VTE is a common complication in patients with malignant disease and can be the earliest signs of an underlying malignancy [15].
Hypercoagulable state occurs in the malignancy due to the ability of tumor cells to activate the coagulation system [16].
Within the liver, hepatocytes are involved in the synthesis of many coagulation factors that can be significantly decreased in patients with liver disease as HCC [17].
In addition, tumor cells produce several procoagulant factors and proinflammatory cytokines such as tissue factor (TF), tumor necrosis factor (TNF-α), cancer procoagulant (CP), vascular endothelial growth factor (VEGF), and interleukin-1β (IL-1β) which support tumor metastasis and invasion [18].
TNF-α, IL-1β, and VEGF reduce activation of the protein C system which is one of the endogenous anticoagulant systems [19].
In this study, there were significantly decreased levels of proteins C and S, lipoprotein (a), and antithrombin in cirrhotic and HCC patients compared to controls. These results were expected because these proteins are synthesized in the liver, and their levels possibly decrease in patients with liver cirrhosis and HCC.
The liver is the main site for lipoprotein (a) synthesis and in chronic liver disease; the level of lipoprotein (a) decreased due to the decrease in its synthesis by damaged liver cells [20].
Hyperhomocysteinemia was also confirmed as a risk factor for recurrent VTE in many studies [21]. Patients with HCC had significantly higher levels of serum homocysteine compared to cirrhotic patients and controls in our study. These results were in agreement with Samonakis et al. [22].
Hyperhomocysteinemia in liver cirrhosis can be explained by impaired liver function and tissue damage that occur directly by increasing homocysteine cell leakage or indirectly by initiating cell repair [23].
Fibrinogen levels in HCC patients showed significantly higher levels than the control and cirrhotic groups. High fibrinogen levels may occur in our study due to their impaired elimination by the damaged liver cells that not only change the concentration of fibrinogen, but also make it structurally and functionally abnormal [24]. Hyperfibrinogenemia is associated with advanced HCC stage, poor prognosis and non-response to treatment [25].
Regarding genetic thrombotic risk factors, our study showed a high prevalence of APCR and FVL mutation in HCC patients but with no significant differences between the groups. This was in agreement with Samonakis et al. [22].
We found that, with univariate analysis, several factors such as prothrombin time, Fbg, protein C and S deficiency, antithrombin deficiency, increased lipoprotein (a), hyperhomocysteinemia, APCR, and FVL mutation were significantly associated with the development of thrombotic complications in HCC patients. While with further multivariate analysis of the potentially important thrombotic parameters identified in univariate analysis, prothrombin time, Fbg, protein C and S deficiency, increased lipoprotein (a), hyperhomocysteinemia, APCR, and FVL mutation showed independent significant association with thrombotic complications in HCC patient.
HCC carries an exclusive situation concerning cancer-associated thrombosis [26]. We found 14 cases with thromboembolic complications, 50% of them had more than 1 risk factor of thrombosis. PVT was a frequent complication of HCC.
PVT is common in HCC and characterized by an aggressive disease progression, worse liver functions, a higher chance of complications due to portal hypertension, and in addition, poorer tolerance to treatment [27].
Since cirrhosis and liver cell failure often precede the development of HCC, the frequency of DVT and PE in patients with cirrhosis was reported to be 0.5–1.0% [28]. PE and DVT are clearly a major cause of morbidity and mortality in HCC [29].
In our study, the etiology of venous thrombosis may be single or combined deficiencies of natural anticoagulant proteins (either acquired or genetic), and the majority of deficiencies were acquired.
Similar results were obtained by Ponziani et al. [30] and DeLeve et al. [31]. They suggested that patients with PVT commonly have acquired cause of anticoagulant protein deficiencies not hereditary genetic defects. However, a minority of PVT patients might have a hereditary anticoagulant protein deficiency [32].
The most important thrombotic risk factors in our HCC patients were hyperhomocysteinemia, increased lipoprotein (a), and APCR.
Therefore, we can suggest that thromboembolic complications in HCC are multifactorial, not only acquired but also genetic disorders.
There were some limitations to our study. First, all patients with HCC were included, irrespective of the etiology. Second, our sample size was relatively small, while larger studies were needed. Third, the rate of VTE might be underestimated if it occurs later.
The validity of our study depends on many issues. We excluded alcoholics and smokers as they are considered risk factors of VTE. In addition, cases with portal vein invasion by tumors were confirmed and excluded. We studied acquired coagulation parameters in addition to some genetic thrombotic risk factors.
