Venous thromboembolism in viral diseases: A comprehensive literature review

Abstract Venous thromboembolism (VTE) is known to be a common respiratory and/or cardiovascular complication in hospitalized patients with viral infections. Numerous studies have proven human immunodeficiency virus infection to be a prothrombotic condition. An elevated VTE risk has been observed in critically ill H1N1 influenza patients. VTE risk is remarkably higher in patients infected with the Hepatitis C virus in contrast to uninfected subjects. The elevation of D‐dimer levels supported the association between Chikungunya and the Zika virus and the rise of clinical VTE risk. Varicella‐zoster virus is a risk factor for both cellulitis and the consequent invasive bacterial disease which may take part in thrombotic initiation. Eventually, hospitalized patients infected with the coronavirus disease of 2019 (COVID‐19), the cause of the ongoing worldwide pandemic, could mainly suffer from an anomalous risk of coagulation activation with enhanced venous thrombosis events and poor quality clinical course. Although the risk of VTE in nonhospitalized COVID‐19 patients is not known yet, there are a large number of guidelines and studies on thromboprophylaxis administration for COVID‐19 cases. This study aims to take a detailed look at the effect of viral diseases on VTE, the epidemiology of VTE in viral diseases, and the diagnosis and treatment of VTE.

Varicella-zoster virus is a risk factor for both cellulitis and the consequent invasive bacterial disease which may take part in thrombotic initiation. Eventually, hospitalized patients infected with the coronavirus disease of 2019 (COVID- 19), the cause of the ongoing worldwide pandemic, could mainly suffer from an anomalous risk of coagulation activation with enhanced venous thrombosis events and poor quality clinical course. Although the risk of VTE in nonhospitalized COVID-19 patients is not known yet, there are a large number of guidelines and studies on thromboprophylaxis administration for COVID-19 cases. This study aims to take a detailed look at the effect of viral diseases on VTE, the epidemiology of VTE in viral diseases, and the diagnosis and treatment of VTE. (DVT) and pulmonary embolism (PE), is a common, significant disease whose frequency is about 1 per 1000 person-years in the overall population. 1 An approximate cost of 4.9-19.8 billion dollars annually is spent on that in America. 2 Since its frequency and risk factors are increasing, prevention and treatment of VTE are of special importance. Additionally, VTE is a preventable disease and, it is crucial to identify high-risk individuals as they often remain unrecognized, so they may benefit from the primary prophylaxis. 1,3 One of the known risk factors is bacterial and viral infections due to the systemic inflammation that they cause. 4 Human immunodeficiency virus (HIV) leads to an increase of about 2-to 10-fold in VTE risk in HIV-positive patients. 5 Although there is little documentation backing the association between Zika and Chikungunya virus and VTE, we should consider the possibility of that in more severe cases as inflammatory processes and immobilization in these patients are overall trigger factors for the progress of VTE. 6,7 Some supplementary studies have reported DVT and cerebral venous thrombosis associated with Herpes Simplex Virus (HSV). 8,9 Hepatitis C virus (HCV) infection accompanies VTE with a prevalence of 0.8%. 10 The most frequent site of vein thrombosis is the portal vein in cirrhotic patients. 11,12 VTE is also one of the hematological complications of infectious mononucleosis, although uncommon in immunocompetent patients. 13 In children with acute Varicella zoster virus (VZV) infection, PE and DVT have been frequently reported. 14 It can also cause stroke in children who suffer from chickenpox. 15 It has been recommended to be watchful for PE in patients with acute respiratory symptoms during the epidemy of influenza. 16 In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) appeared as a novel pathogen causing viral pneumonia.
Billions of people have been affected worldwide, and it has been responsible for more than 350,000 deaths. Thromboembolic complications, which are manifested by DVT, PE, cerebrovascular accident (CVA), limb and mesenteric arterial ischemia, and myocardial infarction (MI) are some of the significant reasons for death. 17,18 It can also happen in asymptomatic patients. 19 Different theories have described the interplay between viral infections, the coagulation pathway, and the hemostasis system.
