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Review Article - (2021) Volume 6, Issue 3

Portal and Severe Mesenteric Vein Thrombosis Associated with Acute Cytomegalovirus Infection: Case Report
Ali Ilgın Olut1*, Burak Şeker1, Hilal Küpeli1, İbrahim Erdinç2 and Selma Tosun1
 
1Department of Infectious Diseases and Clinical Microbiology Izmir Health Science University Izmir Bozyaka Educational and Research Hospital, Turkey
2Department of Cardiovascular Surgery, Health Science University Izmir Bozyaka Educational and Research Hospital, Turkey
 
*Correspondence: Ali Ilgın Olut, Department of Infectious Diseases and Clinical Microbiology Izmir Health Science University Izmir Bozyaka Educational and Research Hospital, Turkey, Tel: 5322643472, Email:

Received: 18-Nov-2019 Published: 24-Sep-2021, DOI: 10.35248/2576-389X.21.6.158

Introduction

Venous thromboembolism (VTE) is relatively a common and potentially fatal disease and is the third leading cause of cardiovascular mortality, with 5% of individuals have at least one VTE episode in their lifetime[1,2]. Idiopathic (unprovoked) venous thromboembolism (IVTE) is defined as VTE which occurs in the absence of triggering circumstances such as prolonged immobilization, a journey lasting for more than 6-8 h, fracture of a lower limb, major surgery, active cancer, antiphospholipid antibody syndrome, pregnancy or drug usage such as oral contraceptive etc[3]. The studies demonstrated that in almost 50% of first VTE, a thrombophilic factor could be identified and the incidence of IVTE is reported as 25-50% in different studies [1-3]. Generally, IVTE requires a special attention as the patient needs careful investigation and periodical monitorization, and in many cases should be treated for a lifetime. When assessing the etiology of IVTE, infectious causes such as cytomegalovirus (CMV) are rarely considered. However, in many recent reports, there is mounting evidence of infections as causes of VTE. A meta-analysis of existing data showed that between 2-9% of patients hospitalized with VTE had an acute CMV infection[4]. Here, we present an otherwise healthy 21 years old male presented with severe VTE in portal and in all branches of inferior and superior mesenteric veins whom diagnosed as having an acute CMV infection by serological and molecular methods.

Case Report

A 21-year-old male was referred to our emergency department with fever of 38.0 Co, acute severe abdominal pain, nausea and vomiting. On medical examination there was a general abdominal tenderness and abnormal laboratory results were as: WBC: 10.500 mm3, AST:191 U/l, ALT:61 U/l, CRP:153 pg/ml, ESR 59 mm/h, total bilurubin:3.8 mg/ml, urine bilirubin (+++). Abdominal CT of the patient revealed diffuse thrombosis of superior and inferior mesenteric veins including all branches and partial thrombosis of portal vein from distal to proximal sites and hepato-splenomegaly. The patient was hospitalized and immediate anti-thrombolytic treatment (enoksaparin 1 mg/kg x2 sc) was started. For investigation of infectious etiology of fever and hepato-splenomegaly, serological tests were performed. Toxoplasma, salmonella, brucella and HIV, hepatitis A, B, C, E, herpes simplex, Epstein–Barr, viruses were all negative and anti- CMV IgG and anti-CMV IgM antibodies were positive (ARCHITECT CMV ELISA-KIT Ireland). Hematologic investigation of patient’s coagulation profile was normal and screening for hereditary thrombophilia panel, protein C resistance, proteins C-protein S and lupus anticoagulant was negative, anti-thrombin activity was normal, and factor VIII activity was within normal range. CMV avidity testing a showed a very low result (<%10) and CMV-DNA was 1444 IU/ml. On detailed medical history he was a non-smoker, had no known chronic disease or drug usage but he donated kidney to his mother 16 months ago in our hospital and serological tests for CMV IgG-IgM were negative at that time. The patient was accepted as having an acute CMV hepatitis complicated by acute portal and mesenteric vein thrombosis. Though he was immunocompetent, due to the high viremia and the critical clinical condition of the patient, i.v ganciclovir therapy was started along with anti-thrombolytic treatment. After ten days of therapy, disappearance of fever and reduction of transaminases was observed, CMV-DNA returned to negative and doppler USG showed regression of thrombosis in both portal and mesenteric veins.

Literature Review

By using the words cytomegalovirus infection & venous thrombosis on 12 February 2019, we found 110 articles in PUBMED and no records in Turkish Medline with using the words sitomegalovirus & tromboemboli. When the search was constricted to only human studies in English literature, including case or cases of VTE in immunocompetent individuals, 32 articles were found, with 61 patient cases[4, 5-36]. Flow diagram presenting the number of studies screened, assessed for eligibility and included in the review are given in Figure 1.

presenting

Figure 1: Flow diagram presenting number of studies screened, assessed for eligibility and included in the review.

