Abstract

Background: Both cancer patients and patients undergoing surgery are thought to be at an increased risk of thrombo-embolic events. Consequently, low-molecular-weight heparin (LMWH) is administered to all such patients perioperatively. There is a lack of consensus in guidelines regarding the timing of administration and the dosage of thromboprophylactic agents. Studies have shown that thrombo-elastography (TEG) is a useful test in assessing global haemostatic function, and has been validated in monitoring the dosage of LMWH. In this study, we assess the coagulation status of patients undergoing thoracic surgery with TEG, and the effectiveness of administered LMWH for thromboprophylaxis. Methods: Thirty patients with primary lung cancer (LC) and 30 with benign lung disease (BL) were studied prospectively. Patients were randomised to receive subcutaneous LMWH 40 mg once or twice per day perioperatively. Their coagulation status was monitored with TEG preoperatively and postoperatively for 3 consecutive days. Results: Preoperative TEG parameters (k time, alpha angle and maximum amplitude (MA)) were within the normal range in both the LC and BL groups. Preoperative r time was prolonged in both the groups, but with no significant difference between the two groups (p > 0.05). Postoperatively, r time was prolonged in some patients receiving LMWH twice daily, suggesting a possible adequate thromboprophylaxis in these patients only. Conclusion: This study demonstrates that the majority of patients with LC are not hypercoagulable. We also showed that LMWH once or twice a day might not provide sufficient thromboprophylaxis. We advocate screening for patients demonstrating hypercoagulable states and ensuring adequate thromboprophylaxis in this group of patients with careful monitoring.

Introduction

Venous thrombo-embolism (VTE) diseases, such as pulmonary embolism (PE) and deep vein thrombosis (DVT), are major causes of morbidity and mortality in cancer patients. VTE is also known to be a terminal event in many cancers. The relationship between cancer and DVT was first described by Trousseau more than 100 years ago [1]. Over the years, the evidence on the association between cancer and VTE has become stronger. The risk of developing VTE in cancer patients has been reported to be five- to sevenfold higher compared to the normal population [2].

The rate of developing VTE varies for different types of malignancies. Haematological malignancies, cancers of the brain, ovary and the pancreas are among those with the highest risk. However, cancers of the lung and breast, being considerably more common, will account for more episodes of VTE in absolute terms [3]. The cause of VTE is thought to be multifactorial and could be as a result of a series of underlying conditions associated with malignancies, such as development of hypercoagulable states due to activated clotting by tumour cells and vessel-wall injury.

In addition, many patient factors, such as immobility, dehydration, age, obesity and insertion of central venous catheters, could add to the risk of VTE in such patients [4]. Almost all hospitalised patients have at least one risk factor for VTE and the incidence of in-hospital VTE has been shown to be 10–40% among medical patients, and as high as 40–60% following major operations [5].

It has also been demonstrated that cancer patients undergoing surgery have at least twice the risk of postoperative DVT and more than three times the risk of fatal PE encountered by non-cancer patients undergoing similar procedures [6]. Moreover, patients undergoing thoracic surgery for cancer are usually elderly, and have delayed mobilisation after surgery due to the chest drains [7].

The routine use of thromboprophylaxis has resulted in a significant reduction in VTE, and low-molecular-weight heparin (LMWH) has been considered the standardised prophylactic regimen for a long time. LMWH has many effects on the coagulation cascade but its main effect is the inhibition of factor Xa, and, to a lesser extent, factor IIa (thrombin). It can also affect platelet function, tissue factor/endothelial cell interactions and anti-thrombin. Therefore, measuring each individual variable of the coagulation cascade is impractical. Their maximum anti-Xa activity occurs 4 h after subcutaneous injection; however, at 12 h, the activity is still up to 50% of the maximum [8].

Different guidelines have been written on prophylaxis for VTE; however, there is a lack of consensus regarding the timing of administration and the dosage of LMWH [4]. It is conceivable that the dosage of administered LMWH in some patients might not be adequate and, under these circumstances, patients would not be receiving adequate thromboprophylaxis. Conversely, the dosage of LMWH might be so high that patients, particularly the elderly and those with renal failure, could have a higher risk of bleeding. Therefore, patients who are at a high risk of developing VTE or bleeding should be identified, and the effect of LMWH should be monitored and the dosage adjusted accordingly.

