REVIEW
published: 25 September 2020
doi: 10.3389/fneur.2020.01031
Acute Ischemic Stroke in COVID-19:
A Case-Based Systematic Review
Tissa Wijeratne 1,2,3*, Carmela Sales 4 , Leila Karimi 2,5 and Sheila Gillard Crewther 2,4
1
Neurology & Stroke, Australian Institute for Musculoskeletal Science, Melbourne Medical School, Sunshine Hospital, The
University of Melbourne, Parkville, VIC, Australia, 2 School of Psychology and Public Health, College of Science, Health and
Engineering, La Trobe University, Melbourne, Parkville, VIC, Australia, 3 Department of Medicine and Dean’s Office, Rajarata
University of Sri Lanka, Anuradhapura, Sri Lanka, 4 Department of Neurology, Australian Institute for Musculoskeletal Science,
Level Three, Western Centre for Health Research and Education, Sunshine Hospital, Western Health & University Melbourne,
St Albans, VIC, Australia, 5 Faculty of Social and Political Sciences, Tbilisi State University, Tbilisi, Georgia
Edited by:
Giorgio Sandrini,
University of Pavia, Italy
Reviewed by:
Giovanni Morone,
Santa Lucia Foundation (IRCCS), Italy
Marina Zettin,
Centro Puzzle, Italy
*Correspondence:
Tissa Wijeratne
twijeratne@gmail.com
Specialty section:
This article was submitted to
Neurorehabilitation,
a section of the journal
Frontiers in Neurology
Received: 17 June 2020
Accepted: 06 August 2020
Published: 25 September 2020
Citation:
Wijeratne T, Sales C, Karimi L and
Crewther SG (2020) Acute Ischemic
Stroke in COVID-19: A Case-Based
Systematic Review.
Front. Neurol. 11:1031.
doi: 10.3389/fneur.2020.01031
Frontiers in Neurology | www.frontiersin.org
Corona virus disease (COVID-19), caused by the severe acute respiratory syndrome
coronavirus2 (SARS-CoV-2) is recognized as a global pandemic by WHO 2020 with
5,934 936 infections, 367,166 deaths and affecting over 200 countries as of 30th
May 2020. Acute Ischemic Stroke (AIS) in brain is also emerging as an important
neurovascular/neurological complication of COVID-19, associated with extreme immune
responses leading to dysregulated coagulation system and generalized thrombo-embolic
status and increased risk of AIS especially among usually less vulnerable younger adults
in this cohort. Thus, in early June 2020, we aimed to review the clinical data on all
published cases of COVID-19 and concomitant AIS, with a view to understanding the
pertinent clinical, laboratory and imaging features. The neutrophil-lymphocyte ratio (NLR)
at time of hospital admission for COVID infection correlates positively with the duration
of time before onset of clinical features of AIS. Higher NLR, C-Reactive protein, serum
ferritin, D-dimer and fibrinogen levels are associated with poor prognosis of AIS in
COVID-19 with 75% of patients dying or being severely disabled at present. Currently
it is too early to comment on the long-term outcomes for survivors.
Keywords: acute ischemic stroke, COVID-19, neurorehabilitation, white blood cells, neutrophil lymphocyte ratio,
hyper coagulopathy, D-dimer, ferritin
KEY FINDINGS
• Acute ischemic stroke is an important, but an under recognized complication of SARS-CoV2
infection, that leaves most recovered patients with significant disabilities as of present stage July
2020 of the pandemic.
• Hypercoagulation markers such as D-dimer are substantially elevated among all patients early
in the disease progression.
• Neutrophil to lymphocyte ratio, C-Reactive protein, and Serum Ferritin levels appear to be
prognostic markers.
• Patients with higher admission neutrophil-lymphocyte ratios demonstrate a shorter interval
between infective symptoms of COVID-19 and the clinical manifestation of Acute
Ischemic Stroke.
• Large vessel occlusion is the main etiologic subtype, with only a minority of patients receiving
standard of care treatment.