Table 1: Flow diagram presenting number of studies screened, assessed for eligibility and included in the review.

In the analysis of cases, the mean age of patients was 37 years with an apparently female predominance (61%). The sites veins affected were as: 28 deep veins of lower extremities, 20 pulmonary, 15 portal, 7 mesenteric, one hepatic and one sinus vein.

Most of the patients (67%) had a concomitant risk factor -either hereditary or acquired such as oral contraceptive (OCP) use- and interestingly in one third of cases no thrombophilic factor other than CMV infection was present. In three cases, any additional risk factor was not sought. Table 1 explains the clinical characteristics of cases of VTE occurring in the course of acute CMV infection in immunocompetent adult patients.

Article     Hypercoagulable Extra-vascular  
Age/sex VTE location state risk factors manifestations Treatment
Inacio et al. (1997)[5] 31 F Mesenteric vein, PVT OCP Hepatitis OA
Ofotokun et al. (2001[6] 50 M PVT None CMV viremia, splenomegaly Ganciclovir
Abgueguen et al. (2003)[7] 32 F DVT, PE FVL NR NR
38 F DVT, PE None CMV colitis
       
Youd et al. (2003[8] 35 M PE NR Hepatitis NR
Rovery et al. (2005[9] 33 M DVT DVT history, FVL CMV viremia NR
Yildiz et al. (2006[10] 30-49 (37.5) 6 DVT All with congenital thrombophilic condition 3 pharyngitis Anticoagulants
9 F, 1 M 3 PE 1 Hepatitis (in 9 for 6 months, in one for 12 months)
  2 mesenteric    
Spahr L et al.(2006)[11] 36 F PVT+hepatic vein+Budd Chiari OCP CMV viremia Heparin
Paran et al. (2007)[12] 21 F DVT Anti-cardiolipin ab NR NR
35 M DVT FVL NR NR
29 M Bilateral DVT OCP NR NR
Squizzato et al. (2007)[13] 34 M PVT None Splenomegaly OA
Ergas et al. (2008)[14] 28 M Mesenteric vein + PE MTHFR NR NR
Ladd et al. (2009)[15] 17 F PVT, PE OCP NR NR
Abgueguen et al. (2010) [17] 32 F PE None Ulcerative colitis OA
38 F PE FVL None OA
82 F PE (bilateral) None None OA
Justo et al. (2011)[4] 29 F PE OCP NR NR
32 M SVT None NR
54 M SVT None NR
Poon et al. (2011)[18] 30 F PE NR Splenic infarct OA
Ticlear et al. (2011) [19] 26 F   OCP NR  
28 F   OCP NR  
36 F All with DVT OCP NR NR
36 F   Surgery CMV Viremia  
36 F   Pregnancy NR  
Kalaitzis et al. (2012)[20] 40 M Mesenteric vein None CMV viremia, Enoxaparin
Small bowel necrosis
Sherman et al. (2012)[21] 70 M Sinus vein thrombosis None NR OA
Schimanski et al. (2012) [22] 29 F DVT + PE Pregnancy    
31 F DVT OCP, F VIII    
38 F DVT OCP    
42 F DVT F VIII, FVL NR NR
46 F DVT None    
58 M DVT FVL    
61 F DVT F VIII    
         
Pichenot et al. (2013)[23] 39 M PVT, PE None CMV viremia OA, valgancyclovir OA
40 F PVT OCP CMV viremia OA, ganciclovir
43 F Bilateral DVT, PE Heavy smoker None  
Galloula et al. (2014)[24] 24 F PVT OCP NR OA
Nakayama et al. (2014) [25] 19 M DVT, PE APL Alveolar hemorrhage OA
CMV viremia
Rinaldi et al. (2014)[26] 62 F PVT Heavy smoker Hepatitis OA, ganciclovir Enoxaparin
20 F PVT None Hepatitis
Vandamme et al. (2014) [27] 30 M Bilateral PE None Myo-pericarditis + Alveolar hemorrhage NR
Bertoni et al. (2015)[28] 39 M Mesenteric vein FVL NR OA
Wang et al. (2015)[29] 61 M PVT None None OA
Chou et al. (2016)[30] 78 M PE NR CMV colitis Heparin, ganciclovir
Bountouris et al. (2017)[31] 25 M DVT, PE None NR rivaroxaban
Vael et al. (2017)[32] 58 F PVT None CMV colitis Thrombolysis,
hemicolectomy, heparin
Kelkar et al. (2017)[33] 46 M PVT None CMV viremia, Hepatitis, CMV colitis Heparin + OA
Puccia et al. (2017)[34] 30 M PVT None CMV viremia, Hepatitis Heparin + ganciclovir
Salembier et al. (2018)[35] 35 M Mesenteric vein, PVT Hereditary Thrombophilia Hepatitis Heparin
Ngu et al. (2018)[36] 27 M DVT None CMV viremia, Hepatitis OA

Table 1: Clinical characteristics of cases of venous thromboembolism occurring in the course of acute cytomegalovirus infection in immunocompetent patients.

