Peculiarities of in-Stent Thrombosis and Restenosis in Coronary Arteries Post-COVID-19: A Systematic Review of Clinical Cases and Case Series

Introduction

Percutaneous coronary interventions (PCI) are currently the most common invasive method of medical care for acute coronary syndrome. More than five million such interventions were performed worldwide in 2019.¹ One of the most dangerous complications of coronary stenting is restenosis and in-stent thrombosis; their prevalence reaches 20–25%.² This is a major challenge to healthcare systems around the world, as it leads to an increase in mortality rates from myocardial infarction.³

The introduction of drug-eluting stents reduced the incidence of thrombotic complications and coronary restenosis up to 2–10% of cases of percutaneous coronary intervention. In the case of stent restenosis, even reimplantation with a drug-eluting stent can lead to its complete occlusion in 15% of cases during the first year.^4,5

Complete or partial in-stent occlusion of the coronary artery in the long term can be caused by thrombosis, restenosis, and newly developed atherosclerosis. Restenosis that develops up to one year is associated with the proliferation and migration of vascular smooth muscle cells, leading to the formation of neointimal hyperplasia. The development of neoatherosclerosis in the stent walls is considered as the main factor responsible for the development of both restenosis and thrombosis for more than a one year after stent implantation.⁶

One of the important factors influencing the formation of restenosis and thrombosis is systemic or infectious inflammation, which can damage the endothelium of the vessel, the plaques and trigger hypercoagulation mechanisms with development of prothrombotic effect. In recent years, the situation has become largely complicated due to the coronavirus pandemic.

COVID-19 is characterized by the ability to cause acute myocardial damage, endothelial dysfunction and thrombus formation.⁷ Despite the fact that the WHO officially announced the end of the pandemic in May 2023, this problem has not lost its relevance, since even in December 2023; peaks in the incidence of COVID-19 of more than 300 thousand cases per day were observed worldwide.⁸ Epidemiological data suggest the emergence of new SARS-CoV-2 variants, which are impacting disease transmission and severity. COVID-19 is characterized by prolonged symptomatic illness (shortness of breath, fatigue, and muscle weakness) lasting several months after initial infection (long COVID). The appearance of new variants may also have a detrimental impact on long COVID-19, with additional associated morbidity and mortality.⁹ In 2024, according to the Infectious Diseases Society of America (IDSA), cases of new variants have increased sharply in the United Kingdom, South Korea, and New Zealand, raising concerns about a new wave of COVID-19.¹⁰ This demonstrates the dynamic nature of the COVID-19 pandemic and emphases the importance of ongoing monitoring and research.

The aim of the systematic review is to evaluate the association between COVID-19 and in-stent thrombosis and restenosis of the coronary arteries in patients with CAD based on the analysis of clinical cases and case series.

Current Concepts of Stent Thrombosis

According to the Academic Research Consortium classification (2006), stent thrombosis is divided into acute (up to 24 hours after previous stenting), subacute (more than 24 hours to 30 days), late (more than 30 days to 1 year), and very late (more than 1 year after previous stenting).^11,12 According to the clinical course, the following types are distinguished: 1) definite (angiographically confirmed) stent thrombosis, when the symptoms correspond to acute coronary syndrome (ACS); 2) probable stent thrombosis, when sudden cardiac death or myocardial infarction is observed in the territory of the stented vessel within 30 days after stenting without angiographic confirmation; 3) possible stent thrombosis, when unexplained death occurs a month or more after stent implantation.¹²

The incidence of stent thrombosis in recent years has tended to decrease due to the use of more effective double and triple antiplatelet therapy;¹³ their frequency ranges from 1 to 4% of all cases of coronary artery stenting.¹⁴ However, despite the rarity of this complication, stent thrombosis is often a catastrophic event associated with complete occlusion of the lumen and the need for a rapid decision on repeated revascularization.^15–17 In the case of multivascular lesions, stent thrombosis rates reached 3%.¹⁸ Almost all cases of stent thrombosis occur within the first month after stenting.¹⁹

