Clinical trial NCT03034850: Thrombin Generation and Platelet Activation in CRS/HIPEC
Official title: Thrombin Generation and Platelet Activation in Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Chemotherapy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Mesothelioma; Peritoneum
Pseudomyxoma Peritonei
Peritoneal Carcinomatosis
Keywords: cytoreductive surgery
hyperthermic intraperitoneal peroperative chemotherapy
platelet function
thrombin generation
thromboelastometry
Lead sponsor: Ziekenhuis Oost-Limburg
Sponsor class: OTHER
First posted: 2017-01-27
Enrollment: 27
Sex: ALL
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This prospective observational pilot study, scheduled between April 2015 and July 2016, included 27 patients from the Ziekenhuis Oost-Limburg, Genk, Belgium, after approval by the local medical ethics committee (Eudract/B nr: B371201524199) and written informed consent.

Brief summary: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal peroperative chemotherapy (HIPEC), indicated for patients with peritoneal metastases from digestive or gynecological malignancies alike, demonstrates a considerable impact on hemostatic metabolism, both on platelet and on coagulation level. The potential hemostatic interference in CRS and HIPEC is phase dependent. This study demonstrates the combined use of ROTEM (rotational thromboelastometry), PACT (platelet activation test) and CAT (thrombin generation test) assays during CRS and HIPEC with a follow-up of 7 days postoperative.

Detailed description: The purpose of this study was to quantitatively assess the impact of CRS and HIPEC, on various components of hemostasis. Routine laboratory assays such as activated clotting time, activated partial thromboplastin time, prothrombin time, or platelet count might, as demonstrated previously, insufficiently provide specificity and/or sensitivity to assess coagulation and platelet disorders. Therefore, additionally thrombin generation (TG) was analyzed by the calibrated automated thrombogram assay (CAT). Also, platelet function was quantitatively assessed by the PAC-t-UB assay and rotational thromboelastometry (ROTEM) was used to elucidate the contribution of platelets, intrinsic and extrinsic coagulation pathways in peri-operative bleeding. The hypothesis of this study was that the procedure exposed an increased thrombotic risk, resulting in a faster and increased TG and hyper platelet function?

Eligibility criteria: Inclusion Criteria:

* a confirmed histological diagnosis of peritoneal disease (e.g., mesothelioma; pseudomyxoma peritonei; colorectal, ovarian, or gastric peritoneal carcinomatosis of colorectal, ovarian, or gastric cancer origin; or abdominal sarcomatosis); and
* age \<80 years; and
* a cardiac, renal, hepatic, and bone marrow function compatible with surgery; and
* informed written consent to participate in the study

Exclusion Criteria:(or)

* inherited coagulation abnormalities,
* active systemic infections,
* interstitial lung disease,
* serious cardiac dysrhythmia or condition, New York Heart Association classification of III or IV, congestive cardiac failure, uncontrolled hypertension (diastolic blood pressure constantly \>100 mm Hg, systolic blood pressure constantly \> 180 mm Hg).
* inadequate bone marrow function at the beginning of the trial, defined as platelet count less than \<150 GPT/L or neutrophil granulocyte count less than \<1.5 GPT/L.
* inadequate renal function at the beginning of the trial, defined as GFR less than \<60 ml/min,
* inadequate liver function at the beginning of the trial, defined as bilirubin \>1.5 times ULN (upper limit of normal), active hepatitis B or C infection,
* female patients who are pregnant or breast feeding
* participation in another therapeutic clinical trial.

