Introduction

Anesthesia and surgery induce a prothrombotic state, while surgery also triggers an inflammatory response. These factors may result in a state of hypercoagulability, mainly in predisposed patients such as those who carry factor V Leiden. DVT is a common and potentially lethal complication in the perioperative period. The pathophysiology of this process is related to alterations of the Virchow’s triad in the peri- and postoperative phases. Venous thromboembolism (VTE) begins with DVT, which is generated in the deep veins of the leg (calf) or pelvis [1]. In some cases, DVT detaches from the vein and moves to the right side of the heart and from there to the pulmonary arteries resulting in pulmonary embolism (PE) [2]. Certain factors predispose patients to develop VTE, including surgery, trauma, hospitalization, immobilization, pregnancy, oral contraceptives, cancer, long non-stop travel, advanced age, obesity, smoking, major medical illness (such as diabetes mellitus, arterial hypertension, chronic inflammatory bowel disease), autoimmune diseases (such as systemic lupus erythematosus and antiphospholipid antibody syndrome) or previous VTE [3, 4] which may also be induced by a genetic component [5]. The main cause of death is due to PE secondary to iliofemoral DVT [6, 7]. DVT and PE are the main causes of morbidity and mortality in the medical and surgical patient, this situation occurs because DVT is frequently asymptomatic, poorly diagnosed, and unrecognized until death; moreover, there is a lack of routine postmortem examinations, and the global public awareness is substantially lower for PE (54%) and DVT (44%) than for heart attack (88%) and stroke (85%) [8]. All these factors result in a marked underestimation of DVT incidence. In the UK, it is responsible for more than 25,000 deaths annually, and it is estimated that throughout Europe the total number of VTE cases amounts to 1,100,000 [9]. In the USA, there are more than 5 million events with a PE incidence of 500 thousand cases annually [10] and a mortality of 200,000 cases [11]. Some data suggest that the incidence of DVT in Mexico is 200,000 cases per year, with a mortality of 10% in patients with previous heart disease [12]. Sigler-Morales et al. [13] from La Raza Medical Center of the Mexican Institute of Social Security (IMSS) in Mexico City reported 15% of PE in 1685 autopsy studies, as a direct cause of death by 20% and indirectly by 62%.

Bemiparin is indicated for the acute treatment of DVT with or without PE, for VTE prophylaxis in surgical and non-surgical patients, and for the prevention of coagulation in the extracorporeal circuit during hemodialysis. Considering the aforementioned conditions summed to the particular lack of Mexican studies on the pharmacological prophylaxis of DVT in PRSx patients, we decided to compare the efficacy and safety of bemiparin, a second-generation low molecular weight heparin (LMWH), with enoxaparin, a first-generation LMWH as reference standard in our country.

Materials and Methods

Eighty patients were enrolled between July 2016 and April 2018. We carried out an unblinded sequential list trial (assigning every incoming individual to a different group with respect to the previous patient) involving two parallel treatments in Group-E (enoxaparin) and Group-B (bemiparin). The present study complied with the Declaration of Helsinki and the General Health Law of Mexico. Approval and authorization were obtained from the Ethics and Research Committee on human research of the ABC Medical Center in Mexico City. The study was registered on http://www.isrctn.com/ Registration ID: International Standard Randomised Controlled Trial Number: ISRCTN (13851176). Registered (27/08/2019).

Seventy-eight individuals were analyzed (39 patients for each group) (Fig. 1).

