Impact of Short-Term Weight Loss on Hemostasis and Thrombosis after Bariatric Surgery

Introduction Obesity causes thrombophilia and many coagulation problems related to slowing the capillary flow. We aimed to evaluate rapid weight loss outcomes in the early period after bariatric surgery on the coagulation system. Materials and Method. A prospective study enrolled 28 patients with a BMI > 40 kg/m2 who underwent bariatric surgery. Preoperative and postoperative (first and third months) demographic criteria—such as age, gender, weight, height, and alcohol and tobacco use, and biochemical parameters such as PLT, PT, aPTT, INR, bleeding time, coagulation time, fibrinogen, D-dimer, albumin, calcium, ionized calcium, vitamin D, and PTH—were analyzed. Results We found that both bleeding and thrombotic parameters increase in early-slowing surgery. The first-month platelet levels were significantly different from the preoperative values (p < 0.001). The prothrombin time in the first (p < 0.001) and third months (p < 0.009) was also comparable. The PTT in the first month was higher than in the preoperative period (p < 0.011). INR in the first month (p < 0.001) was higher than that in the preoperative period and the third month (p = 0.007) value was higher than in the first month. In terms of fibrinogen levels, all parameters indicated statistical significance within each other; preoperative to the first month (p < 0.001), the first month to the third month (p < 0.016). Third-month D-dimer levels were lower than the first month's values (p = 0.032). Conclusion Thromboembolic events have crucial importance in the converse scenario of haemorrhagic diathesis during the first months of bariatric surgery. Vitamin support and antithrombotic agents may be recommended in the early postoperative period.


Introduction
1.1.Background.Metabolic disorders such as defciency of vitamins and electrolyte imbalance may cause coagulation problems after bariatric surgery.In the early postsurgical period, depletion of vitamin K-dependent coagulation factors may increase the risk of haemorrhage.
1.2.Aim and Objectives.We aimed to evaluate rapid weight loss outcomes in the early period after bariatric surgery on the coagulation system.
Today, mankind has been dealing with obesity all over the globe.It has become an epidemic because of fast food, which is cheap and easy to fnd, insufcient exercise, and a sedentary life [1][2][3].Obesity is one of the important problems in public health due to its increasing prevalence, especially in industrialized countries [4,5].
According to the World Health Organization (WHO) data, it has been reported that an increase of 10-30% has been detected in the prevalence of obesity in the last 10 years [6].According to the data of the Ministry of Health and the preliminary study report of "Turkey Nutrition and Health Survey 2010," the prevalence of obesity in Turkey was found to be 20.5% in men, 41.0% in women, and 30.3% in total [7].
Environmental factors and socioeconomic conditions such as behavioural disorders (overeating and lack of physical activity) increase an individual's risk of obesity [8].In addition to environmental factors, some studies show that 40-70% of weight diferences in humans can be determined by genetic factors [9,10].In addition, the main risk factors for the development of obesity are age, female gender, low education level, marriage, number of births, excess weight gained during pregnancy, use of oral contraceptives, early periods of smoking cessation, and alcohol intake [11,12].
In its studies, Te Organisation for Economic Co-operation and Development (OECD) indicates the danger of increased obesity and determines that one out of every fve children in member countries is overweight or obese with an acceleration of obesity.Obesity increases considerably in adults, resulting in economic problems and premature deaths.It also causes serious health problems in new generations with its progressive onset in children at an early age [13].By the way, the inadequacy of diet, exercise, and medical treatment, which has been utilized for many years in the struggle against obesity, and in addition to this, regaining the lost weight increases the popularity of surgical treatment day by day [2,14].
Large-scale studies have been conducted due to the positive results of various bariatric surgery operations, which have increased signifcantly in recent years and are performed under the name of bariatric surgery [2].With bariatric surgery, long-term permanent weight loss can be achieved, and many comorbidities are prevented by ameliorating the metabolic efects of obesity, thereby increasing the survival.Sustainable weight loss can be achieved with the highest rate of bariatric surgery, and more than 50% of excess weight can be lost [15].Individuals who will undergo bariatric surgery are considered risky patients.Terefore, to achieve successful postoperative results, extensive evaluations before and after surgery are as important as the surgical technique.According to studies, obese patients are more frequently exposed to thromboembolic events [16,17].Weight loss and a decrease in body mass index (BMI) in patients undergoing bariatric surgery are expected to improve thromboembolic events [18].
On the other hand, metabolic diseases, vitamin defciencies, and electrolyte disorders that develop after bariatric surgery may cause disorders in the coagulation system [5].Subcutaneous ecchymoses and petechiae that may develop in the postoperative period are the clinical signs of this coagulation disorder [19].