Most of these theories are based on endothelial inflammation and injury caused by uncontrolled viral replication. 13,17,20,21 For instance, pro-inflammatory cytokines produced by Epstein-Barr virus (EBV) and coronavirus disease of 2019 (COVID-19), 13,22 the endothelial infection caused by Cytomegalovirus (CMV) and EBV, elevated levels of Von-Willebrand factor because of COVID-19 and CMV, 17,21 diminished activity of the protein C pathway accrues in pneumonia caused by the influenza virus 23 can lead to thrombosis formation.
Some items have been suggested as VTE risk factors in each viral infection. Older age and male gender in the HCV infection, 10 higher viral load, low CD4 + count, and presence of opportunistic infection such as CMV, malignancy, and thrombophilias in the HIV infection are known mechanisms behind the crosstalk existing between the inflammation and hemostasis system. 3,24,25 However, more research should be considered to better clarify the associations between viral infections and the hemostasis system.
In-hospital immobilization and current smoking are risk factors for VTE in influenza infection. 16 Moreover, oral contraceptives, cancer, obesity, immobilization, diabetes, and lupus anticoagulant (LAC) was related to CMV-associated DVT. There are also some genetic factors such as Factor V G1691A and factor VIII mutation. 4,26,27 Age has a direct association with the pervasiveness of VTE, PE, and DVT in COVID-19, while body mass index (BMI) affects only PE prevalence. Male sex does not count as a risk factor based on a meta-analysis. 28 Other risk factors in COVID-19-associated thromboembolism are immobilization, hypertension, intensive care unit (ICU) admission, central vein catheters, tissue factors, and cytokines. 22 VTE diagnosis primarily rests on two bases, including clinical suspicion and then paraclinical confirmation, 5,15 which can be accomplished by Doppler ultrasound as the initial imaging exam. 24,29 Molecular genetic testing could be considered if one is suspicious of underlying coagulopathies. 24,29 D-dimer is also a reliable parameter; however, it is not specific for VTE. In COVID-19 patients, it has been accounted a biomarker indicating coagulopathy and prognosis of the disease. 20,22 Unfractionated heparin along with low-molecular-weight heparin (LMWH) is the most common therapies used for treatment and prophylaxis in viral-associated VTE such as Zika virus, SARS-CoV-2, and other viral infections causing VTE. If there is any contraindication, mechanical prophylaxis should be considered. 19 In HIV-infected patients, guidelines recommend anticoagulant therapy for those with persisting risk factors. 5,30 Patients with CMV-associated VTE need to receive anticoagulant therapy even if only small vessels are involved. Although no guideline has already clarified the management, clinicians usually administrate LMWH and warfarin. 4,31 Empirical anticoagulation can protect significantly from VTE in H1N1-positive patients; particularly, prophylaxis has been recommended in high-risk patients. 32 Prescribing prophylaxis in COVID-19 patients depends on different factors, and clinicians would better individualize each case. However, a direct-acting oral anticoagulant (DOAC) is usually administered in a prophylactic dose such as Rivaroxaban, Apixaban, or Betrixaban. 33 In this review article, we seek to overview and outline the epidemiology, pathophysiology, diagnostic methods, prophylaxis, and treatment approaches to VTE caused by viral infections to easily compare these issues in different viruses. For this purpose, we reviewed case reports, case controls, review articles, systematic reviews, and cohort studies. Inclusion criteria were in vitro, in vivo, or clinical studies including case series, observational studies, and randomized controlled trials (RCTs) that evaluated the roles of viral infections in VTE. We excluded non-English studies and studies that were not related to the effects of viral infections in VTE. Figure 1 illustrated the selection process of studies included in this review. The references list of included articles was also searched manually for possible relevant studies.

| HIV AND VTE
Several studies recognized HIV infection as a prothrombotic condition. 5,24,34,35 The commonness of its occurrence in HIV patients with is 0.19%-7.63% per year. 36,37 They also reported that the total elevated hazard of VTE in HIV patients is 2-to 10-fold. 36,37 Rasmussen et al. 3 indicated that the 5-year hazard of VTE is 1.5% in noninjecting drug users

| Megestrol
Megestrol acetate is a progestational, orally active, and synthetic agent which is one of the treatments for breast cancer. In cachexia and/or anorexia patients with HIV, it stimulates weight gain and appetite. In HIV-infected patients, thromboembolic phenomena occur as an unfavorable effect of megestrol. 38 However, some studies found no connection. 43

| MALIGNANCY ASSOCIATED WITH HIV
The risk for developing VTE in cancerous patients differs and is estimated to range from 15% to 30%. 70  There is also an elevated risk for the formation of non-AIDS-defining cancers, including cancers related to co-infections (e.g., Hodgkin lymphoma with the presence of EBV, anal and oropharyngeal cancers with the presence of human papillomavirus (HPV), and liver cancer with the presence of hepatitis B and C viruses). 74 143 CMV seropositivity is also associated with arterial thrombosis but is less convincing, with an odds ratio of 1.23. 144,145 according to the study by Atzmony et al., 146 the acute CMV infection-associated thrombosis incidence amongst hospitalized patients was 6.4%: five (3.6%) patients who had arterial thrombosis and four (2.9%) patients who had VTE. However, the true thrombosis incidence is probably higher. The thrombosis incidence amongst outpatients following acute CMV infection has been investigated once by Paran et al. 143 According to this study, the VTE incidence among out 147 hospitalized thrombosis patients has been studied prospectively twice by Tichelaar et al. 148 and Schimanski et al., 149 which respectively showed a 1.9% (n = 5) and 4.3% prevalence.

| Treatment
Despite being a severe complication, CMV-related VTE appears to be benign in adults, and most of the time, we can see a complete resolution; however, newborns and infants seem to have a poor prognosis in comparison to adults. 27 There is no agreement about the administration of antiviral and anticoagulant therapy in patients who are immunocompetent, also the consumption of this treatment in these patients is off-label. besides, its usefulness is not proved. 27 Overall, 30.1% of patients whom most of them had viremia, and have been treated with antivirals, that is, ganciclovir and/or valganciclovir, 21,164,168,169 Antiviral Agents have been used in Immunocompromised patients more than immunocompetent patients. 142 Some researchers 27,170 have reported that they did not apply anticoagulation therapy in patients with CMV-associated splenic infarcts; however, their patients also had coagulation disorders, such as heterozygous factor V Leiden. In the mentioned condition it is suggested to use anticoagulant therapy for about 6-12 months after the first episode of VTE, primarily if related to impermanent risk factors such as the CMV infection. [171][172][173] In some reports, anticoagulation therapy has been continued until the anti-phospholipid antibodies disappeared or the thrombosis is resolved in imaging studies. 21 and CRP serum levels, normal protein C and S levels, normal C3 levels, and elevated C4 levels were seen in these patients. In addition, anticardiolipin antibodies and rheumatoid factor were negative.
Antithrombin therapy (Warfarin) was administered to patients presenting with VTE caused by EBV. 187 Bader et al. 13 192,193 COVID-19 has also been linked to severe coagulopathy, resulting in the development of a novel condition defined as COVID-19-associated coagulopathy, which affects the arterial, venous, and microcirculatory systems. [194][195][196] It is known to induce natural anticoagulant dysregulation, resulting in platelet dysfunction and higher D-dimer levels, as well as possible hyperactivation through inflammatory cascades. [194][195][196][197] with thromboelastograms of whole blood demonstrating heightened coagulation parameters. 198 ( Figure 3). In the following we will review some important topics:

| Fibrinolysis
Acute respiratory distress syndrome (ARDS) activates the fibrinolytic system. [199][200][201] Elevated fibrin deposition inside the vascular and alveolar spaces is caused by increased levels of plasminogen activator inhibitor 1 (PAI-1) in ARDS. In individuals with ARDS, high levels of plasma PAI-1 are linked to death. 202,203 According to one study, 16 individuals with SARS-CoV had a greater level of plasma PAI-1 compared to 19 individuals with different infectious cases of pneumonia and healthy controls. 204 In SARS-CoV-infected mice, the expression of PAI-1 was elevated, and PAI-1/animals had more lung bleeding and died more often, 205 inhibition of fibrinolysis by PAI-1 seems to protect against intrapulmonary bleeding, according to this research. The application of thrombolytic medications to treat COVID-19 was reviewed in a recent study that outlined the fibrinolytic anomalies related to ARDS. In individuals with COVID-19, nebulized plasminogen activators were suggested as a way to break down alveolar fibrin and increase oxygenation. 206 Recent research found that intravenous tissue plasminogen activator restored the respiratory status of three individuals with acute COVID-19 respiratory distress for a short period. 207

| Platelets
Platelets are necessary for arterial integrity, yet they can contribute to thrombosis. Platelets have recently been discovered to take part in the immunological response to infections. 208  individuals who were hospitalized. 217 These indicators suggest that circulating inflammatory mediators may activate the endothelium.
Only IAV H5N1 from avian has been demonstrated to infect pulmonary microvascular endothelial cells in vivo, even though various IAV strains have been found to reproduce in human pulmonary microvascular endothelial cells. 218,219 Importantly, one research discovered that stopping the highly pathogenic H5N1 IAV strain from replicating in the endothelium lowered systemic viral dissemination and death without altering viral replication in infected mice's lungs. 220 In a recent investigation, human capillary organoids generated from induced pluripotent stem cells were shown to be infected with SARS-CoV-2, which was prevented by using soluble, recombinant human ACE2. 221  COVID-19 individuals have a higher circulating neutrophil quantity, and a high neutrophil count has been linked to a bad prognosis. [231][232][233][234][235] By phagocytosing viral particles and releasing NETs, neutrophils help to remove viruses from the lungs. 236

| Complement
By opsonizing viral particles, recruiting inflammatory cells, and killing infected cells, the complement system has a critical part in the host's immunological response to viruses. 249 Complement activation, on the other hand, may harm the host's cells. The complement system is activated in mice infected with SARS-CoV. 250 There are strong hypotheses of the association between coagulation pathways and complement systems. Thus, inhibition of the complement system can be used as a potential target in the treatment of COVID-19. 214

| COAGULOPATHY AND INFLAMMATION
The inflammatory response in COVID-19 individuals is particularly striking, with prolonged fever, increased inflammatory markers levels (such as ferritin, ESR, various cytokines, and CRP, including TNF, IL-1, as well as IL-6), and a hyperinflammatory immune response called a cytokine storm, which is linked to poor outcomes. 232,[258][259][260][261] According to early findings, this inflammatory response was once thought to be similar to that found in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. 247

| THROMBOSIS TARGETING FOR THE TREATMENT OF COVID-19
The high thrombotic complications incidence seen in critically ill patients of COVID-19 has generated considerable interest in the application of antithrombotic drugs for COVID-19 patients. 295 The significant increase in the prevalence of thrombotic complications has led many hospitals to routinely administrate strict VTE prophylaxis by using either unfractionated heparin (UFH) or LMWH, and in several groups, the full or intermediate dose of anticoagulant was used to prevent these thrombotic complications. 296,297 Anticoagulants prevent coagulation via antithrombin-mediated inhibition of FXa or thrombin. 295 Nevertheless, in addition to its anticoagulant effects, heparin seems to have pleiotropic effects that T A B L E 2 Mechanisms involved in the association between viral diseases and VTE.

Mechanisms of causing VTE
Human Immunodeficiency Virus • Low CD4 cell count by inducing hypercoagulable condition 41 • Immune reconstitution inflammatory syndrome upon starting antiretrovirals can lead to hypercoagulable condition and increased risk of VTE 55-57 • Concomitant infection with mycobacterium Avium, mycobacterium tuberculosis, CMV, and pneumocystis Jiroveci pneumonia induce a hypercoagulable state which leads to VTE. In addition, mycobacterium tuberculosis promotes the activation of cytokines such as IL-1, IL-6, and TNF-α. 62 • Higher viral load (HIV RNA) increases the risk of VTE 51 • HIV patients are at higher risk of Kaposi Sarcoma which increases the risk of VTE 74 • Age is an independent risk factor for VTE and in HIV patients, the median age of VTE is lower than the general population 76 • Activation of D-dimer, CRP, soluble TNF receptors, and IL-6 produce hypercoagulable conditions 80 • Higher anticardiolipin antibodies in HIV patients lead to a higher incidence of VTE 82,83 • HIV damages endothelium causing increased activation of plasminogen activator inhibitor-1, vWF, tissue factor, P-selectin, and factor V which increases VTE incidence 92,93 • P-selectin is correlated with VTE in HIV patients 104 • A higher number of monocytes expressing tissue factor was detected in HIV patients 60 • HIV patients with VTE had higher protein C deficiency 108 • HIV patients with VTE had antithrombin deficiency which may be associated with a higher incidence of VTE 110

Cytomegalovirus
• CMV upregulates the expression of VCAM-1, ICAM-1, and tissue factor which leads to higher VTE by platelet aggregation, thrombin formation, and factor X activation 152 Hepatitis C • Vasculopathy caused by chronic inflammation 11,12 • Presence of anticardiolipin and antiphospholipid antibodies 11,12 • Downregulation of anticoagulant proteins and upregulation of procoagulant proteins 11,12 • Higher thrombin generation rates 11,12 • Higher cryoglobulinemia which can cause thrombotic vasculitis 11,12 Herpes Simplex • Reduction in synthesis of heparan sulfate proteoglycan, increase in thrombin generation and platelet binding, decrease in prostacyclin synthesis and preventing binding of antithrombin to its surface 9

COVID-19
• Elevated fibrin deposition inside the vascular and alveolar space caused by increased levels of plasminogen activator inhibitor 1 202,203 • SARS-CoV-2 reduce ACE2 activity which decreases angiotensin I and XII (anti-thrombotic and anti-inflammatory) while increases angiotensin II (prothrombic and pro-inflammatory) 214 • SARS-CoV-2 induces endothelium dysfunction which may contribute to occurrence of VTE 223 • Higher levels of neutrophils and NETs contribute to higher VTE 226,227 • SARS-CoV-2 activates complement system which elevates rate of VTE 250 • Elevated vWF results in higher thromboembolic risk 256,257 • Higher inflammatory cytokine levels (IL-1, IL-6, vWF, fibrinogen, and factor VIII) are associated with abnormal coagulation 258,265 Abbreviations  304 This results in the formation of thrombin and bradykinin activation, in particular, the latter leads to the subsequent activation of complement and the production of the inflammatory cytokines. 305

| ANTIPLATELET AGENTS AS POTENTIAL THERAPEUTICS FOR COVID-19
A recent meta-analysis of randomized controlled trials found no benefit in adding antiplatelets to COVID-19 treatment. 306 Strangely, most of the data linking clinical outcome improvement with antiplatelet therapy relate to aspirin. 307 In this respect, experimental data show that targeting platelets via aspirin precludes neutrophil-mediated microvascular thrombosis and intravascular coagulation in a murine model of bacterial sepsis. 308 Dipyridamole and several other antiplatelet drugs, including nafamostat, are currently being appraised for their potential part in decreasing the COVID-19 severity. 295

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data are available upon request from the corresponding author.

TRANSPARENCY STATEMENT
The lead author Nilufar Alizadeh, Niloofar Deravi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.