Coronavirus disease-19 (COVID-19), caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a multi-system inflammatory disorder, which, in its severe form, is characterized by endothelial damage and hypercoagulability (1). Although the etiology of the arterial and venous thromboembolic events observed in 10-25% of patients admitted with SARS-CoV-2 infection (2) is still being debated, the role of the complex interactions between platelets, the endothelium and SARS-CoV-2 are increasingly recognized. COVID-19-associated thrombosis has been reported in many sites, such as the skin (3), respiratory tract (4, 5), brain (6), gastrointestinal tract (7) and extremities (8), but is particularly catastrophic when the heart is involved (9), especially in the context of a pro-atherosclerotic milieu.

From early on in our understanding of infection with this coronavirus, it has been recognized that underlying cardiac comorbid conditions are important risk factors for COVID-19 infection and that cardiac complications may occur, even in patients with no underlying cardiac disorders, as part of the acute infection. One of the early publications from Wuhan, describing 41 hospitalized cases with COVID-19 pneumonia, noted that 73% of the patients were men, with 32% having underlying co-morbidities, including hypertension in 15% and cardiovascular diseases in 15% (10). A number of complications were noted in the patients, including acute cardiac injury in 12%. Shortly thereafter, several reports confirmed that underlying cardiovascular co-morbidities, as well as cardiac complications due to acute COVID-19 infection, were associated with more severe disease and increased morbidity and mortality (11–16). From these collective publications, it was noted that the most common cardiac complication was acute cardiac injury, defined by significant elevation of cardiac troponins. The acute cardiac injury was secondary to a number of cardiac conditions, including acute myocardial infarction due to acute coronary syndrome (ACS), myocarditis, arrhythmias, and cardiomyopathy, while cardiogenic shock and cardiac arrest were also reported. Thromboembolic disease, both venous and arterial, was also described. The potential mechanisms of cardiovascular complications included direct viral myocardial injury, systemic inflammation induced by the virus, sepsis, arrhythmia, myocardial oxygen supply-demand mismatch, electrolyte abnormalities, and hypercoagulability (17–21). As was noted in 2020, despite many publications there remain many uncertainties regarding the origins of these cardiac complications (22).

The aim of the current manuscript is to review recent data on the clinical manifestations and mechanisms of acute cardiac involvement in patients with SARS-CoV-2 infection. We specifically address acute myocardial injury and ACS, and the potential mechanisms of these complications, especially with regard to the role of platelet-endothelium interactions, concentrating on publications that appeared mainly during 2020/2021.

While underlying cardiovascular comorbidities are a risk factor for COVID-19 infection and severity, the infection itself has the potential to cause a significant impact on the cardiovascular health of millions of people worldwide. The virus can infect the heart, as well as vascular tissue, circulating cells, and various organs, through its interaction with the ACE2 receptor, which it uses as a host cell receptor through its spike protein. It is, therefore, not surprising that cardiovascular events are a common extra-pulmonary manifestation of COVID-19 infection (extensively reviewed in 17 and 18). The potential cardiac manifestations of COVID-19 infection are shown in Table 1 , with the putative mechanisms depicted in Table 2 (17–21).

The cardiac manifestations that may occur during COVID-19 infection include acute cardiac injury, myocarditis, acute myocardial infarction (AMI), heart failure, arrhythmia, cardiomyopathy, hypotension, shock, and cardiac arrest (18, 23, 24). An echocardiographic study of patients with COVID-19 documented pre-existing abnormalities, which prompted the authors to suggest caution with regard to attributing such abnormalities to acute COVID-19 infection (25). Among the vascular complications documented are venous and arterial thrombotic events, which are associated with greater need for respiratory support, vasopressors, and hemodialysis, and a longer hospital stay (24, 26). Autopsy studies from patients who died from COVID-19 infection have demonstrated a range of cardiac abnormalities including cardiac hypertrophy and/or enlargement, ventricular dilatation, infarction, and fibrosis (24).

A number of investigators have shown the potential value of a range of cardiac biomarkers, including high sensitivity troponins (Tn; TnT and TnI), creatinine kinase isoenzyme-MB (CK-MB) and N-terminal pro-brain-type natriuretic peptide (BNP; NT-proBNP), either as early indicators of cardiac involvement in COVID-19 infections and/or as markers of disease prognosis (27–34), while measurement of D-dimers is thought to be potentially important in preventing, diagnosing and managing vascular complications (24).

The troponins TnT and TnI are known as the cardiac troponins, and act on cardiac muscle contraction by regulating the calcium-dependent interactions of actin and myosin (35). The CK component of CK-MB is an enzyme that catalyzes the reversible transformation of creatinine and ATP to creatinine phosphate and ADP (35). Lastly, BNP is a hormone produced by the heart, with both BNP and NT-proBNP being released in response to pressure changes within the heart (36). The former two biomarkers indicate myocardial injury, whereas the latter is a marker of hemodynamic stress (37).