As LMWH has many effects on the coagulation cascade, monitoring the dose of administered LMWH needs to be undertaken with a test that assesses global haemostatic function. Thrombo-elastography (TEG) is a rapid, reproducible, bedside test that assesses the whole dynamic process of clotting. It was originally described by Hartert in 1948 [9]. Although it has been used increasingly as an intra-operative haemostatic monitoring device in cardiac surgery, and shown to significantly reduce blood transfusion rate [10], it is not routinely used in thoracic surgery. TEG has a unique characteristic in detecting hypercoagulable states in patients [11] and has been reported to be more sensitive than prothrombin time and activated partial thromboplastin time in detecting hypercoagulopathy [11–13]. Previous studies have validated the use of TEG in monitoring the dosage of LMWH, represented as a dose-dependent increase in reaction time (r time) and a decrease in alpha angle on TEG [10,14–16].

The objectives of this study were to assess the coagulation status of patients undergoing thoracic surgery with TEG, and to determine the effectiveness of administered LMWH for thrombophylaxis.

Materials and methods

Patients

This study was conducted prospectively and after obtaining permission from our local Ethics Committee. Thirty patients with primary lung cancer (LC) and 30 with benign lung disease (BL), undergoing first-time thoracic surgery under general anaesthesia, were studied. Informed consent was obtained from each patient. The exclusion criteria for the study included nonelective patients and those who were already receiving anticoagulants.

Methods

All our patients received the LMWH, enoxaparin sodium (Sanofi-Aventis, Surrey, UK), as our current practice; however, 50% the patients in each group were randomised to receive 40 mg of enoxaparin once per day (OD) at 20:00 h and the remaining 50% received 40 mg twice per day (BD) at 08:00 h and 20:00 h. The preoperative coagulation status in both the BL and LC groups was assessed with a TEG analyser (TEG 5000 Hemostasis analyser, Haemoscope, Niles, USA). Differences in coagulation status, on each of the first 3 consecutive postoperative days, were compared to the baseline preoperative status. Within each group, the patients receiving enoxaparin OD were compared to their counterparts receiving enoxaparin BD, to assess whether they were receiving adequate prophylaxis. All adverse effects, including bleeding and VTEs, were documented.

TEG assesses global haemostatic function. The strength of a clot is graphically represented as a characteristic cigar-shaped figure. The following parameters of the TEG tracing were noted: r time, k time, alpha angle and the maximum amplitude (MA). These parameters measure different stages of clot development; r time, or reaction time, is the period of time from initiation of the test to the initial fibrin formation and k time is the time from the beginning of a clot formation until the amplitude of thrombo-elastogram reaches 20 mm, and represents the dynamics of the clot formation. Alpha angle is an angle between the line in the middle of the TEG tracing and the line tangential to the developing ‘body’ of the TEG tracing. This represents the acceleration (kinetics) of fibrin build-up and cross-linking. Finally, MA reflects the strength of a clot, which depends on the number and function of platelets and its interaction with fibrin. Fig. 1 demonstrates a normal thrombo-elastogram tracing and the normal ranges for each parameter. As previously described, the effect of anticoagulation by LMWH is monitored by TEG as a dose-dependent increase in r time and a decrease in alpha angle [14]. In hypercoagulable states, r time and k time are shortened.

Fig. 1

A normal thrombo-elastogram, with normal range for each variable. r: reaction time; k: clotting time; MA: maximum amplitude; EPL: estimated percent of lysis; LY30: percentage lysis 30 min after clot formation; LY60: percentage lysis 60 min after clot formation; CI: coagulation index; and PMA: platelet mapping assay.

Fig. 1

A normal thrombo-elastogram, with normal range for each variable. r: reaction time; k: clotting time; MA: maximum amplitude; EPL: estimated percent of lysis; LY30: percentage lysis 30 min after clot formation; LY60: percentage lysis 60 min after clot formation; CI: coagulation index; and PMA: platelet mapping assay.

Prior to the preoperative administration of LMWH, 1.0 ml of venous blood was obtained from each patient. TEG was performed immediately; these baseline parameters were used to assess the coagulation status of patients prior to surgery. The collected blood was inserted into the kaolin vials provided by the manufacturers and mixed five times by gentle inversion of the vial after closing its cap. Then, 360 μl of blood from the vial was pipetted into the TEG analyser cups. The test was completed when all the parameters were defined on the computer monitor. This test was repeated daily on the first 3 consecutive postoperative days.