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has demonstrated that an elevated NLR is associated with
severe disease manifestation (28). The same meta-analysis
has also revealed that along with ESR and IL-6, CRP was
correlated with increased severity among patients with SARSCoV2 infection (28). The role of ferritin as a predictor
of mortality among confirmed SARS-CoV2, has also been
confirmed in another metanalysis of 10 studies involving
more than 1,400 subjects (31). Furthermore, elevated D-dimer
and hyperfibrinogenemia, which are both biomarkers of
inflammation and hypercoagulable state, have also been shown
to predict the severity of the said infection (31, 32). Interestingly,
similar biomarkers predict outcomes in stroke (33–39). In
particular, it is known that patients who show elevated NLR,
ferritin, CRP, D-dimer and fibrinogen have a higher risk for
stroke and equate to potentially poorer clinical outcomes
(33–39).
To date, despite the theoretical association of inflammatory
and procoagulable states linking stroke and SARS-CoV2
infection, there is limited published literature on the actual
co-occurrence of both. There is also limited information
on the biological markers which may be associated with
poor neurological outcomes. Thus, this study aims to
describe the clinical characteristics of patients with acute
ischemic stroke and concomitant SARS-CoV2 infection.
By further analysis of available laboratory data, this will
look at the trend of inflammatory biomarkers such as NLR,
CRP, serum ferritin, fibrinogen and D-dimer and hospital
discharge outcomes.
Currently, there is limited information about the clinical
characteristics and specific neurorehabilitation issues of AIS
patients with SARS-CoV 2 infection (40–43). However, it
is expected that the surge in patient numbers, on-going
issues with personal protective equipment (PPE) shortages,
and associated health care workers anxiety and stress about
the potential of getting infected with COVID-19 (and
actual infection of health care workers and mandatory self
isolation for 14 days even if these members are demonstrating
minimum or no symptoms) will create a significant challenge
to traditional neurorehabilitation practices and pathways,
at least during the pandemic, possibly for a long time to
come. Thus, these circumstances argue a strong case for
converting the catastrophe [Complex rearrangement of hospital
facilities as part of the preparation for the pandemic has
also occasioned significant problems and added resource
problems for health care systems across the world (44–50)
into an opportunity for revamping of rehabilitation protocols].
Currently evidence is emerging for further expansion of
telemedicine type paradigms, with incorporation of tablet
based remote monitoring technology (Melbourne Rapid
Field visual fields, wearable devices and artificial intelligence)
suggesting as the way forward in neurorehabilitation of AIS
in COVID19 pandemic era, at least for the foreseeable future
(43, 51–53).
Thus, this systematic review aims to identify and collate
the clinical and laboratory features, acute and long term
treatment, and outcomes of all published reports on patients with
concomitant diagnosis of confirmed SARS-CoV 2 infection and
• Seventy five percent of the patients with COVID-19 and Acute
Ischemic Stroke died or are still severely disabled.
• The COVID-19 pandemic has created a unique opportunity
to advance the whole field of neurorehabilitation based on
a better biological and scientific underpinning of precision
neurorehabilitation protocols.
INTRODUCTION
In December 2019, a novel corona virus associated with
a series of acute, atypical respiratory diseases was first
detected in Wuhan China. Since then the virus, now
known as SARS-CoV2 (Severe Acute Respiratory Syndrome
coronavirus two), has spread to over 200 countries and is
now recognized as a major world pandemic (1). As of May
30th 2020, the mortality rate of COVID-19 was reported
with the number of confirmed deaths with recorded cases
worldwide. Since the pathogenesis of SARS-CoV2 first began
to emerge, numerous other clinical system manifestations have
been identified.
