key: cord-333176-6v7ficfk
authors: Snell, Jonathan
title: SARS-CoV-2 infection and its association with thrombosis and ischemic stroke: A review COVID-19, thrombosis, and ischemic stroke
date: 2020-09-30
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2020.09.072
sha: 
doc_id: 333176
cord_uid: 6v7ficfk

This review of current literature provides background to the COVID-19 pandemic, as well as an examination of potential pathophysiologic mechanisms behind development of thrombosis and ischemic stroke related to COVID-19. SARS-CoV-2 infection is well-documented to cause severe pneumonia, however, thrombosis and thrombotic complications, such as ischemic stroke, have also been documented in a variety of patient demographics. SARS-CoV-2 infection is known to cause a significant inflammatory response, as well as invasion of vascular endothelial cells, resulting in endothelial dysfunction. These factors, coupled with imbalance of ACE2 and RAS axis interactions, have been shown to create a prothrombotic environment, favoring thromboembolic events. Ischemic stroke is a severe complication of COVID-19 and may be a presenting symptom in some patients.

Coronaviruses are positive-sense single stranded RNA viruses of the coronaviridae family. 1 The genome of coronaviruses contains open reading frames for 16 non-structural SARS-coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). 1 

zoonotic origin in Southern China and leading to over 8,000 confirmed cases with an estimated 9-11% fatality rate. 1,2 MERS-CoV is currently endemic to the Arabian Peninsula and has proven to be a dangerous virus of zoonotic origin with an estimated 36% fatality rate. 1 December 2019 marked the discovery of a new coronavirus in Wuhan, China after an outbreak of severe pneumonia of unknown origin. 3 Isolation and sequencing of this virus from human airway epithelial cells allowed the characterization of the betacoronavirus named SARS coronavirus 2 (SARS-CoV-2) that is the etiologic agent of coronavirus disease 2019 (COVID- 19) . 3, 4 Further characterization of SARS-CoV-2 has demonstrated close genomic similarity to several types of bat coronavirus, indicating bats as a likely reservoir for this virus of zoonotic origin. 4 SARS-CoV-2 shares approximately 79% sequence identity with SARS-CoV, though SARS-CoV-2 has demonstrated a higher rate of transmission than SARS-CoV. 4 Basic reproductive number (R 0 ) is used to represent the transmissibility of a disease and is defined the average number of new cases caused by a single infective person in an unexposed population. 5 The R 0 of SARS-CoV-2 and SARS-CoV are estimated at 2.9 and 1.85 for each virus, respectively. 5,6 This is likely due to the presence of asymptomatic or mildly symptomatic transmission of SARS-CoV-2, and its current prevalence in the human population supports the infective potential of this novel coronavirus. 5, 6 Since its December 2019 emergence, SARS-CoV-Viral entry into cells by coronaviruses is mediated through the interaction between a cellsurface receptor protein and the viral S-protein. 9 Cellular tropism of coronaviruses is dependent on the S-protein-receptor interaction 9 and understanding the tropism of SARS-CoV-2 is the beginning to elucidating the myriad effects this virus may have on human physiology. SARS-CoV-2 shares 73% to 76% amino acid sequence identity in the receptor binding domain of its S-protein with SARS-CoV 4,10 , and the amino acid sequence directly interacting with the cell receptor is highly conserved between the viruses. 4,10 SARS-CoV has been previously determined to use the human transmembrane protein angiotensin converting enzyme 2 (ACE2) as its receptor for viral entry, and SARS-CoV-2 had been speculated to use ACE2 for viral entry as well. 9, 10 Several studies have confirmed that ACE2 is the functional receptor for SARS-CoV-2. 11, 12, 13 ACE2: its location and role in the Renin-Angiotensin System (RAS) Human ACE2 is a transmembrane zinc metalloprotease that acts as a carboxypeptidase in the metabolic degradation of angiotensin I and angiotensin II (ANGII). 14 ACE2 mRNA is expressed in most tissues of the body, with highest expression in the GI tract, kidney, testes, heart, and lungs. 15 ACE2 protein is found expressed on the surface of lung alveolar epithelial cells, enterocytes of the small intestine, arterial smooth muscle cells, and both arterial and venous endothelial cells, including intracranial vessels. 16 While soluble ACE2 exists after cleavage of ACE2 from the apical cell surface, it plays little to no physiologic role. 16 ACE2 primarily catalyzes the conversion of ANGII into angiotensin-(1-7) (ANG1-7), a metabolite that opposes the actions of ANGII and the RAS axis through activation of the Mas receptor. 17 Generation of ANG1-7 can take a more circuitous route through ACE2 catalyzation of angiotensin I into angiotensin-(1-9) followed by ACE catalyzation of angiotensin-(1-9) into J o u r n a l P r e -p r o o f Journal Pre-proof Increased circulating levels of ANG1-7 have been demonstrated to lower blood pressure, improve endothelial function, and attenuate the effects of ANGII in spontaneously hypertensive rats. 17 Additionally, ANG1-7 administered to spontaneously hypertensive rats treated with a nitric oxide synthase inhibitor attenuated the inhibitor's effects on MAP, as well as demonstrated cardioprotective effects in the setting of global cardiac ischemia. 18 ACE2 and ANG1-7 play an essential physiologic role in vasodilation and regulation of endothelial function in opposition to the effects of ANGII. Figure 1 summarizes the production of ANGII and ANG1-7, as well as their effects. Imbalance of ACE and ACE2 products has the potential to cause significant dysfunction and has been implicated as playing a role in the pathogenesis of SARS. 19 Downregulation of ACE2 expression has been demonstrated after SARS-CoV pulmonary and myocardial infection 19, 20 and is linked to the acute pulmonary injury seen in SARS. 19 Hypercoagulability in SARS-CoV-2 infection COVID-19 symptomology is diverse, including shortness of breath, cough, and fatigue with many cases progressing into pneumonia requiring oxygen therapy. 21 COVID-19 patient developed immune thrombocytopenic purpura after heparin treatment was begun. 34 Heparin treatment was ceased after thrombocytopenia developed, though antibody testing for antiplatelet factor 4 and antiplatelet antibodies was negative. 34 These events suggest SARS-CoV-2 infection as the precipitating event for the thrombocytopenia in this case, though causative studies are necessary.

