Excessive intraoperative blood loss independently predicts recurrence of hepatocellular carcinoma after liver transplantation

Characteristics of tumors have been shown to be of prognostic importance for HCC patients after LT [8‐11]. However, other factors may also affect HCC recurrence. In this study, we assessed the relationship between IBL and HCC recurrence after LT through comprehensive evaluation. We found that excessive blood loss, particularly IBL > 4 L, was an independent predictor of HCC recurrence, especially in patients with vascular invasion.

Previous studies have evaluated the relationship of IBL with outcome in HCC patients after hepatectomy. Katzet et al. [3] reported that an IBL volume greater than 1 L during liver resection was significantly associated with poor overall survival, disease-specific survival, and recurrence-free survival. Taketomi et al. [12] found that IBL > 1 L was a significant predictor of extrahepatic recurrence following hepatectomy. Sasaki et al. [13] demonstrated that IBL > 1 L was a predictive factor of cancer-related death within 2 years after hepatectomy for HCC patients without microvascular invasion. However, all of these studies focused on the prognostic value of IBL after liver resection rather than liver transplantation. Previous studies have identified that IBL during LT has adverse effects on post-transplant outcome [14‐17]. However, the results from these studies were mainly obtained from data of patients with benign end-stage liver diseases, without considering HCC patients independently, as well as the relationship between IBL and tumor recurrence. Recently, a study from our center demonstrated that IBL during LT was a significant prognostic factor for long-term survival of HCC patients after LT [18]. Therefore, we further assessed the prognostic value of IBL on HCC recurrence after LT. By using threshold analysis, we found that when IBL was > 4 L, patients showed significantly higher recurrence rates. In multivariate analysis, IBL > 4 L was a significant prognostic factor for cumulative recurrence rates and early recurrence. We also found that tumor characteristics, including serum AFP levels, either macro- or microvascular invasion, and the Milan criteria, were significant independent predictors of HCC recurrence after LT, which is consistent with previous reports [11, 19, 20]. Additionally, we found that patients aged younger than 60 years had higher recurrence rates, probably because of more advanced and aggressive HCC in young people [21].

Previous studies have suggested that perioperative blood transfusion is significantly associated with HCC recurrence after LT [17, 22, 23]. However, we did not find any adverse effects of packed red blood cell transfusion on outcome in our study. In contrast, excessive IBL was a significant predictor of outcome by univariate and multivariate analyses. Because not all of these previous studies included IBL in their analysis, we speculate that the correlation between transfusion and poor oncological outcome might be partly because of unmeasured effects of IBL [3]. IBL is probably a more sensitive predictor of HCC recurrence than blood transfusion.

Because excessive IBL was an important prognostic factor of HCC recurrence after LT, the potential factors affecting profuse hemorrhage need to be investigated. Although blood loss during LT is multifactorial, the major causes of excessive IBL are technical difficulties and pre-existing abnormalities of the hemostatic system [24]. Previous studies have shown that the presence of ascites [25], preoperative MELD score [26], and operation time [16] are risk factors of IBL during LT. Similar to these studies, these factors were determined as independent risk factors of excessive IBL in our study. The presence of ascites and a high MELD score preoperatively indicate more severe liver dysfunction. Additionally, there might be a relationship between ascites and fibrinolytic activity [27]; therefore, severe coagulopathy could be aggravated by ascites.

Although we showed that excessive blood loss was an independent predictor of HCC recurrence after LT, we cannot conclude that excessive IBL directly leads to a worse cancer outcome. There are several potential explanations. Excessive IBL is a consequence of mixed factors and reflects worse pre-transplant conditions combined with technical difficulties. This condition also reflects more manipulation of the liver at the time of hepatectomy, which possibly leads to more tumor shedding at that time [3]. However, profuse hemorrhage may result in tissue hypoperfusion and hypoxia for a long time, which in turn may lead to systemic inflammation and impaired antitumor immunity [28]. Additionally, a hypoxic environment could promote epithelial-mesenchymal transition, which makes the residual tumor cells more aggressive. Because patients with vascular invasion are more likely to harbor micrometastases, the effect of excessive IBL should be greater in these patients. Our study verified this hypothesis. By performing stratified analysis, we found a significant interaction between excessive IBL and vascular invasion. For patients with vascular invasion, IBL > 4 L was an independent predictor of HCC recurrence, in addition to elevated AFP levels and exceeding the Milan criteria.

Several limitations of our study should be noted. First, as a retrospective study, there was a potential for inclusion, exclusion, and recall bias of patients and data. Second, considering that IBL was estimated by the anesthesiologist and circuit nurse, the actual degree of IBL may have been underestimated or overestimated. Assessment of IBL using the concept of red cell mass, which was calculated based on the perioperative change in hematocrit, might be more precise [29]. However, this method is impractical because assessment of hematocrit is not routinely conducted in our center. Additionally, because of the small number of patients (n = 69, 14.4 %) in our single center, further multicenter studies are required to confirm the relationship between IBL and post-transplant tumor recurrence.