Pathogenetic Mechanisms of Restenosis of Coronary Arteries

In-stent restenosis is a decrease in vessel lumen after percutaneous coronary intervention, angiographically defined as a decrease in stent patency by 50% or more.^20–22 One of the well-studied risk factors for in-stent restenosis is chronic kidney disease (CKD). The main pathogenetic mechanism is vascular calcification due to the transdifferentiation of arterial smooth muscle cells.^23,24 It leads to increased stiffness, which makes it difficult to deploy the stent and inflate the balloon. Incomplete deployment of the stent causes disruption of blood flow associated with an inflammatory reaction, accumulation of cytokines and growth factors, thrombus formation and adhesion of leukocytes, expression of endothelial genes, which can subsequently cause neointimal growth.²⁵ Violation of the integrity of the stent structure is also caused by the increased rigidity of the vascular wall. Trauma to a vessel by such a stent is accompanied by local inflammation, subintimal hemorrhages, exposure of the endothelium, release of the drug from the stent coating, activation of vascular smooth muscle cells through excessive proliferation and migration, and, ultimately, hyperplasia of neointimal tissue. Stent fractures occur in 2.6–2.9% of all stenting cases; in such situation, restenosis develops up to 50%.^26–28 In the case of bare-metal stenting, a predictor of stent restenosis can be an increased level of C-reactive peptide, as well as matrix metalloproteinase (MMP) and plasminogen activator inhibitor (PAI-1).^29,30

Vitamin D deficiency may increase the expression of endothelin, tissue factor, and epidermal growth factor by smooth muscle cells, which is accompanied by increased smooth muscle cell migration and accelerated atherosclerotic plaque growth.³¹

All risk factors for coronary artery stent thrombosis can be divided:¹⁴

The Role of Coronavirus Infection in the Development of in-Stent Thrombosis and Restenosis

The coronavirus pandemic has contributed to our understanding of the risk factors for in-stent thrombosis and restenosis.^32,33 Studies by Chinese scientists demonstrate that acute inflammatory myocardial damage is typical for 17–19.7% cases of COVID-19. Acute myocardial damage during COVID-19 is not always accompanied by ischemic manifestations; however, the level of cardiac markers was increased in all cases.^34–36 Among people with COVID-19 being treated in intensive care units, the proportion of patients with elevated troponin levels reached 25%.³⁷

Despite a pronounced decrease in rates of myocardial revascularization during the pandemic,³⁸ the rate of in-stent thrombus formation even increased to 8.1–21%.³⁹ In the UK in 2018–2019, myocardial revascularization rates were consistently between 7000 and 8000 per month. In March 2020, during the first peak of COVID-19, the PCI rate dropped to 4,400 cases. In 2021–2022 there was an increase in cases of emergency medical care with a delay of more than 150 minutes - only 55% of patients received care on time.⁴⁰ These data are correspond with the results of another study, which showed that hospitalization of patients with MI in 2020–2021 decreased by more than 20%. There was an increase in mortality after PCI during the coronavirus pandemic by 10%.⁴¹ During the COVID-19 pandemic, 2.2% of patients had a preoperative diagnosis of coronavirus infection (CVI).⁴² The patients had an increased risk of postoperative mortality compared to patients without CVI⁴³ because CVI can cause direct damage to the heart muscle.^44,45

In the countries and regions with high population density, where there were problems with transporting patients, the strategy of primary thrombolysis was preferred.⁴⁶ However, professional societies have recommended PCI as the primary treatment option even during the COVID-19 pandemic.⁴⁷ Elective surgery should be postponed until complete recovery and compensation of concomitant diseases, since the risks of postoperative complications persist for up to 8 weeks.⁴⁸ Interventions should be delayed for at least 7 weeks after COVID-19 in patients who have not received vaccination.⁴⁹

Pathogenesis of Thrombosis Associated with Coronavirus Infection

The basis for increased thrombus formation during coronavirus infection is an acute systemic inflammatory response, characterized by increased synthesis of inflammatory mediators because of an imbalance in T-cell activation with dysregulation of the release of interleukin (IL)-6, IL-17 and other cytokines. Activation of platelets after inflammatory damage to the vascular endothelium leads to increased synthesis of thromboxane A, thrombin and adenosine diphosphate (ADP), followed by calcium-dependent activation of the process of platelet aggregation and their adhesion to the endothelium of the damaged vessel and among themselves. These processes enhance the prothrombotic environment and increase the risk of thrombosis. An increase in the level of tissue thromboplastin leads to an increase in the level of thrombin and fibrin synthesis with the possible development of disseminated intravascular coagulation syndrome.^50,51 Inflammatory process can lead to plaque rupture, thrombus formation, and risk of local microthromboembolism with subsequent impairment of perfusion or reperfusion in the case of coronary artery stenting.^52,53 The mechanisms of thrombus formation during coronavirus infection are shown schematically in Figure 1.

