key: cord-284910-vjcrhwqz
authors: Kirresh, Ali; Coghlan, Gerry; Candilio, Luciano
title: COVID-19 infection and high intracoronary thrombus burden
date: 2020-07-30
journal: Cardiovasc Revasc Med
DOI: 10.1016/j.carrev.2020.07.032
sha: 
doc_id: 284910
cord_uid: vjcrhwqz

Abstract Coronavirus 2019 (COVID-19) is an acute respiratory disease that has rapidly spread around the world and been declared a global pandemic by the World Health Organization. Emerging evidence demonstrates a strong association with a pro-thrombotic state and we present the first patient admitted with COVID-19 and an inferior ST-segment elevation myocardial infarction (STEMI) with evidence of high intracoronary thrombus burden. We review the mechanism of the high thrombus burden, which may be driven by the significant cytokine storm, endothelial dysfunction, increase risk of coronary plaque rupture and hypercoagulability.

Coronavirus 2019 (COVID-19) is an acute disease that primarily targets the respiratory system (1) . However, mounting evidence suggests that cardiac involvement is common, particularly in hospitalized patients, with a substantial increase in morbidity and mortality (1, 2) . A meta-analysis of six studies from China, including 1527 patients with COVID-19 found an overall mortality rate of 2.3% with a higher risk in patients with hypertension (6%), diabetes (7.3%), and cardiovascular disease (10.5%) (2) . Emerging research has also demonstrated a pro-thrombotic state with various presentations including acute cerebral infarctions (3), venous sinus thrombosis (4), pulmonary embolism (5) and deep vein thrombosis (6). We present the first patient admitted with inferior ST-segment elevation myocardial infarction (STEMI) with evidence of high intracoronary thrombus burden and provide a review of potential underlying mechanisms.

A 43 year old Caucasian male attended the Emergency Department with a one week history of fever, dry cough and breathlessness. He was an ex-smoker with a ten pack year history and well controlled asthma. On examination he had widespread crepitations bilaterally with a respiratory rate of 40/min and oxygen saturations of At this point the patient developed complete heart block with a rate of 30 beats per minute and therefore a temporary pacing wire was inserted. The blood pressure was 80/60mmHg which was being augmented with metaraminol boluses and following discussion within the team, it was decided to stop the procedure at this stage and continue with systemic gpIIb/IIIa infusion. Whilst still in the catheterization laboratory the patient became more hypoxic and sustained a second PEA arrest. A focused transthoracic echocardiogram showed no evidence of pericardial effusion. Several cycles of CPR were attempted to no avail and unfortunately the patient passed away. Subsequently, it was confirmed that the patient's nasopharyngeal swab was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by realtime reverse-transcriptase-polymerase-chain-reaction assay.

The outbreak of COVID-19 occurred in December 2019, in Wuhan, Hubei, China and it has spread rapidly around the world and been declared a global pandemic by the World Health Organization (1). Severe COVID-19 has been defined as respiratory distress with a respiratory rate more than 30 per minute, oxygen saturations ≤ 93% at rest or a PaO2/FiO2 ≤ 300 mmHg (1). However, research has also demonstrated an associated pro-thrombotic state resulting in an increased risk of death (7).

There are emerging theories regarding the mechanism of increased thrombus burden seen in COVID-19, central to which seems to be a significant proinflammatory state (8). This stems from the excess production of inflammatory cytokines tumor necrosis factor, interleukin (IL)-6 and IL-1β resulting in a cytokine storm which ultimately leads to activation of coagulation pathways, vascular hyperpermeability, multi-organ failure and an increased risk of death (9, 10). One of the central components in this is thrombin, which usually promotes clot formation by activating platelets and converting fibrinogen to fibrin (11). Thrombin generation is regulated by feedback loops and physiological anticoagulants, such as antithrombin III, tissue factor pathway inhibitor, and the protein C system (11). During inflammation these mechanisms can become dysfunctional, with reduced anticoagulant concentrations due to diminished production and increased demand.

This predisposes to the development of thrombosis, disseminated intravascular coagulation, and multiorgan failure (8, 12).

Furthermore, the circulating cytokines may also lead to atherosclerotic plaque instability and rupture (13) . Systemic inflammation as well as increased shear stress due to increased coronary blood flow can precipitate plaque rupture resulting in acute myocardial infarction (13) . In related viral studies, the influenza virus induced J o u r n a l P r e -p r o o f acute arterial wall inflammation that was associated with plaque destabilization (14) .