Fig. 1
figure 1

CONSORT flow diagram of the trial sample

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Adult patients (age equal or over 18 years old) were evaluated after signing their informed consent. Both genres were included. Patients were scheduled for major PRSx procedures involving moderate to high thrombogenesis risk (3 points or more) according to Caprini’s classification [14], which has been validated for surgical procedures by the American College of Chest Physicians (ACCP), for procedures of plastic and reconstructive surgery by the American Society of Plastic Surgery (ASPS) [15]. Patients reported a physical condition in accordance with the American Society of Anesthesiologists (ASA) between grades I and III. Exclusion criteria encompassed active bleeding, heparin-induced thrombocytopenia, platelets count less than 100,000, severe renal impairment, coagulopathy, recent intracranial surgery, epidural anesthesia or lumbar puncture during the last 24 h. Preoperative examinations included blood count, blood chemistry, coagulation tests and electrocardiogram. DVT assessment was performed before and after surgery using USG Sonosite Doppler Micromax and multifrequency linear transducer from 4 to 12 MHz, ultrasound study of pelvic limbs in transversal and longitudinal sections, obtaining images in both gray scale and color, with Valsalva maneuvers and compression in all superficial and deep veins, looking for thrombosis or reflux at key points. All patients received general balanced anesthesia induced with propofol 2 mg/kg, fentanyl 2 µg/kg and rocuronium 600 µg/kg. This was sustained with a continuous intravenous infusion of fentanyl and the inhalation of desflurane or sevoflurane and fractionated neuromuscular blocker upon request. Intraoperative monitoring included continuous electrocardiogram, flow-velocity curves, non-invasive blood pressure, pulse oximetry, end-tidal CO2, bispectral index, body temperature, and vigilance of the neuromuscular blockade by the train of four test. Six hours after the end of the surgical procedure patients were assigned according to a sequential list for subcutaneous administration of enoxaparin 40 IU (Group-E) or bemiparin 3500 IU (Group-B) every 24 h (q24h). LMWH treatment was delivered during at least 10 days. Postoperative bleeding was also quantified through surgical drains.

Results

Demographic data and previous medical history are shown in Table 1. Patients were prevalently female (83%). We found 15 cases (19.23%) with inherited or acquired thrombophilia disorders. Median age of Group-E was 51 versus 49 in Group-B (p = 0.916). Baseline weight and body mass index (BMI) were also similar between groups; Preexisting pathologies in the enoxaparin group were led by cardiovascular diseases (43.58%), followed by gastrointestinal diseases (30.76%), chronic lung disease (28.20%), depression (25.64%), thyroid disease and obesity (17.94% each), thrombophilia (11.53%), diabetes and cancer (5.12% each). In the bemiparin group, chronic lung disease (33.3%) was the first, followed by cardiovascular diseases (23.7%), gastrointestinal diseases and depression (15.38%), thyroid diseases (12.82%), cancer, obesity and thrombophilia (7.69%), diabetes (5.12%) and chronic renal failure (2.56%). Comparisons between groups showed no statistical differences on medical history pathologies (Table 1).

Table 1 Baseline demographics and medical history
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Physical status score categories for the whole sample were ASA I (31%), ASA II (59%), and ASA III (10%); Caprini’s thrombogenic risk score was moderate (3–4 points, 58%), high (5–6 points, 29%), and higher (> 6 points, 13%). Surgery and anesthesia lengths as well as surgery types were statistically similar between groups. The most frequent kind of surgery was breast surgery (36%), followed by combined surgery (24.3%), head and neck (18%), abdominoplasty (11.5%), and liposuction (10%). It should be noted that all patients presented a mild to moderate increase in postoperative bleeding quantified through surgical drains, which was not clinically significant. Breast surgery cases reported a median drain persistency of 4 days, while abdominal surgery patients reported 14 (Table 2). Doppler scanning of the lower limbs reported no abnormalities in neither deep veins nor the arterial system of any patient. One patient from the enoxaparin group presented abdominal wall hematoma twelve hours after an abdominoplasty, which required surgical drainage. Anticoagulant therapy was suspended on the third day, and there was no subsequent complication. Another male patient from the same group abandoned the treatment on the second day; both cases were eliminated from the analysis.

Table 2 Evaluation scores and surgery characteristics
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Thrombophilia types among fifteen diagnosed patients were predominantly present in women (93%). The most frequent diagnosis was unspecified thrombophilia (40%), followed by hyperhomocysteinemia (20%), while the remaining thrombophilia types showed 13% each. No statistical differences were found between groups (Table 3).

Table 3 Thrombophilia types
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We have summarized the last 8 years of reports on interventions with either low molecular weight heparin LMWH or unfractionated heparin UFH involving moderate to high thrombogenesis risk (3 ≥) according to Caprini’s classification over several plastic surgery procedures and their implication in DVT, PE, and hematoma development [16,17,18,19,20,21,22,23] (Table 4).

