In this Commentary, we address mechanisms of stroke in patients with coronavirus disease
2019 (COVID-19) due to infection with the severe acute respiratory syndrome coronavirus-2
(SARS-CoV-2). It should be noted that given the recency of the pandemic, most studies
are small case series, so this evaluation should be regarded as preliminary.
A review by a panel of the World Stroke Organization reported that the risk of ischemic
stroke during COVID-19 is around 5% (95% confidence interval [CI]: 2.8–8.7%) .
COVID-19-related hemorrhagic strokes are far less common than ischemic strokes, but
a few cases have been reported [2, 3, 4, 5]. The median time from diagnosis to ischemic
stroke in one small single-center study was 10 days (IQR: 1–19) . Patients with
COVID-19 who had strokes were more likely to be older and have hypertension and higher
levels of D-dimer. Similarly, among 50 patients with ischemic stroke admitted in
Wuhan, China, there was more comorbidity, lower platelet counts and leukocyte counts,
and the patients had higher levels of D-dimers, cardiac troponin I, NT probrain natriuretic
peptide, and interleukin-6 . The strokes are commonly labeled as cryptogenic. In
a retrospective review of 32 patients with COVID-19, 65.6% had cryptogenic stroke
compared with 30.4% of contemporary controls (p = 0.003) and 25% of historical controls
(p < 0.001). The next most frequent stroke category was cardioembolism (22%) .
It should be noted that diagnostic investigations could not be completed in some patients
with COVID-19 and this might have contributed to the high rate of cryptogenic strokes.
Strokes in patients with COVID-19 may be due to usual causes such as atherosclerosis,
hypertension, and atrial fibrillation. In this review, however, we focus on mechanisms
of stroke that appear to be directly related to COVID-19. It seems likely that these
COVID-19-related mechanisms would also increase the risk of stroke in infected persons
who harbor the more conventional stroke risk factors.
Three main mechanisms appear to be responsible for the occurrence of ischemic strokes
in COVID-19 [8, 9] (Fig. 1). These include a hypercoagulable state, vasculitis, and
cardiomyopathy. While the pathogenesis of hemorrhagic strokes in the setting of COVID-19
has not been fully elucidated, it is possible that the affinity of the SARS-CoV-2
for ACE2 receptors, which are expressed in endothelial and arterial smooth muscle
cells in the brain, allows the virus to damage intracranial arteries, causing vessel
wall rupture. In addition, it is possible that the cytokine storm that accompanies
this disorder could be the cause of hemorrhagic strokes, as reported in a COVID-19
patient who developed an acute necrotizing encephalopathy associated with late parenchymal
brain hemorrhages . This massive release of cytokines may also damage and result
in breakdown of the blood-brain barrier and cause hemorrhagic posterior reversible
encephalopathy syndrome (PRES) . Secondary hemorrhagic transformation of ischemic
strokes has also been reported in COVID-19 patients [3, 12]. Such transformation may
occur in the setting of endothelial damage or a consumption coagulopathy accompanying
Lee et al.  reported that 20–55% of patients hospitalized with COVID-19 have laboratory
evidence of coagulopathy, with increased levels of D-dimer to above twice normal,
slight prolongation of prothrombin time (1–3 s above normal), mild thrombocytopenia,
and in late disease, decreased fibrinogen levels. A D-dimer level above 4 times normal
was associated with a 5-fold increase in the likelihood of critical illness.
Thachil et al.  published guidance on recognition and management of coagulopathy
in COVID-19 from the International Society for Thrombosis and Haemostasis. They recommended
monitoring of prothrombin time, D-dimer, platelet count, and fibrinogen and prophylactic
anticoagulation with low-molecular weight (LMW) heparin in all patients with COVID-19.
Yaghi et al.  reported that high levels of D-dimer were more common among patients
with stroke and COVID-19 and suggested that hypercoagulability may underly much of
stroke in this disease. They indicated that a randomized trial of therapeutic anticoagulation
versus prophylactic anticoagulation is underway.
Antiphospholipid antibodies (anticardiolipin and anti-β-glycoprotein I antibodies)
have been documented in COVID-19 patients with multiple hemispheric infarcts and with
concomitant elevation of prothrombin time, activated partial thromboplastin time (aPTT),
fibrinogen, D-dimer, and CRP . The lupus anticoagulant was reported to be present
in 45% of patients with COVID-19 versus only 10% with anticardiolipin antibody in
a study in France (n = 50) . In another study, the lupus anticoagulant was documented
in 31 of 34 (91%) COVID-19 patients who had an elevated aPTT, but the frequency of
venous thromboembolism was low in this group (2 patients; 6%) . The significance
of these findings is unclear as antiphospholipid antibodies were present in subjects
with multiple other features of hypercoagulability, and the isolated finding of lupus
anticoagulant was not associated with high risk of thromboembolism.