Neurological manifestations of SARS-CoV 2 infection were
first reported in a series of patients in Wuhan, China by
Zhou et al. (2). Acute ischemic stroke (AIS) was diagnosed
in 5% of the cases (2). However, a much lower rate of
only 0.9% imaging confirmed AIS i.e., 32/3,556 total patients
case number with COVID-19 was reported in New York
USA (3). Subsequent retrospective reports from Europe have
also confirmed AIS as a common neurovascular complications
of SARS-CoV2 (4, 5). Interestingly Oxley et al. noted an
increased occurrence of younger SARS CoV2 virus-infected
patients with no significant traditional risk factors for AIS,
presenting with large vessel occlusion (6). Putative mechanisms
suggested as inducing AIS in association with SARS CoV2
have included systemic inflammation, inflammatory cytokine
storm, hyper-coagulability, and imbalances in the classical and
alternative Renin Angiotensin System (RAS) in relation to
SARS-CoV-2 spike glycoprotein-ACE2 binding related molecular
mechanisms (3, 7–19). The RAS system comprises both a plasmabased RAS regulating cardiovascular system and tissue-based
RAS regulating long term changes via a complex hormonal
system, endocrine, paracrine, and autocrine in action. Thus,
the RAS controls renal, adrenal and cardiovascular systems
with important implications on blood pressure control as
well as fluid/electrolyte control which are critically important
to maintain life being very susceptible to damage by SARSCoV 2. The inflammatory pathway is core to the various
clinical manifestations of SARS-CoV2 infection. Also referred
to as the “cytokine storm,” it triggers an upsurge of various
inflammatory cytokines such as IL-2, IL-7, IL-10 (20, 21),
induces a state of lymphocytopenia (22–24) and also activates
a spike of acute phase reactants such as CRP and ferritin
(25, 26).
Various parameters have been proposed to predict
prognosis and outcomes among patients with COVID,
including the neutrophil to lymphocyte ratio (NLR) (27–
30). A metanalysis of six studies involving 1,141 patients
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SEARCH RESULTS
acute ischemic stroke and with a special emphasis on clinical and
laboratory features.
Extensive database search yielded 595 citations, and four studies
were added by manual searching. A total of 257 duplicates were
excluded resulting in 342 citations. These titles and abstracts
were further screened yielding 90 final publications of relevance
to consideration of stroke and SARS-COV2 infection, during
the second screening process. One publication was non-existent
despite being cited by multiple authors in their publications.
Further evaluation of the full texts of the 89 studies by two
independent neurologists (TW and CS) excluded 74 citations
with 15 studies. Three further studies were added from hand-held
search by TW and CS with 18 publications that were deemed to
be included in this systematic review by all authors.
PURPOSE
The present study was conducted to provide a systematic review
of AIS and COVID-19 with respect to definition, prevalence,
pathophysiology, clinical characteristics, acute, subacute features,
prognostic markers outcomes.
Participants
Information regarding ischemic stroke patients with confirmed
SARS-CoV2 infection and radiologically or clinically Confirmed
AIS included in published studies from November 2019 to
May 30th 2020 using the search strategy detailed below will be
considered here.
Year and Country of Study
The studies published from 2019 to 2020, Included literature were
originated from North America, Europe, and Asia.
Types of Studies
Study Population
All types of studies including qualitative, systematic reviews,
meta-analyses, case reports and case series, were included.
This study included all patients with SARS-COV2 infection
and a concomitant diagnosis of acute ischemic stroke and/or
acute/subacute outcomes where available.
An electronic search performed on May 10 to 30th, 2020 using
the identified keywords yielded 342 citations after removal of
duplicates. This was further assessed at the title and abstract level
which resulted in 90 articles. After full assessment of the full
text of each, 18 were deemed relevant to the study, in addition
to the three articles which were added from hand-held research.
Figure 1 summarizes the search process.
There were 18 articles included in the study consisting of
87 patients from USA, Italy, Turkey, France, Philippines, and
United Kingdom. Most of the studies were case reports and case
series while three of the included studies were retrospective and
prospective cohorts. Table 1 outlines the characteristics of the
individual studies.
Clinical characteristics of patients are described in Table 2.
The majority of the patients were within the 50–70 age
group while almost one-third of the patients were <50 years
old. The most common comorbidity was hypertension followed
by diabetes, dyslipidemia and less frequently, atrial fibrillation.
Mean hematologic parameters are also described. Neurovascular
imaging either with magnetic resonance angiography (MRA)
or computer tomographic angiography (CTA) was available
for 35 patients, of whom the majority presented with anterior
circulation, large vessel occlusion. Treatment regimens were
also described for the majority of the patients and among
whom a significant number received systemic anticoagulation,
intravenous thrombolysis and mechanical thrombectomy. Of the
87 patients described, 72 outcomes are available, with almost
75% resulting in poor neurological outcomes of Modified Rankin
score (mRS) 4 and above.
