Introduction
The 2 major plaque morphologies that are underlying causes of acute myocardial infarction are plaque rupture (PR) (60%-65%) and plaque erosion (PE) (25%-40%), found in major epicardial coronary arteries.1,2 Thromboembolism from the original sites of PR or PE may also lead to microvascular occlusion and microinfarction.3 On the other hand, among critically ill patients dying due to COVID-19, microthrombi in the absence of epicardial coronary thrombi were observed in 9 of 40 (23%) cases.4 Here, we present histologic images of epicardial thrombi and intramyocardial thromboemboli from cases with PR and PE and intramyocardial microthrombi from a COVID-19–positive case. The management of acute coronary syndromes (ACS) is described from a pathologic point of view.
Learning Objectives
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To understand that the intramyocardial thromboemboli due to PE contain relatively more platelets than fibrin compared with the thromboemboli due to PR. |
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To understand that COVID-19–associated microthrombi are richer in complement C5b-9 compared with PR or PE. |
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Case Presentation
Case 1
A 76-year-old man with a history of hypertension, hypercholesterolemia, and type 2 diabetes was found unresponsive in a room and could not be resuscitated. The postmortem examination showed the acute PR with occlusive thrombus in the proximal right coronary artery (Figure 1A) and intramyocardial coronary thromboembolization in the posterior wall of the left ventricle (Figures 2A and 2B). Immunohistochemistry (IHC) for epicardial thrombi and intramyocardial thromboemboli showed that they were positive for the platelet marker CD61, the fibrin marker fibrin II, and D-dimer, but negative for complement C5b-9 (Figures 1B to 1E and 2C to 2F).
Figure 1Epicardial Luminal Thrombi From PR
(A) A histologic image of the proximal right coronary artery showing epicardial acute thrombi due to PR stained using Movat Pentachrome stain. Immunostaining shows that the epicardial thrombi are positive for (B) CD61, (C) fibrin II, and (D) D-dimer, but negative for (E) C5b-9. (B to E) High-power images of A. PR = plaque rupture.
Figure 2Intramyocardial Thromboemboli From PR
(A and B) A histologic image showing intramyocardial thromboemboli in the posterior left ventricular wall stained using H&E stain. Immunostaining shows that they are positive for (C) CD61, (D) fibrin II, and (E) D-dimer, but negative for (F) C5b-9. (B to F) High-power images of A. H&E = hematoxylin and eosin; other abbreviation as in Figure 1.
Case 2
A 43-year-old man, who was a current smoker, was presented to the emergency department experiencing severe chest pain. He went into cardiopulmonary arrest and, despite advanced cardiovascular life support for more than 30 minutes, he was pronounced dead in the emergency department. The histopathologic examination revealed acute PE with occlusive thrombus in the left main coronary artery (Figure 3A) and focal intramyocardial thromboembolization in the lateral wall of the left ventricle (Figures 4A and 4B). IHC for epicardial thrombi showed that they were positive for CD61, fibrin II, and D-dimer, but negative for complement C5b-9 (Figures 3B to 3E). The IHC for intramyocardial thromboemboli showed that they were strongly positive for CD61, with weak positive staining for fibrin II and D-dimer, but negative for C5b-9 (Figures 4C to 4F).
Figure 3Epicardial Luminal Thrombi From PE
(A) A histologic image of left main trunk showing epicardial acute thrombi due to PE stained using Movat Pentachrome stain. Immunostaining shows that the epicardial thrombi are positive for (B) CD61, (C) fibrin II, and (D) D-dimer, but negative for (E) C5b-9. (B to E) High-power images of A. PE = plaque erosion.
Figure 4Intramyocardial Thromboemboli From PE
(A and B) A histologic image showing intramyocardial thromboemboli in the lateral left ventricular wall stained using H&E stain. Immunostaining shows that they are positive for (C) CD61, and weak positive for (D) fibrin II and (E) D-dimer, but negative for (F) C5b-9. (B to F) High-power images of A. Abbreviations as in Figures 2 and 3.
