Perioperative Coagulation Profile in Major Liver Resection for Cancer: A Prospective Observational Study

Petros Tzimas; Eleftheria Lefkou; Agathi Karakosta; Stellios Argyrou; Evangelia Papapetrou; Despoina Pantazi; Alexandros Tselepis; Patrick Van Dreden; Panagiota Stratigopoulou; Grigoris Gerotziafas; Georgios Glantzounis

doi:10.1055/a-1839-0355

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2022; 122(10): 1662-1672
DOI: 10.1055/a-1839-0355

Coagulation and Fibrinolysis

Perioperative Coagulation Profile in Major Liver Resection for Cancer: A Prospective Observational Study

Petros Tzimas

¹Department of Anaesthesia and Postoperative Intensive Care, Faculty of Medicine, University of Ioannina, Ioannina, Greece

,

Eleftheria Lefkou

²Research Group « Cancer, Haemostasis, Angiogenesis», Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie (IUC), Sorbonne Université, Paris, France

,

Agathi Karakosta

¹Department of Anaesthesia and Postoperative Intensive Care, Faculty of Medicine, University of Ioannina, Ioannina, Greece

,

Stellios Argyrou

³Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece

,

Evangelia Papapetrou

⁴Hematology Laboratory, University Hospital of Ioannina, Ioannina, Greece

,

Despoina Pantazi

³Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece

,

Alexandros Tselepis

³Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece

,

Patrick Van Dreden

²Research Group « Cancer, Haemostasis, Angiogenesis», Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie (IUC), Sorbonne Université, Paris, France

⁵Clinical Research Department, Diagnostica Stago, Gennevilliers, France

,

Panagiota Stratigopoulou

¹Department of Anaesthesia and Postoperative Intensive Care, Faculty of Medicine, University of Ioannina, Ioannina, Greece

,

Grigoris Gerotziafas

²Research Group « Cancer, Haemostasis, Angiogenesis», Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie (IUC), Sorbonne Université, Paris, France

⁶Biological Hematology Department, Thrombosis and Haemostasis Centre, Tenon University Hospital, Sorbonne Université, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France

,

Georgios Glantzounis

⁷HPB Unit, Department of Surgery, Faculty of Medicine, University of Ioannina, Ioannina, Greece

› Author Affiliations

Abstract

Hepatectomy-induced coagulation disturbances have been well studied over the past decade. Cumulative evidence supports the superiority of global coagulation analysis compared with conventional coagulation tests (i.e., prothrombin time or activated partial thromboplastin time) for clinical decision making. Cancer, however, represents an acquired prothrombotic state and liver resection for cancer deserves a more thorough investigation. This prospective observational study was conducted to assess the perioperative coagulation status of patients undergoing major hepatectomies for primary or metastatic hepatic malignancy. Patients were followed up to the 10^th post-operative day by serial measurements of conventional coagulation tests, plasma levels of coagulation factors, and thrombin generation assay parameters. An abnormal coagulation profile was detected at presentation and included elevated FVIII levels, decreased levels of antithrombin, and lag time prolongation in thrombin generation. Serial hematological data demonstrated increased Von Willebrand factor, FVIII, D-dimer, fibrinogen and decreased levels of natural anticoagulant proteins in the early post-operative period predisposing to a hyper-coagulable state. The ratio of the anticoagulant protein C to the procoagulant FVIII was low at baseline and further declined post-operatively, indicating a prothrombotic state. Though no bleeding complications were reported, one patient experienced pulmonary embolism while under thromboprophylaxis. Overall, patients with hepatic carcinoma presenting for elective major hepatectomy may have baseline malignancy-associated coagulation disturbances, aggravating the hyper-coagulable state documented in the early post-operative period.