Study Hypothesis.
Following bariatric surgery, metabolic disorders such as defciency of vitamins and electrolyte imbalance may cause coagulation problems.In the early postsurgical period, depletion of some vitamin K-dependent coagulation factors may increase the risk of haemorrhage; thus, anticoagulant agents may increase the thromboembolic event rate.
Te primary endpoint of this study was to examine the weight loss in the early period in patients who underwent bariatric surgery, and the secondary endpoint was to investigate whether there were signifcant changes in bleeding and coagulation parameters in the early period with weight loss in the frst and third months after surgery.We aimed to evaluate rapid weight loss outcomes in the early period after bariatric surgery on the coagulation system.

Study Design.
A prospective study aimed to evaluate rapid weight loss outcomes in the early period after bariatric surgery on the coagulation system.

Study Setting and Population.
A total of 28 individuals who applied to Bursa Yüksek İhtisas Training and Research Hospital in Turkey's General Surgery outpatient clinic due to morbid obesity have been included in the study.In order for the study to be performed simultaneously by diferent surgeons in the same center, patients who were compatible, did not have comorbidities, or were not taking medication were preferred.Suitable patients were selected within 5 months, and the operations were performed within 1 month.Postoperative follow-up lasted 4 months, and the study was completed in nearly 1 year.

Ethical Considerations.
Ethics committee approval has been granted on protocol number 2011-KAEK-2015/18-02. Informed consent has been obtained from all the patients before the initiation of the study, and the study has been conducted within all the regulations of the declaration of Helsinki.

Inclusion Criteria
(i) Patients with a BMI > 40 kg/m 2 who underwent surgery were prospectively included in the study.

Exclusion Criteria
(i) Subjects who did not volunteer to participate in the study, (ii) İndividuals who had a history of fbrinolytic, antithrombotic, anticoagulant drug (Aspirin, Coumadin) use, (iii) Previous deep vein thrombosis (DVT) or thromboembolic surgery was excluded from the study.In the comparison of dependent groups, the paired samples "t" test was used for those conforming to the normal distribution, and the Wilcoxon signed-rank test was used for those not conforming to the normal distribution.Te statistical signifcance was accepted as a p value of <0.05.

Sociodemographic Analysis.
A total of 31 patients have been operated and reviewed prospectively, but 3 patients were excluded because they did not meet the inclusion criteria.Twenty-fve (89.3%) of the operated patients included in the study were female.Te mean age of the patients was 37.68 years.Te smoking rate has been found at 28.6% and alcohol consumption at 10.7%.Demographic characteristics were given in (Table 1).

Weight Loss Analysis.
Te frst-month % EWL and % EBMIL scores were 21.7% (ranging between 13.0 and 45.6%) and 25.2% (13.8-49.7%),respectively.In the third month, % EWL and % EBMIL scores were 40.6% (ranging between 27.1 and 67.5%) and 45.5% (ranging between 29.4 and 76.6%).Postoperative weight follow-ups were given in Table 2. Te success of the bariatric operation has been elaborated with the weight loss in the frst month compared to the top preoperative period (p < 0.001), the decrease in BMI in the frst month compared to the top preoperative period (p < 0.001), the weight loss in the third month compared to the preoperative period (p < 0.001), the decrease in BMI in the third month compared to the top preoperative period (p < 0.001), the weight loss in the third month compared to the frst month (p < 0.001), and decrease in BMI in the third month compared to the frst month.

Multivariate Analysis.
Te frst-month platelet levels were signifcantly diferent from the preoperative values (p < 0.001).Te prothrombin time in the frst (p < 0.001) and third months (p < 0.009) was also comparable.Te PTT in the frst month was higher than in the preoperative period (p < 0.011).During the analysis of INR the frst-month value (p < 0.001) was higher than the preoperative period and the third month (p � 0.007) value was higher than the frst month.In terms of fbrinogen levels, all parameters indicated statistical signifcance within each other; preoperative to the frst month (p < 0.001), the frst month to the third month (p < 0.016).Tird-month D-dimer levels were lower than the frst month's values (p � 0.032).Tese parameters are elaborated in Table 3.

