Coagulation profile in open and video-assisted thoracoscopic lobectomies: a cohort study

Coagulation profile in open and video-assisted thoracoscopic lobectomies: a cohort study Abstract OBJECTIVES Lung cancer patients are perceived to have a relatively high risk of venous thromboembolic events due to an activation of the coagulation system. In terms of activation of the coagulation system, the difference between video-assisted thoracoscopic surgery (VATS) and open lobectomies for primary lung cancer has not been investigated. The aim of this study was to compare the impact on the coagulation system in patients undergoing curative surgery for primary lung cancer by either VATS or open lobectomies. METHODS In total, 62 patients diagnosed with primary lung cancer were allocated to either VATS (n = 32) or open lobectomies (n = 30). All patients received subcutaneous injections with dalteparin (Fragmin®) 5000 IE once daily. The coagulation was assessed pre- and intraoperatively, and the first 2 days postoperatively by standard coagulation blood tests, thromboelastometry (ROTEM®) and thrombin generation. RESULTS The open lobectomies bled more than the VATS group and had a significantly lower platelet count (109/l) on postoperative Days 1 and 2 (198 vs 231 and 194 vs 243, respectively). The open group also had a higher international normalized ratio on postoperative Days 1 and 2 compared with the VATS group (1.21 vs 1.14 and 1.17 vs 1.09, respectively). There were no differences in thromboelastometry (ROTEM®) and thrombin generation parameters. None of the included patients developed venous thromboembolic events. CONCLUSIONS In patients undergoing curative surgery for early-stage primary lung cancer, we observed a statistical non-significant difference and a similar-sized minor impact on the coagulation system. Venous thrombosis, Blood coagulation test, Thrombin generation, Lung neoplasm, Thoracic surgery INTRODUCTION The risk of venous thromboembolic events (VTEs) consisting of deep venous thrombosis or pulmonary embolism for patients undergoing surgery for primary lung cancer is relatively low with an overall risk of 2%, but with a marked variation among studies (range 0.2–19%) [1]. We have previously published a study where patients undergoing curative surgery for primary lung cancer using video-assisted thoracoscopic surgery (VATS) were randomized to either low-molecular-weight heparin (LMWH) or no thromboprophylaxis [2]. We concluded that LMWH administered once daily did not alter the coagulation profile. VATS surgery differs from an open approach (thoracotomy) with regard to surgical trauma, and it has been advocated that a VATS procedure is less traumatic than an open procedure [3] and, hereby e.g., enhance mobilization. VATS seems to be associated with less postoperative pain and better quality of life compared with an open approach [4] and a reduced risk of complications [5]. No studies have yet evaluated the impact of the 2 different approaches on the coagulation system. The activation of the coagulation system reflects the stress response that patients undergo during and after the surgical procedure. We prespecified hypothesized that an open operation would have a more profound impact on the coagulation system when compared with VATS. The aim of this study was to compare the impact on the coagulation system in patients undergoing curative surgery for primary lung cancer by either VATS or open lobectomies. MATERIALS AND METHODS This is a substudy of a larger randomized controlled trial, and the overall design has been reported elsewhere [2]. Inclusion criteria were as follows: (i) diagnosed with primary lung cancer with a preoperative Stage IA–IB; (ii) surgery with expected lobectomy or bilobectomy; (iii) willingness to participate and ability to give informed oral and written consent; and (iv) >18 years of age. Exclusion criteria were as follows: (i) thromboembolic event (either arterial or venous) within the past 3 months; (ii) pregnant or lactating; (iii) treatment with a vitamin K antagonist or a non-vitamin K antagonist oral anticoagulant and (iv) treatment with a platelet inhibitor if this was not paused for a minimum of 5 days (aspirin, clopidogrel or ticagrelor) or 7 days (prasugrel). No patients had received neoadjuvant chemotherapy and/or radiation therapy prior to surgery. Patients operated with a VATS approach were included from 3 Danish centres [Aarhus University Hospital, Rigshospitalet (University Hospital of Copenhagen) or Odense University Hospital], whereas patients with an open procedure were solely included from Aarhus University Hospital. The patients were included after oral and written consent. The study protocol complied with the Helsinki II declaration and was approved by the local scientific ethics committee (file number 1-10-72-364-12) and The Danish Data Protection Agency. The study was conducted according to Good Clinical Practice standards and was monitored by the Good Clinical Practice unit, Aarhus University Hospital, Aarhus, Denmark. The trial was registered at ClinicalTrials.gov (Identifier: NCT01741506) and at EudraCTno. 2012-002409-23. Patients In total, 62 patients were prospectively included: 30 in the VATS group and 32 in the open procedure group. The patients in the VATS group participated in another trial [2]. The decision to perform an open operation or a VATS procedure was made by the operating surgeon considering the skills of the surgeon, time to perform the procedure and so on. Intervention All operations were performed in general anaesthesia with propofol and fentanyl. The VATS approach used has been described previously in detail [3]. Briefly, an anterior approach with 1 incision and 2 port assist incisions were performed, and 1 chest tube was placed. The open procedure was performed as an anterior thoracotomy, and 1 chest tube was placed. Patients undergoing the open procedure had an epidural catheter. All patients were intubated with a Carlens double-lumen tube and extubated immediately after surgery. Observation period and blood analyses This has previously been described [2]. Blood samples were obtained and analysed at the following 4 time points: (i) preoperatively; the day before surgery (before LMWH was administered); (ii) intraoperatively at the time of stapling the bronchus; (iii) postoperatively 08:00 AM at Day 1; and (iv) postoperatively 08:00 AM at Day 2. The first 2 ml of blood was discarded before drawing blood into tubes containing sodium citrate for ROTEM® analyses, thrombin generation and standard coagulation analyses, including activated partial thromboplastin time, international normalized ratio (INR), fibrinogen (functional), fibrin D-dimer, thrombin time, platelet count and coagulation factor VIII: clot. Blood samples for ROTEM analyses were left at room temperature for 30 min before processing, whereas the remaining analyses were performed either as routine analyses or blood samples were centrifuged at 2800g for 25 min and plasma was stored in aliquots at −80°C until analysis. Regarding thromboelastometry (ROTEM, Tem International GmbH, Munich, Germany), 3 standard assays were performed: INTEM, EXTEM and FIBTEM. We obtained the dynamic parameters of clot initiation (clotting time, s) and clot propagation (maximum velocity of clot formation, mm × 100/s, time to maximum velocity, s). Whole blood clot strength was assessed by maximum clot firmness (mm) × 100. Thrombin generation was evaluated by calibrated automated thrombograms (Thrombinoscope BV, Maastricht, Netherlands) using platelet-poor plasma. The following parameters were analysed: lag time until initial thrombin generation (min), maximum concentration of thrombin (peak, nM), time to peak (min) and the endogenous thrombin potential (nM × min). Reference values for the ROTEM was calculated based on data obtained from 73 healthy individuals previously published [6], whereas the reference values for thrombin generation was obtained from 32 individuals published by Collins et al. [7]. Preoperatively, the following baseline analyses were performed: haemoglobin, leucocyte and platelet counts, creatinine, INR and C-reactive protein. Preoperative (baseline) data in terms of clinical characteristics were collected systematically from medical records. Furthermore, intra- and postoperative data (operating time, bleeding during surgery, total drain loss, VTE and adverse events, length of stay and pathological staging) were registered prospectively. All patients were contacted by phone 30 days after the operation. They were systematically asked about complications, and at that time, they were terminated from the study. Statistical analyses, end-points and sample size Baseline data, intra- and postoperative characteristics and the results of the coagulation analyses were tested for normal distribution and hence presented as mean and standard deviation, median and 95% confidence interval or minimum to maximum values. Normally distributed data were compared using the Student’s unpaired t-test, whereas non-normally distributed data were compared using the Mann–Whitney U-test. Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05). To adjust for potential confounders, the amount of intraoperative bleeding in the 2 treatment groups was compared by linear regression. In the open procedure group, 1 patient bled 5000 ml, while no other patients bled more than 800 ml. This distribution could not be normalized with usual transformation methods, and we chose for the regression analyses to replace the 5000 ml with 800 ml. We adjusted for a number of potential preoperative confounders [age, gender, pack years of smoking, forced expiratory volume in 1 s (% of expected), diffusion capacity of the lung for carbon monoxide (% of expected), body mass index, diabetes mellitus, hypertension, hyperlipidaemia, cardiovascular disease, previous malignant disease, haemoglobin, fibrinogen, platelet count, activated partial thromboplastin time and INR]. The propensity score was calculated with logistic regression, and it was used as a covariate in the adjusted linear regression. GraphPad Prism version 6 for Mac (GraphPad Software, Inc., San Diego, CA, USA) and Stata Release 15 (StataCorp LP, TX, USA) were used for statistical analyses. Due to the explorative nature of the study sample size, calculations were omitted. Analysis was done using the per-protocol principle. RESULTS Figure 1 displays the trial flowchart. Figure 1: View largeDownload slide Trial flow diagram for patients undergoing VATS (n = 32) or open procedure (thoracotomy) (n = 30) lobectomy for primary lung cancer. ASA: acetylsalicylic acid (aspirin); LMWH: low-molecular-weight heparin; n/N: numbers; VATS: video-assisted thoracoscopic surgery. Figure 1: View largeDownload slide Trial flow diagram for patients undergoing VATS (n = 32) or open procedure (thoracotomy) (n = 30) lobectomy for primary lung cancer. ASA: acetylsalicylic acid (aspirin); LMWH: low-molecular-weight heparin; n/N: numbers; VATS: video-assisted thoracoscopic surgery. Patients were enrolled in the period from March 2013 to April 2015. A total of 81 VATS patients were randomized: 40 patients to the LMWH arm and 41 patients to the no intervention group. Patients in the latter group were excluded from this study. In the VATS arm, 8 patients were excluded due to lacking >1 blood sample (n = 5), received ASA (n = 1), not received LMWH (n = 1) and none malignant diagnosis (n = 1). Hence, a total of 32 patients were included in the LMWH arm, and 1 patient was converted to an open procedure. The open procedure group included 35 patients, whereof 5 patients were excluded due to lacking >1 blood sample (n = 1), received ASA (n = 1), not received LMWH (n = 2) and mistakenly included (was a VATS procedure) (n = 1). Thus, a total of 30 patients were included in the open procedure arm. Table 1 shows baseline/preoperative characteristics, and the 2 groups were well matched in terms of all baseline characteristics, except that the open procedure group were younger. Table 1: Baseline (preoperative) data from 62 patients undergoing VATS or an open procedure (thoracotomy) lobectomy for primary lung cancer Characteristics  VATS (N = 32)  Open procedure (N = 30)  P-value  Age (years)  69.8 (7.3)  65.4 (9.8)  0.05  Gender (female/male), n  15/17  9/21    Non-smoker/ex-smoker/active smoker, n  1/24/7  1/23/6    Pack years of smoking  31 (23)  32 (25)  0.85  FEV1 (% of expected)  86 (74–93)  80 (75–90)  0.33  DLCO (% of expected)  71 (60–78)  80 (68–85)  0.42  BMI  26 (4)  26 (5)  0.71  Comorbidity, n (%)a         Diabetes mellitus  3 (9)  2 (7)     Hypertension  13 (41)  13 (43)     Hyperlipidaemia  9 (28)  9 (30)     Cardiac and/or vascular disease  8 (15)  9 (30)     Previous malignant disease  6 (19)  5 (17)    ASA prescribed, n (%)  7 (22)  5 (17)    Laboratory analyses (reference interval)         B-haemoglobin (women 7.3–9.5 mmol/l; men 8.3–10.5 mmol/l)  8.6 (0.9)  8.6 (1.0)  0.99   B-leucocytes (3.5–10.0 × 109/l)  7.9 (1.9)  7.8 (2.3)  0.86   P-creatinine (women 45–90 μmol/l; men 60–105 μmol/l)  70.5 (65.9–80.4)  80.0 (71.0–88.0)  0.11   B-platelet count (145–400 × 109/l)  289 (69)  274 (87)  0.44   P-C-reactive protein (<8 mg/l)  2.6 (3.2–12.1)  5.2 (7.2–22.1)  0.09   P-INR (<1.2)  1.0 (1.0–1.0)  1.0 (1.0–1.1)  0.36   P-APTT (25–38 s)  31 (4)  32 (4)  0.31   P-fibrinogen (5–12 μmol/l)  10 (2)  11 (3)  0.31  Characteristics  VATS (N = 32)  Open procedure (N = 30)  P-value  Age (years)  69.8 (7.3)  65.4 (9.8)  0.05  Gender (female/male), n  15/17  9/21    Non-smoker/ex-smoker/active smoker, n  1/24/7  1/23/6    Pack years of smoking  31 (23)  32 (25)  0.85  FEV1 (% of expected)  86 (74–93)  80 (75–90)  0.33  DLCO (% of expected)  71 (60–78)  80 (68–85)  0.42  BMI  26 (4)  26 (5)  0.71  Comorbidity, n (%)a         Diabetes mellitus  3 (9)  2 (7)     Hypertension  13 (41)  13 (43)     Hyperlipidaemia  9 (28)  9 (30)     Cardiac and/or vascular disease  8 (15)  9 (30)     Previous malignant disease  6 (19)  5 (17)    ASA prescribed, n (%)  7 (22)  5 (17)    Laboratory analyses (reference interval)         B-haemoglobin (women 7.3–9.5 mmol/l; men 8.3–10.5 mmol/l)  8.6 (0.9)  8.6 (1.0)  0.99   B-leucocytes (3.5–10.0 × 109/l)  7.9 (1.9)  7.8 (2.3)  0.86   P-creatinine (women 45–90 μmol/l; men 60–105 μmol/l)  70.5 (65.9–80.4)  80.0 (71.0–88.0)  0.11   B-platelet count (145–400 × 109/l)  289 (69)  274 (87)  0.44   P-C-reactive protein (<8 mg/l)  2.6 (3.2–12.1)  5.2 (7.2–22.1)  0.09   P-INR (<1.2)  1.0 (1.0–1.0)  1.0 (1.0–1.1)  0.36   P-APTT (25–38 s)  31 (4)  32 (4)  0.31   P-fibrinogen (5–12 μmol/l)  10 (2)  11 (3)  0.31  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test were used, and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney U-test) was applied. The normally distributed data are represented as means (standard deviations), whereas the non-normally distributed data are represented as medians (95% confidence intervals). a Defined as the patient being in medical treatment for the disease in question. APTT: activated partial thromboplastin time; ASA: acetylsalicylic acid (aspirin); B: Blood; BMI: body mass index; DLCO: diffusion capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 s; INR: international normalized ratio; N/n: numbers; P: plasma; VATS: video-assisted thoracoscopic surgery. The intra- and postoperative data are displayed in Table 2. In the VATS group (n = 32), there were 28 patients in Stage IA + B and 4 patients in Stage IIA + B. In the open procedure group, (n = 30), there were 25 patients in Stage IA + B and 5 patients in Stage IIA + B. Table 2: Intra- and postoperative data from patients undergoing VATS or open procedure (thoracotomy) lobectomy for primary lung cancer Characteristics  VATS group (N = 32)  Open procedure group (N = 30)  P-value  Type of lobectomy         Right upper lobe  10  11     Right middle lobe  1  6     Right lower lobe  8  1     Left upper lobe  9  7     Left lower lobe  4  4     Bilobectomy  0  1    Operating time (min)  149 (48)  140 (51)  0.45  Bleeding/drainage during surgery (ml)  100 (56–122)  275 (118–780)  <0.0001  Use of inotropes (patients, n)a  17  17    Reoperated (n)  1  0    Total amount of fluid in the chest drain (ml)  760 (50–4356)  2130 (1887–2830)  <0.0001  Complications (n)b  2c  3c    VTE events  0  0    Death (n)  1d  0    Total length of stay (days)  6.3 (5.6–9.8)  5.3 (5.1–6.6)  0.11  Type of cancer         Adenocarcinoma  22  13     Squamous cell carcinoma  8  13     Carcinoid (all types)  0  1     Otherse  2  3    Pathological staging         Stage IA + B  28  25     Stage IIA + B  4  5    Microscopically free resection margins (R0)  32  29    Characteristics  VATS group (N = 32)  Open procedure group (N = 30)  P-value  Type of lobectomy         Right upper lobe  10  11     Right middle lobe  1  6     Right lower lobe  8  1     Left upper lobe  9  7     Left lower lobe  4  4     Bilobectomy  0  1    Operating time (min)  149 (48)  140 (51)  0.45  Bleeding/drainage during surgery (ml)  100 (56–122)  275 (118–780)  <0.0001  Use of inotropes (patients, n)a  17  17    Reoperated (n)  1  0    Total amount of fluid in the chest drain (ml)  760 (50–4356)  2130 (1887–2830)  <0.0001  Complications (n)b  2c  3c    VTE events  0  0    Death (n)  1d  0    Total length of stay (days)  6.3 (5.6–9.8)  5.3 (5.1–6.6)  0.11  Type of cancer         Adenocarcinoma  22  13     Squamous cell carcinoma  8  13     Carcinoid (all types)  0  1     Otherse  2  3    Pathological staging         Stage IA + B  28  25     Stage IIA + B  4  5    Microscopically free resection margins (R0)  32  29    Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test were used and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney U-test) was applied. The normally distributed data are represented as means (standard deviations), whereas the non-normally distributed data are represented as medians (95% confidence intervals). a Predominantly small doses of methaoxidrin or efedrin. b Includes myocardial infarction, apoplexia cerebri and atrial fibrillation. c All events were atrial fibrillation. d Died postoperatively [probably due to bleeding (tamponade)]. e Includes small-cell carcinoma, neuroendocrine and sarcomatoid tumour. N/n: numbers; VATS: video-assisted thoracoscopic surgery; VTE: venous thromboembolic events. The open procedure group had a significantly larger amount of intraoperative bleeding and a significantly larger total amount of fluid in the chest drains. None in the VATS group received transfusion, while in the open procedure group, 1 patient received transfusion in terms