Figure 1 Pathogenesis of in-stent thrombus formation associated with COVID-19.

Materials and Methods

Protocol and Registration

The protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P)⁵⁴ and registered in PROSPERO (ID: CRD42024506976).

Information Sources and Search Strategy

We performed a comprehensive literature search for relevant publications describing cases and case series of restenosis and stent thrombosis associated with coronavirus infection in the PubMed/MEDLINE, EMBASE, Cochrane databases, Scopus, Web of Science, and Google Scholar databases, including case reports published during the period from 2020 to present. Medical Subject Headings (MeSH) were used, including the following keywords: “COVID-19” OR “coronavirus 2019” OR “in-stent thrombosis” OR “in-stent restenosis” OR “thrombosis of coronary stents” AND “case reports” OR “case series”. Additionally, a manual search of reference lists from retrieved articles and relevant journals was performed.

We have selected publications in English that are available in full text. Brief reports and newspaper publications will be excluded. For inclusion, we will independently screen titles and abstracts of publications, and any discrepancies will be resolved by consensus.

Based on the detailed search strategy, the specific research question for this systematic review was “How does COVID-19 impact on formation of in-stent thrombosis and restenosis of coronary artery in the patients with coronary artery disease?”

Eligibility Criteria

Inclusion Criteria

Studies needed to be available as full-text articles and only in the English language. The target studies were case reports and case series included adult patients with in-stent thrombosis or restenosis associated with COVID-19.

Exclusion Criteria

Exclusion criteria: non-English articles, non-original articles, duplicate publications (risk of bias), articles without complete demographic information of each patient, editorial letters, review articles, and case reports and case series included patients with stenosis and thrombosis of the coronary arteries but not in-stent thrombosis or restenosis associated with COVID-19.

Data Extraction

The screening process involved the independent evaluation of titles and/or abstracts retrieved through the designated search strategy and additional sources. Data extracted included authors and year of publication, studied peoples, age, gender and study design; methods of PCI. Two review authors meticulously assessed these documents to identify studies potentially meeting the predefined inclusion criteria. Subsequently, the full texts of these potentially eligible studies were obtained and independently scrutinized for eligibility by two members of the review team. Any disagreements regarding the eligibility of specific studies were resolved through discussion involving a third reviewer. In instances of missing data, efforts were made to obtain the necessary information from the other study authors.

Methodological Assessment of Study Quality

The recommended Newcastle Ottawa Scale modification⁵⁵ checklist was used to assess the quality in all identified and collected full-text articles included in this study. The quality of the included studies was assessed independently by two authors (L.P. and G.B). The scale consists of eight items categorized into four domains: selection, assurance, causality and reporting. Given that Q5 and Q6 are related to the effects of drugs, we excluded them from the analysis of study quality. We rated the case report studies as high quality if there were six positive characteristics (7 studies), five studies were rated as moderate in quality (4 positive characteristics), and three studies were rated as low quality (3 to 1 positive characteristics) (Table 1). To assess the quality of case series studies, we applied the same scale. We rated two of the three studies as high quality and one study as moderate quality (Table 2).

Table 1 Quality Assessment of Included Cases of in-Stent Thrombosis and Stenosis of Coronary Arteries Associated with COVID-19

Table 2 Quality Assessment of Included Case Series of in-Stent Thrombosis and Stenosis of Coronary Arteries Associated with COVID-19

Risk of Bias Assessments

Studies that met the inclusion criteria were assessed using The Joanna Briggs Institute Critical Appraisal tools for use in JBI Systemtic Reviews Checklist for Case Reports and Checklist for Case Series.^73,74 The tool focuses on method selection, sufficient demographics, presentation, diagnosis, and proper intervention. The Case Report Studies scoring from six to eight were considered as a “high quality” (eight studies), scoring from four to five were a “moderate quality” (four studies), and scores of ≤3 were estimated as a “low quality” (three studies) (Table 3). When assessing the risk of bias in Case Series Studies, we classified two studies as high-quality (9–10 positive answers out of 10 questions) and one study as low-quality (4 positive answers) (Table 4).

