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The Looming Risk of Stroke in COVID-19

Coronavirus (COVID-19) is a severe acute respiratory syndrome (SARS) associated with symptoms of fever, dry cough, difficulty breathing, fatigue, and evidence of pneumonia (Chams et al., 2020). COVID-19 is caused by SARS-CoV-2 which is considered to be a part of the coronavirus family causing a variety of illnesses, from common colds to SARS associated with coronavirus (SARS-CoV) (“Basics of COVID-19,” 2021). The virus’ transmission is through coughing, sneezing, and speaking from the mouth (i.e., droplet precautions). The name of the virus stems from the Latin word “corona” which means crown, referring to the spike-like shape of the virus protein used to attach itself to the human cell during infection. This attachment causes the infected cell to replicate and spread to other cells (“Basics of COVID-19,” 2021). COVID-19 is found to be associated with stroke as infected individuals have higher risk of suffering a stroke and deep vein thrombosis (“COVID-19 Increasing Stroke Risks in People of All Ages,” 2022; Novaes et al., 2022). In this article we will explore the science behind the relation of COVID-19 and stroke.


Pathophysiology of COVID-19


COVID-19 enters cells by binding to the receptor of angiotensin converting enzyme 2 (ACE2) protein (Trougakos et al., 2021). ACE2 receptors are present in nearly all human tissue, markedly abundant in the cardiovascular system (Chilamakuri & Agarwal, 2021). The function of ACE2 is to regulate vasoconstriction and vasodilation in vessels by converting ANGII to angiotensin 1-7 (Ang 1-7) (Sriram et al., 2021). The normal role of ANGII is to increase blood pressure and possess vasoconstrictive components, and Ang 1-7 serves as a vasodilator. Once the virus is bound to ACE2, an enzyme called transmembrane protease serine 2 (TMPRSS2) promotes the viral entry of infected ACE2. Viral binding to ACE2 disrupts the normal function of ACE2 in regulating and converting ANGII. A disruption in ANGII conversion can cause injury to blood vessels due to this hormone’s role in vasoconstriction (“Angiotensin”, 2019). The average time period from exposure to symptom onset is approximately five days, and studies have shown that 97.5% of people develop symptoms within 11.5 days (Chilamakuri & Agarwal, 2021; Wiersinga et al., 2020).




Figure 1: Pathogenesis of COVID-19 (Mulinari Turin de Oliveira et al., 2020)

Epidemiology of COVID-19


Patients suffering from severe COVID-19 symptoms are likely to be more contagious than those with mild symptoms. Jin et al. (2020) provided a summary of the proportion of cases with regards to severity: Most cases with mild symptoms can recover in 1–2 weeks. COVID-19 infection can cause five different outcomes: asymptomatically infected persons (1.2%); mild to medium cases (80.9%); severe cases (13.8%); critical cases (4.7%); and death (2.3% in all reported cases).


Infected people are likely to be contagious within 7-10 days of infection (“COVID-19: Epidemiology, Virology, and Prevention,” 2023). COVID-19 is able to be transmitted from a longer distance through airborne transmission, i.e., inhaling viral particles that are present in the air over time (“Basics of COVID-19,” 2021). Older adults and persons with comorbidities are at a higher risk for severe infection. Studies have shown that older adults with COVID-19 are associated with higher hospitalization rates, Intensive Care Units (ICU) admissions, and mortality rates (Chowdhury & Oommen, 2020). Over 81% of COVID-19 related deaths occur in people aged 65 and over (“COVID-19 - Medical Conditions,” 2022). Patient diagnoses such as cardiovascular disease, diabetes, and chronic respiratory disease have been related to severe illness with COVID-19 infection, with one in five cases suffering adverse effects such as hospitalization, requiring mechanical ventilation, and death (Adab et al., 2022).


The Relationship Between COVID-19 and Stroke


Stroke refers to the disruption of blood flow in vessels traveling to the brain causing neurological injury (“Cerebrovascular Disease”, n.d). Strokes have been shown to be a common long-term effect of COVID-19. Studies have reported that people with COVID-19 are twice as likely to suffer a stroke compared to non-infected individuals (“COVID-19 Increasing Stroke Risks in People of All Ages,” 2022). Cerebral venous thrombosis (the blockage of arterial veins caused by blood clots) has been shown to be frequent in COVID-19 patients and can occur in later stages of the viral infection. Research has demonstrated that 21% of patients with COVID-19 suffered deep vein thrombosis (Novaes et al., 2022). Stroke prevalence is seen as an effect of “long COVID-19 syndrome”, referring to patients who suffer prolonged viral symptoms and persistent high levels of inflammatory blood markers that are related to higher risk of stroke events. An inflammatory marker is a blood test used to detect inflammation in the body. As an example, D-Dimer is an inflammatory marker protein indicating a blood clotting issue, and it can be assessed through blood tests. The protein is created when blood clots are dissolved in the bloodstream (“D-Dimer Test: What It Is, What Is It Used For, Risk & Benefits,” 2021). Test results that show a high level of D-dimer in the blood is indicative of a blood clotting disorder, as D-dimer levels tend to rise significantly when increased formation and breakdown of blood clots occur in the body. High levels of D-dimer could be explained through hypercoagulation and increased inflammatory response as a result of COVID-19.