of red blood cells and fresh frozen plasma. In the non-adjusted and adjusted analyses, there was an average difference in bleeding between the 2 groups on 220 ml (95% confidence interval 130–310 ml; P < 0.001) and 203 ml (95% confidence interval 80–326 ml; P = 0.002), respectively. The results of the standard coagulation blood tests, ROTEM and thrombin generation are presented in Tables 3–5. Table 3: Conventional coagulation tests among 62 patients undergoing lobectomy for primary lung cancer using VATS (n = 32) or an open procedure (thoracotomy) (n = 30) Conventional coagulation tests (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  APTT (28–38 s)  31 (4)  32 (4)  0.31  30 (30–34)  31 (31–35)  0.19  32 (31–36)  34 (33–37)  0.08  32 (31–35)  34 (33–37)  0.07  INR (<1.2)  1.0 (1.01–1.06)  1.0 (1.01–1.05)  0.56  1.1 (1.06–1.14)  1.1 (1.09–1.17)  0.12  1.14 (0.11)  1.21 (0.09)  0.01  1.09 (0.1)  1.17 (0.13)  0.02  Fibrinogen (5–12 μmol/l)  10 (10–11)  10 (10–12)  0.70  9 (2)  8 (3)  0.74  11 (2)  11 (3)  0.45  15 (2)  14 (3)  0.82  Platelet count (145–400 × 109/l)  280 (61)  272 (84)  0.66  225 (52)  191 (61)  0.045  231 (48)  198 (59)  0.04  243 (70)  194 (62)  0.02  Thrombin time (<21 s)  17 (1)  18 (2)  0.052  17 (17–18)  18 (17–19)  0.38  16 (16–17)  17 (16–17)  0.93  15 (2)  16 (2)  0.12  Fibrin D-dimer (<0.50 mg/l FEU)  0.49 (0.45–1.03)  0.76 (0.76–1.59)  0.39  0.73 (0.50–1.56)  0.71 (0.71–1.32)  0.66  0.84 (0.57–2.64)  1.68 (1.33–2.47)  0.01  0.73 (0.72–1.15)  1.15 (1.01–1.74)  0.05  Coagulation Factor VIII: clot (0.66–1.55 kiu/l)  1.36 (1.18–1.49)  1.38 (1.29–1.61)  0.63  1.28 (1.16–1.47)  1.26 (1.18–1.45)  0.92  1.68 (0.34)  1.60 (0.37)  0.37  1.85 (1.77–2.01)  2.03 (1.87–2.15)  0.29  Conventional coagulation tests (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  APTT (28–38 s)  31 (4)  32 (4)  0.31  30 (30–34)  31 (31–35)  0.19  32 (31–36)  34 (33–37)  0.08  32 (31–35)  34 (33–37)  0.07  INR (<1.2)  1.0 (1.01–1.06)  1.0 (1.01–1.05)  0.56  1.1 (1.06–1.14)  1.1 (1.09–1.17)  0.12  1.14 (0.11)  1.21 (0.09)  0.01  1.09 (0.1)  1.17 (0.13)  0.02  Fibrinogen (5–12 μmol/l)  10 (10–11)  10 (10–12)  0.70  9 (2)  8 (3)  0.74  11 (2)  11 (3)  0.45  15 (2)  14 (3)  0.82  Platelet count (145–400 × 109/l)  280 (61)  272 (84)  0.66  225 (52)  191 (61)  0.045  231 (48)  198 (59)  0.04  243 (70)  194 (62)  0.02  Thrombin time (<21 s)  17 (1)  18 (2)  0.052  17 (17–18)  18 (17–19)  0.38  16 (16–17)  17 (16–17)  0.93  15 (2)  16 (2)  0.12  Fibrin D-dimer (<0.50 mg/l FEU)  0.49 (0.45–1.03)  0.76 (0.76–1.59)  0.39  0.73 (0.50–1.56)  0.71 (0.71–1.32)  0.66  0.84 (0.57–2.64)  1.68 (1.33–2.47)  0.01  0.73 (0.72–1.15)  1.15 (1.01–1.74)  0.05  Coagulation Factor VIII: clot (0.66–1.55 kiu/l)  1.36 (1.18–1.49)  1.38 (1.29–1.61)  0.63  1.28 (1.16–1.47)  1.26 (1.18–1.45)  0.92  1.68 (0.34)  1.60 (0.37)  0.37  1.85 (1.77–2.01)  2.03 (1.87–2.15)  0.29  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed unpaired t-test was used, and if non-normal distribution in one or both groups Mann–Whitney test was applied. Results of the normally distributed data are shown as mean (standard deviation). Results of the non-normally distributed data are shown as median (95% confidence interval). APTT: activated partial thromboplastin time; FEU: fibrinogen-equivalent units; INR: international normalized ratio; VATS: video-assisted thoracoscopic surgery. Table 4: ROTEM results among 62 patients undergoing lobectomy for primary lung cancer using VATS (n = 32) or an open procedure (thoracotomy) (n = 30) ROTEM variables (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  EXTEM     CT (38–74 s)  58 (54–61)  59 (55–61)  0.55  55 (8)  57 (8)  0.47  58 (55–60)  58 (56–62)  0.51  58 (9)  59 (9)  0.76   MaxVel (8–22 mm/min)  20 (4)  21 (7)  0.23  18 (17–20)  18 (15–20)  0.30  19 (18–21)  18 (17–22)  0.39  22 (5)  21 (6)  0.80   tMaxVel (48–145 s)  91 (26)  92 (20)  0.87  91 (25)  93 (30)  0.81  88 (21)  90 (26)  0.66  76 (74–99)  73 (73–91)  0.61  INTEM     CT (129–181 s)  165 (161–175)  169 (163–174)  0.56  170 (150–173)  160 (155–171)  0.27  164 (160–174)  165 (161–175)  0.26  163 (161–172)  161 (167–178)  0.78   MaxVel (11–25 mm/min)  22 (4)  23 (7)  0.37  21 (4)  21 (7)  0.83  21 (19–25)  19 (18–22)  0.12  22 (4)  23 (6)  0.64   tMaxVel (147–223 s)  190 (185–203)  198 (190–206)  0.28  193 (179–197)  184 (179–199)  0.36  191 (21)  186 (33)  0.45  187 (183–196)  184 (179–205)  0.83  FIBTEM                           MCF (8–20 mm)  19 (18–24)  19 (19–26)  0.85  17 (15–21)  17 (15–21)  0.73  22 (6)  21 (7)  0.42  28 (6)  27 (7)  0.37  ROTEM variables (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  EXTEM     CT (38–74 s)  58 (54–61)  59 (55–61)  0.55  55 (8)  57 (8)  0.47  58 (55–60)  58 (56–62)  0.51  58 (9)  59 (9)  0.76   MaxVel (8–22 mm/min)  20 (4)  21 (7)  0.23  18 (17–20)  18 (15–20)  0.30  19 (18–21)  18 (17–22)  0.39  22 (5)  21 (6)  0.80   tMaxVel (48–145 s)  91 (26)  92 (20)  0.87  91 (25)  93 (30)  0.81  88 (21)  90 (26)  0.66  76 (74–99)  73 (73–91)  0.61  INTEM     CT (129–181 s)  165 (161–175)  169 (163–174)  0.56  170 (150–173)  160 (155–171)  0.27  164 (160–174)  165 (161–175)  0.26  163 (161–172)  161 (167–178)  0.78   MaxVel (11–25 mm/min)  22 (4)  23 (7)  0.37  21 (4)  21 (7)  0.83  21 (19–25)  19 (18–22)  0.12  22 (4)  23 (6)  0.64   tMaxVel (147–223 s)  190 (185–203)  198 (190–206)  0.28  193 (179–197)  184 (179–199)  0.36  191 (21)  186 (33)  0.45  187 (183–196)  184 (179–205)  0.83  FIBTEM                           MCF (8–20 mm)  19 (18–24)  19 (19–26)  0.85  17 (15–21)  17 (15–21)  0.73  22 (6)  21 (7)  0.42  28 (6)  27 (7)  0.37  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test was used and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney test) was applied. Results of the normal distributed data are shown as mean (standard deviation). Results of the non-normal distributed data are shown as median (95% confidence interval). CT: clotting time; MaxVel: maximum velocity; MCF: maximum clot firmness; tMaxVel: time to maximum velocity; VATS: video-assisted thoracoscopic surgery. Table 5: Thrombin generation among 62 patients undergoing VATS (n = 32) or open procedure (thoracotomy) (n = 30) lobectomy for primary lung cancer Thrombin generation for healthy individuals,a mean (SD)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  Lag time (min), 2.4 (0.9)  3.2 (3.0–3.6)  3.1 (2.9–4.1)  0.96  2.8 (2.7–3.2)  2.9 (2.6–3.6)  0.98  3.7 (3.5–5.1)  3.4 (3.1–4.3)  0.37  3.0 (3.2–5.1)  3.2 (3.2–4.3)  0.87  Peak thrombin (nM), 454 (100)  220 (188–235)  225 (211–267)  0.28  241 (54)  241 (49)  0.99  173 (85)  200 (58)  0.16  258 (216–274)  251 (207–262)  0.40  ETP (nM × min), 1681 (281)  1271 (1167–1410)  1353 (915–2840)  0.15  1465 (1303–1460)  1349 (1282–1521)  0.58  1036 (379)  1144 (234)  0.19  1351 (1140–1390)  1249 (1115–1346)  0.34  Time to peak (min), 4.2 (1.2)  6.7 (6.2–7.3)  6.6 (6.2–7.5)  0.84  5.7 (5.4–6.3)  5.5 (5.3–6.4)  0.73  6.9 (6.4–10.8)  6.3 (5.9–7.3)  0.14  5.5 (5.6–8.6)  5.9 (5.7–7.2)  0.81  Thrombin generation for healthy individuals,a mean (SD)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  Lag time (min), 2.4 (0.9)  3.2 (3.0–3.6)  3.1 (2.9–4.1)  0.96  2.8 (2.7–3.2)  2.9 (2.6–3.6)  0.98  3.7 (3.5–5.1)  3.4 (3.1–4.3)  0.37  3.0 (3.2–5.1)  3.2 (3.2–4.3)  0.87  Peak thrombin (nM), 454 (100)  220 (188–235)  225 (211–267)  0.28  241 (54)  241 (49)  0.99  173 (85)  200 (58)  0.16  258 (216–274)  251 (207–262)  0.40  ETP (nM × min), 1681 (281)  1271 (1167–1410)  1353 (915–2840)  0.15  1465 (1303–1460)  1349 (1282–1521)  0.58  1036 (379)  1144 (234)  0.19  1351 (1140–1390)  1249 (1115–1346)  0.34  Time to peak (min), 4.2 (1.2)  6.7 (6.2–7.3)  6.6 (6.2–7.5)  0.84  5.7 (5.4–6.3)  5.5 (5.3–6.4)  0.73  6.9 (6.4–10.8)  6.3 (5.9–7.3)  0.14  5.5 (5.6–8.6)  5.9 (5.7–7.2)  0.81  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test were used and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney U-tests) was applied. The normally distributed data are shown as mean (SD), whereas the non-normally distributed data are shown as median (95% confidence interval). 