In some patients, the combination of thrombocytopenia, prolonged prothrombin time,
increased D-dimer and lactate dehydrogenase levels, and decreased fibrinogen concentrations
is consistent with consumption coagulopathy that typically occurs in disseminated
intravascular coagulation (DIC). Postmortem studies in patients dying of COVID-19
show microvascular platelet-fibrin-rich thrombotic depositions in the lungs as well
as in other organs [18, 19, 20]. It has been suggested that viral invasion of the
vascular endothelium triggers activation of the contact and complement systems which,
in turn, initiates thrombotic and inflammatory cascades leading to internal organ
injury [19, 21]. Weidman et al.  reviewed the role of inflammation in thrombosis
While the relevance of microvascular thrombosis is becoming increasingly clear, a
substantial proportion of patients with severe COVID-19 also develop large vessel
occlusion. Although in situ thrombosis has been postulated to cause large artery occlusion,
this seems unlikely. Red thrombus forms in the setting of stasis; it contains more
entrapped red blood cells and less platelets. White thrombus, which forms in the setting
of fast flow/high shear rates, contains less entrapped red blood cells and more platelet
aggregates [23, 24, 25]. Red thrombus in large arteries probably forms only after
a plaque rupture or arterial dissection and in fusiform aneurysms. Many of the patients
with large artery occlusion have been younger patients with no vascular risk factors,
so unlikely to have large plaques with plaque rupture. Bangalore et al.  report
that 33% of COVID-19 patients with myocardial infarction did not have obstructive
coronary artery disease. At Mt. Sinai Hospital in New York, after thrombectomy, most
of the large arteries with occlusive thrombus appeared normal (M. Alberts, personal
communication, May 28, 2020). Escalard et al.  reported that among 10 patients
with stroke and COVID-19, 5 had large artery occlusions in multiple vascular territories.
This suggests that large artery occlusion in COVID-19 may be mainly cardioembolic/paradoxical.
In 2 studies, deep venous thrombosis occurred in 20–25% of patients admitted to critical
care [28, 29], and in another study this occurred despite prophylaxis with LMW heparin.
Klok et al.  reported that despite prophylaxis with LMW heparin, 31% of the 100
patients with COVID-19 pneumonia admitted to the ICU had an arterial (3.7%) or venous
(96.3%) thrombotic manifestation; all arterial events were strokes, and 81% of all
thrombotic events were pulmonary emboli. They suggested that prophylaxis should be
implemented with higher than usual doses of LMW heparin. In a recent autopsy study
of 12 cases from Germany, fresh thrombus in the deep venous system was detected in
7; in addition, there was a fresh thrombus in the prostatic venous plexus in 6 cases
. In a French study, 79% of 34 patients admitted to the ICU had DVT at 48 h after
admission . These findings suggest that paradoxical embolism could be a plausible
mechanism of stroke in some patients with COVID-19 coagulopathy. Indeed, paradoxical
embolism may account for some or many of the large artery ischemic strokes in young
people, including extracranial occlusion of the common and internal carotid artery
SARS-CoV-2 causes clinical COVID-19 by its affinity for the ACE2 receptors that are
expressed in the lungs, heart, kidneys, and small bowel. These receptors are also
abundant in the vascular endothelium , where infection elicits an inflammatory
response (a lymphocytic “endotheliitis”)  that has been postulated as one of the
substrates for the thrombotic complications of this infection. In a recent pathological
study in patients with COVID-19 infection (2 autopsies and 1 surgical biopsy), Varga
et al.  documented viral inclusions in endothelial cells in the kidneys, heart,
lungs, and small bowel, with associated widespread endothelial dysfunction and apoptosis.
The authors speculated that a virus-induced state of systemic impaired microcirculatory
function in different vascular beds may form the basis for the multiorgan failure
that characterizes the severe cases of COVID-19. Vessels may not only be inflamed
by a direct local effect of SARS-CoV-2 on the ACE2 receptors in the vascular endothelium
but also by a systemic immune response to the pathogen (“cytokine storm”). In the
case of COVID-19, several cytokines, including IL1B, IFNγ, IP10, and MCP1 have been
found to be markedly elevated, especially in patients with severe disease and high
rates of mortality .