Figure 2: Pathogenesis of stroke associated with COVID-19. (Nannoni et al., 2021)

Pathogenesis of Stroke Related to COVID-19


Hypercoagulability, endothelial injury, and hyperviscosity have been reported as symptoms of stroke due to COVID-19 infection (Qi et al., 2021). Hypercoagulability, or exaggerated coagulation with a tendency to form blood clots (Senst et al., 2022), has been seen in mild and severe cases of COVID-19 infection owing to the body’s inflammatory response during infection (COVID-19 Increasing Stroke Risks in People of All Ages,” 2022; Sriram et al., 2021). Severe viral cases increase the activation of cytokines (pro-inflammatory proteins), inducing a hypercoagulative state (Qi et al., 2021; Sadeghmousavi & Rezaei, 2020). Endothelial cells, on the other hand, are cells found on the lining of blood vessels. Endothelial disruption and injury can be caused by COVID-19 binding to its main receptor, ACE2, present in endothelial cells (Sadeghmousavi & Rezaei, 2020). The role of endothelial cell is to control vasodilation and vasoconstriction, as well as hemostasis (normal clotting during blood vessel injury). The change of ACE2 due to the binding of COVID-19, promotes vasoconstriction and lower levels of nitric oxide, a vasodilator with an anti-clotting effect. This causes blood clot formation due to the release of von Willebrand factor (vWF) produced by endothelial cells and binds platelets together. (Xu et al., 2022). Furthermore, hyperviscosity is another risk factor contributing to blood clots. An abnormal inflammatory response causes high levels of fibrinogen. Fibrinogen is a protein involved in the formation of blood clots by red blood cell aggregation. High fibrinogen levels can therefore result in hyperviscosity (Qi et al., 2021). Hyperviscosity can cause endothelial cell damage and cause a hypercoagulative state. In sum, these three factors combine to form what is known as the Virchow’s triad, and serve as key components contributing to blood clot formation (Qi et al., 2021; Sadeghmousavi & Rezaei, 2020). - 28.



Figure 3: Illustration of Virchow’s Triad for venous thromboembolism (VTE). (Kovačič et al., 2019)


A Case Example of COVID-Associated Stroke


Rajae et al. (2021) provided a case report of a 68 year old patient who experienced a stroke associated with COVID-19 infection. The patient demonstrated sudden onset hemiparesis (one-sided body loss of sensation), dysarthria (difficulty with speech), and left facial paralysis. Upon examination, the patient's blood pressure, heart rate, respiratory rate, and oxygen saturation levels (amount of oxygen in the blood) were within normal limits. However, a cerebral computerized tomography (CT) scan showed an ischemic stroke. The authors revealed that on the second day of hospitalization the patient was exhibiting difficulty breathing, dry cough, and an abnormal oxygen saturation of 70% (equal to or above 95% is considered normal). To investigate these novel respiratory symptoms, a chest CT scan was conducted, and it showed signs of pneumonia which created suspicion of COVID-19 infection. The patient was later confirmed positive for COVID-19, and laboratory results showed an elevation in D-dimer levels indicative of COVID-associated thrombosis as the cause of the stroke.


Medical Management of Stroke Associated With COVID-19


Medical management for stroke related to COVID-19 should follow general stroke protocol concerning clinical evaluation and assessment (“Cerebrovascular Disease”, n.d). Aside from clinical presentations of a stroke (i.e., speech difficulty, one-sided body weakness, facial drooping), a thorough medical history should be conducted by clinicians, including questions concerning COVID-19 symptoms: fever, difficulty breathing, myalgia, cough, and travel in the last 14 days. (Venketasubramanian et al., 2021). However, if patients are unable to provide such information due to altered mental status caused by stroke, clinicians should assume potential viral infection and wear proper personal protective equipment to avoid viral transmission (Qi et al., 2021). Infected patients with stroke will require complete diagnostic work-up consisting of brain imaging, vascular imaging, D-dimer test, and cardiac evaluation. Recombinant tissue plasminogen activator (rt-PA) is recommended for patients diagnosed with stroke immediately from symptom onset (approximately 3 to 4.5 hours from symptom onset) (“About stroke,” n.d.; Qi et al., 2021). rt-PA is a pharmaceutical drug which assists in dissolving blood clots that are causing blockage within cerebral vessels. Mechanical thrombectomy (extraction of blood clot) is utilized for occlusion in large vessels and is recommended to be performed within six hours of symptom onset.



Figure 4: Potential mechanisms of stroke related to COVID-19. (Stein et al., 2021)


Conclusion


COVID-19 has shown to increase the risk of thrombosis and stroke due to the virus’ ability to disrupt the body’s hemostasis regulation system (Qi et al., 2021; Sadeghmousavi & Rezaei, 2020). This dysregulation begins by COVID-19 binding to ACE2, causing disruption in converting ANGII to Ang 1-7, resulting in an increase in immune inflammatory response and vasoconstriction (Qi et al., 2021; Xu et al., 2022). A patient presenting stroke-like symptoms should be treated with standard stroke protocol, and clinicians should also include questioning centred towards COVID-19 infection. Prevention of COVID-19 includes social distancing, mask wearing in public spaces, and vaccination against the virus (“Basics of COVID-19,” 2021; Chams et al., 2020; Jin et al., 2020). Implementation of these preventative precautions can be beneficial for patients at higher risk of stroke, such as individuals with vascular comorbidities, to avoid infection and other negative outcomes associated with the virus.


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