Deep vein thrombosis during long-term surveillance of patients with liver transplantation

The long-term survival of patients with liver transplantation increases the probability of deep vein thrombosis associated with physiological ageing, metabolic syndrome, side effects of immunosuppressive therapy, hepatitis B or C recurrence, or simply age-related comorbidities, involving immobilization. The aim of the study is to update the existing data in the literature regarding the occurrence and management of deep venous thrombosis in liver transplant patients over the long-term surveillance period.

After 6 months of double or triple immunosuppressive therapy, monotherapy is given if the haepatic function is appropriate and there is no rejection [9]. Long-term monotherapy involves commonly a calcineurin inhibitor (tacrolimus or cyclosporine) [9‐11]. The most common long-term complications of immunosuppressive therapy in patients with liver transplantation are hypertension, metabolic disease (diabetes mellitus, hyperlipidaemia, obesity), infections, renal insufficiency, malignancy, bone disease and recurrence of liver disease [9]. Hypertension and dyslipidaemia are not associated with a high risk of venous thrombosis, but obesity does [12, 13]. The authors of a study reported that in a period of up to 3 years of post-transplant surveillance, 31% of patients became obese [14]. The creatinine clearance, microalbuminuria, urinary albumin-to-creatinine ratio and chronic kidney disease are also associated with venous thromboembolism [12, 13]. Chronic kidney disease was reported in up to 90% of liver transplantation patients, mainly due to pre-existing disease, nephrotoxic immunosuppressive medication and long-term cardiovascular complications [11]. The end-stage renal disease, previous venous thromboembolism and diabetes are also reported as predictive factors for venous thromboembolism [13, 15]. In 2016, 28.8% of liver transplant recipients in the USA were reported with diabetes [6].

Generally, oral corticosteroids are recommended for about 3–6 months after transplantation, although some transplant centers recommend low-dose treatment for an indefinite period [16]. Administration of corticosteroids increases 1.2 to 2 times the risk of deep vein thrombosis [12]. The risk increases with the cumulative dose of corticosteroids and is independent of the underlying disease [12].

Multiple authors reported that the probability for recurrence of HCV infection is between 60 and 90% and between 12.9 and 38.7% for recurrence of hepatocellular carcinoma on the liver transplant [11, 17‐19]. Martinelli and colleagues reported an incidence rate of venous thrombosis of 1.06 per 100 patient-years in liver transplantation recipients for hepatocellular carcinoma, followed for an average of 7.17 years [20]. The mechanisms of venous thrombosis could be both persistence of fibrin deposition after hepatic transplantation for hepatocellular carcinoma and thrombophilia abnormalities (factor V Leiden and prothrombin G20210A mutation) of the recipients [20].

The risk of venous thromboembolism increases in cancer by four to seven times [1].

Other risk factors: All these factors are associated with an increased risk of DVT in post-transplant long-term surveillance. Acquired or congenital thrombophilia, antiphospholipid syndrome and elevated serum homocysteine are important prothrombotic factors in Caprini risk score, but prophylactic treatment for any patient is still debated, due to the low risk of thrombosis [2, 17].

There are no specific guideline recommendations regarding acute DVT treatment in long-term surveillance after liver transplantation. The special situations exposed by the guidelines for the management of DVT, cancer, chronic kidney disease and obesity need attention [1, 2]. In cancer, low molecular weight heparin (LMWH) is safer as unfractionated heparin (UFH) for initial or long-term treatment of DVT [1, 2]. LMWH or vitamin K antagonist (VKA) is recommended for long-term treatment (3 to 6 months) in patients with cancer [1]. After 6 months, the anticoagulation treatment is individualized [1]. In chronic kidney disease, creatinine clearance less than 30 mL/min is preferred UFH [1], even subcutaneous [2]. The direct oral anticoagulants for DVT/thromboembolism are used in specific conditions [1, 2, 21], but their safety and efficacy in liver transplantation recipients need to be assessed in future trials.