Discussion
Weight loss following bariatric surgery was evaluated by various methods.Total weight loss compared to the patient's weight before surgery, decrease in BMI, weight loss according to the standard weight and BMI, loss of excess weight relative to the standard weight (EWL) based on age and height, or loss in excess BMI based on BMI 25 kg/m 2 (EBMIL) are some of these assessment methods [20].Te rate of weight loss (% EWL), which has been popularly used recently, showed a success target of 50 and above in the frst 1-2 years [21].In our study, % EWL and % EBMIL achieved in the frst 3 months were calculated as 40.6 kg/m 2 and 45.5 kg/m 2 , respectively, and no study in the literature has interpreted weight loss in the frst 3 months.Te previously published data focused on the 1-year results.Surgery Research and Practice By homeostasis, there exists a delicate balance between coagulation and fbrinolysis in the vascular system, and the disruption of this balance leads to pathological events.Te increase in obesity in coronary heart diseases, peripheral vascular diseases, stroke, and arterial and venous thrombosis [22] shows that this balance increases in favour of coagulation.Various clinical and epidemiological studies argue that there is a strong link between obesity and thrombosis [23,24].
Increased fat mass in obesity is not only an increased fat tissue energy store but also an increase in the secretion of a metabolically active fat cell and an increased autocrine, paracrine, and endocrine efect.Leptin secreted from fat cells, adiponectin, resistin, plasminogen activator inhibitor-1 (PAI-1), tissue factor (TF), tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and interleukin-6 (IL-6) all play an active role in thrombosis [18].Increasing leptin in obese people causes an increase in insulin resistance and increases the incidence of stroke and myocardial infarction.Hyperfbrinogenemia found especially in obese women increases the risk of developing coronary and peripheral artery diseases, stroke, and venous thrombosis.Increased fbrinogen indicates the risk of developing arterial and venous thrombosis with fbrin formation, platelet aggregation, deterioration of blood viscosity, and atherosclerosis [25].
In recent years, many studies have been carried out, especially on TF, factor VII, and PAI-1.PAI-1, a serine protease inhibitor and one of the most important coagulating agents providing balance against the fbrinolytic system, has been shown to have a signifcant efect on the increase in morbidly obese patients and the increase in thrombotic events in obesity [26].Along with it, an increase is detected in FVII, thrombin, thrombin-antithrombin complex (TAT), and TF activities, which have a signifcant role in thrombotic events [25,26].
Tere are diferent and sometimes contradictory studies in the literature on the role of thrombocytes in obesity.Te most important risk factors for increased venous thromboembolism in obese patients are infammation, decreased fbrinolysis, increased thrombin formation, and increased platelet activation [17].
A signifcant improvement has been detected in morbidly obese patients in haematological changes in blood fow, such as increased blood and plasma viscosity [26].Morbidly obese patients with either a low-calorie diet [27] or weight loss after bariatric surgery operations had an improvement in increased erythrocyte aggregation that appears in morbid obesity and impairs blood fow, and an improvement in the impaired lipid profle in hyperlipidemia has also been found [24].Weight loss is associated with bariatric surgery and thromboembolic mediators such as PAI-1 and TF reduction, 4 Surgery Research and Practice chronic infammation, and metabolic changes, and provides an improvement in platelet dysfunction [27].Tere are many studies in the literature investigating the individual and social benefts of long-term weight loss achieved with bariatric surgery in terms of socioeconomics and health in general.We wanted to emphasize that obesity is a thrombosis risk factor that can change and improve [18,28].Lupoli et al. reported improvement in impaired fbrinolytic activity in patients after bariatric surgery.In this study, while they recorded a 20% decrease in PAI-1 in the frst months, they found a 10% decrease in t-PA.However, decreases were found in FVII, Protein C, and S [29].Tese factors were related to vitamin K. Te rapidly decreasing fat mass with weight loss may also be the cause of the fat-soluble vitamin K defciency, and it also explains the increased bleeding risk in the early period [29].Te decrease in PAI-1 was found to be between 75 and 80% at 12 months in other studies.In this study by Ferrer et al., it was determined that the platelet volume, not the platelet count, changed in the postoperative 12th month.However, signifcant PT, CT prolongation, and fbrinogen change were also noted [30].
Pulmonary embolism (1%) and deep vein thrombosis from bariatric surgery and deep vein thrombosis (DVT) (1%) are signifcant causes of mortality.In a comprehensive 8-year review of 4293 patients at the Cleveland Clinic by Carmody et al., they found that laparoscopic bariatric surgery and/or postoperative prophylactic anticoagulant therapy did not change the risk of DVT.However, this study was only valid until the 24th post-operative day.In the study, they showed that conversion, increased age, and high BMI increased this risk [31].In the study of Carmody et al., although routine heparin prophylaxis does not reduce this rate, the authors recommend more aggressive prophylaxis [32].
Mineral and vitamin defciencies caused by rapid weight loss have been discussed in the literature [33].In order to focus on the efectiveness of the study, we insisted on taking multivitamins to compensate for the possible vitamin defciency that occurs during obesity surgery.As we stated in our study, patients were discharged with a multivitamin supplement that did not contain vitamin K in the postoperative period.Te signifcant decrease in fbrinogen and platelet in the 1st month we recorded may be associated with an increase in consumptive coagulopathy and accompanying enhanced microembolic events.Prolongation in PT and aPTT and elevation in INR may suggest that intrinsic and extrinsic coagulation pathways are afected.Tese changes may have resulted from the decrease in coagulation factors that depend on hemostasis parameters.Te increase in Ddimer in the 3rd month compared to the 1st month may be due to the partial decrease in consumption.
When these results are evaluated together, in the middle and long term of bariatric surgery there is improvement in hypercoagulopathy, but in the short term, an increase in bleeding diathesis due to some factor defciencies and an increase in thromboembolic events due to various postoperative reasons are detected.
According to the diferent data, we recorded in our study and obtained from the literature, bleeding diathesis is also important along with thromboembolic events in the frst months of bariatric surgery.Te increase in the PT, aPTT, and INR values in the frst and third months compared to the preoperative values, which we stated in the results of our study, was thought to indicate the bleeding diathesis occurring in this period.At the same time, considering the increase in D-dimer values and the subsequent regression in the third month, the risk of early bleeding and simultaneous thromboembolism can be considered in these patients.Terefore, it is important to carry out close follow-ups and laboratory screenings regularly in the frst months [34].Particular attention should be paid to bleeding that may occur in the stapler line after surgery.It may be recommended to use low-molecular-weight heparin (LMWH) for a long time in the early postoperative period together with vitamin support [35,36].
4.1.Limitation of the Study.Te study's main limitation could be attributed to comorbidities.Some of the patients included in the study used antihypertensive and antidiabetic drugs.It is not known whether these drugs will have a different efect on bleeding and coagulation parameters.
Te study was performed at a designated time interval, in a single center with the same devices.Te patients were followed up closely during the preoperative and postoperative periods.Individuals with fbrinolytic, antithrombotic, and anticoagulant use, previous deep vein thrombosis (DVT), or thromboembolic surgery were excluded from the study.