Statistics

Statistical analysis was performed with Analyse-it software version 2.08 (Analyse-It, Leeds, UK). Data were tested for normal distribution using the Shapiro–Wilk test. As the data were not normally distributed, the Mann–Whitney U-test was used to compare the results between groups of numerical data and Spearman’s rank was used for correlations between continuous variables. For categorical data, the chi-square test was used. A p-value of ≪0.05 was considered to be statistically significant.

Results

A total of 60 patients were enrolled in this study, of which 30 were confirmed histologically to be malignant and 30 were benign. Table 1 summarises the patient characteristics, and Table 2 summarises the operations performed and the histology. The two groups were similar in terms of sex, weight, preoperative lung function and duration of the procedure. However, the patients of LC group were significantly older than those of BL group, as might be expected (mean age 68.6 years vs 58.5 years, p = 0.02).

Table 1

Patient characteristics in benign (BL) and malignant (LC) groups.

Table 1

Patient characteristics in benign (BL) and malignant (LC) groups.

Table 2

Operations performed and histology results.

Table 2

Operations performed and histology results.

Table 3 demonstrates the TEG values, preoperatively and on each of the first 3 consecutive postoperative days for both the BL and LC patients. Preoperatively, and prior to the administration of LMWH, the mean k time, alpha angle and MA TEG values were within the normal range in both the BL and LC groups, and the subgroups, studied. The baseline for the mean r times was prolonged in both the BL and LC groups with no significant difference between the two groups. Fig. 2 demonstrates the baseline TEG parameters in the BL and LC groups, when the subsets were combined. Hypercoagulable state, characterised by shortened r time, was demonstrated in only two of the 60 patients studied preoperatively. Both patients were in the BL group; one was undergoing diagnostic surgery for abnormal pleural thickening, with histology reporting chronic inflammation only (r time: 3.5 min) and the other patient had a pleurectomy for recurrent pneumothorax and bullous lung disease (r time: 2.9 min).

Table 3

Results of pre- and postoperative TEG values in benign (BL) and lung cancer (LC) groups.

Table 3

Results of pre- and postoperative TEG values in benign (BL) and lung cancer (LC) groups.

Fig. 2

Comparing the baseline, preoperative, TEG values in both benign lung (BL) and lung cancer (LC) groups.

Fig. 2

Comparing the baseline, preoperative, TEG values in both benign lung (BL) and lung cancer (LC) groups.

TEG values were then analysed on each of the 3 postoperative consecutive days in both the BL and LC groups (Table 3). On postoperative day 1, the mean r times, in both the BL and LC groups receiving enoxaparin either OD or BD, were lower than their respective baseline values. Within each group, the mean r time was slightly higher in patients receiving BD compared to those on DO enoxaparin (9.7 min vs 6.83 min in the BL group and 8.9 min vs 8.3 min in the LC group); however, these differences were not remarkable.

On the second postoperative day, the mean r time in the BL group of patients was slightly more prolonged (9.96 min in patients receiving enoxaparin OD and 10.4 min, in those receiving it BD, p = 0.3) compared with the first postoperative day. These r times, however, were not drastically different from the baseline preoperative r time in the BL group. The mean r time in the LC group of patients receiving enoxaparin OD was lower, but not to significant levels, than the r time in those receiving it BD (7.87 min vs 10.9 min, respectively, p = 0.9). This may indicate that subcutaneous (S.C.) enoxaparin 40 mg OD injection provides less-adequate anticoagulation than injections BD, in this group of patients. The mean r times in both the BL and LC groups of patients (and within each group, i.e. receiving enoxaparin either OD or BD) were generally above the normal range, on postoperative day 2, but not higher than the preoperative values.

This trend was continued on the third postoperative day, with the highest anticoagulation effect of LMWH seen in the BL group receiving LMWH BD (r time: 13.5 min). The BL group with OD LMWH, and both groups of patients receiving either OD or BD of LMWH in the malignant group, also showed prolonged r times on TEG (compared to the normal upper value of 8 min), but this was not significantly higher than their preoperative r times (Fig. 3 ).

Fig. 3

Illustration of the trend of r time for (a) BL and (b) LC groups.

