Portal Vein Thrombosis Due to Concomitant Cytomegalovirus and Epstein-Barr Virus Infection: An Underestimated Complication

Introduction

Portal vein thrombosis (PVT) results from the narrowing or blockage of the portal venous circulation by blood clots and can be a complication of several pathological conditions, including liver cirrhosis, autoimmune diseases, myeloproliferative disorders, and local or systemic inflammatory diseases, among others [1,2]. The incidence of PVT has been estimated at 2 to 4 cases per 100 000 per year, and it has reached up to 24% in patients with liver cirrhosis, as demonstrated by previous reports [3,4]. Acute PVT can be clinically silent, or it can present with abdominal pain, fever, and or nonspecific symptoms. Recently, viral infections have been reported to be associated with an increased risk of venous thromboembolism. During the COVID-19 pandemic, multiple studies and case reports showed an increased risk of thromboembolism associated with COVID-19 infection [5]. Moreover, acute Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections have been linked to an increased risk of PVT in immunocompromised patients. Nevertheless, there is insufficient data on acute PVT resulting from CMV and/or EBV infection in immunocompetent individuals.

Herein, we describe an the case of immunocompetent patient who presented with vague abdominal pain and fever and was found to have acute PVT in the context of concomitant infection with CMV and EBV.

Case Report

Our patient was a 32-year-old, non-smoking man with no significant past medical history. He presented to the emergency department (ED) of a university hospital with fatigue, fever, and vague abdominal pain that started 2 weeks before his presentation. There was no drug allergy, and he was not on any regular medications.

On admission, his vital signs were remarkable for mild tachycardia (105 beats per minute) and a temperature of 38.2°C. Clinical examination revealed mild abdominal tenderness over the right upper quadrant and epigastric area; otherwise, there were no clinically significant findings, including hepatosplenomegaly or lymphadenopathy.

The initial blood test revealed leucocytosis (12 000 cells/mcL), with lymphocyte and neutrophil counts of 57% and 32%, respectively. C-reactive protein was mildly elevated (30 mg/L), procalcitonin was within normal limits, and the lactate dehydrogenase level was 796 units/liter. Liver function tests showed a mild elevation in liver enzymes (alanine aminotransferase: 106 IU/L, aspartate aminotransferase: 162 IU/L). The rest of the investigation was within the normal limits. Chest radiography revealed a normal cardiothoracic ratio with no significant signs of pneumonia. Blood, urine, and sputum cultures were obtained, and empirical antibiotics (ceftriaxone) were initiated. Given the history of fever, abdominal pain, and elevated liver enzymes, an abdominal ultrasound was performed, revealing mild hepatosplenomegaly with normal surface and texture (liver size: 17.2 cm, spleen size: 15.7 cm) and minimal ascites. The common bile ducts were of normal diameter, and there were no gallstones or indications of cholecystitis.

The constellation of elevated liver enzymes, hepatosplenomegaly, and lymphocytosis suggested an acute viral infection. Serological tests for human immunodeficiency virus (HIV), viral hepatitis (A, B, and C), and parvovirus B19 were normal. However, the serological test for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) revealed high titers of immunoglobulin M (IgM) for CMV and EBV (23.27 and 3.17 reactivity index, respectively). The IgG titers for both viruses were negative, suggesting a recent acute infection.

The patient was started on supportive treatment, including intravenous fluids and adequate hydration, and received antipyretics. The following day, his abdominal pain had been increasing and was mainly over the right upper quadrant area. A computed tomography (CT) scan with contrast-enhancing study of the abdomen demonstrated a filling defect involving the posterior branch of the right portal vein, with normal filling of the main and left portal vein branches (Figure 1A, 1B). The patient was transferred to the intensive care unit (ICU), and anticoagulation was started immediately with unfractionated heparin (intravenous bolus of 80 u/kg followed by 18 u/kg/h, target aPTT of 1.5–2.3 control) as recommended by the hematologist. During his ICU stay, an upper endoscopy was performed, which showed normal findings with no evidence of oesophageal or gastric varices. Further workup was done to investigate the causes of PVT, including autoimmune, hematological, and neoplastic causes. Antinuclear antibodies (ANA), antineutrophil-cytoplasmic antibodies (ANCA), lupus anticoagulant, anti-cardiolipin, mitochondrial antibodies, and tumor markers (carcinoembryonic antigen, alpha-fetoprotein, and cancer antigen 19-9) were negative. Results of a thrombophilia workup, including antithrombin-III, protein C and S activities, factor V mutation, and homocysteine levels, were within normal limits. The JAK-2 mutation was negative, and a peripheral blood film showed atypical lymphocytes, which is consistent with viral infection. The bone marrow aspirated did not show any abnormal cells or infiltrate, making a hematological malignancy unlikely.