Keywords

coagulation factors - coagulation inhibitors - malignancy - liver surgery

Full Text

References

References
1 Hoffman M. Coagulation in liver disease. Semin Thromb Hemost 2015; 41 (05) 447-454
2 Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth 2014; 58 (05) 515-523
3 Senzolo M, Burra P, Cholongitas E, Burroughs AK. New insights into the coagulopathy of liver disease and liver transplantation. World J Gastroenterol 2006; 12 (48) 7725-7736
4 Mallett SV, Sugavanam A, Krzanicki DA. et al. Alterations in coagulation following major liver resection. Anaesthesia 2016; 71 (06) 657-668
5 Singh SA, Vivekananthan P, Sharma A, Sharma S, Bharathy KG. Retrospective analysis of post-operative coagulopathy after major hepatic resection at a tertiary care centre in Northern India. Indian J Anaesth 2017; 61 (07) 575-580
6 Siu J, McCall J, Connor S. Systematic review of pathophysiological changes following hepatic resection. HPB (Oxford) 2014; 16 (05) 407-421
7 Tzimas P, Prout J, Papadopoulos G, Mallett SV. Epidural anaesthesia and analgesia for liver resection. Anaesthesia 2013; 68 (06) 628-635
8 Louis SG, Barton JS, Riha GM. et al. The international normalized ratio overestimates coagulopathy in patients after major hepatectomy. Am J Surg 2014; 207 (05) 723-727
9 Dumitrescu G, Januszkiewicz A, Ågren A, Magnusson M, Isaksson B, Wernerman J. The temporal pattern of postoperative coagulation status in patients undergoing major liver surgery. Thromb Res 2015; 136 (02) 402-407
10 Weinberg L, Scurrah N, Gunning K, McNicol L. Postoperative changes in prothrombin time following hepatic resection: implications for perioperative analgesia. Anaesth Intensive Care 2006; 34 (04) 438-443
11 Weinberg L, Scurrah N, Parker FC. et al. Markers of coagulation activation after hepatic resection for cancer: evidence of sustained upregulation of coagulation. Anaesth Intensive Care 2011; 39 (05) 847-853
12 Lim C, Dokmak S, Farges O, Aussilhou B, Sauvanet A, Belghiti J. Reoperation for post-hepatectomy hemorrhage: increased risk of mortality. Langenbecks Arch Surg 2014; 399 (06) 735-740
13 López-Guerra D, Santos-Naharro J, Rojas-Holguín A, Jaen-Torrejimeno I, Prada-Villaverde A, Blanco-Fernández G. Postoperative bleeding and biliary leak after liver resection: a cohort study between two different fibrin sealant patches. Sci Rep 2019; 9 (01) 12001
14 Tzeng CW, Katz MH, Fleming JB. et al. Risk of venous thromboembolism outweighs post-hepatectomy bleeding complications: analysis of 5651 National Surgical Quality Improvement Program patients. HPB (Oxford) 2012; 14 (08) 506-513
15 Potze W, Alkozai EM, Adelmeijer J, Porte RJ, Lisman T. Hypercoagulability following major partial liver resection—detected by thrombomodulin-modified thrombin generation testing. Aliment Pharmacol Ther 2015; 41 (02) 189-198
16 De Pietri L, Montalti R, Begliomini B. et al. Thromboelastographic changes in liver and pancreatic cancer surgery: hypercoagulability, hypocoagulability or normocoagulability?. Eur J Anaesthesiol 2010; 27 (07) 608-616
17 Cerutti E, Stratta C, Romagnoli R. et al. Thromboelastogram monitoring in the perioperative period of hepatectomy for adult living liver donation. Liver Transpl 2004; 10 (02) 289-294
18 Gasteiger L, Eschertzhuber S, Tiefenthaler W. Perioperative management of liver surgery-review on pathophysiology of liver disease and liver failure. Eur Surg 2018; 50 (03) 81-86
19 Barton JS, Riha GM, Differding JA. et al. Coagulopathy after a liver resection: is it over diagnosed and over treated?. HPB (Oxford) 2013; 15 (11) 865-871
20 Oo J, Allen M, Loveday BPT. et al. Coagulation in liver surgery: an observational haemostatic profile and thromboelastography study. ANZ J Surg 2020; 90 (06) 1112-1118
21 Reddy SK, Barbas AS, Turley RS. et al. A standard definition of major hepatectomy: resection of four or more liver segments. HPB (Oxford) 2011; 13 (07) 494-502
22 Arshad F, Lisman T, Porte RJ. Hypercoagulability as a contributor to thrombotic complications in the liver transplant recipient. Liver Int 2013; 33 (06) 820-827
23 Tripodi A, Primignani M, Chantarangkul V. et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009; 137 (06) 2105-2111
24 Gerotziafas GT, Depasse F, Busson J, Leflem L, Elalamy I, Samama MM. Towards a standardization of thrombin generation assessment: the influence of tissue factor, platelets and phospholipids concentration on the normal values of Thrombogram-Thrombinoscope assay. Thromb J 2005; 3: 16
25 Spronk HM, Dielis AW, De Smedt E. et al. Assessment of thrombin generation II: validation of the calibrated automated thrombogram in platelet-poor plasma in a clinical laboratory. Thromb Haemost 2008; 100 (02) 362-364
26 Dargaud Y, Wolberg AS, Luddington R. et al. Evaluation of a standardized protocol for thrombin generation measurement using the calibrated automated thrombogram: an international multicentre study. Thromb Res 2012; 130 (06) 929-934