Table 4 Studies on deep vein thrombosis prophylaxis in plastic and reconstructive patients
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Discussion

Plastic and reconstructive surgery, together with major orthopedic surgery, oncological surgery, and pelvic surgery, presents the highest thrombogenic incidence in the surgical patient. According to the ACCP, a third of the 200,000 annual deaths related to DVT occur after surgical events [24]. In 2001, the ASPS estimated that there were annually 18,000 cases of DVT in patients undergoing PRSx procedures, varying between 0.5 and 2% [25]. While this rate may seem low, these numbers only represent symptomatic patients, and about two thirds of patients with DVT are clinically asymptomatic, leading to a substantial delay in diagnosis and treatment [26]. During the last two decades, there has been a remarkable increase in PRSx due in part to the need of the young adult population (mostly female) to improve their personal image and increase their self-esteem. According to a survey by the International Society of Aesthetic Plastic Surgery, Mexico ranks third in PRS demand in the Americas and fourth overall worldwide [27]. Defective adherence to globally accepted prophylaxis guidelines is unfortunately the main cause of thromboembolism. A large number of reports in Canada and the USA have shown that 68% of VTE cases did not receive prophylaxis [28, 29]. The severity of this condition is such that of all patients undergoing surgery of any kind without thromboprophylaxis, almost a fifth presents asymptomatic DVT; among these, 90% of thrombi spontaneously lysed and 10% may present PE, resulting in a 30% mortality within the event’s first hour [28]. In PRSx procedures, the incidence of VTE among patients undergoing head and neck surgery is 27.5%, among burned patients 23%, 4.2% in abdominoplasty patients, 1.32% in breast reconstruction surgery, and 0.59% in liposuction patients [30]. VTE results in a significant health burden, requiring prolonged anticoagulant therapy, and carries a substantial risk of post-thrombotic syndrome, post-thrombotic chronic pulmonary hypertension, and VTE recurrence. The annual mortality rate after a VTE event rises up between 20 and 25% [31].