Discussion

CMV infection was first suspected to be a cause of venous thromboembolism (VTE) at 1974, when Vorlicky et al. reported a case of an infant with congenital CMV infection and renal vein thrombosis[37]. By then, many cases of CMV related thrombosis has been reported in immunocompromised patients and in immunocompetent individuals. Reports have described CMV-associated thrombosis in many different anatomical sites, such as the lower limbs as DVT’s, splanchnic vein thrombosis (SpVT), portal vein thrombosis (PVT), mesenteric vein thrombosis (MVT), splenic vein thrombosis (SVT), pulmonary embolism (PE), and the Budd-Chiari syndrome (BCS) [11]. The first documented case of thrombosis in the course of acute CMV infection in an immunocompetent patient was documented by Inacia et al. at 1997, whom reported a case of a heavy smoker 31-year-old woman that was using oral contraceptive pills and developed acute portal vein thrombosis during the course of an acute CMV infection[5]. The authors suggested a relationship between endothelial cell-damaging effects of the virus and thrombosis. At 2001, Otofokun et al. reported a previously healthy adult with acute CMV infection that was complicated by extensive mesenteric arterial and venous thrombosis. This was the first reported case of VTE in an immunocompetent individual that had no predisposing risk factors for thrombosis[6].

To determine the incidence of thrombosis in acute CMV infection, the first cohort study was performed by Atzmony et al. at 2010 whom retrospectively analyzed the incidence of venous as well as arterial thromboses among 140 patients with acute CMV infection and 140 matched controls. They found the incidence of thrombosis as 6.4% in case and %0 in control group[16]. Later at 2012, Schimanski et al. reported a prospective study among 166 hospitalized venous thrombosis patients and stated the incidence of acute CMV infection as: 4.3% of all venous thrombosis and 7.4% of unprovoked venous thrombosis patients[22]. In a case control study by Ticlear et al., among 258 DVT and 139 control patients, authors reported five cases of acute CMV infection and viremia in case group: all were females age below 37 and they stated that as 31 of 258 patients with VT (12%) were younger than 37 years, 16% of all VT patients younger than 37 years had an active cytomegalovirus infection[19]. A retrospective study by Yildiz et al. at 2016 also suggested that among VTE patients, VTE’s with acute CMV infection are comparatively younger (37.5 years’ vs 56.6 years, P = 0.0088) with female predominance (90% vs 56%; p = 0.026) a similar finding with the analysis of our literature review[10].

To explain the pathophysiology of thrombophilia in CMV infection, several theories were suggested such as; the virus infects endothelial cells and enhances the expression of adhesion molecules that triggering platelet adhesion and aggregation on vessel walls, activation of factor X by the virus that leads thrombin formation, the capacity of the virus to increase circulatory levels of Von-Willebrand factor and factor VIII[38,39]. But up to date, the most accepted theory is that, acute CMV infection is associated with transient appearance of anti-phospholipid antibodies and causes a hypercoagulable status. This theory has been demonstrated in vitro and in vivo in several studies[40,41].

In, Mandell, Dolin and Bennett’s Principles & Practice of Infectious Diseases (2015) and in the Red Book (The Authority on Pediatric Infectious Diseases from the American Academy of Pediatrics - 2018) thrombosis is not mentioned as a complication of CMV disease, neither in immunocompetent nor in immunodeficient patients[42,43]. Actually, it seems thrombophilia associated with acute CMV infection is not as rare as thought and the role of CMV in vasculopathy and venous thrombosis has been underestimated. In our case, we believe that severe splanchnic VTE in an immunocompetent, 21- year old, non-smoker male without any chronic disease or drug usage, with no documented hereditary thrombophilic condition and serologically tested negative for CMV IgG-IgM (as he was a kidney donor) in recently, is a strong evidence for association of acute CMV infection with the patient’s condition.

By this case report and literature review, principally, we hope to increase the awareness of association with acute CMV infection and thrombosis/thromboembolic events especially in patients with idiopathic thromboses. Secondly, as the results of the studies clearly indicated that patients who suffered from a first unprovoked VTE have an 8-10% annual risk of recurrence, long term and as in some VTE guidelines (such as American Thoracic Society 2016) lifelong anticoagulant treatment is advised at the expense of bleeding risk, costs and inconvenience to the patients[4,44]. In case of VTE’S with transient or reversible causes such as CMV related VTE, identification of such a subset of patients may prevent lifelong anticoagulation and potentially harmful complications.

REFERENCES

Citation: Olut AI(2021) Portal and severe mesenteric vein thrombosis associated with acute cytomegalovirus infection: Case report. J Infect Dis Diagn.6:156

Copyright: © 2021 Olut AI. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.