Ackermann et al.  reported an autopsy series of 7 cases of COVID-19 compared with
7 cases of influenza. They noted that distinctive pulmonary features in COVID-19 included
diffuse alveolar damage with perivascular T-cell infiltration, severe endothelial
injury associated with the presence of intracellular virus and disrupted cell membranes,
widespread thrombosis with microangiopathy, and angiogenesis .
The role that these various vascular and immune-mediated factors play in the pathogenesis
of stroke in COVID-19 patient remains unclear. More data are needed regarding angiographic
and postmortem studies of the cervical-cerebral vasculature in order to evaluate the
presence and magnitude of vasculitis and its potential role in in-situ clot formation
as a potential mechanism of ischemic stroke. It seems unlikely that angiography will
disclose an endotheliitis, although it may show large vessel occlusion. The large
vessel occlusions are also in atypical locations, such as extensive thrombus emanating
from the common carotid artery. Whether such large artery thrombi form at the site,
or are embolic, remains to be determined. As discussed above and below, it seems likely
that some or many of the large artery occlusions may be embolic.
The clinical stroke observations have included instances in which predominantly large-vessel
territorial infarcts have occurred in subjects with conventional risk factors (age,
hypertension, diabetes, atrial fibrillation, and ischemic heart disease) who were
infected by SARS-CoV-2 and had high levels of inflammatory markers (such as CRP and
ferritin) and markers of coagulation and fibrinolysis (such as D-dimer, fibrinogen,
and lupus anticoagulant) . The vascular images provided were indicative of large
vessel occlusion without features to suggest an alternative mechanism such as multifocal
or widespread vascular wall inflammation (vasculitis). A recent report from Italy
compared stroke patients with (n = 43) and without (n = 68) COVID-19. Baseline characteristics
including age, sex, and vascular risk factors were similar between the 2 groups .
Hemorrhagic strokes were less common in COVID-19 patients (7.0 vs. 13.4%). However,
initial stroke severity, measured by the NIHSS, was greater in COVID-19 than in non-COVID-19
patients (10 vs. 4), suggesting involvement of large vessels. Unfortunately, neither
vessel images nor stroke subtype classification were reported. Other small series
have confirmed cases of large vessel vascular occlusion, and some authors have stressed
a high frequency of stroke in young COVID-19 subjects (ages 33–49) with a low prevalence
of conventional stroke risk factors and elevated markers of inflammation (ferritin)
and coagulation (D-dimer and fibrinogen) . The high frequency of ischemic stroke
in young subjects with COVID-19 and a paucity of vascular risk factors raises the
possibility that mechanisms peculiar to COVID-19 may be responsible. These could include
abnormalities in the vascular endothelium related to direct viral invasion and inflammation
(“endotheliitis”), along with the results of a “cytokine storm” (commonly observed
in this patient group).
A virus-induced prothrombotic state may play an additional role, potentially synergistic,
in the pathogenesis of ischemic strokes of all types in COVID-19 patients. An additional
prothrombotic factor is impaired endothelial expression of heparan sulfate, which
promotes thrombosis . It is clear that more data in this area are required in
order to establish more precisely the potential contribution of these various processes
in the pathogenesis of stroke in COVID-19 patients.
There are a number of mechanisms for cardiac involvement in COVID-19 patients [38,
39, 40]. There may be direct invasion by the virus, causing a myocarditis, with resultant
injury and even death of cardiomyocytes. This may due to the affinity of the virus
for ACE2, a membrane-bound aminopeptidase, which acts as a portal of viral entry,
and downregulation of ACE2, leading to myocardial dysfunction . The heart may
also be indirectly affected by the systemic inflammatory state during the severe phase
of the infection related to the cytokine storm where many “bystander” end-organs are
There is also increased cardiac stress due to respiratory failure and hypoxemia from
the infection, leading to stress cardiomyopathy. An additional possible mechanism
for cardiac damage in COVID-19 is stimulation of the sympathetic nervous system, predisposing
to stress cardiomyopathy and cardiac arrhythmias [41, 42]. These may lead to arrhythmias
and heart failure with preserved ejection fraction. The consequent intracardiac thrombus
formation, possibly compounded by the hypercoagulable states, raises the risk of subsequent
cardioembolic stroke. Some of the published case series of stroke during COVID-19
have not evaluated cardioembolic mechanisms [8, 9].
