The Unbearable Thrombus of COVID-19

Corresponding Author

In this issue of the Journal, Choudry et al. (1) present a single-center experience with primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) during the coronavirus disease-2019 (COVID-19) pandemic. STEMI registries during the COVID-19 pandemic are a rainbow of unique colors. The London experience with primary PCI focused a narrow lens onto COVID-19 STEMI to ask an important question: for patients with an acute culprit lesion, are there unique features of the PCI procedure that warrant caution and concern? Via detailed angiographic comparison to a COVID-19–negative control group, they observed a dramatic increase in thrombus burden that may compliment prior insights into the pathophysiology of the COVID-19 pandemic.

The Rainbow of COVID-19 STEMI Registries

The inclusion criteria of COVID-19 STEMI registries vary widely: some include COVID-19–positive patients, some do not. And, the pathophysiology in COVID-19 STEMI registries represent a spectrum of disease from a typical coronary culprit plaque requiring primary PCI to nonobstructive coronary artery disease with type II myocardial infarction or myocarditis. This rainbow-like spectrum of COVID-19–related STEMI registries is exemplified by looking at 4 recent examples spanning the globe (1, 2, 3, 4) (Table 1 ).

Table 1.

4 Registries of Primary PCI During the COVID-19 Pandemic

Registry Characteristics	London, England (N = 115) (1)	Lombardy, Italy (N = 28) (2)	New York City, United States (N = 18) (3)	Hong Kong, China (N = 125) (4)
Study design	2 arms concurrent comparison, single center	Single arm multicenter	Single arm multicenter	2 arms, historical comparison, single center
Patient population	COVID-19 positive primary PCI (n = 39) COVID-19 negative primary PCI (n = 76)	Consecutive COVID-19 positive patients with STEMI undergoing coronary angiography	Consecutive COVID-19 positive patients with STEMI	Primary PCI patients during the COVID-19 pandemic (n = 7) Primary PCI patients during 2018–2019 (n = 108) All COVID-19 negative
STEMI without obstructive CAD	None	Yes, n = 11 (39.3% of the cohort)	Yes, ≥50% of the cohort (not all patients had angiography)	None
Mechanical ventilation	COVID+: 12.8% COVID−: 6.6%	Not reported	Total: 67% myocardial infarction: 62% myocardial injury, no CAD: 70%	Not reported
Delay in STEMI reperfusion times	No delay for both groups	Not reported	Not reported	Yes, all intervals marked prolongation of symptom onset to device time
Hospital mortality	COVID-19 positive: 17.9% COVID-19 negative: 6.5% (p = 0.10)	Total: 39.3% No culprit lesion: 45.5% Culprit lesion: 35.3%	Total: 72% Myocardial infarction: 50% Myocardial injury, no CAD: 90%	Not reported
Key observation	Large thrombus burden: COVID-19 +: 75.0% COVID-19 −: 31.4% (p = 0.0006)	COVID-19 patients may present with STEMI: nearly 40% have no culprit lesion	COVID-19 patients with STEMI have variable pathophysiology: ≥50% of patients have no culprit lesion	STEMI systems of care are impacted by the COVID-19 pandemic

CAD = coronary artery disease; COVID-19 = coronavirus disease-2019; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction.

The Hong Kong experience during the COVID-19 pandemic (N = 125) provided insights into delays in STEMI presentation (4). The authors observed a prolongation of symptom onset to first medical contact (as well as door-to-device) time intervals compared with a historical control period; the observation of delayed or decreased STEMI patient presentations correlated with other STEMI registries, suggesting that patients avoided emergency room evaluation during the pandemic (5,6). Only 7 patients in the sample underwent primary PCI during the COVID-19 pandemic (compared with 118 primary PCI patients in the non–COVID-19 historic control groups) and none of the patients were COVID-19 positive. The insights from New York City (N = 18) and Lombardy Italy (N = 28) are completely different: 1) >40% of COVID-19–positive patients with ST-segment elevations do not actually have a thrombotic culprit coronary artery lesion; and 2) STEMI mortality rates in COVID-19–positive patients are high (39% in Lombardy, 72% in New York) (2,3).

The London group brings a new color to the spectrum of COVID-19 STEMI registries. This study included both COVID-19–positive patients and a concurrent control group of COVID-19–negative patients presenting with STEMI (diagnosed by nasal swab or convincing radiological findings/symptoms immediately after PCI). This study is unique in exploring a single manifestation of COVID-19–related STEMI: patients who demonstrated a culprit lesion requiring immediate PCI. The simplest conclusion from this focused lens on COVID-19–related STEMI is that primary PCI is technically more complicated in the setting of acute coronavirus infection. The complexity is centered upon the unique burden of coronary thrombus (Table 1):

• •Large thrombus burden (modified thrombus grade 4/5) is twice as likely in patients with COVID-19 and STEMI compared with those without COVID-19 (75.0% vs. 31.4%; p = 0.0006).
• •Multivessel thrombosis was seen in 17.9% of COVID-19 STEMI patients compared with none of the COVID-19–negative patients, as seen in a prior case report (7); stent thrombosis as the initial presentation was also 10 times more likely (p < 0.05 for both comparisons).
• •Angiographic complexity led operators to enhanced use of glycoprotein IIb/IIIa inhibitors and thrombectomy to manage these challenging lesion characteristics.