Primary outcomes:
measure: Blood loss
timeFrame: From surgical incision to 7 days postoperative
Secondary outcomes:
measure: Red blood cell count
timeFrame: From surgical incision to 7 days postoperative
measure: White blood cell count
timeFrame: From surgical incision to 7 days postoperative
measure: Platelet count
timeFrame: From surgical incision to 7 days postoperative
measure: Fibrinogen levels
timeFrame: From surgical incision to 7 days postoperative
measure: Prothrombin Time (PT)
timeFrame: From surgical incision to 7 days postoperative
measure: Activated Partial Thromboplastin Time (aPTT)
timeFrame: From surgical incision to 7 days postoperative
measure: Endogenous Thrombin Potential (Thrombin generation assay (CAT))
timeFrame: From surgical incision to 7 days postoperative
measure: Lag Time (Thrombin generation assay (CAT))
timeFrame: From surgical incision to 7 days postoperative
measure: Time-to-Thrombin Peak (Thrombin generation assay (CAT))
timeFrame: From surgical incision to 7 days postoperative
measure: Thrombin Peak (TP) (Thrombin generation assay (CAT))
timeFrame: From surgical incision to 7 days postoperative
measure: P-selectin expression (Platelet activation test (PACT))
timeFrame: From surgical incision to 7 days postoperative
measure: αIIbβ3 activation (Platelet activation test (PACT))
timeFrame: From surgical incision to 7 days postoperative
measure: A5 EXTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: A5 FIBTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: A5 HEPTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: A30 EXTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: A30 FIBTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: A30 HEPTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: Alpha EXTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: Alpha FIBTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: Alpha HEPTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: Coagulation Time CT EXTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: Coagulation Time CT FIBTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: Coagulation Time CT HEPTEM (Rotational thromboelastometry (ROTEM))
timeFrame: From surgical incision to 7 days postoperative
measure: Clot Formation Time CFT EXTEM (Rotational thromboelastometry (ROTEM)
timeFrame: From surgical incision to 7 days postoperative
measure: Clot Formation Time CFT FIBTEM (Rotational thromboelastometry (ROTEM)
timeFrame: From surgical incision to 7 days postoperative
measure: Clot Formation Time CFT HEPTEM (Rotational thromboelastometry (ROTEM)
timeFrame: From surgical incision to 7 days postoperative
measure: Maximum Lysis (ML) EXTEM Rotational thromboelastometry (ROTEM)
timeFrame: From surgical incision to 7 days postoperative
measure: Maximum Lysis (ML) FIBTEM Rotational thromboelastometry (ROTEM)
timeFrame: From surgical incision to 7 days postoperative
measure: Maximum Lysis (ML) HEPTEM Rotational thromboelastometry (ROTEM)
timeFrame: From surgical incision to 7 days postoperative
Other outcomes:
Locations:
Study officials:
affiliation: Ziekenhuis Oost-Limburg
name: Sven Van Poucke, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995 Jan;221(1):29-42. doi: 10.1097/00000658-199501000-00004.
citation: Elias DM, Ouellet JF. Intraperitoneal chemohyperthermia: rationale, technique, indications, and results. Surg Oncol Clin N Am. 2001 Oct;10(4):915-33, xi.
citation: Van der Speeten K, Govaerts K, Stuart OA, Sugarbaker PH. Pharmacokinetics of the perioperative use of cancer chemotherapy in peritoneal surface malignancy patients. Gastroenterol Res Pract. 2012;2012:378064. doi: 10.1155/2012/378064. Epub 2012 Jun 13.
citation: Urano M, Ling CC. Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro. Int J Hyperthermia. 2002 Jul-Aug;18(4):307-15. doi: 10.1080/02656730210123534.
citation: Perez-Ruixo C, Valenzuela B, Peris JE, Bretcha-Boix P, Escudero-Ortiz V, Farre-Alegre J, Perez-Ruixo JJ. Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery. Cancer Chemother Pharmacol. 2013 Mar;71(3):693-704. doi: 10.1007/s00280-012-2060-2. Epub 2012 Dec 30.
citation: Schmidt C, Creutzenberg M, Piso P, Hobbhahn J, Bucher M. Peri-operative anaesthetic management of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Anaesthesia. 2008 Apr;63(4):389-95. doi: 10.1111/j.1365-2044.2007.05380.x.
citation: Desantis M, Bernard JL, Casanova V, Cegarra-Escolano M, Benizri E, Rahili AM, Benchimol D, Bereder JM. Morbidity, mortality, and oncological outcomes of 401 consecutive cytoreductive procedures with hyperthermic intraperitoneal chemotherapy (HIPEC). Langenbecks Arch Surg. 2015 Jan;400(1):37-48. doi: 10.1007/s00423-014-1253-z. Epub 2014 Oct 16.
citation: Kajdi ME, Beck-Schimmer B, Held U, Kofmehl R, Lehmann K, Ganter MT. Anaesthesia in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: retrospective analysis of a single centre three-year experience. World J Surg Oncol. 2014 May 1;12:136. doi: 10.1186/1477-7819-12-136.