Case 3
An 82-year-old man with no history of coronary artery disease was presented with respiratory failure and was diagnosed with COVID-19 infection. Despite the ventilatory support, he died 16 days after admission. Histopathologic analysis showed a microthrombi in the intramyocardial coronary arteries (Figures 5A and 5B), although there were no thrombi or severe atherosclerosis in the epicardial coronary arteries. IHC on microthrombi showed that they were strongly positive not only for CD61, fibrin II, and D-dimer, but also for C5b-9 (Figures 5C to 5F).
Figure 5Intramyocardial Microthrombi From COVID-19
(A and B) A histologic image showing intramyocardial microthrombi (arrow) in the mid ventricular septal wall stained using H&E stain. Immunostaining shows that they are positive for (C) CD61, (D) fibrin II, (E) D-dimer, and (F) C5b-9. (B to F) High-power images of A. Abbreviation as in Figure 2.
Discussion
These 3 cases illustrate the importance of the characteristics of epicardial and intramyocardial thrombi components in PR, PE, and COVID-19 infection. Our comparison of thrombi constituents between these 3 dissimilar causes of ACS, to the best of our knowledge, has not been previously reported.
A previous pathologic study showed that the typical morphology of PR includes a thinned fibrous cap, causing a disruption of the intimal layer, whereas PE is characterized by a nonruptured, thick fibrous cap and the local absence of endothelial cells overlying the plaque surface.1 In PR, fibrin was more abundant than platelets in coronary thrombi, whereas platelets and fibrin were equally observed in PE.5 As for thromboembolization to the downstream myocardium, the incidence of embolization was significantly higher in PE compared with PR in autopsy cases without percutaneous coronary intervention (PCI) (71% and 42%, respectively; P = 0.01).3 On the other hand, in patients undergoing PCI, patients with PR more frequently had distal embolization after PCI, compared with those with PE (36.4% and 3.6%, respectively; P = 0.001).6 Now, the stent-less strategy has become one of the options for the management of ACS according to the EROSION (Effective Anti-Thrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography–Based Management in Plaque Erosion) study, which showed that 47 of 60 (78%) achieved >50% reduction of thrombus volume at 1 month without stent implantation in patients with PE.7 Therefore, the optimal antiplatelet and anticoagulant treatments after ACS are essential for minimizing the myocardial necrosis due to thromboembolization with or without stent implantation. Further work in this area is needed to determine the optimal pharmacologic or interventional strategy.
Previous studies of hospitalized patients with COVID-19 showed 20%-60% of subjects demonstrated elevation of cardiac troponin and/or abnormalities of electrocardiogram/echocardiogram, suggesting that COVID-19 may be involved in myocardial damage.4,8,9 Most of these clinical studies demonstrated that patients hospitalized with COVID-19 with myocardial injury exhibited poor prognosis.9 Autopsy studies from similar types of subjects revealed that COVID-19 infection caused intramyocardial microthrombi formation and focal myocyte necrosis.4 According to an angiographic study, patients with COVID-19 infection had worse thrombolysis in myocardial infarction flow grade at baseline and after PCI.10 As shown in Figure 5, case 3 had multiple microthrombi in intramyocardial microvessels, which is likely one of the main causes of elevated cardiac troponin in the setting of COVID-19 infection and portends a poor prognosis. Furthermore, as shown in Figure 5E, microthrombi IHC in case 3 showed that they were strongly positive for CD61, fibrin II, D-dimer, and C5b-9. This finding suggests that not only proper anticoagulant treatment but also the inhibition of complement pathways might be considered for the management of patients with severe COVID-19 infection.
Conclusions
These 3 cases suggested that the intramyocardial thromboemboli due to PE contain relatively more platelets than fibrin compared with PR, and COVID-19–associated microthrombi are richer in complement C5b-9 compared with PR or PE. Further pathologic studies on a large number of cases are needed to confirm these findings and speculate the recommendations for antithrombotic therapy.