Fig. 3

Illustration of the trend of r time for (a) BL and (b) LC groups.

In addition, k time, which mainly demonstrates the function and activity of platelets, remained within the normal range, on each of the 3 postoperative days, as did the alpha angle and the MA.

We observed two adverse events in this study. One patient in the LC group who received enoxaparin OD, and who had a slightly shortened r time of 3.6 min on postoperative day 2, developed an embolic stroke, despite having no risk factors or previous history. Another patient who underwent lobectomy for bronchial adenocarcinoma had significant intrathoracic bleeding noted on the chest X-ray (CXR) on the third postoperative day, which necessitated a further procedure to evacuate haematoma, on postoperative day 3. This patient, who was receiving enoxaparin 40 mg BD, had a significantly prolonged r time on postoperative day 2 (14.1 min), and no bleeding point was identified during the second operation.

Discussion

Trousseau first described the high incidence of developing VTE in malignancy [1]. Hypercoagulable states seen in these patients are due to a number of variables, including hyperactivity of the coagulation cascades, the production of procoagulant factors by tumour cells and a rise in the platelet count frequently associated with malignancies [17]. The incidence of VTE after surgery is also believed to be increased. Thus, the incidence of VTE in LC patients undergoing surgery would be expected to be particularly high.

Consequently, a number of guidelines have been written on the prevention of VTE following surgery, and, in particular, the use of LMWH [7,18]. Recommendations on the dosage and the timing of administration of LMWH have been very unclear. The most recent of these guidelines, by the American College of Chest Physicians [7], for example, recommend the use of routine thromboprophylaxis with LMWH (grade 1C evidence), for patients undergoing major thoracic surgery, but give no advice on the dosage or the timing of administration. These guidelines only advise taking into account patients’ renal function or history of bleeding, when prescribing LMWH. Similarly, recent National Institute for Health and Clinical Excellence (NICE) guidelines have recommended the use of LMWH for thromboprophylaxis in high-risk patients undergoing thoracic surgery, without giving any guidance on the dosage or the duration of administration, or making recommendations for monitoring the effectiveness of the administered LMWH [18].

LMWH primarily inhibits the coagulation factor Xa and it produces therapeutic anticoagulant effects within 2–4 h after S.C. administration. Peak plasma levels occur 4 h after S.C. administration and decrease to 50% of peak values 12 h after injection. Standard perioperative tests of coagulation do not reflect the extent of anticoagulation resulting from LMWH. Antifactor Xa activity (anti-Xa) has been used to monitor LMWH dosing but this is not measured in routine clinical practice. LMWH has many effects on the coagulation cascade. Besides inhibiting factor Xa, platelet function, tissue factor/endothelial cell interactions and anti-thrombin activity are also affected. Thus, measuring each individual variable of the coagulation cascade is impractical. To better evaluate clinical anticoagulation, a broad measure of the cascade is necessary.

TEG is a unique test that provides an overall global assessment of the clotting process from fibrin formation to clot lysis. TEG has been used increasingly in surgical procedures, particularly cardiac surgery, to monitor intra- and postoperative haemostasis, to identify the type of coagulopathy and to aid in the appropriate correction [10]. Several studies have also used TEG to demonstrate hypercoagulable states (which are characterised by short r time and k time, and conversely prolonged alpha angle and MA). In different patient groups, this was shown to be associated with increased morbidity [11–13]. McCrath et al., for example, showed higher incidence of VTE and myocardial infarction postoperatively in patients demonstrating hypercoagulability [11]. These authors measured TEG before and after noncardiac surgical procedures, and observed that patients with abnormal TEG and prolonged MA have a higher chance of developing thrombo-embolic events (TEEs) compared with those with normal TEG values (8.4% vs 1.4%). In addition, the same group observed a 6.5% risk of developing cardiac events following surgery in patients with abnormal TEG, and none in patients with normal TEG values [11].

The use of TEG in monitoring the dosage of LMWH has been previously validated in a number of studies [9,15]. Zmuda et al. showed that enoxaparin sodium caused a dose-dependent inhibition of clotting of normal blood on TEG with increased r time [15]. Hence, we used TEG to identify hypercoagulability status, and to monitor the effect of the administration of two different doses of LMWH, in a selected group of patients undergoing thoracic surgery for LC.