citation: Bell JC, Rylah BG, Chambers RW, Peet H, Mohamed F, Moran BJ. Perioperative management of patients undergoing cytoreductive surgery combined with heated intraperitoneal chemotherapy for peritoneal surface malignancy: a multi-institutional experience. Ann Surg Oncol. 2012 Dec;19(13):4244-51. doi: 10.1245/s10434-012-2496-y. Epub 2012 Jul 18.
citation: Cooksley TJ, Haji-Michael P. Post-operative critical care management of patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC). World J Surg Oncol. 2011 Dec 19;9:169. doi: 10.1186/1477-7819-9-169.
citation: Korakianitis O, Daskalou T, Alevizos L, Stamou K, Mavroudis C, Iatrou C, Vogiatzaki T, Eleftheriadis S, Tentes AA. Lack of significant intraoperative coagulopathy in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) indicates that epidural anaesthesia is a safe option. Int J Hyperthermia. 2015;31(8):857-62. doi: 10.3109/02656736.2015.1075606. Epub 2015 Oct 8.
citation: Falcon Arana L, Fuentes-Garcia D, Roca Calvo MJ, Hernandez-Palazon J, Gil Martinez J, Cascales Campos PA, Acosta Villegas FJ, Parrilla Paricio P. Alterations in hemostasis during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis. Cir Esp. 2015 Oct;93(8):496-501. doi: 10.1016/j.ciresp.2015.01.012. Epub 2015 Apr 14. English, Spanish.
citation: Kusamura S, Moran BJ, Sugarbaker PH, Levine EA, Elias D, Baratti D, Morris DL, Sardi A, Glehen O, Deraco M; Peritoneal Surface Oncology Group International (PSOGI). Multicentre study of the learning curve and surgical performance of cytoreductive surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei. Br J Surg. 2014 Dec;101(13):1758-65. doi: 10.1002/bjs.9674. Epub 2014 Oct 20.
citation: Canda AE, Sokmen S, Terzi C, Arslan C, Oztop I, Karabulut B, Ozzeybek D, Sarioglu S, Fuzun M. Complications and toxicities after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 2013 Apr;20(4):1082-7. doi: 10.1245/s10434-012-2853-x. Epub 2013 Mar 2.
citation: Newton AD, Bartlett EK, Karakousis GC. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a review of factors contributing to morbidity and mortality. J Gastrointest Oncol. 2016 Feb;7(1):99-111. doi: 10.3978/j.issn.2078-6891.2015.100.
citation: Hemker HC, Giesen P, AlDieri R, Regnault V, de Smed E, Wagenvoord R, Lecompte T, Beguin S. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb. 2002 Sep-Dec;32(5-6):249-53. doi: 10.1159/000073575.
citation: Roest M, van Holten TC, Fleurke GJ, Remijn JA. Platelet Activation Test in Unprocessed Blood (Pac-t-UB) to Monitor Platelet Concentrates and Whole Blood of Thrombocytopenic Patients. Transfus Med Hemother. 2013 Apr;40(2):117-25. doi: 10.1159/000350688. Epub 2013 Mar 28.
citation: Ninivaggi M, Feijge MA, Baaten CC, Kuiper GJ, Marcus MA, Ten Cate H, Lance MD, Heemskerk JW, van der Meijden PE. Additive roles of platelets and fibrinogen in whole-blood fibrin clot formation upon dilution as assessed by thromboelastometry. Thromb Haemost. 2014 Mar 3;111(3):447-57. doi: 10.1160/TH13-06-0493. Epub 2013 Nov 21.
citation: Etulain J, Lapponi MJ, Patrucchi SJ, Romaniuk MA, Benzadon R, Klement GL, Negrotto S, Schattner M. Hyperthermia inhibits platelet hemostatic functions and selectively regulates the release of alpha-granule proteins. J Thromb Haemost. 2011 Aug;9(8):1562-71. doi: 10.1111/j.1538-7836.2011.04394.x.
citation: Cardenas JC, Rahbar E, Pommerening MJ, Baer LA, Matijevic N, Cotton BA, Holcomb JB, Wade CE. Measuring thrombin generation as a tool for predicting hemostatic potential and transfusion requirements following trauma. J Trauma Acute Care Surg. 2014 Dec;77(6):839-45. doi: 10.1097/TA.0000000000000348.
citation: Kuiper GJ, Henskens YM. Rapid and Correct Prediction of Thrombocytopenia and Hypofibrinogenemia with Rotational Thromboelastometry in Cardiac Surgery Reconsidered. J Cardiothorac Vasc Anesth. 2016 Dec;30(6):e55-e56. doi: 10.1053/j.jvca.2016.04.009. Epub 2016 Apr 12. No abstract available.
citation: Perez-Ruixo C, Valenzuela B, Peris JE, Bretcha-Boix P, Escudero-Ortiz V, Farre-Alegre J, Perez-Ruixo JJ. Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin. AAPS J. 2016 Jan;18(1):239-50. doi: 10.1208/s12248-015-9839-0. Epub 2015 Nov 17.
citation: Votanopoulos K, Ihemelandu C, Shen P, Stewart J, Russell G, Levine EA. A comparison of hematologic toxicity profiles after heated intraperitoneal chemotherapy with oxaliplatin and mitomycin C. J Surg Res. 2013 Jan;179(1):e133-9. doi: 10.1016/j.jss.2012.01.015. Epub 2012 Mar 10.
citation: McGovern KF, Lascola KM, Smith SA, Clark-Price SC, McMichael M, Wilkins PA. Assessment of acute moderate hyperglycemia on traditional and thromboelastometry coagulation parameters in healthy adult horses. J Vet Emerg Crit Care (San Antonio). 2012 Oct;22(5):550-7. doi: 10.1111/j.1476-4431.2012.00792.x. Epub 2012 Aug 29.
citation: Gielen CL, Grimbergen J, Klautz RJ, Koopman J, Quax PH. Fibrinogen reduction and coagulation in cardiac surgery: an investigational study. Blood Coagul Fibrinolysis. 2015 Sep;26(6):613-20. doi: 10.1097/MBC.0000000000000307.