Pre-existing hypercoagulability in patients undergoing ... - Surgery

Pre-existing hypercoagulability in patients undergoing potentially curative cancer resection Chad M. Thorson, MD, MSPH, Robert M. Van Haren, MD, MSPH, Mark L. Ryan, MD, Emiliano Curia, MD, Danny Sleeman, MD, FACS, Joe U. Levi, MD, FACS, Alan S. Livingstone, MD, FACS, and Kenneth G. Proctor, PhD, Miami, FL

Background. Rotational thromboelastometry (ROTEM) is a new point-of-care test that allows a rapid and comprehensive evaluation of coagulation. We were among the first to show that ROTEM identifies baseline hypercoagulability in 40% of patients with intra-abdominal malignancies and that hypercoagulability persists for $1 month after resection. The purpose of this follow-up study was to confirm and extend these observations to a larger population in outpatient preoperative clinics. The hypothesis is that pre-existing hypercoagulability is present in patients undergoing surgery for malignant disease and that coagulation status varies by tumor type. Methods. After informed consent, preoperative blood samples were drawn from patients undergoing exploratory laparotomies for intra-abdominal malignancies and analyzed with ROTEM. Results. Eighty-two patients were enrolled, including 72 with a confirmed pathologic diagnosis and 10 age-matched controls with benign disease. The most common cancers involved the pancreas (n = 23; 32%), esophagus (n = 19; 26%), liver (n = 12; 17%), stomach (n = 7; 10%), and bile ducts (n = 5; 7%). Preoperative hypercoagulability was detected in 31% (n = 22); these patients were more likely to have lymphovascular invasion (88% vs 50%; P = .011), perineural invasion (77% vs 36%; P = .007), and stage III/IV disease (80% vs 62%; P = .039). More patients with pancreatic tumors (9/23, 39%) were hypercoagulable than with esophageal (3/19, 16%) or liver (2/13, 15%, P = .034) tumors. When only resectable malignancies were considered, clot formation was more rapid (low clot formation time, high alpha) with enhanced maximum clot strength (high maximum clot firmness) in pancreatic versus esophageal or liver cancers and in all cancers versus those with benign disease. Conclusion. Preoperative hypercoagulability can be identified with ROTEM and is associated with lymphovascular/perineural invasion and advanced-staged disease in cancer. Compared with other tumor types, pancreatic adenocarcinomas have the greatest risk for hypercoagulability. (Surgery 2014;155:13444.) From the Divisions of Surgical Oncology, General Surgery, Trauma, and Surgical Critical Care, DewittDaughtry Family Department of Surgery, University of Miami Miller School of Medicine and Jackson Memorial Hospital, Miami, FL

VENOUS THROMBOEMBOLISM (VTE) affects an estimated 300,000–600,000 individuals in the United Supported in part by Grants #N140610670 from the Office of Naval Research and W81XWH1120098 from U.S. Army Medical Research and Material Command. Presented at 98th Annual Clinical Congress of the American College of Surgeons; Surgical Forum, Chicago, IL, September 30–October 4, 2012. Accepted for publication June 28, 2013. Reprint requests: Kenneth G. Proctor, PhD, Professor, Daughtry Family Department of Surgery, Divisions of Trauma and Surgical Critical Care, University of Miami Miller School of Medicine, Ryder Trauma Center, 1800 NW 10th Ave, Miami, FL 33136. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.06.053

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States each year.1,2 VTE is among the most common complications in cancer patients, and the association of thrombophilia and cancer has long been recognized. In the 1860s, Trousseau3 astutely observed migratory thrombosis in the setting of occult visceral malignancies. Unfortunately, 2 years after his seminal lecture ‘‘phlegmasia alba dolens,’’ he diagnosed himself with the syndrome and then succumbed to gastric cancer.4 Malignant neoplasms impart nearly a 7-fold increased risk of VTE, and the overall incidence in hospitalized patients is twice that of noncancer patients.5,6 Symptomatic VTE occur in 10–20% of those with malignancies, but upwards of 50% will have VTE on autopsy.7-9 The rate also varies by primary tumor site, with pancreatic cancer imparting the greatest risk.6