1 See Collins et al. [7]. ETP: endogenous thrombin potential; SD: standard deviation; VATS: video-assisted thoracoscopic surgery. Overall, no patients exhibited a hypercoagulable state prior to surgery. Intra- and postoperatively, the open procedure group had a significantly lower, albeit not critically low, platelet count compared with the VATS group. The postoperative INR was significantly higher in the open procedure group than in the VATS group. However, the higher INR did not have any clinical impact, since it was merely a minor difference (<0.1 INR value). A lower level of fibrin D-dimer was found on postoperative Days 1 and 2 in the VATS group, statistically significant on the postoperative Day 1, but not on postoperative Day 1. There was no difference between the 2 groups regarding the ROTEM results and thrombin generation parameters. DISCUSSION The main finding of this study was that the use of VATS or open lobectomy in patients undergoing curative surgery for primary lung cancer had a similar-sized minor impact on the coagulation system. Furthermore, the lung cancer patients were not hypercoagulable preoperatively. To our knowledge, this is the first study to compare changes in the activation of the coagulation system in these 2 procedures used for primary lung cancer surgery. Different types of coagulation analyses have been used in previously published studies: thromboelastography [8], thrombin generation [9], markers of thrombin degradation (prothrombin fragment 1 + 2) [10] and standard coagulation parameters [10]. The results of these analyses have been reported to correlate with clinical events such as bleeding [11] and VTE [12]. Davies et al. [13] found that abnormal parameters of ROTEM correlated with the long-term risk of VTE in lung cancer patients. These coagulation analyses may therefore all potentially serve as surrogate parameters regarding the VTE risk [14]. It should be emphasized that thrombin generation parameters obtained by calibrated automated thromboelastography is determined ex vivo and thereby estimate the thrombin generation potential in the patient, which not necessarily reflects activity in vivo. To reflect in vivo activity in the coagulation system and depict whether a patient is actively producing thrombin and/or fibrin, measurement of prothrombin fragment 1 + 2 or thrombin–antithrombin should be used. In this study, measurement of thrombin generation was used to describe the clotting potential and to depict active coagulation processes measurement of fibrin D-dimer was included. In this study, we did not find that patients undergoing potentially curative surgery for lung cancer were hypercoagulable in the preoperative state. This is in accordance with the findings by Attaran et al. [15]. Świniarska et al. [16] concluded that pneumonectomy compared with lobectomy resulted in an increased activation of the coagulation system at Day 7 post-surgery. Preoperative data were, however, not reported. In this study, we only included lobectomies and hence cannot elaborate regarding pneumonectomies or the degree of activation of the coagulation system beyond Day 2 post-surgery. Studies have found a lower incidence of complications [5], a reduced length of stay, an improved quality of life, reduced postoperative pain [4], with VATS compared with an open approach. We found that an open procedure resulted in a significantly higher blood and drain loss during and after surgery, which potentially increases the risk of transfusion and hereto related complications [17]. This finding is in coherence with previous findings of Falcoz et al. [5]. However, based on our results, the VATS and open approach have an equal low impact on the coagulation system, so these 2 surgical techniques are comparable regarding this. The higher volume of blood loss in the open group is not surprising, since the incision is larger and potentially could bleed more. We used an anterior thoracotomy, which is potentially less traumatic than the more widely used posterolateral incision [18], so we cannot extrapolate our results to patients undergoing the latter approach. It would be relevant to relate the coagulation with different tumour stages or TNM factors. Yet we included only early-stage patients, and therefore, such a comparison was not possible in this study. However, it could be interesting to investigate this in a future study. The staging of the cancer was equally distributed in both groups, and a comparison of different tumour stages would therefore unfortunately not provide any useful information in our study. The strengths of this study are the use of a wide spectrum of advanced and validated coagulation analyses. We adjusted for several potential confounders between the 2 treatment groups, and there was no significant difference regarding bleeding in the non-adjusted and adjusted analyses, with the open procedure group bleeding significantly more than the VATS group. Our 2 groups were accordingly well matched. Limitations Our study has some limitations as we used surrogate and not clinical end-points in terms of VTE and bleeding events and it was not a randomized trial. Participants with missing data were simply excluded from the analysis. This was done, because the missing data were randomly distributed between the 2 groups and were not associated with the outcome. We analysed our data as treated. However, missing data were always a potential reason for bias. CONCLUSIONS In patients undergoing curative surgery for early-stage primary lung cancer, we observed a statistical non-significant difference and a similar-sized minor impact on the coagulation system. ACKNOWLEDGEMENTS We wish to thank research nurse Vibeke Laursen for helping and co-ordinating all the practical issues with regard to conducting this study, laboratory technician Mai Stenulm Therkelsen and Vivi Bo Mogensen for blood sampling and analysis, Svend Juul for performing the propensity score analysis and Hans Pilegaard and Vibeke E. Hjortdal for making the study practically feasible. Funding The work was supported by Arvid Nilssons fond, Snedkermester Sophus Jacobsen og hustru Astrid Jacobsens Fond and Fru Agnes Niebuhr Andersons Cancerforskningsfonds pris. The work was done independent of the funders. Conflict of interest: Thomas Decker Christensen has been on the speaker bureaus for AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche Diagnostics, Takeda, Bristol-Myers Squibb and Merck Sharp & Dohme (MSD) and has been in an Advisory Board for Bayer, MSD and Boehringer-Ingelheim. Anne-Mette Hvas has received speaker’s fees from CSL Behring, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb and Leo Pharma and unrestricted research support from Octapharma, CSL Behring and Leo Pharma. Mads Nybo has received speaker’s fees from Astra Zeneca, Pfizer and Roche Diagnostics. Peter Licht has received speaker’s fees from Ethicon Endo-Surgery. All other authors declared no conflict of interest. REFERENCES 1 Christensen TD, Vad H, Pedersen S, Hvas A-M, Wotton R, Naidu B. Venous thromboembolism in patients undergoing operations for lung cancer: a systematic review. Ann Thorac Surg  2014; 97: 394– 400. Google Scholar CrossRef Search ADS PubMed  2 Christensen TD, Vad H, Pedersen S, Hornbech K, Zois NE, Licht PB et al.   Coagulation profile in video-assisted thoracoscopic lobectomy: a randomized, controlled trial. PLoS One  2017; 12: e0171809. Google Scholar CrossRef Search ADS PubMed  3 Laursen LØ, Petersen RH, Hansen HJ, Jensen TK, Ravn J, Konge L. Video-assisted thoracoscopic surgery lobectomy for lung cancer is associated with a lower 30-day morbidity compared with lobectomy by thoracotomy. Eur J Cardiothorac Surg  2016; 49: 870– 5. Google Scholar CrossRef Search ADS PubMed  4 Bendixen M, Jørgensen OD, Kronborg C, Andersen C, Licht PB. Postoperative pain and quality of life after lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung cancer: a randomised controlled trial. Lancet Oncol  2016; 17: 836– 44. Google Scholar CrossRef Search ADS PubMed  5 Falcoz P-E, Puyraveau M, Thomas P-A, Decaluwe H, Hürtgen M, Petersen RH et al.   Video-assisted thoracoscopic surgery versus open lobectomy for primary non-small-cell lung cancer: a propensity-matched analysis of outcome from the European Society of Thoracic Surgeon database. Eur J Cardiothorac Surg  2016; 49: 602– 9. Google Scholar CrossRef Search ADS PubMed  6 Andersen MG, Hvas CL, Tønnesen E, Hvas A-M. Thromboelastometry as a supplementary tool for evaluation of hemostasis in severe sepsis and septic shock. Acta Anaesthesiol Scand  2014; 58: 525– 33. Google Scholar CrossRef Search ADS PubMed  7 Collins PW, Macchiavello LI, Lewis SJ, Macartney NJ, Saayman AG, Luddington R et al.   Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. Br J Haematol  2006; 135: 220– 7. Google Scholar CrossRef Search ADS PubMed  8 De Pietri L, Montalti R, Begliomini B, Scaglioni G, Marconi G, Reggiani A et al.   Thromboelastographic changes in liver and pancreatic cancer surgery: hypercoagulability, hypocoagulability or normocoagulability? Eur J Anaesthesiol  2010; 27: 608– 16. Google Scholar CrossRef Search ADS PubMed  9 Papageorgiou C, Vandreden P, Marret E, Bonnet F, Robert F, Spyropoulos A et al.   Lobectomy and postoperative thromboprophylaxis with enoxaparin improve blood hypercoagulability in patients with localized primary lung adenocarcinoma. Thromb Res  2013; 132: 584– 91. Google Scholar CrossRef Search ADS PubMed  10 Ay C, Pabinger I. VTE risk assessment in cancer. Who needs prophylaxis and who does not? Hamostaseologie  2015; 35: 319– 24. Google Scholar CrossRef Search ADS PubMed  11 Ay C, Dunkler D, Simanek R, Thaler J, Koder S, Marosi C et al.   Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna cancer and thrombosis study. J Clin Oncol  2011; 29: 2099– 103. Google Scholar CrossRef Search ADS PubMed  12 Fenger-Eriksen C, Jensen TM, Kristensen BS, Jensen KM, Tønnesen E, Ingerslev J et al.   Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial. J Thromb Haemost  2009; 7: 795– 802. Google Scholar CrossRef Search ADS PubMed  13 Davies NA, Harrison NK, Sabra A, Lawrence MJ, Noble S, Davidson SJ et al.   Application of ROTEM to assess hypercoagulability in patients with lung cancer. Thromb Res  2015; 135: 1075– 80. Google Scholar CrossRef Search ADS PubMed  14 Hincker A, Feit J, Sladen RN, Wagener G. Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. Crit Care  2014; 18: 549. Google Scholar CrossRef Search ADS PubMed  15 Attaran S, Somov P, Awad WI. Randomised high- and low-dose heparin prophylaxis in patients undergoing thoracotomy for benign and malignant disease: effect on thrombo-elastography. Eur J Cardiothorac Surg  2010; 37: 1384– 90. Google Scholar CrossRef Search ADS PubMed  16 Świniarska J, Żekanowska E, Dancewicz M, Bella M, Szczęsny TJ, Kowalewski J. Pneumonectomy due to lung cancer results in a more pronounced activation of coagulation system than lobectomy. Eur J Cardiothorac Surg  2009; 36: 1064– 8. Google Scholar CrossRef Search ADS PubMed  17 Turan A, Yang D, Bonilla A, Shiba A, Sessler DI, Saager L et al.   Morbidity and mortality after massive transfusion in patients undergoing non-cardiac surgery. Can J Anesth  2013; 60: 761– 70. Google Scholar CrossRef Search ADS PubMed  18 Fibla JJ, Molins L, Mier JM, Hernandez J, Sierra AA. randomized prospective study of analgesic quality after thoracotomy: paravertebral block with bolus versus continuous infusion with an elastomeric pump. Eur J Cardiothorac Surg  2015; 47: 631– 5. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

