COVID-19 and Cerebrovascular Diseases

Angiotensin-Converting Enzyme 2 (ACE2) Dysregulation

The proposed mechanism of entry of SARS-CoV into the epithelial cells of the respiratory system relates to the expression of the metallopeptidase ACE2 indicating that ACE2 is a functional receptor for the virus. Hamming et al. investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain) and found that there was a surface expression of ACE2 protein not only on lung alveolar epithelial cells and enterocytes of the small intestine, but also in arterial and venous endothelial cells, and arterial smooth muscle cells in all organs studied. This epithelial expression in the lung and small intestine, together with the presence of ACE2 in vascular endothelium, provided a first step in understanding the pathogenesis of the main disease manifestations. Evidence also exists that ACE2 is present in glial cells and neurons.

Binding of the SARS-CoV-2 virus to the ACE2 causes inactivation of the receptor, resulting in reduced conversion of Angiotensin II (Ang II), a potent vasoconstrictor and angiogenic factor, to Angiotensin (1–7) (Ang 1–7), a factor with vasodilatory and several antiinflammatory properties. This imbalance in turn leads to overactivation of the classical renin-angiotensin-aldosterone system (RAAS) axis, as well as underactivation of the alternative RAAS signaling in the brain. The downstream effects are enhanced vasoconstriction, neuroinflammation, blood–brain barrier permeability, oxidative stress, and thrombogenesis, all of which can contribute to stroke pathophysiology during SARS-CoV-2 infection ( Fig. 4.1 ). Blood pressure elevations can occur, which can be particularly important in the pathogenesis of intracerebral hemorrhage (ICH), although data available to date suggest that patients with ICH in the context of COVID-19 present with lower blood pressure levels compared to those with spontaneous, non-COVID-19 related ICH.

ACE2 inactivation may also result in endothelial dysfunction of the brain arteries and has been considered important in the pathogenesis of stroke, ischemic, and hemorrhagic. ACE2 dysregulation can also play a major role in the inflammation cascade after acute ischemia, which in turn can result in larger infarct volumes as a result of decreased perfusion.

Coagulation Disorders and the Hypercoagulable States

Several studies have addressed the issue of hypercoagulability associated with severe COVID-19 illness, which may be associated with several diverse factors, including dehydration, inflammation, hyperfibrinogenemia, endothelial cell injury, and platelet activation.

The severe inflammatory state secondary to COVID-19 leads to a severe derangement of hemostasis that has been recently described as a state of disseminated intravascular coagulation (DIC) and consumption coagulopathy, defined as decreased platelet count, increased fibrin degradation products such as D-dimer, as well as low fibrinogen. Often, however, this coagulation disorder does not meet the criteria for DIC.

In a study of thromboelastrography in patients with severe COVID-19, the parameters were consistent with a state of hypercoagulability. Platelet count was normal or increased, prothrombin time (PT) and activated partial thromboplastin time (aPTT) were near normal, fibrinogen, D-dimer was dramatically increased, C-reactive protein, factor VIII, von Willebrand factor, and protein C were all increased, and antithrombin was marginally decreased, results that were in support of hypercoagulability in the context of a severe inflammatory state.

COVID-19 coagulopathy may also manifest with the development of antiphospholipid antibodies, usually the lupus anticoagulant, anticardiolipin IgA and antibodies against β2-glycoprotein-I. Often these antibodies can cause a hypercoagulable state, but they can also appear in conditions characterized by intense immune activation where they may have no apparent pathogenic role.

Another important part of the pathogenicity of the hypercoagulable state in COVID-19 is the development of a potent cytokine storm. This is not unique to COVID-19 and has been described in MERS and SARS, both of which are closely related coronaviruses. IL-6, TNF, and IL-1β, all proinflammatory cytokines, are central in this process. The inflammatory state seen in COVID-19 is closely associated with a procoagulant state, caused by consumption of anticoagulant factors, overproduction of prothrombotic factors, and endothelial injury. This leads to microthrombosis, DIC, and venothrombotic events frequently seen in COVID-19 patients and is associated with a worse prognosis. Thrombin and Factor Xa have proinflammatory properties via activation of proteinase-activated receptors (PARs) and, therefore, their antagonists, such as Factor Xa inhibitors (e.g., apixaban and rivaroxaban) and low-molecular-weight heparins (LMWH) (e.g., enoxaparin), could not only have anticoagulant properties but antiinflammatory ones as well.

