Elevated Thrombin Generation and Venous Thromboembolism Incidence in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Compared with Minimally Invasive Rectal Surgery

Mikkel Lundbech; Andreas E. Krag; Lene H. Iversen; Birgitte Brandsborg; Nina Madsen; Anne-Mette Hvas

doi:10.1055/a-2413-4989

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2025; 125(05): 460-469
DOI: 10.1055/a-2413-4989

Coagulation and Fibrinolysis

Elevated Thrombin Generation and Venous Thromboembolism Incidence in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Compared with Minimally Invasive Rectal Surgery

Mikkel Lundbech

¹Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

,

Andreas E. Krag

²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

³Department of Plastic and Breast Surgery, Aarhus University Hospital, Aarhus, Denmark

,

Lene H. Iversen

²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

⁴Department of Surgery, Aarhus University Hospital, Aarhus, Denmark

,

Birgitte Brandsborg

²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

⁵Department of Anesthesiology South, Aarhus University Hospital, Aarhus, Denmark

,

Nina Madsen

²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

⁶Department of Radiology, Aarhus University Hospital, Aarhus, Denmark

,

Anne-Mette Hvas

⁷Faculty of Health, Aarhus University, Aarhus, Denmark

› Author Affiliations

Abstract

Introduction

Surgical treatment of colorectal cancer carries a risk for venous thromboembolism (VTE). We investigated changes in coagulation and fibrinolysis and the VTE incidence within 30 days in patients undergoing open cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) for peritoneal metastases from colorectal cancer and minimally invasive surgery (MIS) for localized rectal cancer.

Methods

This cohort study included 45 CRS + HIPEC and 45 MIS patients. Blood samples were obtained preoperatively, at the end of surgery, and postoperative day (POD) 1, 3 to 4, and 5 to 7. Systematic ultrasonographic screening for VTE was performed between POD 3 and 7. Computed tomography scan was performed if complications were suspected. The primary endpoint was the difference in mean change (Δ) with [95% confidence intervals] from preoperative to end of surgery in prothrombin fragment 1 + 2 (F1 + 2) levels. Secondary endpoints were the difference in mean change in biomarkers of coagulation and fibrinolysis from preoperative to POD 5 to 7 and the VTE incidence.

Results

F1 + 2 levels increased from preoperative to the end of surgery in both groups. The mean increase from preoperative to end of surgery in F1 + 2 levels was significantly greater in CRS + HIPEC patients than MIS patients: Δ1,322 [1,040:1,604] pmol/L, p < 0.01. The VTE incidence was significantly higher after CRS + HIPEC than MIS (24 vs. 5%, p = 0.01).

Conclusion

F1 + 2 levels were increased after both procedures, but to a far greater extent following CRS + HIPEC. The VTE incidence within 30 days was significantly higher in patients treated with CRS + HIPEC than in MIS patients.

Keywords

blood coagulation - coagulation - hyperthermic intraperitoneal chemotherapy - neoplasms - surgical procedures - operative - cytoreductive surgery - minimally invasive surgical procedures