An early report from China and the previous report from Singapore on SARS-CoV-1 infection
developing stroke during that 2002–2003 outbreak demonstrated cardioembolic mechanisms
in 36 and 60% of their cases, respectively . Yaghi et al.  reported that stroke
patients with COVID-19 were more likely to be young men with elevated troponin levels
compared with historical controls.
Implications for Therapy
All patients admitted to intensive care should receive prophylaxis against venous
thrombosis, with at least LMW heparin . In patients with stroke, a cardioembolic
mechanism should be strongly suspected, and if there are findings to support that
suspicion, such as infarction in multiple cerebral vascular territories (or systemic
and cerebral emboli), cardiomyopathy with significant ventricular dyskinesia, atrial
fibrillation, or right-to-left shunt, the patient should probably receive therapeutic
doses of anticoagulation .
A theoretical consideration, based on the experience of Klok et al. , is that
perhaps DOACs (which target only one clotting factor) might be less effective than
heparin or warfarin, which target multiple clotting factors [45, 46]. Warfarin interferes
with the synthesis of factors II, VII, IX, and X . Atarashi et al.  suggested
that the reason warfarin causes more intracerebral hemorrhage is that it targets factor
VII. It seems likely that interference with multiple clotting factors may be why warfarin
is more effective than DOACs in patients with mechanical heart valves [48, 49, 50].
Tang et al.  reported that anticoagulation reduced mortality in COVID-19 patients
with coagulopathy. In reply, Asakura and Ogawa  noted that some features of the
coagulopathy in COVID-19 suggest DIC and recommended a combination of heparin and
nafamostat mesylate, a treatment used for DIC in Japan. Thachil et al.  responded
with a discussion of possible benefits of unfractionated heparin versus LMW heparin.
Besides anticoagulation, there may be reason to consider thrombolytic therapy. Wang
et al.  suggested from a small case series that tissue plasminogen activator may
be beneficial in acute respiratory distress syndrome in COVID-10.
Based on their benefit as anti-inflammatory agents in cardiovascular clinical trials,
therapies such as IL-6R monoclonal antibodies (tocilizumab), TNF-α inhibitors (etanercept
and infliximab), and IL-1β antagonists (the monoclonal antibody canakinumab and the
anti-cytokine anakinra) have been suggested as potentially beneficial for COVID-19
patients . However, the main concern related to the use of immunosuppression,
including corticosteroids, is that it may delay the elimination of the virus 
and increase the risk of secondary infection, especially in those with an impaired
immune system .
Though there is no evidence from randomized controlled trials, anti-inflammatory agents,
including corticosteroids, are empirically used for severe complications in patients
with COVID-19, such as ARDS, and acute cardiac and renal involvement . Whether
systemic corticosteroids or other anti-inflammatory agents can be of value in the
selected cases of stroke in which vasculitis is suspected is a matter of debate. Neurologists
should carefully balance the risk and benefit ratio before starting anti-inflammatory
Beigel et al.  reported that in a randomized controlled trial in 1,059 patients
hospitalized for COVID-19, remdesivir was associated with a shorter median recovery
time (11 days, 95% CI: 9–12), compared with placebo (15 days, 95% CI: 13–19), and
a lower 14-day mortality of 7.1% with remdesivir versus 11.9% with placebo (hazard
ratio for death, 0.70; 95% CI: 0.47–1.04). Stroke was not mentioned in the report.
The list of clinical trials registered at ClinicalTrials.gov can be found at https://clinicaltrials.gov/ct2/results?cond
= COVID-19. Important therapeutic targets in these trials include virus neutralization,
prevention and treatment of thrombotic complications, and inhibition of the cytokine
storm. Such trials test a wide range of therapies from convalescent and hyperimmune
plasma for virus neutralization to tissue plasminogen activator for treatment of microvascular
thrombosis and from hemodialysis with reconditioning of immune cells to complement
inhibitors, selective cytokine inhibitors, and colchicine to prevent the cytokine
storm, based on a study on coronary artery disease .
A number of mechanisms are involved in stroke in COVID-19, including a hypercoagulable
state, DIC, necrotizing encephalopathy, vasculitis, and cardiomyopathy. It seems likely
that anticoagulation will play a substantial role in the management of stroke in COVID-19.
Further evidence is needed from larger studies.
Conflict of Interest Statement
Dr. Ay is employed by Takeda Pharmaceutical Company Limited; none of the other authors
has a disclosure that is relevant to this topic.
J.D.S. wrote the first and final draft; each of the other authors contributed to revisions.