More than 40 years ago, the classic multicenter reference study conducted by Kakkar et al. (1975), across 28 medical centers in more than 4000 surgical patients demonstrated that small doses of ultra-fractionated heparin (UFH), reduced the DVT rate from 24.7% in the placebo group to 7.7% in the heparin group with a corresponding reduction in fatal PE from 0.8 to 0.1% [32]. Even more remarkable was the meta-analysis conducted by Collins 13 years later among 13,000 patients in 70 medical centers, which reaffirmed the results of the original study; the incidence of DVT was reduced from 22.4 to 9% by the administration of UFH in patients of general, gynecological, orthopedic and urological surgery, where once again the incidence of fatal PE was reduced from 0.9% in the control group to 0.3% in the heparin group [33]. Seventeen years later (2005), Haas et al. reported the results of a double-blind randomized comparative study between UFH and LMWH (certoparin) in 23,078 surgical patients, demonstrating that the incidence of fatal PE was 0.15% [34]. Throughout all these years, multiple consensus conferences have concluded that high-risk surgical patients should be protected with anticoagulants. The latest consensus guidelines (2012) indicate that the incidence of DVT without prophylaxis rates between 40 and 80% while PE rises up to 5% in some of these patients without prophylaxis [24, 35, 36]. It should be assumed that after all these years and considering the evidence accumulated around the world, DVT prophylaxis should be uniformly administered in high-risk surgical patients. A decade ago, the multinational multicenter study ENDORSE was conducted in 358 hospitals across 32 countries where a sample of 30,827 surgical patients revealed that 64% were at risk of developing DVT and only 59% received adequate antithrombotic prophylaxis [37]. DVT prevention remains an important issue within the plastic surgery community; however, there is little consensus about its prophylaxis regarding patients undergoing the most common surgical procedures. Bemiparin is a second-generation LMWH that has been less studied respect to heparin. It has been used in Europe, reported in a study conducted by Kakkar et al. in 298 patients with total hip replacement who were randomized to receive 3500 U of bemiparin every 24 h or 5000 U of UFH twice a day, two hours before surgery and continuously for 8–12 days. Bemiparin showed greater efficacy when evaluated through venography and a safety profile similar to UFH [38]. Even though this study was performed on orthopedic surgery, we used the same dosage of 3500 U every 24 h and observed no thrombotic effect while using venous Doppler instead of venography. In another multicenter study performed by Navarro et al. in 381 patients receiving a total knee prosthesis, 2 groups were randomized to receive either 3500 U of bemiparin 6 h after surgery, or 40 U of enoxaparin 12 h before surgery. These dosages were then sustained every 24 h. The incidence of DVT was 32.1% in the bemiparin group and 36.9% in the enoxaparin group, the difference in absolute risk was of 4.6% in favor of bemiparin, significant bleeding was observed in 3 patients of each group, and no deaths were reported. This study showed that bemiparin is as effective in the postoperative period as enoxaparin before surgery in the prevention of DVT [39]. Moreover, bemiparin was employed at the same dosage, administration timing, and duration. In our study, such differences in favor of bemiparin were not observed; nevertheless, we also did not observe any of the significant bleeding with either anticoagulant. In another report by Sayed, 100 critically ill patients at high DVT risk were assigned to receive 3500 U of bemiparin or 40 U of enoxaparin and were followed for 60 days. DVT confirmation was observed in 2 bemiparin patients (4%) and 10 enoxaparin patients (20%) (p < 0.05). PE was documented in 7 patients (14%) of the enoxaparin group and no case in the bemiparin group (p < 0.05); no deaths were reported in any group [40]. In 2014, a study by Briones et al. from the General Hospital of the Secretary of Health in Mexico City enrolled obstetric patients in critical condition at high DVT risk of; 25 patients received 3500 daily units of bemiparin during their internment; none presented DVT and there were no deaths or adverse effects. Researchers concluded that the pharmacological profile of bemiparin allows its consideration as a first-line drug [41]. While these two studies reported similar effects at the same dose of bemiparin as ours, they cannot be compared to it since no surgical procedure was involved in either of them. In our study, there was no documented presence of DVT presented by any patient in either group; only one patient in the enoxaparin group (2.56%) presented an abdominal wall hematoma after an abdominoplasty that required surgical drainage. Undoubtedly, additional research is required in both plastic and reconstructive surgery and other surgical specialties to add more clinical evidence on the usefulness of bemiparin as an alternative drug in the prophylaxis and treatment of patients with a high risk of DVT. Castañeda et al. conducted a retrospective cohort trial aiming to detect patients with thrombophilia at the ABC Medical Center in Mexico City. They found that, in a period of 6 years, 3010 out of 15,485 thrombophilia studies performed on 3893 patients were positive (19.4%). This high rate of positive cases may be explained by the individuals’ characteristics: they were high-risk patients [42]. In our study, we found a similar incidence of (19.23%) thrombophilia disorders. Perhaps this is associated with the genetic background of our hospital’s population where European components are much less mixed with others (thrombophilia being a rare disease among the larger Mestizo population of our country). This could be an epidemiological finding in need of future studies to verify it. Finally, there is not enough clinical evidence to suggest a recommendation on the optimal duration of thromboprophylaxis using LMWH. Based on the results of some randomized double-blind clinical trials that have shown the efficacy and safety of LMWH in preventing DVT and PE, they are currently widely recommended for inpatient hospital use [43,44,45]. However, in some patients, the risk of DVT may persist for a few weeks [46,47,48] after having been discharged from the hospital, such as patients undergoing pelvic or abdominal cancer surgery who are in a twofold increased risk of developing DVT, and three times higher of developing fatal PE as compared to patients without cancer in similar surgeries [49, 50]. A meta-analysis of three randomized trials, one double-blind and two open trials, which included 1104 patients with and without cancer, showed that patients who received extended thromboprophylaxis with LMWH for one month reported a significant reduction in proximal and total DVT when compared to patients who received only thromboprophylaxis within the hospital [51]. Additional clinical evidence was reported by Kakkar et al. in a multicenter randomized double-blind study on 626 patients undergoing abdominal and pelvic cancer surgery who received 3500 U of bemiparin once a day for 8 days. They were randomized in 2 groups, where one group received bemiparin and the other a placebo for another 20 days; relative risk reduction was observed in the group of bemiparin by 82.4% (95% CI 21.5–91.6%, p = 0.010), with no significant increase in bleeding complications [52]. A study conducted in the USA in 2011 by Clavijo-Alvarez et al., 4081 surveyed registered members of the American Society of Plastic Surgery via e-mail; 596 complete answers were received (14.6%). Out of the participant plastic surgeons, 83% practiced privately, whereas 17% did so academically. DVT was reported by 40% of the inquired surgeons, 34% reported PE, and 7% reported having had one death imputable to PE during the postoperative period; 39% to 48% reported not having administered any DVT prophylaxis whatsoever to their patients. The most common reason for not including any routine prophylaxis was the fear of bleeding (84%), followed by the lack of specific evidence in the practice of plastic surgery. Academic surgeons used more chemoprophylaxis when compared with non-academic ones (p < 0.05) [53]. A similar study was conducted in Denmark in 2016 by Nielsen et al., through an e-mail survey in 42 clinics (8 public and 34 private sites); all public and 13 private clinics answered the survey. Overall, 89% of participants declared they had guidelines for DVT prophylaxis (100% of public clinics, 85% private). The most frequent prophylaxis measures are an adequate position, compression through elastic stockings, and early mobilization (68%). None reported the use of intermittent pneumatic compression stockings. The most recurrent pharmacological prophylaxis administered LMWH in the postoperative period (37%), followed by preoperative administration (21%). All public institutions reported using pharmacological prophylaxis while only half of the private ones did so (54%); four private clinics mentioned the use of other modalities. In those cases where DVT prophylaxis was absent, arguments were similar to those reported in the USA: fear of bleeding, lack of evidence in plastic surgery, and also some financial aspects. More than a quarter of the participant surgeons (26%) reported dealing with at least one DVT case over the last 5 years, 33% in public clinics and 23% in private clinics, but no deaths at all [54]. The research asserted that the risk of DVT in plastic surgery should not be ignored and that conclusive evidence is necessary to establish risk stratification models as well as implementing institutional prophylaxis plans. In the ABC Medical Center in Mexico City, which is a private institution, our specific surgical team followed the recommendations of DVT prophylaxis issued by the consensus of the American College of Chest Physicians (ACCP) in the year 2012 [24]. Enoxaparin treatment was considered as the best comparative intervention, being the first-generation LMWH in our country which has been widely studied around the world in different clinical scenarios during the last three decades. Table 4 includes the only case/control prospective study on DVT chemoprophylaxis with enoxaparin (Hatef, 2008) [16], where only abdominoplasty patients reported a significant difference (no thrombosis whatsoever) respect to the control group. This is consistent with our results on thrombogenic events (none) when using enoxaparin. There are no Bemiparin reports on plastic surgery patients to be compared with our data.