Coagulation profile in open and video-assisted thoracoscopic lobectomies: a cohort study

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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10.1093/icvts/ivx328
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Abstract

Abstract OBJECTIVES Lung cancer patients are perceived to have a relatively high risk of venous thromboembolic events due to an activation of the coagulation system. In terms of activation of the coagulation system, the difference between video-assisted thoracoscopic surgery (VATS) and open lobectomies for primary lung cancer has not been investigated. The aim of this study was to compare the impact on the coagulation system in patients undergoing curative surgery for primary lung cancer by either VATS or open lobectomies. METHODS In total, 62 patients diagnosed with primary lung cancer were allocated to either VATS (n = 32) or open lobectomies (n = 30). All patients received subcutaneous injections with dalteparin (Fragmin®) 5000 IE once daily. The coagulation was assessed pre- and intraoperatively, and the first 2 days postoperatively by standard coagulation blood tests, thromboelastometry (ROTEM®) and thrombin generation. RESULTS The open lobectomies bled more than the VATS group and had a significantly lower platelet count (109/l) on postoperative Days 1 and 2 (198 vs 231 and 194 vs 243, respectively). The open group also had a higher international normalized ratio on postoperative Days 1 and 2 compared with the VATS group (1.21 vs 1.14 and 1.17 vs 1.09, respectively). There were no differences in thromboelastometry (ROTEM®) and thrombin generation parameters. None of the included patients developed venous thromboembolic events. CONCLUSIONS In patients undergoing curative surgery for early-stage primary lung cancer, we observed a statistical non-significant difference and a similar-sized minor impact on the coagulation system. Venous thrombosis, Blood coagulation test, Thrombin generation, Lung neoplasm, Thoracic surgery INTRODUCTION The risk of venous thromboembolic events (VTEs) consisting of deep venous thrombosis or pulmonary embolism for patients undergoing surgery for primary lung cancer is relatively low with an overall risk of 2%, but with a marked variation among studies (range 0.2–19%) [1]. We have previously published a study where patients undergoing curative surgery for primary lung cancer using video-assisted thoracoscopic surgery (VATS) were randomized to either low-molecular-weight heparin (LMWH) or no thromboprophylaxis [2]. We concluded that LMWH administered once daily did not alter the coagulation profile. VATS surgery differs from an open approach (thoracotomy) with regard to surgical trauma, and it has been advocated that a VATS procedure is less traumatic than an open procedure [3] and, hereby e.g., enhance mobilization. VATS seems to be associated with less postoperative pain and better quality of life compared with an open approach [4] and a reduced risk of complications [5]. No studies have yet evaluated the impact of the 2 different approaches on the coagulation system. The activation of the coagulation system reflects the stress response that patients undergo during and after the surgical procedure. We prespecified hypothesized that an open operation would have a more profound impact on the coagulation system when compared with VATS. The aim of this study was to compare the impact on the coagulation system in patients undergoing curative surgery for primary lung cancer by either VATS or open lobectomies. MATERIALS AND METHODS This is a substudy of a larger randomized controlled trial, and the overall design has been reported elsewhere [2]. Inclusion criteria were as follows: (i) diagnosed with primary lung cancer with a preoperative Stage IA–IB; (ii) surgery with expected lobectomy or bilobectomy; (iii) willingness to participate and ability to give informed oral and written consent; and (iv) >18 years of age. Exclusion criteria were as follows: (i) thromboembolic event (either arterial or venous) within the past 3 months; (ii) pregnant or lactating; (iii) treatment with a vitamin K antagonist or a non-vitamin K antagonist oral anticoagulant and (iv) treatment with a platelet inhibitor if this was not paused for a minimum of 5 days (aspirin, clopidogrel or ticagrelor) or 7 days (prasugrel). No patients had received neoadjuvant chemotherapy and/or radiation therapy prior to surgery. Patients operated with a VATS approach were included from 3 Danish centres [Aarhus University Hospital, Rigshospitalet (University Hospital of Copenhagen) or Odense University Hospital], whereas patients with an open procedure were solely included from Aarhus University Hospital. The patients were included after oral and written consent. The study protocol complied with the Helsinki II declaration and was approved by the local scientific ethics committee (file number 1-10-72-364-12) and The Danish Data Protection Agency. The study was conducted according to Good Clinical Practice standards and was monitored by the Good Clinical Practice unit, Aarhus University Hospital, Aarhus, Denmark. The trial was registered at ClinicalTrials.gov (Identifier: NCT01741506) and at EudraCTno. 2012-002409-23. Patients In total, 62 patients were prospectively included: 30 in the VATS group and 32 in the open procedure group. The patients in the VATS group participated in another trial [2]. The decision to perform an open operation or a VATS procedure was made by the operating surgeon considering the skills of the surgeon, time to perform the procedure and so on. Intervention All operations were performed in general anaesthesia with propofol and fentanyl. The VATS approach used has been described previously in detail [3]. Briefly, an anterior approach with 1 incision and 2 port assist incisions were performed, and 1 chest tube was placed. The open procedure was performed as an anterior thoracotomy, and 1 chest tube was placed. Patients undergoing the open procedure had an epidural catheter. All patients were intubated with a Carlens double-lumen tube and extubated immediately after surgery. Observation period and blood analyses This has previously been described [2]. Blood samples were obtained and analysed at the following 4 time points: (i) preoperatively; the day before surgery (before LMWH was administered); (ii) intraoperatively at the time of stapling the bronchus; (iii) postoperatively 08:00 AM at Day 1; and (iv) postoperatively 08:00 AM at Day 2. The first 2 ml of blood was discarded before drawing blood into tubes containing sodium citrate for ROTEM® analyses, thrombin generation and standard coagulation analyses, including activated partial thromboplastin time, international normalized ratio (INR), fibrinogen (functional), fibrin D-dimer, thrombin time, platelet count and coagulation factor VIII: clot. Blood samples for ROTEM analyses were left at room temperature for 30 min before processing, whereas the remaining analyses were performed either as routine analyses or blood samples were centrifuged at 2800g for 25 min and plasma was stored in aliquots at −80°C until analysis. Regarding thromboelastometry (ROTEM, Tem International GmbH, Munich, Germany), 3 standard assays were performed: INTEM, EXTEM and FIBTEM. We obtained the dynamic parameters of clot initiation (clotting time, s) and clot propagation (maximum velocity of clot formation, mm × 100/s, time to maximum velocity, s). Whole blood clot strength was assessed by maximum clot firmness (mm) × 100. Thrombin generation was evaluated by calibrated automated thrombograms (Thrombinoscope BV, Maastricht, Netherlands) using platelet-poor plasma. The following parameters were analysed: lag time until initial thrombin generation (min), maximum concentration of thrombin (peak, nM), time to peak (min) and the endogenous thrombin potential (nM × min). Reference values for the ROTEM was calculated based on data obtained from 73 healthy individuals previously published [6], whereas the reference values for thrombin generation was obtained from 32 individuals published by Collins et al. [7]. Preoperatively, the following baseline analyses were performed: haemoglobin, leucocyte and platelet counts, creatinine, INR and C-reactive protein. Preoperative (baseline) data in terms of clinical characteristics were collected systematically from medical records. Furthermore, intra- and postoperative data (operating time, bleeding during surgery, total drain loss, VTE and adverse events, length of stay and pathological staging) were registered prospectively. All patients were contacted by phone 30 days after the operation. They were systematically asked about complications, and at that time, they were terminated from the study. Statistical analyses, end-points and sample size Baseline data, intra- and postoperative characteristics and the results of the coagulation analyses were tested for normal distribution and hence presented as mean and standard deviation, median and 95% confidence interval or minimum to maximum values. Normally distributed data were compared using the Student’s unpaired t-test, whereas non-normally distributed data were compared using the Mann–Whitney U-test. Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05). To adjust for potential confounders, the amount of intraoperative bleeding in the 2 treatment groups was compared by linear regression. In the open procedure group, 1 patient bled 5000 ml, while no other patients bled more than 800 ml. This distribution could not be normalized with usual transformation methods, and we chose for the regression analyses to replace the 5000 ml with 800 ml. We adjusted for a number of potential preoperative confounders [age, gender, pack years of smoking, forced expiratory volume in 1 s (% of expected), diffusion capacity of the lung for carbon monoxide (% of expected), body mass index, diabetes mellitus, hypertension, hyperlipidaemia, cardiovascular disease, previous malignant disease, haemoglobin, fibrinogen, platelet count, activated partial thromboplastin time and INR]. The propensity score was calculated with logistic regression, and it was used as a covariate in the adjusted linear regression. GraphPad Prism version 6 for Mac (GraphPad Software, Inc., San Diego, CA, USA) and Stata Release 15 (StataCorp LP, TX, USA) were used for statistical analyses. Due to the explorative nature of the study sample size, calculations were omitted. Analysis was done using the per-protocol principle. RESULTS Figure 1 displays the trial flowchart. Figure 1: View largeDownload slide Trial flow diagram for patients undergoing VATS (n = 32) or open procedure (thoracotomy) (n = 30) lobectomy for primary lung cancer. ASA: acetylsalicylic acid (aspirin); LMWH: low-molecular-weight heparin; n/N: numbers; VATS: video-assisted thoracoscopic surgery. Figure 1: View largeDownload slide Trial flow diagram for patients undergoing VATS (n = 32) or open procedure (thoracotomy) (n = 30) lobectomy for primary lung cancer. ASA: acetylsalicylic acid (aspirin); LMWH: low-molecular-weight heparin; n/N: numbers; VATS: video-assisted thoracoscopic surgery. Patients were enrolled in the period from March 2013 to April 2015. A total of 81 VATS patients were randomized: 40 patients to the LMWH arm and 41 patients to the no intervention group. Patients in the latter group were excluded from this study. In the VATS arm, 8 patients were excluded due to lacking >1 blood sample (n = 5), received ASA (n = 1), not received LMWH (n = 1) and none malignant diagnosis (n = 1). Hence, a total of 32 patients were included in the LMWH arm, and 1 patient was converted to an open procedure. The open procedure group included 35 patients, whereof 5 patients were excluded due to lacking >1 blood sample (n = 1), received ASA (n = 1), not received LMWH (n = 2) and mistakenly included (was a VATS procedure) (n = 1). Thus, a total of 30 patients were included in the open procedure arm. Table 1 shows baseline/preoperative characteristics, and the 2 groups were well matched in terms of all baseline characteristics, except that the open procedure group were younger. Table 1: Baseline (preoperative) data from 62 patients undergoing VATS or an open procedure (thoracotomy) lobectomy for primary lung cancer Characteristics  VATS (N = 32)  Open procedure (N = 30)  P-value  Age (years)  69.8 (7.3)  65.4 (9.8)  0.05  Gender (female/male), n  15/17  9/21    Non-smoker/ex-smoker/active smoker, n  1/24/7  1/23/6    Pack years of smoking  31 (23)  32 (25)  0.85  FEV1 (% of expected)  86 (74–93)  80 (75–90)  0.33  DLCO (% of expected)  71 (60–78)  80 (68–85)  0.42  BMI  26 (4)  26 (5)  0.71  Comorbidity, n (%)a         Diabetes mellitus  3 (9)  2 (7)     Hypertension  13 (41)  13 (43)     Hyperlipidaemia  9 (28)  9 (30)     Cardiac and/or vascular disease  8 (15)  9 (30)     Previous malignant disease  6 (19)  5 (17)    ASA prescribed, n (%)  7 (22)  5 (17)    Laboratory analyses (reference interval)         B-haemoglobin (women 7.3–9.5 mmol/l; men 8.3–10.5 mmol/l)  8.6 (0.9)  8.6 (1.0)  0.99   B-leucocytes (3.5–10.0 × 109/l)  7.9 (1.9)  7.8 (2.3)  0.86   P-creatinine (women 45–90 μmol/l; men 60–105 μmol/l)  70.5 (65.9–80.4)  80.0 (71.0–88.0)  0.11   B-platelet count (145–400 × 109/l)  289 (69)  274 (87)  0.44   P-C-reactive protein (<8 mg/l)  2.6 (3.2–12.1)  5.2 (7.2–22.1)  0.09   P-INR (<1.2)  1.0 (1.0–1.0)  1.0 (1.0–1.1)  0.36   P-APTT (25–38 s)  31 (4)  32 (4)  0.31   P-fibrinogen (5–12 μmol/l)  10 (2)  11 (3)  0.31  Characteristics  VATS (N = 32)  Open procedure (N = 30)  P-value  Age (years)  69.8 (7.3)  65.4 (9.8)  0.05  Gender (female/male), n  15/17  9/21    Non-smoker/ex-smoker/active smoker, n  1/24/7  1/23/6    Pack years of smoking  31 (23)  32 (25)  0.85  FEV1 (% of expected)  86 (74–93)  80 (75–90)  0.33  DLCO (% of expected)  71 (60–78)  80 (68–85)  0.42  BMI  26 (4)  26 (5)  0.71  Comorbidity, n (%)a         Diabetes mellitus  3 (9)  2 (7)     Hypertension  13 (41)  13 (43)     Hyperlipidaemia  9 (28)  9 (30)     Cardiac and/or vascular disease  8 (15)  9 (30)     Previous malignant disease  6 (19)  5 (17)    ASA prescribed, n (%)  7 (22)  5 (17)    Laboratory analyses (reference interval)         B-haemoglobin (women 7.3–9.5 mmol/l; men 8.3–10.5 mmol/l)  8.6 (0.9)  8.6 (1.0)  0.99   B-leucocytes (3.5–10.0 × 109/l)  7.9 (1.9)  7.8 (2.3)  0.86   P-creatinine (women 45–90 μmol/l; men 60–105 μmol/l)  70.5 (65.9–80.4)  80.0 (71.0–88.0)  0.11   B-platelet count (145–400 × 109/l)  289 (69)  274 (87)  0.44   P-C-reactive protein (<8 mg/l)  2.6 (3.2–12.1)  5.2 (7.2–22.1)  0.09   P-INR (<1.2)  1.0 (1.0–1.0)  1.0 (1.0–1.1)  0.36   P-APTT (25–38 s)  31 (4)  32 (4)  0.31   P-fibrinogen (5–12 μmol/l)  10 (2)  11 (3)  0.31  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test were used, and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney U-test) was applied. The normally distributed data are represented as means (standard deviations), whereas the non-normally distributed data are represented as medians (95% confidence intervals). a Defined as the patient being in medical treatment for the disease in question. APTT: activated partial thromboplastin time; ASA: acetylsalicylic acid (aspirin); B: Blood; BMI: body mass index; DLCO: diffusion capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 s; INR: international normalized ratio; N/n: numbers; P: plasma; VATS: video-assisted thoracoscopic surgery. The intra- and postoperative data are displayed in Table 2. In the VATS group (n = 32), there were 28 patients in Stage IA + B and 4 patients in Stage IIA + B. In the open procedure group, (n = 30), there were 25 patients in Stage IA + B and 5 patients in Stage IIA + B. Table 2: Intra- and postoperative data from patients undergoing VATS or open procedure (thoracotomy) lobectomy for primary lung cancer Characteristics  VATS group (N = 32)  Open procedure group (N = 30)  P-value  Type of lobectomy         Right upper lobe  10  11     Right middle lobe  1  6     Right lower lobe  8  1     Left upper lobe  9  7     Left lower lobe  4  4     Bilobectomy  0  1    Operating time (min)  149 (48)  140 (51)  0.45  Bleeding/drainage during surgery (ml)  100 (56–122)  275 (118–780)  <0.0001  Use of inotropes (patients, n)a  17  17    Reoperated (n)  1  0    Total amount of fluid in the chest drain (ml)  760 (50–4356)  2130 (1887–2830)  <0.0001  Complications (n)b  2c  3c    VTE events  0  0    Death (n)  1d  0    Total length of stay (days)  6.3 (5.6–9.8)  5.3 (5.1–6.6)  0.11  Type of cancer         Adenocarcinoma  22  13     Squamous cell carcinoma  8  13     Carcinoid (all types)  0  1     Otherse  2  3    Pathological staging         Stage IA + B  28  25     Stage IIA + B  4  5    Microscopically free resection margins (R0)  32  29    Characteristics  VATS group (N = 32)  Open procedure group (N = 30)  P-value  Type of lobectomy         Right upper lobe  10  11     Right middle lobe  1  6     Right lower lobe  8  1     Left upper lobe  9  7     Left lower lobe  4  4     Bilobectomy  0  1    Operating time (min)  149 (48)  140 (51)  0.45  Bleeding/drainage during surgery (ml)  100 (56–122)  275 (118–780)  <0.0001  Use of inotropes (patients, n)a  17  17    Reoperated (n)  1  0    Total amount of fluid in the chest drain (ml)  760 (50–4356)  2130 (1887–2830)  <0.0001  Complications (n)b  2c  3c    VTE events  0  0    Death (n)  1d  0    Total length of stay (days)  6.3 (5.6–9.8)  5.3 (5.1–6.6)  0.11  Type of cancer         Adenocarcinoma  22  13     Squamous cell carcinoma  8  13     