The COVID-19 hypercoagulable state is associated with an increased risk of arterial ischemic stroke or cerebral venous thrombosis, and also a high incidence of deep vein thrombosis. The latter can result in paradoxical embolism in the presence of a right-to-left circulation shunt. Patent foramen ovale is a common finding in the general population and it is important in the etiopathogenesis of ischemic stroke especially in young patients with no underlying stroke risk factors, especially when an underlying hypercoagulable state is present, such as the one associated with COVID-19. Right-to-left circulation shunts can also occur at the pulmonary level, usually related to pulmonary arteriovenous malformations or vascular dilatations. In a recent very important study in mechanically ventilated COVID-19 patients, contrast-enhanced transcranial Doppler detected microembolic signals in 83% of patients, the PaO ₂ :FIO ₂ ratio was inversely correlated with the number of microbubbles, and the number of microbubbles was inversely correlated with lung compliance. The authors suggested that pulmonary microvascular dilatations were the culprit for right-to-left circulation shunt and that these explain the disproportionate degree of hypoxemia in some patients with COVID-19 lung injury. However, the presence or absence of PFO was not assessed in this study.

The other face of coagulopathy, especially in the setting of severe COVID-19, is that of dysfunctional hemostasis, prolonged coagulation parameters, and a bleeding disorder. As already mentioned, the COVID-19 coagulopathy shares some features with DIC, but the overall combination of hematological findings suggests a different form of coagulation disorder. Nevertheless, it can result in an increased risk of intracranial hemorrhage, especially given the frequent use of therapeutic anticoagulation in this setting.

Endotheliitis and Vasculitis of the central nervous system (CNS)

In a postmortem study of patients with COVID-19, viral elements were found within endothelial cells of various organs, including the kidney, heart, lungs, and small bowel in postmortem studies. The investigators of this study found no evidence of myocarditis or inflammatory changes of the other organs. In one case, in particular, the patient developed acute reduction of the cardiac ejection fraction with mesenteric ischemia and histological evidence of endotheliitis of the submucosal vessels. In another patient, there was histological evidence of myocardial infarction without evidence of lymphocytic myocarditis. These findings suggested that SARS-CoV-2 can cause widespread endotheliitis, without necessary associated vasculitis or myocarditis. Since then, similar observations have been made at postmortem examination of frontal lobe tissue from a patient who died from COVID-19, where the virus was found in neural and capillary endothelial cells. In another series, brain biopsies showed signs of thrombotic microangiopathy, endothelial injury, and resulting hemorrhagic predisposition. These findings support the notion that SARS-Cov-2 is a neurotropic and endotheliotropic virus that causes major endothelial dysfunction and subsequent degeneration ( Fig. 4.2 ).

SARS-CoV-2 has been implicated in triggering a CNS vasculitis, which is often the case with several other viral infections, such as varicella zoster, hepatitis C, cytomegalovirus, human immunodeficiency virus and others, presumably due to the severe inflammatory response related to the cytokine storm. However, most reports do not refer to solid histological evidence from biopsy or autopsy specimens but rather to combinations of clinical and imaging findings, which do not establish the diagnosis of definite vasculitis. It is possible that some of the reported cases were due to brain vasculitis, given the evidence of multiple coincidental ischemic and hemorrhagic strokes, but the lack of histological confirmation could still lend support to the possibility that most of these cases were actually related to endotheliitis.

Reversible cerebral vasoconstriction syndrome has also been reported in the context of COVID-19. This can mimic primary angiitis of the central nervous system, and typically presents with recurrent thunderclap headaches, and small subarachnoid bleeds in the brain convexities.

Cardiac Dysfunction and Cardiogenic Embolism

Although COVID-19 clinical manifestations are mainly respiratory, virus-related cardiac injury leading to major cardiac complications are being reported. Proposed mechanisms of SARS-CoV-2 cardiac injury include direct viral injury, up- and downregulation of ACE2, cytokine release syndrome, hypoxia, aggravation of the underlying cardiac disease, and drug-induced toxicity. Specifically, COVID-19 can be complicated with myocarditis, coronary artery disease, and acute coronary syndromes, as well as cardiac arrhythmias, including atrial fibrillation. Autopsies have indeed revealed infiltration of myocardium by interstitial mononuclear inflammatory cells, providing strong evidence for COVID-19-induced myocarditis. Additionally, in a small review, 38 patients with COVID-19 met clinical criteria for stress (Takotsubo) cardiomyopathy but the prevalence of the syndrome was not thought to be necessarily higher than in pre-COVID-19 times. In one case, the patient presented with an acute ischemic stroke and Takotsubo. Whether the cardiomyopathy was the cause, the result or a mere coincidence is subject to speculation. Cardiac imaging, and more specifically cardiac MRI, plays a major role in the diagnosis of COVID-19-related myocarditis. Cardiac wall motion abnormalities and reduced cardiac output have the potential to be pathogenetic mechanisms for ischemic stroke in patients with COVID-19 through cardiogenic embolism and cerebral hypoperfusion.

Critical Illness Due to COVID-19

A significant fraction of patients with COVID-19, in some series up to approximately 30%, present with severe manifestations requiring intensive care unit management, which may include intubation and mechanical ventilation, resulting in prolonged hospitalizations. In this set of patients, systemic hypotension and hypoxia can result in additional cerebral ischemic complications, such as hypoxic/anoxic encephalopathy and hypoperfusion-induced brain ischemia.