Inflammatory and coagulation markers of individual patients
were also analyzed. Neurological outcomes were classified
as either good (mRS 3 and below) or poor (mRS 4 and
above). Respective inflammatory parameters such as neutrophil
to lymphocyte ratio, C-reactive protein and serum ferritin
Search Methods
Published articles in English and on human subjects that were
published from November 2019 until 30th May 2020 were the
inclusion criteria for the search. The following search strategy
was adopted:
1. In the first step MEDLINE, Cochrane and CINAHL databases
were searched, followed by title and abstract search.
2. In the second step, the keywords were used when searching
on Ovid MEDLINE, Cochrane, PubMed, CINAHL, and
EMBASE databases.
3. In the third step, a manual search was carried out to ensure no
study was inadvertently left out.
The keywords used to conduct the search were: Stroke,
thrombosis,
coronavirus,
neurological
complication,
neurorehabilitation, COVID19, SARS-COV2.
Data Extraction
The Arksey and O’Malley methodological framework was
employed in this review (54).
The
bibliographies
of
individual
studies
were
further hand-searched. Articles were screened by two
independent investigators.
4. In the fourth step the secondary analysis was carried out
as follows.
Clinical and laboratory data of every patient was extracted.
Demographics and details of their respective laboratory details
were also investigated. In particular, the following routine
laboratory values were of interest to the researchers: NLR, CRP,
ferritin, fibrinogen, and D-dimer. Individual patient outcomes
were also accounted for and classified as good [with modified
Rankin Scores (mRS) of 0, 1, 2, and 3 and poor mRS of 4, 5,
6]. Patients with no available laboratory data and outcomes were
excluded in the quantitative analysis.
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FIGURE 1 | PRISMA Flowchart.
The relationship between the NLR on admission and the time
interval from onset of SARS-CoV2 symptoms to the appearance
onset of symptoms of stroke was established. As shown in
Figure 3, patients who have higher NLR at the onset have
a shorter time interval between infective symptoms and the
occurrence of the ischemic event.
were analyzed for each group. The same was performed for
coagulation markers such as D-dimer and fibrinogen. Patients
with good neurological outcomes had lower mean NLR, CRP
and serum ferritin (4.39 ± 1.44, 53.09 ± 92.70 mg/L, 449 ±
482.3 ug/L, respectively), compared to patients with mRS 4
and above (7.51 ± 5.84, 88.69 ± 70.45 mg/L, 1,086 ± 1,220
ug/L, respectively). Similar trends were observed in terms of
coagulation markers, with D-dimer and fibrinogen showing
levels of 2,509 ± 4,093 ug/L and 4.70 ± 1.70 g/L, respectively,
for patients with mRS 3 and below, while values for patients with
poor neurological outcomes were 7,223 ± 6,781 ug/L for D-dimer
and 6.086 ± 2.69 g/L for fibrinogen respectively. Summary of the
said values are plotted in Figures 2A–E.
Frontiers in Neurology | www.frontiersin.org
DISCUSSION
To date, there is no comprehensive review describing the
potential role of inflammatory and coagulation biomarkers in
determining the clinical outcomes of patients with SARS-CoV2
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However, it remains unclear whether this is due to a mechanism
related to thrombosis or embolism or the lack of brain imaging.
Unfortunately, there are no studies to date, which fully report
autopsy findings of the deaths recorded among the stroke
patients with SARS-CoV infection. In a different, though recent,
study describing the autopsy results of 12 SARS-CoV2 patients
in a German center, the majority of cases showed massive
venous thromboembolism with no arterial thrombosis being
reported (73). Mechanisms which may contribute to intracranial
arterial thrombosis include the cytokine-induced initiation of
thrombin formation that triggers the activation of platelets
that subsequently result in the development of micro and
macrothrombi (74–87). This is worsened by the free conversion
of fibrinogen to fibrin and inflammation-induced depletion of
physiological anticoagulants such as antithrombin III, tissue
factor pathway inhibitor, and the protein C system (74–88).