Surgery Volume 155, Number 1 Hypercoagulability increases the risk for VTE,10 but traditional coagulation tests, such as prothrombin time and partial thromboplastin time, are generally not helpful in the diagnosis of hypercoagulability. On the other hand, viscoelastic hemostatic assays, such as the thromboelastogram (TEG), provide a global assessment of hemostatic function. Since TEG was introduced by Hartert in 1948,11 it has been used to identify coagulopathy, predict the need for massive transfusion, and engage goal-directed therapy in trauma, cardiac, and transplant surgery.12-14 TEG has also been used to detect hypercoagulable conditions in trauma,15 after surgery,16,17 and in patients with various malignancies.18-21 Rotation thromboelastometry (ROTEM) is a recently US Food and Drug Administration (FDA)–approved viscoelastic hemostatic assay similar to the TEG. ROTEM has the added advantage of triggering coagulation by different activators, allowing for separate evaluation of the intrinsic (INTEM), extrinsic (EXTEM), and final common pathways (FIBTEM). Recently, we were among the first to show that ROTEM identifies baseline hypercoagulability in more than one third of patients with intraabdominal malignancies and that hypercoagulability persists for $1 month after resection.22 The purpose of this present study was to confirm and extend these observations to a larger population and test the hypothesis that preexisting coagulation abnormalities are present in patients undergoing surgery for malignant disease and that coagulation status varies by tumor type. MATERIALS AND METHODS This prospective, observational protocol with informed consent was approved by the institutional review boards of the University of Miami and the clinical trials office of Jackson Memorial Hospital. The main study population was comprised of patients under the care of a surgical oncologist and 2 hepatobiliary surgeons who were screened over a 12-month period from February 2011 to February 2012. Patients were evaluated and consented in outpatient preoperative clinics for those undergoing potentially curative cancer resection. Inclusion criteria were patients >18 years old undergoing surgery for malignant tumors of the upper gastrointestinal tract (esophagus, stomach, duodenum), hepatobiliary system (liver, pancreas, bile ducts, gallbladder), or retroperitoneum with a confirmed pathologic diagnosis. Only patients consented as an outpatient were included in the study; those with preoperative hospitalization/ inpatient were not included. In response to

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reviewers’ suggestions, additional data were included from age-matched patients, with almost identical preoperative characteristics and cared for by the same physicians, but who had benign disease. After obtaining informed consent, blood samples were drawn before operative incision. For those with arterial access, standard 3-cm 20-gague radial arterial catheters were used to obtain samples. The remainder were obtained by venipuncture with 22-gague butterfly needles. Each 6-mL sample was drawn after 3 mL of blood was evacuated as waste, and subsequently transferred into two, 2.7-mL vacuum-sealed tubes (BD Vacutainer, Franklin Lakes, NJ) containing 3.2% sodium citrate. The ROTEM Coagulation Analyzer (Rotem, Inc, Durham, NC) has been described in detail elsewhere.23 Briefly, ROTEM tests (EXTEM, INTEM, and FIBTEM) were performed according to the manufacturer’s instructions using standardized equipment and test reagents. The blood was recalcified with 20 mL of 0.2 mol/L calcium chloride (star-TEM reagent; Rotem, Inc) and coagulation was activated by tissue factor from rabbit brain (EXTEM) or with partial thromboplastin phospholipids made from rabbit brain and ellagic acid (INTEM). In the FIBTEM test, the contribution of platelets to whole blood coagulation is inhibited by the platelet-neutralizing reagent cytochalasin D. Only ROTEM parameters with standard US reference ranges were used for the study; additional experimental parameters provided by the device were not examined (Appendix Table; see http://www.roteminc.com). The clot time (CT) represents the time from the start of measurement until initiation of clotting; clot formation time (CFT) is the time from initiation of clotting until a clot firmness of 20 mm is detected; alpha-angle reflects the rapidity of clot formation; and maximum clot firmness (MCF) represents the quality of the clot. Overall, CFT and alpha characterize the clot kinetics and MCF signifies clot strength. Hypercoagulability is reflected by a rapid CT or CFT (low value), high MCF, and/or a high alpha-angle. Patients were considered hypercoagulable if $1 of the 9 ROTEM parameters evaluated (CT, CFT, MCF in EXTEM or INTEM, MCF in FIBTEM) were outside the established reference range. Additional data including demographics (age, gender), operative details (preoperative diagnosis, procedure), and tumor facts (organ involved, size, histologic type) were collected. Pathology reports were reviewed to determine tumor grade, marginal

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status, and presence of lymphovascular or perineural invasion. Tumors were staged based on the TNM classification used by the American Joint Committee on Cancer. Development of symptomatic VTE, surgical complications, and mortality were also recorded. Using PASW statistical software version 19.0 (PASW, Chicago, Ill), categorical data (gender, presence of hypercoagulability, tumor characteristics) were compared using Chi-square or Fisher’s exact tests. Group data with a normal distribution were compared using the Student’s t test and nonparametric data were compared with a Mann–Whitney U test. Comparisons between tumor types were performed with 1-way analysis of variance with a post-hoc Bonferroni correction. Values are expressed as means ± standard deviation, median (interquartile range), or number (percentage) as appropriate. RESULTS Demographics. The study population was comprised of 82 patients who underwent exploratory laparotomies; 72 patients underwent exploratory laparotomy for intra-abdominal tumor resection. Demographic data for the study cohort are shown in Table I. The mean age was 67 ± 10 (range, 43–86). The majority of patients were male (63%). The most common tumor locations were the pancreas (32%), esophagus (26%), and liver (17%), with the majority being resectable at the time of operation (85%). On pathologic examination, there was a high proportion of patients with positive nodes, lymphovascular/perineural invasion, and high tumor grade. Likewise, 60% of patients had stage III or IV disease on final pathology. The average length of follow-up was 124 ± 107 days, with the longest being 14 months; 88% of patients were followed for >1 month. Demographic data were similar in a comparator group of 10 patients who underwent exploratory laparotomy but had no malignancy on pathologic examination. The mean age was 62 ± 13 (range, 43–88). The operations included subtotal or distal pancreatectomy/splenectomy (n = 6), liver resection (n = 1), pylorus-sparing Whipple (n = 1), and esophagectomy (n = 2). Hypercoagulability. Preoperative hypercoagulability was detected in 31% (n = 22). The distribution of coagulation cascade abnormalities in these patients is shown in Fig 1. The majority had abnormalities in multiple pathways (n = 10; 45%), with the remainder exhibiting isolated derangements in the extrinsic (n = 8; 36%), intrinsic (n = 2; 9%) or final common (n = 2; 9%) pathways.

Surgery January 2014

Table I. Study cohort Demographic data Age (y) Male Female Follow-up (d) Tumor location Pancreas Esophagus Liver Stomach Bile duct Duodenum Gallbladder Retroperitoneum Surgical/pathologic characteristics Tumor size (cm) Resected Margins positive Lymph nodes positive Lymphovascular invasion Perineural invasion Histologic grade (n = 61) Well differentiated Moderately differentiated Poorly differentiated Tumor stage (n = 64) I II III IV

67 ± 10 45 (63%) 27 (38%) 124 ± 107 23 19 12 7 5 2 2 2

(32%) (26%) (17%) (10%) (7%) (3%) (3%) (3%)

4 61 9 34 31 25

(2) (85%) (13%) (47%) (43%) (35%)

1 (1.4%) 26 (36%) 34 (47%) 8 13 27 16

(11%) (18%) (38%) (22%)

Data presented as mean values ± standard deviation, median (interquartile range), or n (%) as appropriate.

Fig 1. Distribution of coagulation abnormalities.

Data for the 22 hypercoagulable patients are shown in Table II. Hypercoagulability was most common in patients with pancreatic (n = 9/23, 39%) or biliary (n = 4/5, 80%) tumors, followed by gastric (n = 3/7, 43%), esophagus (n = 3/19,

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Surgery Volume 155, Number 1

Table II. Distribution of ROTEM abnormalities in hypercoagulable patients ROTEM abnormalities Age/gender

Organ

Histology

INTEM

EXTEM

FIBTEM

MCF CT CFT, MCF, Alpha

MCF

70/M 71/F 78/M

Pancreas Pancreas Pancreas

Adenocarcinoma Adenocarcinoma Adenocarcinoma

53/F 59/F 59/F 73/F 76/M 71/F

Pancreas Pancreas Pancreas Pancreas Pancreas Pancreas

76/F

64/M 77/M 75/F

Bile duct, Klatskin Bile duct, cystic Bile duct, pancreatic Bile duct, common Stomach Stomach Stomach