Carcinoid (all types)  0  1     Otherse  2  3    Pathological staging         Stage IA + B  28  25     Stage IIA + B  4  5    Microscopically free resection margins (R0)  32  29    Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test were used and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney U-test) was applied. The normally distributed data are represented as means (standard deviations), whereas the non-normally distributed data are represented as medians (95% confidence intervals). a Predominantly small doses of methaoxidrin or efedrin. b Includes myocardial infarction, apoplexia cerebri and atrial fibrillation. c All events were atrial fibrillation. d Died postoperatively [probably due to bleeding (tamponade)]. e Includes small-cell carcinoma, neuroendocrine and sarcomatoid tumour. N/n: numbers; VATS: video-assisted thoracoscopic surgery; VTE: venous thromboembolic events. The open procedure group had a significantly larger amount of intraoperative bleeding and a significantly larger total amount of fluid in the chest drains. None in the VATS group received transfusion, while in the open procedure group, 1 patient received transfusion in terms of red blood cells and fresh frozen plasma. In the non-adjusted and adjusted analyses, there was an average difference in bleeding between the 2 groups on 220 ml (95% confidence interval 130–310 ml; P < 0.001) and 203 ml (95% confidence interval 80–326 ml; P = 0.002), respectively. The results of the standard coagulation blood tests, ROTEM and thrombin generation are presented in Tables 3–5. Table 3: Conventional coagulation tests among 62 patients undergoing lobectomy for primary lung cancer using VATS (n = 32) or an open procedure (thoracotomy) (n = 30) Conventional coagulation tests (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  APTT (28–38 s)  31 (4)  32 (4)  0.31  30 (30–34)  31 (31–35)  0.19  32 (31–36)  34 (33–37)  0.08  32 (31–35)  34 (33–37)  0.07  INR (<1.2)  1.0 (1.01–1.06)  1.0 (1.01–1.05)  0.56  1.1 (1.06–1.14)  1.1 (1.09–1.17)  0.12  1.14 (0.11)  1.21 (0.09)  0.01  1.09 (0.1)  1.17 (0.13)  0.02  Fibrinogen (5–12 μmol/l)  10 (10–11)  10 (10–12)  0.70  9 (2)  8 (3)  0.74  11 (2)  11 (3)  0.45  15 (2)  14 (3)  0.82  Platelet count (145–400 × 109/l)  280 (61)  272 (84)  0.66  225 (52)  191 (61)  0.045  231 (48)  198 (59)  0.04  243 (70)  194 (62)  0.02  Thrombin time (<21 s)  17 (1)  18 (2)  0.052  17 (17–18)  18 (17–19)  0.38  16 (16–17)  17 (16–17)  0.93  15 (2)  16 (2)  0.12  Fibrin D-dimer (<0.50 mg/l FEU)  0.49 (0.45–1.03)  0.76 (0.76–1.59)  0.39  0.73 (0.50–1.56)  0.71 (0.71–1.32)  0.66  0.84 (0.57–2.64)  1.68 (1.33–2.47)  0.01  0.73 (0.72–1.15)  1.15 (1.01–1.74)  0.05  Coagulation Factor VIII: clot (0.66–1.55 kiu/l)  1.36 (1.18–1.49)  1.38 (1.29–1.61)  0.63  1.28 (1.16–1.47)  1.26 (1.18–1.45)  0.92  1.68 (0.34)  1.60 (0.37)  0.37  1.85 (1.77–2.01)  2.03 (1.87–2.15)  0.29  Conventional coagulation tests (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  APTT (28–38 s)  31 (4)  32 (4)  0.31  30 (30–34)  31 (31–35)  0.19  32 (31–36)  34 (33–37)  0.08  32 (31–35)  34 (33–37)  0.07  INR (<1.2)  1.0 (1.01–1.06)  1.0 (1.01–1.05)  0.56  1.1 (1.06–1.14)  1.1 (1.09–1.17)  0.12  1.14 (0.11)  1.21 (0.09)  0.01  1.09 (0.1)  1.17 (0.13)  0.02  Fibrinogen (5–12 μmol/l)  10 (10–11)  10 (10–12)  0.70  9 (2)  8 (3)  0.74  11 (2)  11 (3)  0.45  15 (2)  14 (3)  0.82  Platelet count (145–400 × 109/l)  280 (61)  272 (84)  0.66  225 (52)  191 (61)  0.045  231 (48)  198 (59)  0.04  243 (70)  194 (62)  0.02  Thrombin time (<21 s)  17 (1)  18 (2)  0.052  17 (17–18)  18 (17–19)  0.38  16 (16–17)  17 (16–17)  0.93  15 (2)  16 (2)  0.12  Fibrin D-dimer (<0.50 mg/l FEU)  0.49 (0.45–1.03)  0.76 (0.76–1.59)  0.39  0.73 (0.50–1.56)  0.71 (0.71–1.32)  0.66  0.84 (0.57–2.64)  1.68 (1.33–2.47)  0.01  0.73 (0.72–1.15)  1.15 (1.01–1.74)  0.05  Coagulation Factor VIII: clot (0.66–1.55 kiu/l)  1.36 (1.18–1.49)  1.38 (1.29–1.61)  0.63  1.28 (1.16–1.47)  1.26 (1.18–1.45)  0.92  1.68 (0.34)  1.60 (0.37)  0.37  1.85 (1.77–2.01)  2.03 (1.87–2.15)  0.29  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed unpaired t-test was used, and if non-normal distribution in one or both groups Mann–Whitney test was applied. Results of the normally distributed data are shown as mean (standard deviation). Results of the non-normally distributed data are shown as median (95% confidence interval). APTT: activated partial thromboplastin time; FEU: fibrinogen-equivalent units; INR: international normalized ratio; VATS: video-assisted thoracoscopic surgery. Table 4: ROTEM results among 62 patients undergoing lobectomy for primary lung cancer using VATS (n = 32) or an open procedure (thoracotomy) (n = 30) ROTEM variables (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  EXTEM     CT (38–74 s)  58 (54–61)  59 (55–61)  0.55  55 (8)  57 (8)  0.47  58 (55–60)  58 (56–62)  0.51  58 (9)  59 (9)  0.76   MaxVel (8–22 mm/min)  20 (4)  21 (7)  0.23  18 (17–20)  18 (15–20)  0.30  19 (18–21)  18 (17–22)  0.39  22 (5)  21 (6)  0.80   tMaxVel (48–145 s)  91 (26)  92 (20)  0.87  91 (25)  93 (30)  0.81  88 (21)  90 (26)  0.66  76 (74–99)  73 (73–91)  0.61  INTEM     CT (129–181 s)  165 (161–175)  169 (163–174)  0.56  170 (150–173)  160 (155–171)  0.27  164 (160–174)  165 (161–175)  0.26  163 (161–172)  161 (167–178)  0.78   MaxVel (11–25 mm/min)  22 (4)  23 (7)  0.37  21 (4)  21 (7)  0.83  21 (19–25)  19 (18–22)  0.12  22 (4)  23 (6)  0.64   tMaxVel (147–223 s)  190 (185–203)  198 (190–206)  0.28  193 (179–197)  184 (179–199)  0.36  191 (21)  186 (33)  0.45  187 (183–196)  184 (179–205)  0.83  FIBTEM                           MCF (8–20 mm)  19 (18–24)  19 (19–26)  0.85  17 (15–21)  17 (15–21)  0.73  22 (6)  21 (7)  0.42  28 (6)  27 (7)  0.37  ROTEM variables (reference interval)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  EXTEM     CT (38–74 s)  58 (54–61)  59 (55–61)  0.55  55 (8)  57 (8)  0.47  58 (55–60)  58 (56–62)  0.51  58 (9)  59 (9)  0.76   MaxVel (8–22 mm/min)  20 (4)  21 (7)  0.23  18 (17–20)  18 (15–20)  0.30  19 (18–21)  18 (17–22)  0.39  22 (5)  21 (6)  0.80   tMaxVel (48–145 s)  91 (26)  92 (20)  0.87  91 (25)  93 (30)  0.81  88 (21)  90 (26)  0.66  76 (74–99)  73 (73–91)  0.61  INTEM     CT (129–181 s)  165 (161–175)  169 (163–174)  0.56  170 (150–173)  160 (155–171)  0.27  164 (160–174)  165 (161–175)  0.26  163 (161–172)  161 (167–178)  0.78   MaxVel (11–25 mm/min)  22 (4)  23 (7)  0.37  21 (4)  21 (7)  0.83  21 (19–25)  19 (18–22)  0.12  22 (4)  23 (6)  0.64   tMaxVel (147–223 s)  190 (185–203)  198 (190–206)  0.28  193 (179–197)  184 (179–199)  0.36  191 (21)  186 (33)  0.45  187 (183–196)  184 (179–205)  0.83  FIBTEM                           MCF (8–20 mm)  19 (18–24)  19 (19–26)  0.85  17 (15–21)  17 (15–21)  0.73  22 (6)  21 (7)  0.42  28 (6)  27 (7)  0.37  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test was used and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney test) was applied. Results of the normal distributed data are shown as mean (standard deviation). Results of the non-normal distributed data are shown as median (95% confidence interval). CT: clotting time; MaxVel: maximum velocity; MCF: maximum clot firmness; tMaxVel: time to maximum velocity; VATS: video-assisted thoracoscopic surgery. Table 5: Thrombin generation among 62 patients undergoing VATS (n = 32) or open procedure (thoracotomy) (n = 30) lobectomy for primary lung cancer Thrombin generation for healthy individuals,a mean (SD)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  Lag time (min), 2.4 (0.9)  3.2 (3.0–3.6)  3.1 (2.9–4.1)  0.96  2.8 (2.7–3.2)  2.9 (2.6–3.6)  0.98  3.7 (3.5–5.1)  3.4 (3.1–4.3)  0.37  3.0 (3.2–5.1)  3.2 (3.2–4.3)  0.87  Peak thrombin (nM), 454 (100)  220 (188–235)  225 (211–267)  0.28  241 (54)  241 (49)  0.99  173 (85)  200 (58)  0.16  258 (216–274)  251 (207–262)  0.40  ETP (nM × min), 1681 (281)  1271 (1167–1410)  1353 (915–2840)  0.15  1465 (1303–1460)  1349 (1282–1521)  0.58  1036 (379)  1144 (234)  0.19  1351 (1140–1390)  1249 (1115–1346)  0.34  Time to peak (min), 4.2 (1.2)  6.7 (6.2–7.3)  6.6 (6.2–7.5)  0.84  5.7 (5.4–6.3)  5.5 (5.3–6.4)  0.73  6.9 (6.4–10.8)  6.3 (5.9–7.3)  0.14  5.5 (5.6–8.6)  5.9 (5.7–7.2)  0.81  Thrombin generation for healthy individuals,a mean (SD)  Preoperative   Intraoperative   Postoperative Day 1   Postoperative Day 2   VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  VATS  Open  P-value  Lag time (min), 2.4 (0.9)  3.2 (3.0–3.6)  3.1 (2.9–4.1)  0.96  2.8 (2.7–3.2)  2.9 (2.6–3.6)  0.98  3.7 (3.5–5.1)  3.4 (3.1–4.3)  0.37  3.0 (3.2–5.1)  3.2 (3.2–4.3)  0.87  Peak thrombin (nM), 454 (100)  220 (188–235)  225 (211–267)  0.28  241 (54)  241 (49)  0.99  173 (85)  200 (58)  0.16  258 (216–274)  251 (207–262)  0.40  ETP (nM × min), 1681 (281)  1271 (1167–1410)  1353 (915–2840)  0.15  1465 (1303–1460)  1349 (1282–1521)  0.58  1036 (379)  1144 (234)  0.19  1351 (1140–1390)  1249 (1115–1346)  0.34  Time to peak (min), 4.2 (1.2)  6.7 (6.2–7.3)  6.6 (6.2–7.5)  0.84  5.7 (5.4–6.3)  5.5 (5.3–6.4)  0.73  6.9 (6.4–10.8)  6.3 (5.9–7.3)  0.14  5.5 (5.6–8.6)  5.9 (5.7–7.2)  0.81  Data were tested for normal distribution using the D’Agostino and Pearson Omnibus normality test (alpha set to 0.05); if normally distributed, unpaired t-test were used and if non-normal distribution in one or both groups was found, a non-parametric test (Mann–Whitney U-tests) was applied. The normally distributed data are shown as mean (SD), whereas the non-normally distributed data are shown as median (95% confidence interval). 