlooked. According to our study results, while investigating the presence of DVT in patients with SG, the inclusion of IVC in the Doppler USG examination may allow detection of occult microthrombi.

Conclusion

Microthrombi may occur in the postoperative period in extremity veins and lung tissue especially due to obesity and additional risk factors in patients undergoing SG, even if there are no physical examination and radiologic findings for DVT and PE. We think that administration of bemiparin once a day for 30 days can be a safe and effective treatment method for prevention of microthrombi following SG. Additional prospective human trials are needed to evaluate the best regimen and time for VTE prevention after SG.

Ethical Approval

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Footnotes

Author Disclosure Statement

No author in our study has any conflicts of interest and the material described is not under publication or consideration for publication elsewhere.

Funding Information

No funding was received for this article.

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