Ductal adenocarcinoma CFT, MCF, Alpha CFT, MCF, Alpha Ductal adenocarcinoma CFT, MCF, Alpha Ductal adenocarcinoma MCF Ductal adenocarcinoma MCF Ductal adenocarcinoma CT Intraductal papillary MCF mucinous carcinoma Adenocarcinoma CFT, MCF, Alpha

69/M

Esophagus

58/M 73/M 67/M

Esophagus Esophagus Liver

72/M 83/F 85/F

73/F 52/M

CFT

Adenocarcinoma

CT

Mucoepidermoid carcinoma Neuroendocrine carcinoma Adenocarcinoma Adenocarcinoma Mucinous adenocarcinoma Adenocarcinoma

MCF

Adenocarcinoma Adenocarcinoma Metastatic colon adenocarcinoma Liver Hepatocellular carcinoma Retroperitoneum Sarcoma

MCF

MCF

Pancreatic fistula

MCF MCF MCF Recurrence Unresectable MCF Unresectable, DVT

MCF

CT MCF Alpha

Outcome

Unresectable

MCF

CT MCF

DVT, neck fistula MCF

MCF Alpha CT

CT

CFT, MCF, Alpha CFT, MCF, Alpha

MCF

DVT

CT, Clotting time; CFT, clot formation time; DVT, deep vein thrombosis; EXTEM, extrinsic ROTEN; FIBTEM, final common pathway ROTEN; INTEM, intrinsic ROTEN; MCF, maximum clot formation; ROTEN, rotational thromboelastometry.

16%), and liver (n = 2/13, 15%) tumors. The most common abnormalities were in clot strength (elevated MCF; n = 26) and clot kinetics (low CFT, n = 8; high alpha, n = 9). Overall, 86% of hypercoagulable patients had EXTEM abnormalities, whereas 45% and 32% had abnormalities with FIBTEM and INTEM. Comparisons by coagulation status. Table III compares patients with normal preoperative ROTEM coagulation values (n = 50) versus those with hypercoagulability (n = 22). Patients were similar with respect to demographics (age, gender), tumor characteristics (size, margins, resectability), and some pathologic characteristics (lymph node status, tumor grade). Of note, there were 25 patients who received neoadjuvant chemotherapy. The majority of patients receiving chemotherapy were those with

esophageal pathology (n = 16), with 19% (n = 3) in this cohort demonstrating hypercoagulability. The rates of hypercoagulability were similar between those receiving chemotherapy (6/25, 24%) versus those not receiving chemotherapy (12/47 [26%]; P = .99). Six patients had a response to chemotherapy with a downstaging of their tumor at the time of operation, all of whom had normal ROTEM coagulation profiles preoperatively. Preoperative hypercoagulability was associated with lymphovascular invasion (88% vs 50%) and perineural invasion (77% vs 36%) on histologic examination. Likewise, hypercoagulable patients were more likely to have advanced disease (stage III/IV) on final pathology (80% vs 62%; Table II). With regard to outcomes, there was an overall VTE rate of 7% (5/72). Although the VTE rate was clinically higher in those who were hypercoagulable

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Table III. Stratification by coagulation status Demographics Age (y) Gender, n (%) male Neoadjuvant chemotherapy Response to neoadjuvant Surgical tumor characteristics Size (cm) Positive surgical margins Residual disease Unresectable disease Pathologic characteristics Lymph nodes examined Lymph nodes involved Positive nodal status Grade, poorly differentiated Lymphovascular invasion Perineural invasion Stage I II III IV Outcomes Venous thromboembolism Tumor recurrence Mortality Other complication

Normal (n = 50)

Hypercoagulable (n = 22)

P value

66 ± 10 33 (66%) 19 (39%) 6 (33%)

69 ± 9 12 (55%) 6 (29%)

.211 .355 .414 .102

3.2 4 32 8

3.5 5 17 3

(1.6) (28%) (77%) (14%)

.662 .119 .266 .99

15 ± 8 1 (3) 21 (42%) 21 (53%) 17 (50%) 12 (36%)

13 ± 8 2 (4) 13 (59%) 13 (62%) 14 (88%) 13 (77%)

.351 .259 .181 .482 .011 .007

8 9 14 13

4 (20%) 13 (65%) 3 (15%)

(2.3) (10%) (64%) (16%)

(18%) (21%) (32%) (30%)

2 (4%) 3 (6%) 8 (16%)

.039

3 (14%) 3 (14%) 5 (23%)

.163 .026 .548 .518

Residual disease defined as positive lymph nodes, positive margins or metastasis. Data are number (percentage). Data are presented as mean values ± standard deviation or median (interquartile range).