Limited evidence also shows that the SARS coronavirus may also be associated with an increased risk of plaque instability (15) . Plaque rupture results in an increase in tissue factor (TF), collagen and platelet activation causing increased fibrin production and a higher thrombus burden (16) . . Indeed, endothelial dysfunction has previously been associated with a high coronary thrombus burden (20) . Intact endothelium typically prevents the formation of thrombi, but endothelial dysfunction or injury exposes the intima which interacts with and activates platelets and induces early pathological processes such as inflammation and thrombosis (20) . The degree J o u r n a l P r e -p r o o f of endothelial injury has been shown to correlate positively with thrombus burden (21) .

Anti-phospholipid antibodies have also been detected in patients with COVID-19 (22) . The mechanism by which these antibodies create the conditions for thrombosis is not fully understood but is thought to depend upon two hits. The first is antiphospholipid antibodies binding to endothelial cells inducing a pro-coagulant and pro-inflammatory phenotype and promoting platelet aggregation. A second hit such as that caused by infection, results in complement activation and this is thought to cause thrombus formation (23) . Therefore, the conditions seen in COVID-19 would Interestingly, bleeding risk in those receiving anticoagulation was no different to those not on anticoagulation (3% vs 1.9%, respectively, p = 0.2) (30). However, there was an observed increased risk of bleeding events amongst patients requiring mechanical ventilation compared to those not ventilated (7.5% vs 1.35%) (30) . It should be noted that direct oral anticoagulants have been associated with an increased risk of major bleeding compared to low molecular weight heparin (LMWH) (relative risk 1.70; 95% CI, 1.02-2.82) and therefore LMWH should be prescribed in inpatients with COVID-19 (31) . Thrombosis guidelines are under continuous review with current recommendations supporting the routine prescription of thromboprophylaxis for all patients, unless contraindicated (27, 28).

To the best of our knowledge this is the first case that reports an association between increased coronary thrombus and COVID-19. In our case, despite multiple runs with an aspiration catheter and aggressive intracoronary and systemic pharmacotherapy we were unable to reduce the clot burden and re-establish J o u r n a l P r e -p r o o f coronary flow reflecting the challenge in this patient group. High thrombus burden in myocardial infarction is a real challenge and has an increased risk of no reflow, slow reflow, and distal embolization (16) . Furthermore, it may also result in a larger area of myocardial damage, cardiac rupture, malignant arrhythmias, and heart failure due to insufficient pericardial and myocardial perfusion (16) .

Another potential treatment option in this case may have been intravenous cangrelor, a direct P2Y12 receptor antagonist which can achieve maximal platelet inhibition within five minutes and demonstrates continuous efficacy throughout the infusion (32) . Loading with oral ticagrelor offers maximal platelet inhibition within 2 -4 hours and whilst crushing tablets reduces this by around one hour (32), this does not lead to immediate platelet inhibition (33). Given the hemodynamic instability due to cardiogenic shock seen in this case, gastrointestinal absorption and subsequent antiplatelet effect of ticagrelor via the nasogastric tube may have been reduced (34, 35) . Therefore, the intravenous administration of cangrelor may have been beneficial in our case. In a pooled analysis of the CHAMPION trials (36) , cangrelor reduced the rate of stent thrombosis by 41% compared to clopidogrel or placebo (0.5 vs 0.8%, p = 0.0008) with no difference in primary safety outcome (36, 37) . Furthermore, the early use of cangrelor may reduce the need for glpIIb/IIIa agents (37) .

Unfortunately, due to the rapid nature of the patient's deterioration and respiratory arrest we were unable to consider extracorporeal membrane oxygenation (ECMO), with the nearest service located around 30 minutes away from our centre. 

Early coronary angiography in these cases may be indicated to diagnose the high thrombus burden and facilitate immediate administration of both intracoronary and systemic anti-thrombotics. Aspiration of intracoronary thrombus may also have a role, though further guidance is required. Modulation of the cytokine storm may be a possible treatment avenue to reduce the pro-thrombotic state and trials are currently underway with therapies such as the IL-6 receptor antagonist tocilizumab which has already been used successfully in patients with cytokine storm syndrome (24).

Ultimately, more research is needed to identify the optimal management in these cases but the mechanism of high thrombus burden is progressively becoming more evident (Figure 7) . 

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A Case of Coronavirus Disease 2019 With Concomitant Acute Cerebral Infarction and Deep Vein Thrombosis

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Review Article -High thrombus burden: a review of mechanisms and treatments

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Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis

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