In the first instance, we sought to determine whether patients with LC were in fact more hypercoagulable, and thus, at higher risk of developing VTE, compared with those having BL. Our results demonstrate that there was no statistical difference in baseline hypercoagulability status between these two groups and, if anything, they were hypocoagulable with prolonged r times. This finding was somehow unexpected, in the light of previous preconceptions of patients with malignant disease, being hypercoagulable, and we are unable to offer an explanation for this finding. We also tried to determine whether a single dose of LMWH resulted in prolongation of the baseline TEG parameters (time to clot formation), or whether two doses were more effective in providing, what might be, adequate prophylaxis. Our results demonstrate that almost all patients receiving a single dose of LMWH, and the majority receiving LMWH BD, were still not adequately anticoagulated as their r times were only slightly prolonged compared to their preoperative values, and this did not reach statistical significance. These results indicate possible inadequate prophylaxis even with enoxaparin BD regime. Therefore, we believe that it is incorrect to assume that a single, or even a double, dose of LMWH could provide adequate thromboprophylaxis in all patients, especially in high-risk patients. This finding stresses the importance of monitoring the effects of the administered LMWH to ensure that each individual patient is adequately anticoagulated.

Monitoring the effects of anticoagulation with LMWH is also important to minimise the risks of overdosage. The rate of bleeding associated with the use of LMWH for thromboprophylaxis, in patients without any previous risk factors, has been reported to be as high as 10% [19]. Major haemorrhagic complications have been reported to be between 0.5% and 4%, with higher incidence in elderly patients, with renal and liver disease, and patients who receive other forms of anticoagulants, such as aspirin and clopidogrel. In addition, several cases of epidural haematomas have been reported with the use of LMWH and epidural catheters in thoracic surgical patients [20]. As most patients undergoing thoracic surgery for malignancy are elderly with other co-morbidities, the risks of bleeding are real. In our study, one patient receiving LMWH BD underwent re-operation on the third postoperative day for evacuation of a haematoma. This patient had a prolonged r time on TEG, suggesting that he was well anticoagulated. However, because of the complex mechanism of action of LMWH, it is possible that a single test, such as r time on TEG, will never provide a complete measure of anticoagulant activity in all patients and, hence, risk of bleeding.

We also know that patients receiving LMWH thromboprophylaxis do still develop VTE, and the incidence has been reported to be around 2–7% in different studies [21–23]. This might be due to the ineffective anticoagulation with LMWH. Leonard et al., for example, did not observe any abnormality in TEG by administration of a single dose of LMWH 12 h before surgery [24]. In their study, patients received either LMWH or saline on the night before surgery, and TEG and factor Xa activity were measured in both the groups 12 h later. No obvious clotting abnormalities were demonstrated on TEG or factor Xa activity in either group, suggesting inadequate thromboprophylaxis. Similarly, Klein et al. demonstrated prolonged r times on TEG, on the third postoperative day, after injections BD of 30 mg enoxaparin, in only 25% of his patients undergoing orthopaedic surgery [25]. This indicates that even S.C. injections BD of LMWH are ineffective in the majority of patients, and emphasises the importance of monitoring adequacy of anticoagulation in all patients.

In our study, one patient in the LC group, receiving enoxaparin 40 mg OD, developed an embolic stroke on the second postoperative day. He was hypercoagulable on TEG, with a shortened r time pre- and postoperatively. This unfortunate complication could have been prevented by administering more LMWH than he was prescribed, and ensuring that he was adequately anticoagulated with prolonged r times on TEG.

But what constitutes adequate anticoagulation, and prophylaxis against VTE, in patients receiving LMWH? Also, at what r time are patients adequately protected against VTEs, but not at significantly increased risk of bleeding? There are recommended activated partial thromboplastin time (APTT) ranges for patients receiving unfractionated heparin, and international normalised ratio (INR) ranges for patients receiving warfarin, for anticoagulation; however, currently, there are no recommendations with regard to ideal r times, or any other parameter, for patients receiving LMWH. Further studies to answer these questions need to be undertaken.

One limitation of our study is that the TEG tests were performed each morning, and not at a particular time related to the administration of enoxaparin sodium. Under these circumstances, we could have been missing the effects of the peak plasma levels and troughs of the administered enoxaparin either OD or BD, when performing the TEG measurements.

