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

Background: The liver plays a key role in the complex and dynamic process of blood coagulation. Consequently, after liver resection the equilibrium between procoagulant and anticoagulant activity is often deranged. Major hepatectomies have been associated with excessive intraoperative blood loss, hemodynamic instability, massive fluid shifts, and coagulopathy. Alterations of the coagulation profile are always present post-operatively even in case of normal pre-operative coagulation function. Cumulative evidence supports the superiority of global coagulation analysis compared with conventional coagulation for clinical decision-making.

Aim: The purpose of this study was to assess the perioperative coagulation status of patients undergoing major hepatectomies for primary or metastatic hepatic malignancy. Conventional coagulation tests, plasma levels of coagulation factors, and TGA measurements were used for longitudinal documentation of the coagulation activity.

Methods: Patients included in the study were referred for major liver resection which was defined as a resection of three or more liver segments, and were followed up to the 10th post-operative day by serial measurements of conventional coagulation tests, plasma levels of coagulation factors, and thrombin generation assay parameters. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were determined by STA Neoplastin R, and STA-Cephascreen, Fibrinogen by STA-Liquid Fib, D-dimer STA Liatest D-DI Plus, all from Diagnostica Stago, France. Coagulation factor activity for FII, FV, FVII, FVIII, FIX, FX, was measured by clotting assay using coagulation factor deficient plasma, vWFAg , and vWFAc by vWFAg and Innovance vWFAc, from Siemens Healthcare Diagnostics, Germany. Thrombin generation (TG) was assessed in samples of PPP with the TF 5 pM PPP-Reagent on Calibrated Automated Thrombogram (Stago, France).

Results: Changes over time for FII, FV, FVII and FX were statistically significant (p <0.05). Factor VIII level was above normal values at baseline. A steady rise was observed for fibrinogen, FVIII, and vWF antigen throughout the study period, but only vWF antigen exhibited statistically significant changes over time. Levels of coagulation inhibitors, AT, PC and PS, decreased significantly during the first postoperative day and then increased reaching baseline values by POD5 for protein C and S, but AT, remained low by POD10. INR increased after surgery, reaching a peak on the first post-operative day and decreasing toward baseline levels from then on (p <0.001). The aPTT remained within normal range throughout the study period (Table 1). TG conducted at baseline, on POD1, POD5, and POD10 showed elevated of Lag time and time to peak at baseline, whereas the rest thrombin generation parameters were within reference range. ETP decreased significantly over time, reaching lower values by POD5 and sustaining those low values by POD10. Peak height fluctuated in a similar manner, but changes over time did not bear any statistical significance. Lag-time, which was prolonged at baseline, exhibited a steady rise throughout the study period, bearing borderline statistical significance (Table 2) . A statistically significant positive correlation was detected between AT and time to Peak (ttPeak) at baseline, however any other significant difference between coagulation factors, natural coagulation inhibitors, and TGA parameters was observed.

Conclusion: This study shows that patients with hepatic malignancy have systematic endothelial activation and hyper-coagulability as indicated by increased FVIII levels and lag time prolongation in thrombin generation. These patients are in a hyper-coagulable state in the early post-operative period, as shown by increased vWF, FVIII, D-dimer, fibrinogen and decreased levels of natural coagulation inhibitors AT, PC, and PS. Measurements of INR, PT, aPTT are not useful in this setting and could be misleading. Global coagulation analysis may be more appropriate for clinical guidance. To the best of our knowledge this is the first report in literature documenting the pre-existing coagulation disturbances in patients with hepatic carcinoma and their impact on the coagulation status after major hepatectomy. However, the clinical implications of our findings deserve further investigation.

No relevant conflicts of interest to declare.