The complement system has also been implicated in the pathophysiology of SARS-CoV-2 infection. A series of patients with severe COVID-19 were determined to have significant deposits of terminal complement proteins and signs of systemic complement activation were present. 35 Complement was also co-localized with SARS-CoV-2 S-protein in these patients, indicating complement targeting of virally-infected endothelium. 35 Previous studies of complement activation in SARS-CoV infection indicated endothelial dysfunction as the source of complement activation, and murine C3 protein knockout models demonstrated less severe infection with SARS-CoV. 36 Activation of the complement system has the potential to increase the risk of thrombus formation, both through C3a stimulation of platelets and insertion of terminal complement components into membranes. 37 Imbalance of the interactions between ACE2 and the RAS axis may also contribute to the thromboembolic events seen in SARS-CoV-2 infection. ANG1-7, the major product of ACE2, and ANGII have competing effects on blood pressure and endothelial activation: where ANGII serves to increase blood pressure and activate the endothelium, ANG1-7 reverses these actions J o u r n a l P r e -p r o o f Journal Pre-proof through the Mas receptor ( figure 1 ). 17,38 ANG1-7 has also been shown to decrease thrombus formation through the production of nitric oxide and prostacyclin by both platelets and endothelial cells. [39] [40] [41] This is contrasted by the actions of ANGII, which has been shown to accelerate thrombus formation through induction of tissue factor production and generation of free radicals that scavenge free nitric oxide. 42, 43 Downregulation of ACE2 by SARS-CoV-2 infection 20 may result in an imbalance of these systems, leading to predisposition to thromboembolic events.

Cerebrovascular events can be a significant consequence of uncontrolled thrombotic states, and represent a global burden to both quality of life and national economics. 44, 45 Ischemic stroke due to occlusion of large arteries has been a documented complication of SARS-CoV infection in patients with minimal to no risk factors. 46 SARS-CoV-2 infection seems to also increase risk of developing ischemic stroke, among other neurological consequences. 78 of 214 patients in a retrospective case series of hospitalized patients in Wuhan, China demonstrated nervous system dysfunction (CNS, peripheral nervous system, and/or skeletal muscle dysfunction). 47 Of these 78 patients, 6 developed ischemic strokes; 5 of these patients had been categorized as severe COVID-19 and 1 had been categorized as non-severe. 47 Unexplained encephalopathic features in 13 of 58 patients were seen in another case series of COVID-19 patients. 48 Ischemic stroke was diagnosed in 3 of these 13 patients (2 small acute and 1 sub-acute strokes). 48 

Genetic Recombination, and Pathogenesis of Coronaviruses

A Novel Coronavirus from Patients with Pneumonia in China

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

The reproductive number of COVID-19 is higher compared to SARS coronavirus

Transmission Dynamics of 2019 Novel Coronavirus (2019-NCoV). Social Science Research Network

Centers for Disease Control and Prevention

WHO Director-General's opening remarks at the media briefing on

An Overview of Their Replication and Pathogenesis

Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

A Human Homolog of Angiotensin-converting Enzyme CLONING AND FUNCTIONAL EXPRESSION AS A CAPTOPRIL-INSENSITIVE CARBOXYPEPTIDASE

Quantitative mRNA expression profiling of

Transgenic Angiotensin-Converting Enzyme 2 Overexpression in Vessels of SHRSP Rats Reduces Blood Pressure and Improves Endothelial Function

Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with l-NAME

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Upsurge of deep venous thrombosis in patients affected by COVID-19: Preliminary data and possible explanations

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet

Fibrinolysis Shutdown Correlation with

Thromboembolic Events in Severe COVID-19 Infection

Severe Acute Respiratory Syndrome and Venous Thromboembolism in Multiple Organs

The clinical pathology of severe acute respiratory syndrome (SARS): a report from China

Endothelial cell infection and endotheliitis in COVID-19

Endothelial dysfunction: a marker of atherosclerotic risk

Interactions between the innate immune and blood coagulation systems

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Immune Thrombocytopenic Purpura in a Patient with Covid-19

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis?

Links Between Complement Activation and Thrombosis

The ACE2/Angiotensin

Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2−/− mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation

An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect

The Antithrombotic Effect of Angiotensin-(1-7) Involves Mas-Mediated NO Release from Platelets

Roles of coagulation and fibrinolysis in angiotensin II enhanced microvascular thrombosis

Prothrombotic effects of angiotensin

Epidemiology and the global burden of stroke

Human and economic burden of stroke

Large artery ischaemic stroke in severe acute respiratory syndrome (SARS)

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Stroke in a young COVID -19 patient

Surprise Diagnosis of COVID-19 following Neuroimaging Evaluation for Unrelated Reasons during the Pandemic in Hot Spots

COVID-19-related strokes in adults below 55 years of age: a case series

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

Prothrombotic state induced by COVID-19 infection as trigger for stroke in young patients: A dangerous association. eNeurologicalSci

Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Ischemic Stroke