In summary, we have shown that the majority of patients with LC do not show hypercoagulable states, either before or after surgery. We also showed that LMWH OD or BD might not provide sufficient thromboprophylaxis. Therefore, we advocate screening for patients demonstrating hypercoagulable states and ensuring adequate thromboprophylaxis in this group of patients by careful monitoring with TEG.

Presented at the 23rd Annual Meeting of the European Association for Cardio-thoracic Surgery, Vienna, Austria, October 18–21, 2009.
☆☆
This article was judged for the Young Investigator award.

Appendix A

Conference discussion

Dr G. Varela (Salamanca, Spain): I would like to congratulate the group for selecting a very difficult topic to deal with, because the literature on this topic is really scanty and sometimes not conclusive at all. I think this is exactly the type of study we need in thoracic surgery to improve the quality of our clinical practice.

In your study you have shown that neither lung cancer patients nor patients with benign conditions had a hypercoagulable status preoperatively. I am not surprised by this fact since the majority of patients operated on for lung cancer are classified in early stages of the disease, and hypercoagulation, as you know, depends not only on the type of tumour but also on the number of tumour cells; that is, the anatomical extension. I have not seen either in your paper or in your presentation any data on the anatomical extension, and maybe you could complement some information on that.

My second question, I would like to know what is the gold standard test for the diagnosis of thrombo-embolic events. In one of the papers you have cited, it is demonstrated that if you routinely use some screening tests to demonstrate thrombo-embolic episodes that are asymptomatic, the rate of postoperative events increases considerably. So I would like to know what the gold standard is in your study.

Dr Attaran: The answer to the first question, you are absolutely right. Cancer patients mainly show hypercoagulopathy and hypercoagulable state at a later stage. Our study was only on 30 cancer patients with different cancer types such as adenocarcinomas, mesotheliomas, squamous carcinoma and even malignant melanoma. Therefore it is almost impossible to compare their coagulation status. Moreover, they weren’t end-stage, so that is probably why they didn’t demonstrate hypercoagulopathy. On the other hand, hypercoagulable state is not only related to the cancer itself. It can be as a result of radiotherapy or chemotherapy in these patients, and none of our patients had chemo- or radiotherapy preoperatively. I didn’t exactly understand the second question. Was that gold standard for using TEG for our patients?

Dr Varela: No, I mean gold standard for diagnosis. I suppose you did your diagnosis because of clinical symptoms or clinical findings, and this is probably not exactly the type of diagnosis that is needed.

Dr Attaran: Yes, our diagnosis was based on clinical symptoms. However, it is impossible with our findings on 60 patients to establish a gold standard, especially with such a low incidence of thrombo-embolic events. That's what this study triggers, and the aim is not to treat the ones who have developed thrombo-embolic events, but to prevent using TEG. Therefore TEG is helpful as the number of clinically diagnosed thrombo-embolic events is far less compared to its real incidence and TEG can identify those at risk, and not only the ones who have suffered from these events. To standardise the treatment, we need large number of patients. For example targets for INR and APTT have been set after several large scale studies. Similarly for TEG, several studies are required to decide on the gold standard.

Dr P. Van Schil (Edegem, Belgium): But what is your standard clinically? Did you check for deep vein thrombosis, for pulmonary emboli?

Dr Attaran: We don’t do any further investigations to detect any subclinical thrombosis. What we are doing now is checking the TEG routinely for our patients, and if the r time is shortened, we increase the dosage of administered Clexane for that patient. We also observe for any thrombo-embolic events to change our treatment strategy.

Dr R. Freeman (Indianapolis, Indiana, USA): I understand the use of TEG, because it's readily available with bypass nearby in most of our operating suites. Did you look at factor Xa at all before treatment and after treatment? And do you use Lovenox with patients who require continuous epidural anaesthesia?

Dr Attaran: As you know, and as I was explaining to the audience, low-molecular-weight heparin will stop factor Xa, and it also has an effect on factor II. Unfortunately, in the clinical setting, it's not possible to measure these factors routinely.

The second question regarding epidural anaesthesia, yes, some patients required epidural catheters, but not continuously, and this did not affect our study as the catheters were removed in the morning after surgery, 12 hours after the last dose of Clexane and we know that the half-life of Clexane is about 12 hours.

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