Thromboembolic Disease and Cardiac Thrombotic Complication in COVID-19: A Systematic Review

Abstract

The coronavirus 2019 pandemic has affected many healthcare systems worldwide. While acute respiratory distress syndrome (ARDS) has been well-documented in COVID-19, there are several cardiovascular complications, such as myocardial infarction, ischaemic stroke, and pulmonary embolism, leading to disability and death. The link between COVID-19 and increasing thrombogenicity potentially occurs due to numerous different metabolic mechanisms, ranging from endothelial damage for direct virus infection, associated excessive formation of neutrophil extracellular traps (NETs), pathogenic activation of the renin-angiotensin-aldosterone system (RAAS), direct myocardial injury, and ischemia induced by respiratory failure, all of which have measurable biomarkers. A search was performed by interrogating three databases (MEDLINE; MEDLINE In-Process and Other Non-Indexed Citations, and EMBASE). Evidence from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were evaluated for the processing of the algorithm and treatment of thromboembolic disease and cardiac thrombotic complications related to COVID-19 during SARS-CoV-2 infection. Studies out with the SARS-Cov-2 infection period and case reports were excluded. A total of 58 studies were included in this analysis. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining thromboembolic disease and cardiac thrombotic complication in COVID-19. Some of the mechanisms of activation of these pathways, alongside the involved biomarkers noted in previous studies, are highlighted. Inflammatory response led to thromboembolic disease and cardiac thrombotic complications in COVID-19. NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, thromboembolic complications in COVID-19 remain an entity that substantially impacts the health care system, with long-term effects that remain uncertain. Continuous monitoring and research are required.

Keywords: COVID-19; SARS-CoV-2 infection; coronary artery thrombosis; neutrophil extracellular traps (NETs).

Figure 1

SARS-CoV-2 has spread with dissimilarity rates of the infection among population, and it has been characterized by distinct case fatality rates, across various regions and countries. Inflammatory response, increased age, and bedridden status, which are more frequently observed in severe coronavirus disease 2019 (COVID-19), may contribute to thrombosis and adverse outcomes. Abbreviations: CTC, cardiac thrombotic complication; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; TED, thromboembolic disease.

Figure 2

PRISMA 2020 flow diagram.

Figure 3

Patients who are infected with SARS-CoV-2 and develop COVID-19 experience consistent hemostatic abnormalities, of which, the most relevant comprise mild thrombocytopenia and increased D-dimer levels, which are related with a greater risk of demanding the benefit of mechanical ventilation, intensive care unit (ICU) admission, or death. Disease gravity may reveal variability of the modification of other coagulative parameters, such as a prolongation of the PT, international, and TT. The increased troponin level is associated with higher risk of STEMI and death. Abbreviations ICU, intensive care unit; PT, prothrombin time; TT, thrombin time. Ref [9,10,11,17,27,28,30,35,36,39,42,43,44,45,46,67,75,76,79,80,90,91].

Figure 4

Depicts the potential intersection of acute and chronic phases of COVID-19 and risk of heart failure with preserved ejection fraction. Population at higher risk of infection and development of disease may experience an acute illness or progression toward a long-term illness. Direct viral infiltration or indirect inflammatory response, as well as adverse cardiac remodelling, can lead to chronic heart and pulmonary disease. Abbreviations: COVID-19 indicates coronavirus disease 2019; IL: interleukine; HF, heart failure; LDH, lactate dehydrogenase; PAI-1, plasminogen activator inhibitor 1; TNF, tumor necrosis factor.

Figure 5

Depiction of the interaction between antiviral medicaments and antiplatelet drugs on CYP3A4 metabolism. In the marked red box, antiviral agents are represented. Lopinavir and ritonavir drive an inhibitory action on the cytochrome. This activity may increase the exposure of ticagrelor (marked yellow box), leading to a dysregulation of hemostasis (highlighted in the picture being the only depicted potential effect). Conversely, remdesivir (marked red box) is an inducer of CYP3A4 function. Differently from ticagrelor, prasugrel (marked yellow box) is metabolized by several cytochromes (2C19, 2C9, 3A4/3A5, 2B6, and 2D6), thus its effects seem to be unmodified by ritonavir or lopinavir interaction. Abbreviations: CYP3A4: cytochrome P450 3A4, ADP P2Y12 receptor: adenosine 5′diphosphate P2Y12 receptor.

Figure 6

The acute clinical manifestations of COVID-19 are well-characterized by inflammatory response, endothelial dysfunction and overlapping infection that can evolve into major arterial and venous thromboembolism, major adverse cardiac event, and symptomatic venous thromboembolism. In COVID, heart condition patients may reveal a range of increased cardiovascular risks. Abbreviations: COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory syndrome-coronavirus-2.