In terms of treatment, while 30 cases were reported to have
large vessel occlusion, only 20 mechanical thrombectomies
were performed. A comprehensive stroke center in Barcelona,
Spain reported an 18 and 23% drop in the number of strokes
codes and mechanical thrombectomies during the start of the
pandemic, respectively, albeit without any changes in reperfusion
and clinical outcomes (89) The World Stroke Organization
recognizes the said difficulties and emphasizes the utility of
telemedicine as well as best practice sharing to further optimize
and streamline stroke processes (90, 91).
While not depictive of the true epidemiologic picture, it is
clear that patients with AIS and SARS-CoV2 infection have
poor neurologic outcomes of either death or severe disability.
Aggarwal et al. (92) concluded in a point analysis of four studies
that patients with a previous history of stroke have a 2.5-fold
increase in the odds of severe COVID infection but did not show
any significant association with mortality (92). A retrospective
cohort study of ischemic stroke reports a mortality rate close
to 50% (3) while a prospective study involving 10 AIS patients
resulted in four deaths (55) Clearly, more prospective studies
involving a larger number of individual patients is necessary to
ascertain the true mortality rate in this population.
In this study, there is a trend that patients with good outcomes
have lower NLR, CRP, and serum ferritin compared to patients
who died or remained critically ill. NLR has been shown to have
a good predictive value in assessing patients who are likely to
have severe SARS-CoV2 infection (30, 93–96). In particular, it
has been proposed that patients who are older and have NLR
values of more than 3 are likely to require intensive care (27).
Yan et al. also predicted that high NLR values on admission
is associated with greater odds of complications related to
COVID-infection (97). On the other hand, it is known that
high NLR is used as a poor prognosticating factor for patients
with cerebral ischemia, intracerebral hemorrhage and post-stroke
complications (98–107). The dual consequence of COVIDrelated lymphopenia along with migration of the neutrophils to
the ischemic tissue may contribute to the significant increase in
the NLR levels in patients with stroke and concomitant SARSCoV2 infection (107).
Another hyperinflammatory biomarker which has been
shown to stratify outcomes in patients with SARS-CoV2
TABLE 1 | Characteristics of studies included.
Author
Country
Study design
Number of
patients with
confirmed
SARS-CoV2
infection and AIS
Yaghi et al. (3)
USA
Retrospective cohort
Lodigiani et al. (4)
Italy
Prospective cohort
8
Berekashvilli et al.
(55)
USA
Prospective cohort
10
32
Wang et al. (38)
USA
Case series
5
Beyroutti et al. (56)
UK
Case series
6
Avula et al. (57)
USA
Case series
4
Tunc et al. (58)
Turkey
Case series
4
Oxley et al. (6)
USA
Case series
5
Morassi et al. (59)
Italy
Case series
4
Viguier et al. (60)
France
Case report
1
Co et al. (61)
Philippines
Case report
1
Deliwala et al. (62)
USA
Case report
1
Al Saiegh et al. (63)
India
Case report
1
González-Pinto
et al. (64)
Spain
Case report
1
Gunasekaran et al.
(65)
USA
Case report
1
Valderrama et al.
(66)
USA
Case report
1
Moshayedi et al.
(67)
United Kingdom Case report
1
Goldberg et al. (68)
USA
1
Case report
infection and concomitant acute ischemic stroke. The data
presented will also supplement currently limited information
on the occurrence of neurovascular events among patients with
SARS-CoV2 infection.
To date a number of theoretical models have been proposed to
account for the occurrence of neurovascular events among SARSCoV2 patients. Most build on the idea of the SARS-CoV2 virus
infection inducing inflammation and associated immunological
release of cytokines from blood and endothelial cells and the
concurrent activation of platelets resulting in micro thrombosis
(69). The depletion of the cardioprotective and neuroprotective
ACE-2 receptors throughout the body and on microglia in the
brain, as a result of the receptors being the preferential cellular
target of the virus invasion, has also been proposed as another
neuropathologic mechanism irrespective of age (8). However, the
hypercoagulable state of SARS-COV2 infection as the sole basis
of this mechanism is debateable given that vascular workups
for cryptogenic stroke have not been detailed in most of the
case studies. Furthermore, the increase in “burden of disease”
especially in the elderly is likely to be further exacerbated by
the expected age-related depletion in ACE-2 receptors resulting
in the predominance of the end-organ damaging effects of
increasing the ACE-1/Angiotensin II ratio (70–72).