In one systematic review and meta-analysis the pooled incidence of elevated levels of TnI, CK-MB and CK in COVID-19 cases were 15.16%, 10.92%, and 12.99%, respectively (38). Another detailed review indicated that troponin levels were elevated in 12% to 28% of cases with SARS-CoV-2 infection (18). While studies have indicated significant differences in biomarker levels in patients with differing COVID-19 infection severity, these levels also depended on whether the biomarkers were measured early on, or later, in the course of the infection (32, 38). Importantly, in COVID-19 cases, particularly those with underlying pre-existing cardiac disease, the prognostic cut-off values of these biomarkers may be lower than the reference standards (39). Furthermore, studies have shown that TnI, CKMB, and Pro-BNP are higher in non-survivors compared with survivors among critically ill patients with COVID-19 infection (28).

Lastly, it is important to be aware that cardiovascular sequelae can occur even in patients with mild COVID-19 infections, as well as in asymptomatic carriers of SARS-CoV-2 who may not even have been tested for this virus, and who may be at risk of developing cardiovascular disorders as bystander effects of the virus (40, 41). It remains essential to recognize and manage cardiovascular events during COVID-19 infection as soon as possible, as they are associated with worse outcomes (26, 42).

Platelets play an important role in the development of thrombo-inflammatory conditions and complications and are thus recognized as critical participants in the development of AMI (62). Platelet activation is a complex and multistep process (which is beyond the scope of the current review), principally mediated by specific platelet receptors that control adhesion and activation (62). Notable amongst these are the platelet collagen receptor: Fc receptor: γ-chain (FcR γ) co-expressed with glycoprotein (GP) VI. Patients with ACS have been reported to express higher numbers of GPVI receptors (63), have altered GPVI signaling (64) and an increased aggregation response (64).

Various platelet surface activation markers, such as CD62P (P-selectin), CD40L, platelet factor 4 and GP IIb/IIIa, as well as biological markers, primarily platelet micro-particles, have been associated with inflammation, atherosclerosis, and thrombosis (65). Platelet-monocyte aggregates, which persist in peripheral blood for longer than the surface markers and are therefore viewed as more sensitive markers of in vivo platelet activation (65), are an early marker of acute MI and have also been linked to myocardial no-reflow in STEMI patients (66, 67). Indirect markers of platelet activation, such as increased mean platelet volume (68), as well as higher levels of von Willebrand factor (69), and serotonin (70), have also been observed during acute MI.

In addition to expression of the low-affinity receptor for the Fc fragment of immunoglobulin G, which may promote viral entry, platelets also express TLR7, as mentioned above, which enables these cells to interact with viral single-stranded RNA (71, 72). Both of these mechanisms, as well as others (73), may contribute to viral persistence and hyperreactivity of platelets. In the case of ACE2, the major SARS-Cov-2 cell entry receptor and its associated transmembrane serine protease 2 (TMPRSS2), expression of this viral receptor and enzyme by platelets has been reported by some (74), but challenged by others (75). Because a direct role, if any, for the spike (S) protein of SARS-Cov-2 in mediating platelet hyperreactivity and thrombocytopenia in severe disease remains to be established, this section of the review is largely focused on severe COVID-19 that is associated with endothelial infection, activation and dysfunction as significant contributors to platelet overdrive and development of vascular disease.

Although platelets do not normally interact with intact vascular endothelium, they nevertheless play a critical role in maintaining vascular homeostasis via continuous monitoring of endothelial integrity. This is accomplished by preventing and repairing vascular leaks such as those associated with leukocyte extravasation (76). However, in the setting of the excessive endothelial activation and dysfunction that occur during serious SARS-CoV-2 infection, platelets acquire a more aggressive phenotype. Notwithstanding platelet activation mediated by thrombin and collagen, as well as autocrine activation by adenosine 5’-monophosphate and thromboxane A_2, this is augmented by interaction of platelet Toll-like receptor 7 (TLR7) with viral single stranded RNA. Platelet activation is characterized by increased expression of CD62P and tissue factor, as well as platelet/leukocyte aggregate formation, which contribute significantly to the pathogenesis of thrombotic disease (77–79).

In this setting, the interaction of platelets with stressed vascular endothelium involves most of the adhesive mechanisms that also maintain vascular homeostasis. However, the transition from homeostatic regulation to vascular disease is determined by the extent of endothelial dysfunction and the associated increase in the intensity and duration of platelet adhesion and activation that drives the recruitment of highly reactive neutrophils and monocytes.

Mechanisms that promote the adhesion of platelets to inflamed vascular endothelium are numerous and these have been extensively reviewed elsewhere (80, 81). Prominent among these are initial adhesive events that promote “rolling” of platelets along endothelium, particularly the interaction of the major platelet membrane receptor, GP1b (CD42)-1X-V with von Willebrand factor released from endothelial cells (ECs). This type of rolling action is reinforced by interactions that involve upregulated expression of CD62P, present on both cell types, with its counter receptor, P-selectin glycoprotein ligand-1 (PSGL-1), also expressed on both cell types, albeit weakly in the case of platelets (81).