Full Text

References

References
1 Fernandes CJ, Morinaga LTK, Alves Jr JL. et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev 2019; 28 (151) 180119
2 Sørensen HT, Pedersen L, van Es N, Büller HR, Horváth-Puhó E. Impact of venous thromboembolism on the mortality in patients with cancer: a population-based cohort study. Lancet Reg Health Eur 2023; 34: 100739
3 Hayes JW, Ryan EJ, Boland PA, Creavin B, Kelly ME, Beddy D. The prevalence of venous thromboembolism in rectal surgery: a systematic review and meta-analysis. Int J Colorectal Dis 2019; 34 (05) 849-860
4 Lavikainen LI, Guyatt GH, Sallinen VJ. et al. Systematic reviews and meta-analyses of the procedure-specific risks of thrombosis and bleeding in general abdominal, colorectal, upper-gastrointestinal and hepatopancreatobiliary surgery. Ann Surg 2023
5 Cervantes A, Adam R, Roselló S. et al; ESMO Guidelines Committee. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023; 34 (01) 10-32
6 Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995; 221 (01) 29-42
7 Lundbech M, Krag AE, Iversen LH, Hvas AM. Postoperative bleeding and venous thromboembolism in colorectal cancer patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a systematic review and meta-analysis. Int J Colorectal Dis 2022; 37 (01) 17-33
8 The Danish Council for the use of Expensive Hospital Medicines. Behandlingsvejledning inklusiv lægemiddel- rekommandation for tromboseprofylakse til parenkymkirurgiske patienter. Assessed May 27, 2024; available at: https://rads.dk/media/2728/bgn-parenkymkirurgi-version-21-juni-2016.pdf (in Danish)
9 Lundbech M, Damsbo M, Krag AE, Hvas AM. Changes in coagulation in cancer patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy treatment (HIPEC)-a systematic review. Semin Thromb Hemost 2024; 50 (03) 474-488
10 Dranichnikov P, Mahteme H, Cashin PH, Graf W. Coagulopathy and venous thromboembolic events following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2021; 28 (12) 7772-7782
11 Swellengrebel HA, Zoetmulder FA, Smeenk RM, Antonini N, Verwaal VJ. Quantitative intra-operative assessment of peritoneal carcinomatosis - a comparison of three prognostic tools. Eur J Surg Oncol 2009; 35 (10) 1078-1084
12 Ravn S, Grønfeldt JM, Thaysen HV, Iversen LH. The impact of the extent of surgery on late adverse effects following cytoreductive surgery and HIPEC. Eur J Surg Oncol 2024; 50 (01) 107105
13 Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon 2005; 51 (2–3): 70-78
14 Ninivaggi M, de Laat-Kremers R, Tripodi A. et al. Recommendations for the measurement of thrombin generation: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2021; 19 (05) 1372-1378
15 Larsen JB, Hvas AM. Fibrin clot formation and lysis in plasma. Methods Protoc 2020; 3 (04) 67
16 Rubak P, Villadsen K, Hvas AM. Reference intervals for platelet aggregation assessed by multiple electrode platelet aggregometry. Thromb Res 2012; 130 (03) 420-423
17 Krag AE, Kiil BJ, Hvas CL, Hvas AM. Effect of remote ischemic preconditioning on hemostasis and fibrinolysis in head and neck cancer surgery: a randomized controlled trial. PLoS One 2019; 14 (07) e0219496
18 The Danish Colorectal Cancer Group (DCCG). Cytoreduktiv kirurgi (CRS) og HIPEC behandling af peritoneale metastaser (PM) til patienter med kolorektalkræft. Assessed May 23, 2024; available at: https://www.dmcg.dk/siteassets/kliniske-retningslinjer—skabeloner-og-vejledninger/kliniske-retningslinjer-opdelt-pa-dmcg/dccg/dccg_peritoneal-karcinose_crs_hipec_v2.0_admgodk020523.pdf (in Danish)
19 Larsen JB, Hvas AM. Thrombin: a pivotal player in hemostasis and beyond. Semin Thromb Hemost 2021; 47 (07) 759-774
20 Modrau IS, Halle DR, Nielsen PH. et al. Impact of minimally invasive extracorporeal circulation on coagulation-a randomized trial. Eur J Cardiothorac Surg 2020; 57 (06) 1145-1153
21 Ay C, Vormittag R, Dunkler D. et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27 (25) 4124-4129
22 Gyldenholm T, Hvas AM, Christensen TD, Larsen JB. Thrombin generation markers as predictors of cancer-associated venous thromboembolism: a systematic review. Semin Thromb Hemost 2023
23 Iversen LH, Thorlacius-Ussing O. Relationship of coagulation test abnormalities to tumour burden and postoperative DVT in resected colorectal cancer. Thromb Haemost 2002; 87 (03) 402-408
24 Vedovati MC, Becattini C, Rondelli F. et al. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Ann Surg 2014; 259 (04) 665-669
25 McKenna NP, Bews KA, Behm KT, Habermann EB, Cima RR. Postoperative venous thromboembolism in colon and rectal cancer: do tumor location and operation matter?. J Am Coll Surg 2023; 236 (04) 658-665
26 Khan S, Kelly KJ, Veerapong J, Lowy AM, Baumgartner JM. Incidence, risk factors, and prevention strategies for venous thromboembolism after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2019; 26 (07) 2276-2284
27 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline update. J Clin Oncol 2020; 38 (05) 496-520
28 Walker AJ, West J, Card TR, Humes DJ, Grainge MJ. Variation in the risk of venous thromboembolism in people with colorectal cancer: a population-based cohort study from England. J Thromb Haemost 2014; 12 (05) 641-649
29 Kimura Y, Oki E, Ando K, Saeki H, Kusumoto T, Maehara Y. Incidence of venous thromboembolism following laparoscopic surgery for gastrointestinal cancer: a single-center, prospective cohort study. World J Surg 2016; 40 (02) 309-314
30 Stender MT, Nielsen TS, Frøkjaer JB, Larsen TB, Lundbye-Christensen S, Thorlacius-Ussing O. High preoperative prevalence of deep venous thrombosis in patients with colorectal cancer. Br J Surg 2007; 94 (09) 1100-1103
31 Traby L, Kaider A, Schmid R. et al. The effects of low-molecular-weight heparin at two different dosages on thrombin generation in cancer patients. A randomised controlled trial. Thromb Haemost 2010; 104 (01) 92-99

Supplementary Material

Supplementary Material