To date, the majority of AIS lesion sites in the patients
described in the literature, are related to large vessel occlusion.
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TABLE 2 | Clinical characteristics of patients described.
Age (years) (N = 87)
Comorbidities (N = 87)
29 (33%)
>70
50–70
38 (43%)
<50
21 (24%)
Hypertension
46 (53%)
Diabetes
32 (37%)
Dyslipidemia
21 (24%)
Atrial Fibrillation
Time from SARS-CoV2 symptoms to onset of stroke (days) N = 60
Laboratories
8 (9%)
> 14
19 (31%)
7–14
17 (28%)
<7
24 (40%)
Mean hemoglobin (g/L)
129 (94–155)
Mean white cell count (/mm3 )
10.23 (0.5–23.05)
Mean platelet count (/mm3 )
269.41 (135–408)
Neutrophil to lymphocyte ratio (NLR)
6.99 (0.91–17.4)
Mean creatinine (umol/L)
129.81 (55–537)
Mean fibrinogen (g/L)
5.52 (1–9.7)
Mean D-dimer (ug/L)
9,800.47 (52–000)
Mean INR
1.48 (0.99–3.6)
Mean APTT (s)
31.66 (24–42.7)
CRP (mg/L)
Neuroimaging N = 35
Treatment N = 69
5 (13%)
Middle cerebral artery occlusion
15 (43%)
ICA/CCA occlusion
8 (23%)
Anterior cerebral artery occlusion
1 (3%)
Tandem occlusion
2 (6%)
Posterior cerebral artery occlusion
2 (6%)
Basilar artery occlusion
1 (3%)
Posterior inferior cerebellar artery occlusion
1 (3%)
Alteplase only
4 (6%)
Thrombectomy
3 (4%)
Alteplase and thrombectomy
8 (12%)
Alteplase and thrombectomy and antiplatelet/anticoagulation
5 (7%)
Thrombectomy and antiplatelet
32 (46%)
Antiplatelet only
8 (12%)
5 (7%)
MRS 3 and below
17 (24%
MRS 4 and above
55 (76%)
infection is CRP. Aside from predicting severity and mortality,
it has prognosticating value in determining which patients
will eventually require mechanical ventilation (108–110).
Published literature noted that elevated CRP is associated
with poor outcomes in patients with neurovascular conditions
(111, 112). There is also evidence to suggest that CRP is
not just a “marker” but a “maker” of the atherogenesis
(110). It has been demonstrated in experimental studies
that exogenous CRP promotes atherogenesis by promoting
the expression of adhesion molecules and cell mediators
along with the decrease of arterial vasodilators (113–115).
A meta-analysis of nine studies also provides evidence on the
dose-dependent relationship of CRP and increased risk of venous
thromboembolism (112). Whether the elevation of CRP is the
Frontiers in Neurology | www.frontiersin.org
4 (6%)
Anticoagulation only
Anticoagulation and antiplatelet
Outcomes N = 72
131.817742 (4–366)
Any stenosis
causative etiology or the sequelae of a multifactorial process
linking SARS-CoV2-infection to inflammation, atherogenesis or
embolism needs further exploration.
Hyperferritinemia, which implies a heightened state of
immunologic reactivity has also been associated with increased
mortality in recent publications related to the SARS-CoV2
infection (116). It signals the activation of the macrophages and
the reticuloendothelial system resulting in end-organ damage
(117). Patients with SARS-CoV2 treated for pneumonia with
Toculizumab had a marked decrease in the inflammatory
markers such as CRP and ferritin, along with significant clinical
improvement post-infusion (118). In patients with acute stroke,
this iron storage protein can potentially worsen the irondependent oxidative stress in the ischemic penumbra which can
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FIGURE 2 | (A–C) Mean inflammatory markers among patients with stroke and confirmed SARA-CoV2 infections. (D–E) Mean coagulation markers among patients
with stroke and confirmed SARS-CoV2 infection.
lead to further neurologic decline (119). This is further validated
in a study which shows a direct correlation between serum
ferritin and markers of neural and blood-brain barrier disruption
such as glutamate, interleukin-6, matrix metalloproteinase-9
and cellular fibronectin among patients receiving thrombolysis
(39). The complementary inflammatory sequelae of SARSCoV2 infection and ischemic stroke is the likely culprit of
hyperferritinemia in SARS-CoV2 related strokes.