(n = 3, 14%) versus those with normal coagulation (n = 2, 4%), this apparent difference was not significant. However, the 2 patients with normal preoperative coagulation status who developed VTE were in fact found to be hypercoagulable based on repeat ROTEM at the time of VTE development. One had a symptomatic pulmonary embolism on postoperative day 1 and the other suffered a fatal pulmonary embolism before discharge. The 3 events in the hypercoagulable patients were symptomatic lower extremity DVTs. All VTEs occurred in the hospital while patients were on standard thromboprophylaxis (unfractionated heparin 5,000 U TID or dalteparin 5,000 U/d). Forty percent (2/5) of VTEs occurred in those who received neoadjuvant chemotherapy. There were 3 cancer recurrences (pancreatic adenocarcinoma with portal vein thrombosis, gastric cancer metastatic to liver, esophageal recurrence in the sternum), all of which were in patients who were hypercoagulable preoperatively (P = .026). Stratified by tumor type. The cohort was stratified by the 3 most common tumor locations, including pancreas (n = 19), esophagus (n = 17),

and liver (n = 8); only resected malignant lesions were included. These patients were similar with regards to baseline conditions. In pancreas versus esophagus versus liver, age (64 vs 68 vs 62 years; P = .252), gender (88% vs 56% vs 63% male; P = .097), and disease stage (82% vs 57% vs 63% stage III/IV; P = .296) were all similar. The corresponding preoperative ROTEM values for each tumor are shown in Table IV. Patients with pancreatic malignancies exhibited more rapid clot kinetics, reflected by lower CFT in the INTEM and EXTEM pathways and higher alpha in the INTEM pathway. In addition, there was enhanced clot strength (higher MCF) in all 3 pathways. All of these values taken together reflect a relative hypercoagulability in patients with pancreatic malignancies compared with other tumors (eg, Fig 2). DISCUSSION The present study showed that 31% of patients with intra-abdominal malignancies were hypercoagulable by ROTEM. Most commonly, the EXTEM pathway was affected. Preoperative hypercoagulability was associated with advanced disease, including

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Table IV. ROTEM values in resectable intra-abdominal malignancies Pancreatic (n = 16) Intrinsic pathway (INTEM) CT (sec) 175 ± 25 CFT (sec) 59 ± 13* Alpha (8) 78 ± 2* MCF (mm) 64 ± 5* Extrinsic pathway (EXTEM) CT (sec) 55 ± 13 CFT (sec) 69 ± 19* Alpha (8) 77 ± 4 MCF (mm) 68 ± 6 Final common pathway (FIBTEM) MCF (mm) 22 ± 6*

Esophageal (n = 17)

Liver (n = 8)

Benign (n = 10)

P value

171 77 76 60

± ± ± ±

23 19 3 4

182 80 75 58

± ± ± ±

39 14 2 4

204 88 73 61

± ± ± ±

58 38 6 6

.123 .010 .009 .009

59 81 75 64

± ± ± ±

10 21 4 4

57 90 73 62

± ± ± ±

12 21 6 5

56 93 74 62

± ± ± ±

19 33 5 7

.823 .043 .193 .050

18 ± 4

16 ± 4

17 ± 6

.032

*P < .05. Post-hoc Bonferroni test. Data are presented as mean values ± standard deviation or median (interquartile range). CFT, Clot formation time; CT, clot time; MCF, maximum clot firmness; ROTEN, rotational thromboelastometry.

