A Case of Acute Coronary Syndrome and Ischemic Stroke After Symptomatic Resolution of COVID-19

Background: There is increasing evidence that thromboembolic events are a major cause of morbidity and mortality in COVID-19 patients. We present a case with two suspected thromboembolic events – acute coronary and ischemic stroke – after the resolution of infectious symptoms. A 66-year-old male presented to the emergency department complaining of sudden onset of vision loss. He had no known medical history, but two weeks earlier presented to an outside hospital with fevers and was diagnosed with COVID-19. Brain CT revealed bilateral posterior cerebral artery territory infarcts, with subsequent MRA showing basilar artery attenuation as a likely source of embolization. Additionally, Troponin T was moderately elevated on admission (155 ng/ml) and reached a peak (1025 ng/mL) at 24 hours. Serial EKG showed dynamic changes since admission but the patient refused full cardiac workup. He was treated with dual anti-platelet therapy, high-intensity statin and ACE-inhibitor and was discharged with a stable visual decit.

Labs (Table 1) revealed normal CBC with elevations of serum D-dimer (770 mcg/mL), LDH (244 units/L), and ferritin (474.1 ng/mL). ESR (108 mm/hr) and CRP (22.9 mg/L) were both elevated. He had moderately prolonged APTT (38.1 sec) with normal PT/INR (12.8sec/1.08). Hemoglobin A1c was found to be elevated (7.8%) with normal lipid pro le. On of admission Troponin T was moderately elevated (155 ng/ml) and subsequent labs showed elevation to a peak (1025 ng/mL) at 24 hours. Chest X-Ray ( Fig. 1) revealed bilateral airspace disease. EKG on admission was unable to be located but documented to show normal sinus rhythm. Serial EKG at 24 hours (Fig. 2) showed dynamic changes with new non-speci c ST/T-wave changes, T-wave inversions in leads V4-6, and T-wave abnormalities in II, III, aVF. CT head on day of admission (Fig. 3A) showed bilateral posterior cerebral artery territory infarcts and MRI brain on hospital day three (Fig. 3B) con rmed bilateral acute infractions within the posterior circulation. MRA on hospital day three (Fig. 3C) showed left vertebral artery stenosis at the level of the foramen magnum.
Cardiac echo showed mild left ventricular dysfunction but the patient refused additional cardiac workup.
The patient was treated with dual anti-platelet therapy and started on high-intensity statin and ACEinhibitor. He was discharged with a stable visual de cit on the fth day of hospitalization.

Discussion
There is increasing evidence that thromboembolic events are a major cause of morbidity and mortality in COVID-19 patients (1). While severe infection often affects patients with independent risk factors such as diabetes, hypertension, advanced age, and pulmonary disease, (2,3) reports have shown an increased risk of thrombosis in COVID-19 patients as compared with controls admitted to the same level of inpatient care (4,5), so there appears to be a disease-speci c effect.
COVID-19 hypercoagulability is likely multifactorial, but seems tied to the in ammatory response and immunocompromised individuals have been suggested to have fewer pulmonary complications when infected with the virus (6). While the underlying pathophysiology remains to be fully understood, a particular concern is the pro-in ammatory "cytokine storm" (7), activating many endogenous triggers of coagulation. Of note, infection is associated with increased in ammatory markers such D-dimer, brin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and brinogen-degradation products (8-10). This in ammatory state is thought to promote hypercoagulation through mechanisms including up-regulation of tissue factor, thereby triggering the intrinsic and extrinsic coagulation pathways (11). D-dimer has also been suggested as a predictive marker of severe illness (12,13), so its value as a measure of coagulopathy in this setting is unknown.
Recent studies have also implicated the role of neutrophils via production of neutrophil-derived extracellular traps (NETs) -composed of proteins and extracellular DNA -in the pathologic thrombosis seen COVID-19. While NET formation is known to aid in the clearance of bacterial and viral pathogens, dysregulation of this process by respiratory viruses such as SARS-CoV2 is thought to promote microvascular thrombosis and end-organ damage (14). Elevated circulating levels of NETs have been shown in serum of COVID-19 patients (15) and post-mortem analysis samples from lungs of COVID-19 patients have shown extensive neutrophil in ltration of the pulmonary vascular and alveolar space (16).
In addition to these systemic effects, there is evidence that SARS-CoV-2 can induce microthrombosis by direct invasion of endothelial cells via the ACE-2 (angiotensin-converting enzyme 2) receptor, which is expressed on the endothelial cell surface, and post-mortem analysis ofvarious organ tissue have shown viral inclusion structures in endothelial cells of COVID-19 patients (17). Viral invasion of the endothelium is thought to disrupt the innate brinolytic function of these cells, predisposing to local thrombus formation (18).
Endothelial dysfunction may explain several important observations. For example, clinical and postmortem studies have shown the absence of DVT in most COVID-19 patients with pulmonary vascular obstruction, suggesting that pulmonary thrombi in COVID-19 patients may often result from local hypercoagulability, rather than embolization from the lower limbs (19,20). Additionally, cardiac microthrombi in the absence of epicardial coronary occlusion appear as hallmarks of COVID-19 (21), and therefore also likely represent local hypercoagulability.
In the case we present, the patient had two clinically signi cant intravascular sequelae of COVID-19 affecting posterior cerebral and coronary arteries. With regards to the CVA, a cardioembolic origin was unlikely due to bilateral involvement of the cerebral vasculature. Additionally, MRA revealed left vertebral artery attenuation, which is a likely source of embolization to this region. We therefore suspect disruption of a longstanding atherosclerotic plaque as the mechanism of posterior cerebral ischemia. The mechanism for troponin elevation, however, is unclear given the absence of coronary imaging, but could relate to thrombo-embolic or microvascular processes as previously discussed.
The timeline in this case is revealing and consistent with observations that thromboembolic risk of SARS-CoV-2 persists substantially longer than the infectious symptoms. In fact, a new disease entity, termed multisystem in ammatory syndrome in adults (MIS-A) (22), has emerged to describe the diverse extrapulmonary manifestations of SARS-CoV-2 in the days to weeks following the resolution of the acute illness. MIS-A is de ned by severe dysfunction of one or more extrapulmonary systems -in the absence of respiratory symptoms -with elevated in ammatory markers and laboratory evidence SARS-CoV-2 infection (22), as seen in the case we present. An important component of MIS-A appears to be a persistently elevated risk of thromboembolic events and case reports highlight ndings of large vessel stroke (23) and cardiac complications (24) in otherwise low-risk patients. Post-mortem studies have shown small vessel vasculitis and endotheliitis as the cause of end-organ dysfunction, re ecting an in ammatory process.
While many institutions have adopted guidelines for continued anticoagulation in high-risk patient following hospital discharge (12), these ndings raise interesting questions about the role of antiin ammatory treatment in the prevention of post-COVID-19 sequelae.