SARS-CoV2-related coagulopathy is responsible for various
thrombotic events linked to mortality. Described as a fibrinolytic
“shut-down,” SARS-CoV2 infection promotes a pro and
hypercoagulable states resulting in disseminated (intravascular
coagulation (DIC), microthrombi and other venous and arterial
thrombotic phenomena (4, 120–122). D-dimer and fibrinogen
are both recognized as important biomarkers of the severity of
coagulopathy in patients with SARS-CoV 2 infection (123, 124).
Olive et al. in a retrospective analysis of 21 patients with
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SARS-CoV infection concludes that D-dimer was associated
with increased risk of pulmonary embolism (125). A similar
observation was made in a larger study that suggests that
D-dimer levels above 1 µg/mL may help in stratifying patients
with poor prognosis at the onset (26). Fibrinogen increase
was also observed among patients with severe SARS-CoV2
related pneumonia compared to mild presentation (126). The
disproportionate increase of these biomarkers, especially at
the early stages, warrant screening of thromboembolic events
and initiation of thromboprophylaxis (124). The trend in these
coagulation biomarkers are similarly observed in non-COVID
related strokes. In the ARISTOTLE trial, patients with AF
and increased D-dimer values had higher incidence of stroke,
systemic embolism and all-cause mortality (127). Choi and
colleagues also propose that D-dimer can be used as a biomarker
for recurrence among patients with previous AF and nonAF related strokes (128). The EUROSTROKE study likewise
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to the alloimmune hypothesis, which has been demonstrated
in rodents (129). The development of auto-antibodies to other
ACE-2 receptors such as on the microglia in the brain after the
onset of viral infection presumably resulted in the exponential
increase in the cytokine storm and significant tissue destruction
which may be linked to the delayed onset of the vascular event
after the viral prodrome (129).
Lastly as the COVID-19 pandemic is distressing national
health systems worldwide, a tsunami wave of neurorehabilitation
needs and challenges regarding the long-term effects of the
pandemic must be expected to begin to unfold soon. Thus,
we believe that with strong humanity and collaboration across
disciplines, this is the time to convert this situation into an
opportunity that with vision, creativity, innovation, and use of
smart technology can be harnessed with the aim of surviving this
global health crisis (43, 130).
FIGURE 3 | Relationship between NLR and the occurrence of stroke from
onset of SARS-CoV2 symptoms.
CONCLUSION
Stroke is an important neurovascular complication of SARSCoV2 infection. The aetiopathogenesis of cerebral ischemia is
related to the overactivation of immune and hypercoagulable
mechanisms. This is supported by the disproportionate
increase of biomarkers such as NLR, CRP, serum ferritin,
D-dimer and fibrinogen among patients who died or were
critically ill. An elevated NLR on admission also implies an
increased burden of inflammation at the onset of SARS-CoV
infection which may result in early manifestation of cerebral
ischemic events.
confirms the utility of fibrinogen in predicting patients who are
at risk for stroke (36). The said risk is equated to various clinical
risks such as smoking, DM, MI, and HDL cholesterol (36). In
this study, we have provided a scaffold on the potential trend
between outcomes and coagulation parameters for SARS-CoV2
related strokes. While the most accepted mechanism behind this
phenomenon is sepsis-induced disruption of the coagulation
system, Iba et al. propose that more complex procoagulant
responses resulting in a distinct interaction between the host’s
immunologic and the coagulation systems (124).
This study also highlights the occurrence of the ischemic event
days to weeks after the onset of SARS-CoV2 symptoms. More
importantly, we have established an inverse relationship between
the inflammatory biomarker, NLR on admission and the duration
between the stroke and the onset of SARS-CoV2 symptoms. This
is likely related to the inflammatory burden which triggers a
pro-coagulable cascade. Furthermore, Amiral et al. relate this
AUTHOR CONTRIBUTIONS
TW and LK conceived of the presented idea. TW, SC, and
LK developed the theory. TW and CS performed the literature
search. TW wrote the manuscript with support from CS, LK, and
SC. All four authors approved the final manuscript.
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
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