Although there is a consensus about sustained anticoagulation in high-risk patients, future studies are necessary to determine an optimal time range to maintain pharmacological prophylaxis in these patients. Thromboembolic disease is the leading cause of morbidity and mortality in hospitalized surgical and non-surgical patients worldwide. Despite the fact that, over the last decades, multiple studies have reported information related to the epidemiology, detection, prophylaxis, and treatment of DVT in surgical patients, a significant proportion of surgeons still refrain from adequate protection to patients at high DVT risk. Numerous studies have shown that the use of adequate thromboembolic prophylaxis is safe and effective both therapeutically and financially. In spite of this evidence, DVT prophylaxis is often far from adequate, which is why it is necessary to adopt thrombogenic risk assessment scales at an institutional level in all hospitalized surgical patients (Caprini) and also non-surgical patients (Padua), in order to implement prophylaxis protocols to reduce the high rates of morbidity and mortality that largely affect them still. The degree of anticoagulation and the duration of prophylaxis remain as problems to implement antithrombotic therapy guidelines due to the low awareness regarding postoperative thrombosis risks, in addition to concerns upon bleeding and the complexity of anticoagulation with available drugs. There are currently multiple methods and therapeutic options to treat different DVT risk degrees, which imply small but important differential effects to consider. Anticoagulants increase the risk of bleeding, so it is necessary to adapt treatment strategies incorporating etiology, risk, benefit, cost and patient preference; although great progresses have been made, further studies are necessary to understand the individual risks of patients to make ideal treatment decisions.

Conclusions

In this study, bemiparin performed adequately against DVT during the immediate postoperative period in patients at moderate to high thrombogenic risk undergoing PRSx procedures. This performance included no clinically significant increase in postoperative bleeding, and there were no adverse effects. All patients were comfortable with the subcutaneous administration of the drug; its cost–benefit ratio makes it a serious competitor respect to enoxaparin. Bemiparin can be considered as an alternative drug to prevent DVT in PRSx patients at significant thrombogenic risk. Although there is controversy in the literature over chemoprophylaxis in outpatients, based on the results of our study and other authors’ recommendations, we are convinced such patients should receive this treatment. Each patient should be medicated taking into account thrombogenic risk, personal background, clinical condition, and the kind of procedure to be performed.