Outcomes for COVID-19–positive patients described in the London registry elicits insight, opportunities, and challenges for primary PCI programs during the pandemic. Importantly, unlike the cohort undergoing primary PCI in Hong Kong (4), median door to device times are not prolonged for either the COVID-19–positive or –negative patients (approximately 50 min in both groups). Second, unlike the New York and Lombardy experiences (2,3), hospital mortality for COVID-19–positive STEMI patients was not in the 40% to 75% range; hospital mortality was nonsignificantly higher than in the COVID-19–negative group (17.9% COVID-19 positive vs. 6.5% COVID-19 negative; p = 0.10), but mortality rates were reasonable given that approximately one-fourth of the COVID-19–positive patients experienced a cardiac arrest. Prior studies of primary PCI have demonstrated increased mortality among patients with large thrombus burden (8): larger sample sizes and longer-term follow-up of COVID-19–positive primary PCI patients are needed to confirm the interaction of coronavirus, large thrombus burden, and death.

Surrogate endpoints of reperfusion in this registry suggest that such a COVID-19–related clinical risk will be demonstrated in larger studies. For example, final myocardial blush grades of 2 to 3 were achieved in only 53.8% of COVID-19–positive primary PCI patients (compared with 93.3% of COVID-19–negative primary PCI patients; p < 0.001), a surrogate endpoint that has previously correlated with clinical outcomes (9). Thus, the London experience with reasonable time-based parameters and outcomes supports proposals recommending efficient primary PCI programs as the routine strategy for STEMI patients during the COVID-19 pandemic (10); at the same time, the findings of a potential mortality and myocardial reperfusion risk provide an impetus to understand the pathophysiology that makes primary PCI more complex and higher-risk for COVID-19–positive STEMI patients.

COVID-19 and the Burden of Thrombus

Three-quarters of COVID-19–positive STEMI patients have a large coronary thrombus burden: can this finding compliment prior observations on the pathophysiology of COVID-19 infection? A marked inflammatory reaction occurs in the setting of COVID-19 infection (11): this inflammatory response to the virus can be measured by multiple serological parameters including C-reactive protein and D-dimer (12). The connection between inflammation and thrombosis is previously established and occurs via activation of leukocytes, platelets, endothelium, and smooth muscle cells (13). Furthermore, the association of viral infection and enhanced risk of myocardial infarction has been described with respect to influenza, and an inflammatory mediation of risk is plausible (14,15).

Does COVID-19 elicit a particularly intense inflammatory response that triggers thrombosis across multiple vascular beds, with STEMI-related large thrombus burden being 1 of many potential manifestations? A generalized hypercoagulability among critically ill COVID-19 patients has been demonstrated using thromboelastography (16). Clinical manifestations of an inflammation-thrombosis-hypercoagulability cascade are supported by registries identifying an increased risk of deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation, and stroke among patients with COVID-19 (12). Although increased risk of myocardial infarction with viral infection is previously described (14), COVID-19 may be a special viral infection: for example, a comparison of ischemic stroke rates among patients with COVID-19 compared with patients with influenza infection noted a strikingly increased rate of ischemic stroke associated with COVID-19 (odds ratio: 7.6; 95% confidence interval: 2.3 to 25.2) (17).

None of these registry associations can prove causality for a coronavirus-inflammation-thrombosis–mediated mechanism of STEMI or other ischemic events. But, the current London coronary thrombus data supports a fundamental hypothesis regarding the pathophysiology of COVID-19: coronavirus may induce an intense inflammatory reaction that manifests as thrombotic events across a broad spectrum of vascular beds. This conclusion may have therapeutic implications, including a potential role for enhanced anticoagulation strategies among patients critically ill with COVID-19 (18). To demonstrate a potential link among COVID-19, thrombosis, and inflammation, the authors examined the association of modified thrombus grade and myocardial blush grade with D-dimer blood levels: the significant correlation is supportive of the inflammation-triggered mechanism. But, the overall correlation is still fairly weak (r < 0.50 for both correlations with D-dimer). Thus, the current registry study is neither mechanistic nor definitive: enhanced tools like optical coherence tomography could provide insight into underlying coronary plaque pathophysiology.

The authors are to be congratulated for their observations during the pandemic: they have performed a unique registry of COVID-19–positive STEMI patients with a concurrent COVID-19–negative control group and provided insight into the feasibility and challenges of primary PCI. Their detailed analysis of angiographic data supports a broader hypothesis: patients with COVID-19 infection are at a specially enhanced risk of inflammation-triggered thrombus burden. These results need to be confirmed in a larger, multicenter registry with an adequate control group. And, if confirmed, the next step is both obvious and challenging: how will we prevent and optimally treat the thrombus-generating pathophysiology that appears to be fundamental to COVID-19 infection?