Table 3 Risk of Bias Assessment for Included Case Reports for in-Stent Thrombosis and Stenosis of Coronary Arteries Associated with COVID-19

Table 4 Risk of Bias Assessment for Included Case Series of in-Stent Thrombosis and Stenosis of Coronary Arteries Associated with COVID-19

Data Analysis

We used tabulation and analysis, which reflected the characteristics of the included studies (age and sex, data about COVID-19, Chest X-Ray, SpO2, previous revascularization, current revascularization, coronary angiography, EhoCG (EF), ECG, risk factors, outcomes).

Statistical tests to assess heterogeneity, including the χ²-test and the I² statistic, demonstrated a high degree of heterogeneity among the publications included in the studies. This fact did not allow us to conduct a qualitative meta-analysis of the results.

Results

Search of Literature

We used the “The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)” checklist to write the systematic review. A total of 38 full-text publications were found in the databases, which were manually screened to select relevant publications and further analyze them (Figure 2).

Figure 2 PRISMA flow diagram.

Twenty publications were excluded from the analysis because they related to thrombosis of non-coronary arteries (5 cases), or they did not contain information about COVID-19 (1 case) or the patients did not have prior revascularization before the current in-stent thrombosis or restenosis (12 cases) or stent thrombosis was associated with vaccination against coronavirus infection (2 cases). After screening, a total of 18 publications remained for further analysis. As a result of assessing the quality of publications and the risk of bias, we selected 10 high-quality publications (8 cases and 2 case series) for further synthesis.

Characteristics of Cases of in-Stents Thrombosis and Restenosis Associated with Coronavirus Infection

After assessing the quality of publications and the risk of errors, we selected 10 articles from scientific literature describing cases of thrombosis and restenosis of stents in individuals with coronavirus infection, of which only 2 publications were case series (from 4 to 10 cases) (Tables 5 and 6). 31.8% of people included in the study were aged from 40 to 59 years, 68.2% were over 60 years old. All patients were admitted to emergency departments with clinical signs of ACS or MI (typical chest pain, hemodynamic instability, shortness of breath). Most of the cases presented were thrombotic lesions of coronary stents due to the current coronavirus infection; only in seven cases, we encountered restenosis of previously implanted stents.

Table 5 Characteristics of Included Case Report Studies

Table 6 Characteristics of Included Case Series Studies

In the structure of restenosis and thrombosis, 59.1% (13 cases) were very late (more than one year from previous revascularization), 9.1% (2 cases) were late (from one month to one year from revascularization); 18.2% (4 cases) were considered as subacute events (from one day to one month) and 13.6% (3 cases) as acute events (within 24 hours from previous revascularization). All cases presented in this article were classified as definite because they were angiographically confirmed.

In one patient, a previous case of revascularization had undergone CABG, and given the bypass occlusion, LAD stenting was performed. In another case, stenting was previously performed, and now, due to the multivessel disease of the coronary arteries, emergency CABG was performed. In the remaining cases, repeated stenting of the affected vessel was observed, followed by balloon dilation and thrombus aspiration in case of arterial thrombosis.

The main localization of restenosis or thrombosis was the left coronary artery (13 cases or 51.1%), thrombosis of the right coronary artery occurred in six cases (27.3%), thrombosis of the circumflex artery - in five cases (22.7%). The left marginal artery had thrombotic lesions in only one case (4.5%).

All patients had a current or previous COVID-19, confirmed by PCR test or the immunoglobulins G and M. In 12 patients (54.5%), an X-ray examination showed bilateral polysegmental infiltration, corresponding to imagine of COVID-19 associated pneumonia; in other cases, the patients were asymptomatic or had mild symptoms of coronavirus infection.

Most patients had a significant decrease in left ventricular ejection fraction (18 cases or 81.8%). In addition to angiography, acute coronary syndrome or MI were confirmed by ECG data. Additional risk factors for in-stent restenosis and thrombosis of the coronary arteries were arterial hypertension (72.7%), type 2 diabetes mellitus (45.5%), hyperlipidemia (13.6%), hypothyroidism (4.5%), chronic kidney disease (18 0.2%), and previous strokes (13.6%).

Considering the cases of deceased patients (5 cases), it can be noted that two of them were aged 48–51 years. Four patients had diabetes mellitus as risk factors, and all patients suffered from hypertension. Four patients had symptoms of severe COVID-19 infection with bilateral polysegmental pneumonia and signs of acute respiratory distress syndrome characterized by low oxygen saturation; two of them developed sepsis with acute kidney injury due to bacterial superinfection. The remaining patients did not have pronounced symptoms of coronavirus infection, but a positive PCR result gave grounds to conclude that coronavirus infection could act as a trigger factor for launching the coagulation cascade, leading to acute or subacute stent thrombosis. All patients experienced severe hemodynamic disturbances with the development of cardiogenic shock and fatal arrhythmias leading to death. In three out of five cases, acute or subacute stent thrombosis was observed.