lymphovascular invasion, perineural invasion, American Joint Committee on Cancer stage III or IV on final pathology, and postoperative tumor recurrence. In addition, patients with pancreatic tumors demonstrated more profound coagulation disturbances than those with esophageal or liver disease. Laboratory assessment of global coagulation status was difficult until the introduction of TEG in 1948.11 This method offered numerous advantages over plasma-based traditional tests (prothrombin time, partial thromboplastin time) by allowing the examination of whole blood viscoelastic properties. Since the introduction of TEG, it has been used in a wide range of hypo- and hypercoagulable conditions, including the diagnosis/treatment of hemophilia,24 goal-directed transfusion therapy.12,14 and to identify traumainduced hypercoagulability.15 It has also been used before, during, and after surgery to predict postoperative thrombotic events, including myocardial infarction25 and VTE.17,26 In 1976, Caprini et al27 demonstrated enhanced coagulability by TEG in patients with malignancy; cancer was predicted in 88 of 90 patients (sensitivity, 98%; specificity, 100%). Subsequently, Haid28 identified an elevated TEG index in 5 of 6 women with carcinoma and normal values in 11 of 14 with benign disease. With a test accuracy of 80%, he suggested that the TEG index be used as an adjunct for breast cancer screening. Despite these initial promising findings, the use of TEG has been relatively limited in cancer. The majority of investigations have been in patients with breast or colon cancer,19,21 demonstrating hypercoagulability relative to healthy controls. However, not all studies agree. Because of the limited information about patients with liver or

pancreatic tumors, De Pietri et al18 recently examined these subpopulations. Their group reported TEG values consistently within the range of normal in patients undergoing resection of tumors either in the liver (n = 38) or pancreas (n = 18). These findings are in stark contrast with our data, where 39% of patients with pancreatic tumors, 80% of bile duct tumors, and 15% of liver tumors were hypercoagulable preoperatively. In addition, our data suggest that patients with pancreatic tumors are relatively hypercoagulable compared with those with esophageal and/or liver disease. These discrepancies are not easily explained, but might be attributed to different severity of disease, heterogeneous populations, or the use of different assays. Despite the discordant findings between our studies, the overall VTE rates were similar (7%).18 Recently, ROTEM has been developed as a newer modification of the classic TEG that avoids the technical limitations, such as sensitivity to vibration and/or mechanical shock.23 In addition, each portion of the coagulation cascade can be examined independently, and the contribution of platelets and fibrinogen can be determined by comparing ROTEM tests. Although it has been available in Europe for over a decade, it has only recently gained FDA approval in the United States. ROTEM correlates with standard hemostatic parameters (platelets, fibrinogen) during liver transplant,29,30 diagnoses hemodilution-induced changes during cardiac surgery,31 and identifies patients who require massive transfusion after trauma.32,33 To our knowledge, except for our recent study,22 there were only 2 previous ROTEM studies in cancer and both were relatively inconclusive.34,35 In 2007, Papa et al34 found no difference in standard ROTEM variables (CT, CFT, MCF) in

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Fig 2. A, INTEM: Maximum clot formation (MCF). B, ESTEM: Alpha angle.

patients with solid cancers of the digestive tract versus healthy controls. However, they did discover differences in novel research parameters (maximum velocity, area under the concentration-time curve) derived from the ROTEM curve. Two years later, Akay et al35 investigated 78 patients with diverse cancers (28 gastrointestinal, 27 respiratory, 23 miscellaneous) and found no difference in ROTEM parameters between the various tumor types. However, patients with cancer demonstrated accelerated clot formation (shortened CFT) and increased clot strength (increased MCF), relative to healthy controls. The present study investigated ROTEM parameters in a population of patients with intraabdominal malignancies that had not been

previously examined, including a large proportion of hepatobiliary and esophageal cancers. We demonstrated preoperative abnormalities in clot strength (elevated MCF) and/or clot kinetics (low CFT, high alpha) in 31% of patients studied. Multiple coagulation pathways were often affected (45%), but the EXTEM pathway was the most commonly affected pathway, with 86% of hypercoagulable patients having abnormalities on EXTEM. Interestingly, there was a subset of patients who exhibited a downstaging response to chemotherapy, all of whom had normal ROTEM at the time of surgery. Preoperative hypercoagulability was also seen in all 3 patients who developed tumor recurrence during postoperative follow-up.

