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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
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
,
Andreas E. Krag
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
3   Department of Plastic and Breast Surgery, Aarhus University Hospital, Aarhus, Denmark
,
Lene H. Iversen
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
4   Department of Surgery, Aarhus University Hospital, Aarhus, Denmark
,
Birgitte Brandsborg
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
5   Department of Anesthesiology South, Aarhus University Hospital, Aarhus, Denmark
,
Nina Madsen
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
6   Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
,
Anne-Mette Hvas
7   Faculty of Health, Aarhus University, Aarhus, Denmark
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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

Supplementary Material



Publication History

Received: 15 April 2024

Accepted: 02 September 2024

Accepted Manuscript online:
11 September 2024

Article published online:
29 September 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMed
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 6 Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995; 221 (01) 29-42
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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)
    PubMed
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 13 Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon 2005; 51 (2–3): 70-78
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 15 Larsen JB, Hvas AM. Fibrin clot formation and lysis in plasma. Methods Protoc 2020; 3 (04) 67
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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)
    PubMed
  • 19 Larsen JB, Hvas AM. Thrombin: a pivotal player in hemostasis and beyond. Semin Thromb Hemost 2021; 47 (07) 759-774
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar