Infection, atherothrombosis and thromboembolism beyond the COVID-19 disease: what similar in physiopathology and researches.

The recent Sars-Cov-2 pandemic (COVID-19) has led to growing research on the relationship between thromboembolism and Sars-Cov-2 infection. Nowadays, endothelial dysfunction, platelet activation, coagulation, and inflammatory host immune response are the subject of extensive researches in patients with COVID-19 disease. However, studies on the link between microorganisms or infections and thrombotic or thromboembolic events met fluctuating interest in the past. We, therefore, aimed to briefly summarize previous evidence on this topic, highlighting common points between previous data and what experienced today with SARS-COV2 infections.

Introduction

Infections may increase the risk of cardiovascular events. Respiratory infections are associated with an increased risk of thrombotic vascular disease such as myocardial infarction, ischemic stroke and venous thrombosis [1]. Up to one-third of patients hospitalized with pneumococcal pneumonia may be affected by major adverse cardiac events during or after pneumonia [2]. An increased risk of cardiovascular mortality has been observed after pneumonia [3]. Apparently, for every infection type, an increased likelihood of venous thromboembolism (VTE) may be observed. In subjects with pneumonia, either due to S. Pneumoniae or influenza virus, VTE occurrence was even higher [4, 5]. Furthermore, lung infection is complicated by platelet aggregation [6] and clotting system activation (up-regulation of tissue factor and down-regulation of activated protein C) [3]. Thromboprophylaxis in critically ill patients with acute infections is recommended [7], mainly in the case of pulmonary infections.

The recent severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) pandemic, characterized in many cases by severe acute respiratory syndrome and thrombotic complications, has boosted research on the relationship between thromboembolism and Sars-CoV-2 infection.

We have already reported on thrombotic complications and thromboembolism in coronavirus disease-19 (COVID-19) [8], emphasizing the fundamental role of the endothelial dysfunction, platelet activation, clotting system and inflammatory host immune response. However, studies on the link between microorganisms or infections and thrombotic or thromboembolic events met fluctuating interest in the past (Table 1). We, therefore, aimed to briefly summarize previous evidence on this topic, highlighting common points between previous data and what experienced today with SARS-COV2 infections.

Table 1

Infections with thrombotic and throemboembolic complications and possible similarities to those of infection SARS-CoV-2

Infectious agent	Thrombotic or thromboembolic complications	Therapeutic possibilities
HIV infection	VTE Pulmonary hypertension Endothelial dysfunction Inflammation	Anticoagulants Pulm. vasodilatator Anti-inflammatory drugs
HCV infection	VTE Pulmonary hypertension	Anticoagulants Pulm. vasodilatator
Respiratory infections	Myocardial Infarction Ischemic stroke Venous thrombosis	Anticoagulants Thrombolysis Antiaggregants
Pneumococcal pneumonia	Major adverse cardiac events (total death, Myocardial infarction, ischemic stroke, HF hospitalization)	Antiaggregants
S. pneumoniae or flu pneumonia	VTE Atherosclerotic events	Anticoagulants Antiaggregants
Chlamydia pneumoniae	Coronary artery disease	Antibiotic therapy
Helicobacter pylori	Coronary artery disease	Antibiotic therapy
Mycoplasma pneumoniae	Coronary artery disease	Antibiotic therapy

HIV human immunodeficiency virus, VTE venous thromboembolism, HCV hepatitis C virus, HF heart failure, Pulm pulmonary, S streptococcus

Methods

We performed a systematic research using Embase and PubMed, using the keywords and mesh terms relative to the infection and thromboembolism or thrombotic complications. Boolean operators ‘AND’, ‘OR’, ‘NOT’ were used where appropriate. Inclusion criteria were: (a) publication between January 2000 and June 2020, (b) epidemiological relevance, and (c) clinical impact. We excluded publications that: (a) were not directly focused on thrombosis or thrombotic complications, (b) provided information overlap with larger studies or more recent articles. The use of a combination of the inclusion criteria provided the most recent information.

Infection and thromboembolism

Generally, infection and immobilization had an addictive effect on the thromboembolic risk, and this effect is present in COVID-19 patients, too. However, hospitalization with infection is a strong thromboembolic stimulus also in non-immobilized patients [9].

SARS-CoV-2 is frequently associated with coagulopathy with possible large vessel thrombosis and major thromboembolic complications, including pulmonary embolism [10]. Beyond the association between thromboembolism and COVID-19 disease [11-13], several etiologic agents have been correlated with thromboembolism. A higher incidence of venous thromboembolism (VTE) in patients with HIV infection has been described [14]. Interestingly, HIV patients may develop VTE and precapillary pulmonary hypertension (PH) [15]. HIV-PH is included in group 1 PH group classification and need a multidisciplinary approach [16]. Thrombotic complications in COVID-19 patients may also need a similar multidisciplinary approach (pneumologists, cardiologists, infectious disease specialists, intensivists). The physiopathology of PH is characterized by endothelial dysfunction. The endothelial function in patients with cardiovascular diseases may be hampered by the SARS-CoV-2 infection: inflammatory cytokines may increase the expression of adhesion molecules and further inflammation activation, resulting in procoagulant changes, endothelial activation and, finally, in worsening microvascular perfusion [17].

Restoring nitric oxide may contribute to pulmonary vasodilatation and may be a potential treatment for SARS-CoV-2. In patients with pulmonary arterial hypertension (PAH) (group 1 of the PH classification), progressive disease with thrombotic findings, characterized by increased pulmonary vascular pressure and right heart failure, specific pulmonary vasodilators are strongly recommended [18].

A special condition occurs in patients with HCV and cirrhosis of various etiologies, being at increased risk of several types of thromboembolic events. Porto-pulmonary hypertension (PoPH), a relatively common pulmonary vascular complication of advanced liver disease [19], is also included in the group 1 of the PH classification and need specific pulmonary vasodilators and a multidisciplinary approach.

Infection in atherothrombosis

Infection and products of the endogenous microbiome might modulate atherosclerosis and its complications, either directly or indirectly, by eliciting local and systemic responses. [20] Previous studies have identified markers of nucleic acid and antigens of viral and bacterial pathogens within atherosclerotic plaques, allowing to speculate that infection could play a role in precipitating atherosclerotic events. Furthermore, bacterial products can stimulate vascular inflammation [21, 22] and Gram-negative bacterial endotoxin may strongly elicit inflammatory responses from endothelial cells. Chronic infections, not in the vascular district, could provide a stimulus that contributes to inflammatory burden [23]. The body responses induced by the infection may precipitate complications of atherosclerosis or enhance their consequences because acute consequences of bacterial infections can increase myocardial oxygen requirements, decrease oxygen availability, promote clot formation, and impair the endogenous fibrinolytic system. In particular, during sepsis, tachycardia and fever can lead to a hyperkinetic state that increase oxygen demands and may predispose to acute coronary syndromes; in case of patients with coronary heart disease, the decreased oxygen supply due to hypoxemia can worsen myocardial ischemia.

Increased rates of cardiovascular events and thrombosis in patients with pneumonia have shown how respiratory infections can affect clinical outcomes [3]; previous observational and pathophysiologic evidence supports the association between recent respiratory infections [24-27] or influenza [28] and atherosclerotic events. It was also demonstrated that pneumonia may accelerate the progression of atherosclerosis [25]. A randomized open-label study showed that acetyl-salicylic acid may be beneficial in the reduction of acute coronary syndrome complications and cardiovascular mortality in patients with pneumonia [29]. Different viruses and bacteria may be associated with atherosclerotic diseases. Previous data support the hypothesis that a previous influenza virus infection may be associated with acute myocardial infarction [30, 31]. Chlamydia pneumoniae infection was considered a risk factor for atherosclerosis and coronary heart disease (CAD) [32] The level of Chlamydia pneumoniae and Helicobacter pylori-specific IgG antibodies have been found elevated in CAD patients; their presence has been associated with the development of the CAD and correlated to cholesterol levels. Chlamydia pneumoniae-specific IgG were significantly correlated with hsCRP, suggesting an important role of these organisms in the development of CAD by altering lipid profile and induction of inflammation [33]. Previous studies showed the presence of Chlamydia pneumoniae, chlamydial antigens or nucleic acid in atherosclerotic plaques [34]. None of the known risk factors for cardiovascular disease was significantly associated with Chlamydia pneumoniae seropositivity IgG [35]. Mycoplasma pneumonia patients exhibited a 37% increase in the risk of subsequently developing ACS [36].

However, trials with antibiotics did not reduce the recurrence of cardiovascular events. Treatment with macrolides such as azithromycin, or fluoroquinolones or gatifloxacin showed no reduction of cardiovascular events in the tested patients [37]. Vaccination also has not yet achieved the desired results in reducing cardiovascular events in [20].

Coronary thrombosis [38], coronary stent thrombosis [39], acute myocardial infarction [40] and failed fibrinolytic therapy [41] have been reported in COVID-19 patients. However, SARS-CoV-2 has not been identified in coronary plaque so far. Mechanisms linking SARS-CoV-2 to plaque instability can be hypothesized. Immune-mediated inflammation may play a key role in the pathogenesis of COVID-19 and persistent anti-viral immune response may elicit an important hyperinflammatory response (like a cytokine storm) causing cells damage. Other suspected factors are the hypercoagulability and the development of coronary microvascular thrombosis [42], the diffuse endothelial injury and ‘endothelitis’ as a direct consequence of SARS-CoV-2 viral involvement and/or resulting from host inflammatory response [43], and, the same inflammation causing coronary plaque rupture.

Despite a widespread use of broad-spectrum antibacterials in COVID-19 patients [44], in the absence of documented cases of bacterial coinfections, preliminary data show that early administered antibiotics in COVID-19 patients do not seem to significantly affect mortality or delay hospital-acquired infections in critically ill patients [45]. Instead, anti-inflammatory interventions such as anticytokine therapy and colchicine have shown some efficacy in CAD. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) showed that reducing inflammation by administering an anti-IL-1 beta antibody in men and women who had a prior heart attack and residual inflammation despite standard-of-care therapy can reduce recurrent events [46, 47]. The anti-inflammatory therapy yielded a significant 15% reduction in the primary endpoint of “hard” major adverse cardiovascular events. Anticytokine therapy (IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids) and colchicine have been tested also for SARS-CoV-2 [48]. Further studies are needed to establish the efficacy of these drugs in COVID-19 patients.

According to Libby et al. [20], inflammation, immunity, and infection can contribute to atherogenesis or trigger atherosclerotic events without diminishing the role of classic risk factors; such factors should be rather considered as adjunctive to classic pathobiological processes than alternative (Fig. 1). COVID-19 patients are frequently characterized by increased inflammation, pro-thrombotic state, and coagulopathy with important interactions between these systems [49]. Also in COVID-19 infection, inflammation response and immunity can contribute to atherogenesis or trigger atherosclerotic events, making the pathobiological process very complex and perhaps causing variability in antithrombotic or anticoagulant therapy effect. Recently, growing interest in intestinal microflora in the cardiometabolic disease was reported [50, 51]. Bacteria in the gastrointestinal tract provides a rich source of bacterial products such as endotoxins. In cases of the impaired epithelial barrier, these bacterial products might convey into the circulation and provide another source of inflammatory stimuli. Gut microbiota is considered as an endocrine organ with metabolic capacity to produce multiple messengers that through circulation can reach distant districts. Recently, Carnevale et al. [52] hypothesized that, in particular, conditions (as in leaky gut), a penetration of LPS produced by Escherichia coli through the bloodstream into the coronary bed, where it may exert a thrombogenic effect, leading to the acute coronary syndrome.

Fig. 1

Infection, inflammation and immunity contribute to atherogenesis without replacement of traditional risk factors. Infection, inflammation and immunity contribute to atherogenesis or trigger atherosclerotic events without diminishing the role of classic risk factors but they are an addition to the classic pathobiological process than a replacement of the specific agents

Evidence synthesis

Infections are independent risk factors for venous thromboembolism and should be considered as potential indications for venous thromboembolism prophylaxis [53]. Microbial products, increased inflammation and pro-thrombotic state can promote the thromboembolism in several infections. While direct infection may not be a common driver of atherogenesis, remote infections and bacterial products from extra-vascular infections may promote atherosclerosis. Acute bacterial infections such as Gram-negative sepsis can precipitate type 2 acute coronary syndromes. Thrombotic complications due to increased inflammation, pro-thrombotic state, and endothelial dysfunction were detected in the novel disease (Covid-19) due to SARS-CoV-2 infection, responsible for the recent pandemic. Serious coagulation abnormalities may occur in several critically ill COVID-19 patients.

Conclusions

Infections may influence several diseases, either directly or indirectly, acutely or chronically. Pneumonia may accelerate the progression of atherosclerosis. In patients with pneumonia, increased rates in cardiovascular events and thrombosis have been demonstrated. A novel disease COVID-19 due to SARS-CoV-2 infection is characterized by coagulation abnormalities and inflammation with thrombotic and thromboembolism complications. Studies on the link between microorganisms or infections and thrombotic or thromboembolic events met fluctuating interest in the past. Looking back to what is known and what is currently discovered in SARS-CoV-2 infection, could be of help in the development of new therapies for the prevention of thrombotic complication in COVID-19.