Conclusion
As obesity rates increase, the efectiveness of surgical treatment is obvious.Researching every aspect of obesity surgery increases the success of the treatment.New fndings on this subject reduce possible complications.It can enlighten us about the precautions that can be taken to reduce the risk of clotting and bleeding that we have introduced.Terefore, new, prospective, randomized, large-scale case studies on bariatric surgery are needed.TNF-α: Tumour necrosis factor-alpha WHO: World Health Organization CT: Coagulation time BT: Bleeding time.
Te ideal BMI was 25 kg/m 2 , and the ideal weight was taken as the average of the metropolitan index.Excess weight (EW) was calculated by subtracting the ideal weight from the measured patient weight.Percent excess weight loss (% EWL) and excess body mass index loss (% EBMIL) were calculated according to the following formulas: Data Resource and Measurement.Bleeding and clotting times were evaluated manually.Hemogram and platelet count after taking into appropriate tubes (Mindray BC-6800 Auto Hematology Analyzer, Germany), measurement of hormones (Advia Centaur XP, USA), biochemistry values (Mindray BS 2000 Biochemistry Analyzer, Germany), and D-dimer (AQT90 fex, Denmark) devices.It was investigated whether there were signifcant changes in bleeding and coagulation parameters with the recorded weight loss.Te data from 28 patients obtained were analyzed.2.8.Statistical Methods.Statistical analysis was conducted in the SPSS 22.0 package program.Te eligibility of the obtained data was interpreted with the Shapiro-Wilk test for normal distribution.Descriptive statistics for continuous variables were given as mean ± standard deviation for those showing a normal distribution and the median (minimum-maximum) for those not showing a normal distribution.
2.6.Variables.Te following data were recorded in the preoperative (just before the surgery) and postoperative 1st and 3rd months in patients who underwent bariatric surgery: age, gender, weight, height, alcohol-smoking use, laboratory results (PLT, PT, aPTT, INR, bleeding time, clotting time, fbrinogen, D-dimer, albumin, calcium, ionized calcium, osteocalcin, vitamin D, and parathormone).In our preoperative clinic, routine blood count and detailed blood analysis, hormone analysis, coagulation tests, pulmonary function test, electrocardiogram, chest X-ray, gastroscopy, endocrinology consultation, psychiatry consultation, cardiology consultation and, if necessary, dietitian consultation are performed.Demographic information (age, gender, weight, and height) of eligible patients and smoking and alcohol habits were recorded.Body mass index (BMI) was calculated by dividing the body weight in kilograms (kg) by the square of 2 Surgery Research and Practice the height in meters (m).

Table 1 :
Baseline demographics of the study population.

Table 2 :
Loss of excess weight and body mass index in the frst and third months.

Table 3 :
Comparison of the treatment group parameters with preoperative values.