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Recently, we used ROTEM to test the hypothesis that the cancer-induced hypercoagulable state would improve after operative resection.22 In 35 patients, preoperative ROTEM identified hypercoagulability in 40%. After operative resection, patients actually became progressively more hypercoagulable. By week 1, 86% had abnormal ROTEM values, including 81% who had normal coagulation profiles preoperatively. In fact, 86% remained hypercoagulable at 3–4 weeks.22 This was among the first studies to identify preoperative hypercoagulability in more than one third of patients with intra-abdominal malignancies and that a progressive hypercoagulability persists for $1 month after resection.22 Normal coagulation depends on a complex interplay between pro- and anti-thrombotic mechanisms, with thrombosis developing whenever the homeostatic regulatory balance is disrupted in favor of procoagulants. In cancer, increased fibrin/fibrin degradation products, altered fibrinogen, and elevated or reduced levels of factors V, VII, IX, or XI have all been documented.7,36,37 Hyperfibrinogenemia is found in 50–80% of cancer patients.38 More important, tumor cells are known to express tissue factor39,40 and cancer procoagulant41 on cell surfaces. These molecules activate the extrinsic cascade via factor VII and the final common pathway via factor X, respectively. In contrast with normal cells, tumor cells express tissue factor constitutively,8 and circulating tissue factor has been identified in patients with cancer.42,43 Our findings are in line with this molecular data; MCF (representing fibrinogen and platelet function) was the most common abnormality, and EXTEM was affected in the vast majority of hypercoagulable cancer patients. The detection of a hypercoagulable state by viscoelastic assays such as the TEG or ROTEM is only truly meaningful if there is a functional correlate. Many authors have used the TEG to predict development of VTE or other thrombotic complications. However, a recent meta-analysis showed wide variation (odds ratio, 1.5–27.7) for a hypercoagulable state to be detected by TEG in a patient with a VTE compared with one without.17 This may be owing to the heterogeneous surgical populations and variable definitions of hypercoagulability. In patients with known lower extremity DVT compared with healthy controls, Spiezia et al44 showed relative hypercoagulability on ROTEM. Despite a well-recognized increased risk for VTE development in cancer, the majority of studies describe few18,19 or no events.20,34,35 There are several potential limitations of the present study. First, this was a descriptive,

observational study of preoperative coagulation status in patients with malignancies undergoing surgical therapy. A significant percentage of patients in the cohort had advanced disease, which may limit generalizability to all cancer patients. Second, because the current guidelines45,46 do not support routine venous duplex ultrasonography, we did not screen for asymptomatic VTE. Instead, the detection of events was based on clinical suspicion by the treating physician. In addition, the present study is underpowered to detect differences in ROTEM based on VTE rates, because the overall rate is relatively low (7%). Although the low VTE rate may be surprising, this is in line with current data.47,48 Third, we did not investigate specific biochemical coagulation markers (fibrin, fibrinogen, platelets, coagulation pathway factors). We chose to do this because these tests have been shown by others to correlate with TEG/ROTEM parameters, and are often more difficult to interpret and use clinically.18,19,21,34,35 Last, we recognize the limitations with the use of ROTEM in cancer patients based on the present study and our previous work.22 The ROTEM has only recently gained FDA approval. To prove useful, it must first be able to identify changes in coagulation status before it can be used to guide treatment decisions. Future studies are warranted to translate ROTEM to routine bedside use and patient outcomes. In conclusion, we have demonstrated that preoperative hypercoagulability can be identified with the use of ROTEM. Hypercoagulability before operative intervention was associated with advanced disease, including lymphovascular/perineural invasion, stage III/IV disease, and tumor recurrence. This hypercoagulable state is common in patients with intra-abdominal malignancies, most often affecting those with pancreatic or bile duct tumors. The authors recognize the efforts of several volunteers/staff, including Alexander Busko, BS, Gerardo A. Guarch, MD, and Jose M. Barrera, MD, who assisted with patient enrollment and blood processing, and Ronald Manning, RN, BSN, MSPH who serves as our research coordinator. The authors thank the surgical oncology, hepatobiliary, and preoperative staff for their cooperation with the study. REFERENCES 1. The Surgeon General’s call to action to prevent deep venous thrombosis and pulmonary embolism. Washington, DC: US Department of Health and Human Services; 2008. 2. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med 2010;38(4 Suppl):S495-501.

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Appendix Table. ROTEM reference ranges INTEM EXTEM FIBTEM

CT (sec)

CFT (sec)

Angle (8)

MCF (mm)

122–208 43–82 —

45–110 48–127 —

70–81 65–80 —

51–72 52–70 7–24

CFT, Clot formation time; CT, clotting time; EXTEM, extrinsic ROTEN; FIBTEM, final common pathway ROTEN; INTEM, intrinsic ROTEN; MCF, maximum clot formation; ROTEN, rotational thromboelastometry.