1 See Collins et al. [7]. ETP: endogenous thrombin potential; SD: standard deviation; VATS: video-assisted thoracoscopic surgery. Overall, no patients exhibited a hypercoagulable state prior to surgery. Intra- and postoperatively, the open procedure group had a significantly lower, albeit not critically low, platelet count compared with the VATS group. The postoperative INR was significantly higher in the open procedure group than in the VATS group. However, the higher INR did not have any clinical impact, since it was merely a minor difference (<0.1 INR value). A lower level of fibrin D-dimer was found on postoperative Days 1 and 2 in the VATS group, statistically significant on the postoperative Day 1, but not on postoperative Day 1. There was no difference between the 2 groups regarding the ROTEM results and thrombin generation parameters. DISCUSSION The main finding of this study was that the use of VATS or open lobectomy in patients undergoing curative surgery for primary lung cancer had a similar-sized minor impact on the coagulation system. Furthermore, the lung cancer patients were not hypercoagulable preoperatively. To our knowledge, this is the first study to compare changes in the activation of the coagulation system in these 2 procedures used for primary lung cancer surgery. Different types of coagulation analyses have been used in previously published studies: thromboelastography [8], thrombin generation [9], markers of thrombin degradation (prothrombin fragment 1 + 2) [10] and standard coagulation parameters [10]. The results of these analyses have been reported to correlate with clinical events such as bleeding [11] and VTE [12]. Davies et al. [13] found that abnormal parameters of ROTEM correlated with the long-term risk of VTE in lung cancer patients. These coagulation analyses may therefore all potentially serve as surrogate parameters regarding the VTE risk [14]. It should be emphasized that thrombin generation parameters obtained by calibrated automated thromboelastography is determined ex vivo and thereby estimate the thrombin generation potential in the patient, which not necessarily reflects activity in vivo. To reflect in vivo activity in the coagulation system and depict whether a patient is actively producing thrombin and/or fibrin, measurement of prothrombin fragment 1 + 2 or thrombin–antithrombin should be used. In this study, measurement of thrombin generation was used to describe the clotting potential and to depict active coagulation processes measurement of fibrin D-dimer was included. In this study, we did not find that patients undergoing potentially curative surgery for lung cancer were hypercoagulable in the preoperative state. This is in accordance with the findings by Attaran et al. [15]. Świniarska et al. [16] concluded that pneumonectomy compared with lobectomy resulted in an increased activation of the coagulation system at Day 7 post-surgery. Preoperative data were, however, not reported. In this study, we only included lobectomies and hence cannot elaborate regarding pneumonectomies or the degree of activation of the coagulation system beyond Day 2 post-surgery. Studies have found a lower incidence of complications [5], a reduced length of stay, an improved quality of life, reduced postoperative pain [4], with VATS compared with an open approach. We found that an open procedure resulted in a significantly higher blood and drain loss during and after surgery, which potentially increases the risk of transfusion and hereto related complications [17]. This finding is in coherence with previous findings of Falcoz et al. [5]. However, based on our results, the VATS and open approach have an equal low impact on the coagulation system, so these 2 surgical techniques are comparable regarding this. The higher volume of blood loss in the open group is not surprising, since the incision is larger and potentially could bleed more. We used an anterior thoracotomy, which is potentially less traumatic than the more widely used posterolateral incision [18], so we cannot extrapolate our results to patients undergoing the latter approach. It would be relevant to relate the coagulation with different tumour stages or TNM factors. Yet we included only early-stage patients, and therefore, such a comparison was not possible in this study. However, it could be interesting to investigate this in a future study. The staging of the cancer was equally distributed in both groups, and a comparison of different tumour stages would therefore unfortunately not provide any useful information in our study. The strengths of this study are the use of a wide spectrum of advanced and validated coagulation analyses. We adjusted for several potential confounders between the 2 treatment groups, and there was no significant difference regarding bleeding in the non-adjusted and adjusted analyses, with the open procedure group bleeding significantly more than the VATS group. Our 2 groups were accordingly well matched. Limitations Our study has some limitations as we used surrogate and not clinical end-points in terms of VTE and bleeding events and it was not a randomized trial. Participants with missing data were simply excluded from the analysis. This was done, because the missing data were randomly distributed between the 2 groups and were not associated with the outcome. We analysed our data as treated. However, missing data were always a potential reason for bias. CONCLUSIONS In patients undergoing curative surgery for early-stage primary lung cancer, we observed a statistical non-significant difference and a similar-sized minor impact on the coagulation system. ACKNOWLEDGEMENTS We wish to thank research nurse Vibeke Laursen for helping and co-ordinating all the practical issues with regard to conducting this study, laboratory technician Mai Stenulm Therkelsen and Vivi Bo Mogensen for blood sampling and analysis, Svend Juul for performing the propensity score analysis and Hans Pilegaard and Vibeke E. Hjortdal for making the study practically feasible. Funding The work was supported by Arvid Nilssons fond, Snedkermester Sophus Jacobsen og hustru Astrid Jacobsens Fond and Fru Agnes Niebuhr Andersons Cancerforskningsfonds pris. The work was done independent of the funders. Conflict of interest: Thomas Decker Christensen has been on the speaker bureaus for AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche Diagnostics, Takeda, Bristol-Myers Squibb and Merck Sharp & Dohme (MSD) and has been in an Advisory Board for Bayer, MSD and Boehringer-Ingelheim. Anne-Mette Hvas has received speaker’s fees from CSL Behring, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb and Leo Pharma and unrestricted research support from Octapharma, CSL Behring and Leo Pharma. Mads Nybo has received speaker’s fees from Astra Zeneca, Pfizer and Roche Diagnostics. Peter Licht has received speaker’s fees from Ethicon Endo-Surgery. All other authors declared no conflict of interest. REFERENCES 1 Christensen TD, Vad H, Pedersen S, Hvas A-M, Wotton R, Naidu B. Venous thromboembolism in patients undergoing operations for lung cancer: a systematic review. Ann Thorac Surg  2014; 97: 394– 400. Google Scholar CrossRef Search ADS PubMed  2 Christensen TD, Vad H, Pedersen S, Hornbech K, Zois NE, Licht PB et al.   Coagulation profile in video-assisted thoracoscopic lobectomy: a randomized, controlled trial. PLoS One  2017; 12: e0171809. Google Scholar CrossRef Search ADS PubMed  3 Laursen LØ, Petersen RH, Hansen HJ, Jensen TK, Ravn J, Konge L. Video-assisted thoracoscopic surgery lobectomy for lung cancer is associated with a lower 30-day morbidity compared with lobectomy by thoracotomy. Eur J Cardiothorac Surg  2016; 49: 870– 5. Google Scholar CrossRef Search ADS PubMed  4 Bendixen M, Jørgensen OD, Kronborg C, Andersen C, Licht PB. Postoperative pain and quality of life after lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung cancer: a randomised controlled trial. Lancet Oncol  2016; 17: 836– 44. 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Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. Crit Care  2014; 18: 549. Google Scholar CrossRef Search ADS PubMed  15 Attaran S, Somov P, Awad WI. Randomised high- and low-dose heparin prophylaxis in patients undergoing thoracotomy for benign and malignant disease: effect on thrombo-elastography. Eur J Cardiothorac Surg  2010; 37: 1384– 90. Google Scholar CrossRef Search ADS PubMed  16 Świniarska J, Żekanowska E, Dancewicz M, Bella M, Szczęsny TJ, Kowalewski J. Pneumonectomy due to lung cancer results in a more pronounced activation of coagulation system than lobectomy. Eur J Cardiothorac Surg  2009; 36: 1064– 8. Google Scholar CrossRef Search ADS PubMed  17 Turan A, Yang D, Bonilla A, Shiba A, Sessler DI, Saager L et al.   Morbidity and mortality after massive transfusion in patients undergoing non-cardiac surgery. Can J Anesth  2013; 60: 761– 70. 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Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Mar 1, 2018

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