Our study demonstrates that autoimmune conditions are strongly associated with PVTE. A possible association between oncologic conditions and PVT was also found. In addition, PVT at the time of transplantation was a strong predictive factor for the development of postoperative VT.
Chronic liver disease is associated with thrombotic complications throughout the perioperative period with the overall incidence of venous thrombosis varying between 0.5 and 6.3 % [8–10]. Hepatic artery thrombosis specifically, was found in 3–9 % cases and usually occurred after transplantation. It is, however, associated with significant morbidity resulting in up to 53 % of all post-transplant graft losses .
Another major factor contributing to perioperative morbidity is PVT. The prevalence of PVT in liver transplant candidates prior to transplantation is 8–25 % [11–13]. Post-transplant PVT occurs in 2–4 % of patients and is associated with significant postoperative mortality [1, 14].
Although the cause of PVTE is likely multifactorial, hypercoagulability associated with ESLD is frequently underestimated as a contributing factor. It has been demonstrated that despite significant decreases in the concentration of both coagulation and anticoagulation factors, patients with ESLD have a compensatory increased concentration of liver-independent factors such as Factor VIII, von Willibrand factor (VWF), and Plasminogen Activator Inhibitor-1 (PAI-1) [15–19]. Both the plasma level and activity of VWF and PAI-1 remain increased up to 10 days after transplantation [14, 20, 21]. It has also been demonstrated that the concentration of ADAMTS13 (protein responsible for splitting VWF) is significantly decreased during and after OLT . Taking into consideration that modern platelet function tests have failed to identify platelet dysfunction in patients with ESLD , a VWF/ADAMTS13 imbalance might be responsible for the hypercoagulability often seen in this patient population [14, 21]. Other factors, such as increased levels of thrombin , lipopolysaccharides and tissue factor (TF), as well as resistance to thrombomodulin [24, 25] also contribute to the hypercoagulable state seen in patients with ESLD. This hypercoagulability is enhanced if the ESLD is caused by oncologic or autoimmune diseases.
Our study demonstrates an increased incidence of preoperative PVT in patients with HCC. Previous investigations found the incidence of PVT in association with HCC to be between 20 and 65 % [4, 5]. PVT after transplantation in patients with HCC is also associated with an increased mortality (OR 2.05, p = 0.004) [26, 27]. It has been suggested that increased TF expression might be responsible for both PVT and systemic venous thrombosis [26, 28, 29].
Our investigation demonstrated a significant association between PBC, PSC, AIC, and postoperative VT. All these conditions are autoimmune and include characteristics contributing to hypercoagulability which include: chronic inflammation (release of cytokines, expression of tissue factors, endothelial dysfunction, inhibition of protein C), increased levels of PAI-1 and antiphospholipid antibodies, as well as a number of other factors such as elevated levels of fibrinogen and TF [6, 7, 30–33].
It has been reported that preoperative PVT might be a risk factor for recurrent postoperative thromboses resulting in an increased risk of re-transplantation [25, 34]. We also found that preoperative PVT was associated with postoperative thrombotic complications. It has been suggested that an underlying hypercoagulability related to rebalanced hemostasis might be responsible for this phenomena .
Our study demonstrated a significant association between DM and PVT. Previous investigations have shown an increased risk of venous thrombosis in patients with DM [35, 36]. This finding is likely related to an increased concentration of circulating microparticles, as well as elevated thrombin and estrogen levels seen in patients with DM [37, 38]. Taking into consideration that patients with ESLD have elevated estrogen levels at baseline, the increase seen in patients with ESLD and DM might contribute to the development of PVTE in this population.
There were a number of other important findings in our investigation. Patients extremely over- or underweight had a higher incidence of PVTE. The relationship between obesity and thrombotic complications is well known [39–45]. The association between thromboses and being underweight has not been previously described and is most likely underappreciated. Pelletier, et al., found that patients with a BMI ≤20 had a significantly higher risk of death while on the transplant waiting list (OR = 1.61, p < 0.0001) . The cause of this phenomenon is not completely clear, but malnutrition-related mechanisms, such as increased platelet aggregation with a concomitant elevation in thromboxane A , and decreased vitamin B6 levels resulting in hyperhomocysteinemia, might play an important role [48, 49]. The problems related specifically to being underweight and having a liver transplant should be evaluated more extensively in the future.
Recent publications have demonstrated that postoperative thrombotic complications can be successfully prevented using antithrombotic medications [50, 51]. Villa, et al., demonstrated the effectiveness of enoxaparin in preventing PVT in patients with advanced cirrhosis . It has been shown that either aspirin administration  or an infusion of low dose heparin  was effective in the prevention of postoperative HAT. In their study, no bleeding complications were observed.
Considering that autoimmune-related ESLD is associated with up to a twofold increased risk of perioperative thrombotic complications, prophylaxis and treatment of PVTE in patients at risk must be considered.
The relationship between TIPS and PVT has been previously demonstrated . In our study, we also demonstrated this association. TIPS placement for PVT treatment was previously described in a small patient population as an experimental procedure . More recently, trans-splenic portal vein recanalization in conjunction with TIPS placement has been reported . With the development of this new TIPS procedure to treat PVT, some of the TIPS placements listed in the database may have been inadvertently included in our analysis of TIPS as the cause of PVT. It is difficult to estimate how this may have affected our statistical results. Considering that TIPS for PVT treatment was established after 2012 and until now not performed routinely in US centers, we expect the statistical impact to be negligible. The association between TIPS and thrombotic complications remains incompletely understood and needs further evaluation.
Our analysis of the UNOS database has a number of limitations.
Considering the retrospective character of this evaluation, prospective randomized trials are necessary to establish definitive recommendations for routine perioperative antithrombotic prophylaxis for ESLD patients with autoimmune conditions.
While performing this study, we found a significant limitation in the structure of the UNOS database. The number of potentially confounding factors, such as perioperative transfusion of blood products and coagulation factors, the use of antifibrinolytics, intraoperative blood loss, and type of surgical technique were not listed in the database and could not be included in our statistical analysis. Many transplant centers have independently established protocols for perioperative anticoagulation. This information was also not available for analysis. Although these factors which were not included in the data base may confound, to a limited extent, the effects of the predictors included in our model, they would not change the direction of our modeled effects nor impact the validity of our results. Considering the significant statistical power of this analysis and the large number of available variables known to be related to thrombotic complications, we are confident our results demonstrate a true clinical association between autoimmune conditions and PVTE’s.
The type and timing of postoperative VT was not defined in the database. Taking into consideration that only VT’s resulting in graft failure were listed, the vast majority of postoperative thromboses were likely related to HAT as previously described . Problems with the hepatic artery anastomosis are a common cause of HAT especially in the pediatric population . Considering the significant statistical power of our study, we assumed a normal distribution of technical problems in all analyzed patients and excluded pediatric patients. Taking into account these considerations, our results demonstrate an increased postoperative VT risk in patients with autoimmune conditions. More detailed risk stratification, including the type of postoperative thrombotic complication, may be obtained from future research.
Another limitation of the database is that only 2 types of thrombotic complications were listed. This could result in the appearance of a disproportional incidence of pre- and postoperative thrombosis in patients with PBC and PSC. These autoimmune conditions can potentially be associated with other types of thromboses such as deep venous, pulmonary, and others not listed.
The limited types of thrombotic events listed might account for our finding that HCC was not associated with thrombotic events. A significant number of patients with HCC undergo transarterial chemoembolization (TACE). This potentially results in arterial damage with subsequent thrombosis . In our investigation, however, we were not able to demonstrate a relationship between HCC and postoperative VT despite significant patient numbers.