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-specific effect.
COVID-19 hypercoagulability is likely multifactorial, but seems tied to the inflammatory 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-inflammatory "cytokine storm” (7), activating many endogenous triggers of coagulation. Of note, infection is associated with increased inflammatory markers such D-dimer, fibrin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and fibrinogen-degradation products (8-10). This inflammatory 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 infiltration 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 fibrinolytic 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 significant 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 inflammatory 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 defined by severe dysfunction of one or more extrapulmonary systems – in the absence of respiratory symptoms – with elevated inflammatory 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 findings 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, reflecting an inflammatory process.
While many institutions have adopted guidelines for continued anticoagulation in high-risk patient following hospital discharge (12), these findings raise interesting questions about the role of anti-inflammatory treatment in the prevention of post-COVID-19 sequelae.