A diagnosis of acute PVT secondary to co-infection with acute CMV and EBV was made. The patient was transferred from the ICU and switched to oral anticoagulation (apixaban) after 4 days of unfractionated heparin infusion. His symptoms gradually improved, and he was discharged home on oral anticoagulation without the need for antiviral therapy. Four weeks later, he was feeling well, and his liver enzymes and white blood cell count had returned to normal levels.

Discussion

Non-cirrhotic non-malignant PVT is a rare condition characterized by the development of a thrombus in the main portal vein and/or its branches [6]. The estimated incidence of PVT is approximately 0.7 per 100 000 population per year [7]. The risk factors for PVT can be classified according to the underlying causes into inherited thrombophilia, such as protein C, S, or antithrombin 3 deficiency; factor V mutation, acquired thrombophilia, such as myeloproliferative, antiphospholipid antibodies, paroxysmal nocturnal hemoglobinuria, and neoplasms; hormonal factors; and systemic or local inflammation [8,9] (Table 1). Viral infection has recently been considered a risk factor for venous thromboembolism. Coronavirus disease 2019 (Covid-19) is associated with an increased risk of venous thromboembolism. A Covid-19 patient with thromboembolism has a higher risk of morbidity and mortality [10]. Acute CMV or EBV viral infection has been reported to be associated with the risk of thrombosis (pulmonary or deep venous thrombosis). However, PVT in the context of acute CMV or EBV viral infection in an immunocompetent patient is a rare complication. Venous thromboembolism following acute viral infection mostly occurs in immunocompromised patients, predominantly post-transplant or HIV-positive patients [11]. Moreover, there is little information on the association of PVT and acute CMV infection. In 2010, a case-control study conducted by Atzmony et al showed that the incidence of acute CMV infection-associated thrombosis reached up to 6.4% [12]. Similarly, Justo et al reported an increase in the incidence of venous thromboembolism associated with acute CMV infection; however, most of the patients had prothrombotic risk factors [11].

Data on the association between acute EBV infection and risk of thromboembolism are scarce. However, during the literature review, we found 1 case report of extensive venous thromboembolism complicated with cardiac arrest secondary to acute EBV infection in an immunocompetent patient [13]. It is noteworthy that the incidence of thrombosis associated with EBV could be higher than what we expect, as patients with acute EBV infection are not routinely investigated for thromboembolism. Moreover, we found only 1 case report of acute PVT associated with acute EBV infection [14].

Multiple mechanisms have been proposed to explain the association between viral infection and risk of thromboembolism. The most widely accepted mechanism is the transient production of anti-phospholipid antibodies [15], but the level is only detectable during the acute phase of infection. Another proposed mechanism is the generation of systemic inflammatory response syndrome following acute viral infection, leading to activation of the coagulation cascade through cytokine production and endothelial dysfunction [16]. Although 1 or more of the above mechanisms might cause the procoagulant state, the effect appears to be transient. It has been previously demonstrated that antiphospholipid antibodies are cleared after a few months after CMV infection and acute thrombosis [11]. A prospective study conducted by Paran et al demonstrated that the greatest risk of thromboembolism was at around 6 months after acute CMV infection [17]; therefore, it is important to actively identify patients with transient or reversible risk factors, including viral infection, as lifelong anticoagulation will be unnecessary for those patients.

We hope that this case report will enhance physician awareness of the risk of thromboembolism linked with viral infections and help future research into the association and mechanism of virus-induced thrombosis.

Conclusions

The recent literature has emphasized the increased prevalence of virus-induced thrombosis. Acute non-cirrhotic PVT secondary to concomitant infection with CMV and EBV in immunocompetent patients is rare, and it could be an underestimated disease, as its symptoms are discrete or nonspecific. Identifying CMV and/or EBV infection as a risk factor for venous thromboembolism will help with early diagnosis and avoid unnecessary complications such as bowel ischemia. Moreover, considering it as a provoked factor for thrombosis can help avoid extended anticoagulation. More research is needed to identify viral infection as a trigger for thromboembolism and to decide the most appropriate anticoagulant.