27 Fotiou D, Sergentanis TN, Papageorgiou L. et al. Longer procoagulant phospholipid-dependent clotting time, lower endogenous thrombin potential and higher tissue factor pathway inhibitor concentrations are associated with increased VTE occurrence in patients with newly diagnosed multiple myeloma: results of the prospective ROADMAP-MM-CAT study. Blood Cancer J 2018; 8 (11) 102
28 Legendre P, Verstraete E, Martin M. et al. Hypocoagulability as assessed by thrombin generation test in newly-diagnosed patients with multiple myeloma. Blood Cells Mol Dis 2017; 66: 47-49
29 Yigit E, Gönüllü G, Yücel I, Turgut M, Erdem D, Cakar B. Relation between hemostatic parameters and prognostic/predictive factors in breast cancer. Eur J Intern Med 2008; 19 (08) 602-607
30 Battistelli S, Stefanoni M, Lorenzi B. et al. Coagulation factor levels in non-metastatic colorectal cancer patients. Int J Biol Markers 2008; 23 (01) 36-41
31 Minnema MC, Fijnheer R, De Groot PG, Lokhorst HM. Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment. J Thromb Haemost 2003; 1 (03) 445-449
32 Vormittag R, Simanek R, Ay C. et al. High factor VIII levels independently predict venous thromboembolism in cancer patients: the cancer and thrombosis study. Arterioscler Thromb Vasc Biol 2009; 29 (12) 2176-2181
33 Rietveld IM, Lijfering WM, le Cessie S. et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J Thromb Haemost 2019; 17 (01) 99-109
34 Patmore S, Dhami SPS, O'Sullivan JM. Von Willebrand factor and cancer; metastasis and coagulopathies. J Thromb Haemost 2020; 18 (10) 2444-2456
35 Zanetto A, Senzolo M, Campello E. et al. Influence of hepatocellular carcinoma on platelet aggregation in cirrhosis. Cancers (Basel) 2021; 13 (05) 1150
36 Zanetto A, Campello E, Bulato C. et al. More pronounced hypercoagulable state and hypofibrinolysis in patients with cirrhosis with versus without HCC. Hepatol Commun 2021; 5 (12) 1987-2000
37 Zanetto A, Senzolo M, Vitale A. et al. Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma. Dig Liver Dis 2017; 49 (04) 440-445
38 Kawecki C, Lenting PJ, Denis CV. von Willebrand factor and inflammation. J Thromb Haemost 2017; 15 (07) 1285-1294
39 Lelas A, Greinix HT, Wolff D, Eissner G, Pavletic SZ, Pulanic D. Von Willebrand factor, factor VIII, and other acute phase reactants as biomarkers of inflammation and endothelial dysfunction in chronic graft-versus-host disease. Front Immunol 2021; 12: 676756
40 Zhang J, Defelice AF, Hanig JP, Colatsky T. Biomarkers of endothelial cell activation serve as potential surrogate markers for drug-induced vascular injury. Toxicol Pathol 2010; 38 (06) 856-871
41 Maeda K, Wada H, Shinkai T, Tanemura A, Matsumoto T, Mizuno S. Evaluation of hemostatic abnormalities in patients who underwent major hepatobiliary pancreatic surgery using activated partial thromboplastin time-clot waveform analysis. Thromb Res 2021; 201: 154-160
42 Thai C, Oben C, Wagener G. Coagulation, hemostasis, and transfusion during liver transplantation. Best Pract Res Clin Anaesthesiol 2020; 34 (01) 79-87
43 Leiba M, Malkiel S, Budnik I. et al. Thrombin generation as a predictor of thromboembolic events in multiple myeloma patients. Blood Cells Mol Dis 2017; 65: 1-7
44 Bos S, van den Boom B, Ow TW. et al. Efficacy of pro- and anticoagulant strategies in plasma of patients undergoing hepatobiliary surgery. J Thromb Haemost 2020; 18 (11) 2840-2851
45 Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 2009; 22 (01) 49-60
46 Wun T, White RH. Venous thromboembolism (VTE) in patients with cancer: epidemiology and risk factors. Cancer Invest 2009; 27 (Suppl. 01) 63-74
47 Kim BJ, Day RW, Davis CH. et al. Extended pharmacologic thromboprophylaxis in oncologic liver surgery is safe and effective. J Thromb Haemost 2017; 15 (11) 2158-2164
48 Chen Y, Zhao J, Zhang Z. et al. Construction and validation of a nomogram for predicting the risk of deep vein thrombosis in hepatocellular carcinoma patients after laparoscopic hepatectomy: a retrospective study. J Hepatocell Carcinoma 2021; 8: 783-794
49 Tripodi A. Thrombin generation assay and its application in the clinical laboratory. Clin Chem 2016; 62 (05) 699-707
50 Ay C, Dunkler D, Simanek R. 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 (15) 2099-2103
51 Samama MM, Bara L, Gerotziafas GT. Mechanisms for the antithrombotic activity in man of low molecular weight heparins (LMWHs). Haemostasis 1994; 24 (02) 105-117
52 Gerotziafas GT, Petropoulou AD, Verdy E, Samama MM, Elalamy I. Effect of the anti-factor Xa and anti-factor IIa activities of low-molecular-weight heparins upon the phases of thrombin generation. J Thromb Haemost 2007; 5 (05) 955-962
53 Fukuda T, Kamisato C, Honda Y. et al. Impact of antithrombin deficiency on efficacy of edoxaban and antithrombin-dependent anticoagulants, fondaparinux, enoxaparin, and heparin. Thromb Res 2013; 131 (06) 540-546

Supplementary Material

Supplementary Material