Discussion

Research data indicate that the main risk factors for late and very late thrombosis of coronary artery stents are diabetes mellitus, multivessel disease requiring implantation of more than two stents, acute myocardial infarction, CKD, implantation of a sirolimus-eluting stent, impaired dilation after PCI, as well as bad adherence to antiplatelet therapy.⁷⁵

Analysis of the cases that we reviewed allows us to consider systemic infectious inflammation with the release of inflammatory mediators, such as cytokines (interleukin 6, tumor necrosis factor), as a factor that can cause endothelial damage and trigger the coagulation cascade. One of the key biochemical processes in COVID-19 is the interaction between the viral spike protein and the ACE2 receptor on host cells. This interaction allows the virus to enter host cells and replicate, leading to virus spread and disease progression. In addition, the virus causes a pro-inflammatory response through the activation of various immune cells, which leads to the release of cytokines and tissue damage.^76,77 A study conducted by Chinese scientists showed that in people hospitalized due to COVID-19 associated pneumonia, coagulopathies occurred in 19%, heart failure in 23%, and acute cardiac injury in 17%. Among the deceased, coagulopathies were found in 50%, heart failure - in 52% of cases, acute cardiac injury - in 59%. The main risk factors for mortality in these patients were diabetes mellitus (OR=2.85), arterial hypertension (OR=3.05) and smoking (OR=2.23).³⁵

All of the described patients had a coronary history before CVI, they were all prescribed dual antiplatelet therapy (aspirin and a P2Y12 receptor inhibitor), and they demonstrated good adherence to treatment. However, against the background of a viral infection, despite correctly prescribed antiplatelet therapy and additional prescription of anticoagulants (heparin, unfractionated and low molecular weight heparins) progression of the thrombus formation process was noted. This progression can also be explained by the development of heparin resistance, which some authors discussed previously.^78,79 On the other hand, concomitant use of antiviral drugs with direct oral anticoagulants may increase the risk of bleeding. This effect is caused by the inhibition of cytochrome isoenzymes by antiviral drugs, which disrupts the metabolism of anticoagulants and increases their concentrations in the blood.^80,81

A limitation of our study is the lack of information about anamnestic data, as well as laboratory parameters indicating both the severity of systemic inflammation and the lipid spectrum, coagulation activity, bacterial superinfection, and the state of immunity in patients in the cases we examined. This shortage can be explained by the limited time and resources during the initial period of the coronavirus pandemic, which caused a slowdown in hospitalization and medical care in catheterization laboratories, as well as the urgency of the situation in patients with ACS or MI. In the current literature, we could only find case study designs and case series. These studies were characterized by a high degree of heterogeneity, making statistical analysis and meta-analysis of the results impossible.

Conclusion

In the structure of restenosis and thrombosis, 75% of cases were late and very late events, only 6.25% occurred within 24 hours of the previous revascularization. The main localization of restenosis or thrombosis was the left coronary artery (71.9%). Risk factors for restenosis and thrombosis of the coronary arteries were arterial hypertension (56.25%), type 2 diabetes mellitus (37.5%), smoking (12.5%), hyperlipidemia (9.4%), hypothyroidism (6.25%), chronic kidney disease (12.5%), severe obesity (6.25%), and previous strokes (9.4%). Analysis of cases allows us to consider systemic infectious inflammation as a factor capable of causing endothelial damage and triggering the coagulation cascade. Considering that COVID-19 continues to infect the residents of all countries up to present time, special attention should be paid to persons suffering from coronary heart disease who have undergone revascularization. Since this category of patients has an increased risk of complications, in case of COVID-19 infection they should be provided with access to the fastest possible examination of the cardiovascular system (ECG, EchoCG, laboratory tests), coronary angiography and confirmation of coronavirus infection (PCR test, study of immunoglobulins G and M). It is necessary to monitor the adherence of such patients to antiplatelet therapy and inform them about the risks associated with COVID-19. To more accurately determine the relationship between coronavirus infection and restenosis and stent thrombosis, it is necessary to continue clinical studies on large groups of patients using thematic registers and databases.