Stabilization of platelet/EC interactions requires the cooperation of two key integrins and three endothelial-associated, pro-adhesive molecules. These are the integrins, α_IIbβ₃ and α_vβ_3, expressed on platelets and ECs, respectively, and the proteins, fibrinogen and fibronectin, as well as the glycoprotein, von Willebrand factor, which act as bridges linking the platelet and EC integrins to achieve firm binding. This is intensified via the fibrinogen-dependent interactions of α_IIbβ₃ with intercellular adhesion molecule-1 (ICAM-1; CD54) expressed on ECs, as well as by the association of EC-bound GP1b-IX-V/von Willebrand factor with platelet α_IIbβ₃ (81).

In addition to these platelet-endothelium interactions, other prominent mechanisms by which prolonged platelet activation poses risks to cardiovascular health include the following:

These platelet-driven inflammatory mechanisms are summarized in Table 3 .

In addition to the direct proinflammatory/prothrombotic and cytotoxic effects of the SARS-Cov-2 S protein on vascular endothelium, as well as impairment of the renin-angiotensin-aldosterone system (83), prolonged platelet activation in severe COVID-19 infection also amplifies endotheliopathy (89) In this context, a very recent study by Barrett et al. described potential mechanisms by which activated platelets exacerbate endothelial activation and damage (90). Using a strategy based on integration of endothelial cells and platelets isolated from patients hospitalized with COVID-19, transcriptomic analysis of mRNA expression extracted from endothelial cells exposed to platelet releasate revealed alterations in processes involved in maintenance of tight junction barrier integrity, coagulation and inflammation, characteristic of an “inflammatory, hypercoaguable phenotype” (90).

Systematic genetic analysis enabled the authors to identify the genes encoding the calcium-binding proteins, SA100A8 and SA100A9, also known as myeloid-related proteins (MRP) 8 and 14, respectively, as being the most prominent platelet-derived mediators of endothelial activation. These proteins are stored in platelet granules and dimerize to form the potent, proinflammatory protein, calprotectin (MRP8/14). Interacting with CD36 on vascular endothelium, calprotectin weakens cell-cell interactions and initiates release of the proinflammatory cytokines, IL-6, and IL-8 (90–92).

Importantly, the systemic levels of MRP8/14 were found to be significantly higher in the cohort of patients hospitalized with COVID-19 relative to those of control subjects and were associated with development of thrombosis and other adverse events (90).

Very recently, Bye et al. described another mechanism operative in patients with severe COVID-19 by which platelets may augment endothelial activation and dysfunction (93). In this setting, platelets that have adhered to SARS-CoV-2-infected endothelial cells via von Willebrand factor make contact with surface-bound immune complexes formed between the S protein and heavily Fc region-galactosylated immunoglobulin G antibodies, which effectively bind to and activate the platelet FcγRIIA receptor (93).

Notwithstanding the involvement of cells of the innate and adaptive immune systems, there is increasing recognition of the key role played by the vascular endothelium in the development of the prothrombotic state and hypercoagulability that precede the occurrence of arterial and venous complications in patients with severe SARS-CoV-2 infection, particularly those with preexisting, procoagulant tendencies (94–97). Of the 29 SARS-CoV-2 proteins, it is the S protein in particular and, to a lesser extent, the nucleocapsid protein (NP) that drive virus-mediated endothelial damage. Of these two viral proteins, the former is cytotoxic, causing loss of endothelial structural integrity, while the latter induces a proinflammatory endothelial phenotype. Importantly, ECs do not express TLR7, excluding putative proinflammatory interactions with viral single-stranded RNA (98).

Endothelial damage precedes the adhesion and activation of platelets, neutrophils, and monocytes. This event, in turn, results in the development of a procoagulant state due to the loss of EC-derived anti-coagulant proteins such as thrombomodulin and anti-thrombin III, as well as the prostanoid, prostacyclin. These procoagulant mechanisms are intensified, in turn, by potentiation of platelet activation via endothelial leakage of von Willebrand factor and by increased synthesis and expression of tissue factor by ECs. Inflammatory events that occur on an essentially intact endothelium in the setting of a low shear stress predispose for the development of venous thrombosis (114). In the case of arterial thrombosis, disruption of the endothelial barrier in the setting of high shear stress, exposure of the sub-endothelial extracellular matrix, platelet accumulation, and, in particular, the existence of a pre-atherosclerotic milieu, are likely to predispose for development of MI and stroke. These processes are depicted in Figure 1 .

COVID-19 is a systemic disease affecting various systems, including the cardiovascular system, where it leads to significant mortality. While our understanding of the pathogenesis of COVID-19 and associated complications is evolving, evidence is emerging about the very important role of platelets per se together with endotheliitis and its attendant role in platelet recruitment and activation. These events create a SARS-CoV-2-driven cycle of intravascular inflammation and coagulation, which contributes significantly to a poor clinical outcome in patients with severe disease. Clearly, the role of platelet-endothelium interactions in the pathogenesis of COVID-19 needs further intense exploration to enable optimization of the treatment of the infection and its complications with the ultimate goal of improving outcomes.

TR, RA, and CF contributed equally to the conceptualization and compilation of the manuscript, while all four authors (TR, RA, PM, and CF) were involved in reviewing and finalizing the manuscript and approved its submission. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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