COVID-19 Disease and Hypercoagulability Leading to Acute Ischemic Stroke

Abstract

Introduction:

SARS-Coronavirus-2 infection leading to COVID-19 disease presents most often with respiratory failure. The systemic inflammatory response of SARS-CoV-2 along with the hypercoagulable state that the infection elicits can lead to acute thrombotic complications including ischemic stroke. We present 3 cases of patients with COVID-19 disease who presented with varying degrees of vascular thrombosis.

Cases:

Cases 1 and 2 presented as cerebral ischemic strokes without respiratory failure. Given their exposure risks, they were both tested for COVID-19 disease. Case 2 ultimately developed respiratory failure and pulmonary embolism. Cases 2 and 3 were found to have simultaneous arterial and venous thromboembolism (ischemic stroke and pulmonary embolism) as well as positive antiphospholipid antibodies.

Conclusion:

Our case series highlight the presence of hypercoagulability as an important mechanism in patients with COVID-19 disease with and without respiratory failure. Despite arterial and venous thromboembolic events, antiphospholipid and hypercoagulable panels in the acute phase can be difficult to interpret in the context of acute phase response and utilization of thrombolytics. SARS-CoV-2 testing in patients presenting with stroke symptoms may be useful in communities with a high case burden or patients with a history of exposure.

Introduction

Severe Acute Respiratory Coronavirus-2 (SARS-COV-2) first appeared in December 2019 in Wuhan, China, and rapidly emerged as the first non-influenza pandemic of the 21st century.¹ The resultant syndrome due to infection by SARS-CoV-2 was named Coronavirus disease 2019 (COVID-19). This infection leads to severe respiratory illness which can progress to multi-organ failure including intravascular coagulopathy. As a result, reports of both venous and arterial thromboembolism have emerged and may be related to the systemic inflammatory response, diffuse intravascular coagulation and an overall trend toward a state of hypercoagulability.²

The neurological manifestations of COVID-19 disease have been reported in several retrospective cohorts of patients, including a case study by Mao et al of 214 patients with SARS-CoV-2 infection in which patients with severe disease had less typical symptoms of fever, respiratory symptoms but had higher burden of neurological manifestations.^2,3 Acute cerebrovascular complications of COVID-19 disease may be associated with arterial thromboembolism as a result of the diffuse inflammation and hypercoagulability induced by SARS-CoV-2.^2,3

Acute cerebrovascular complications may be underestimated in patients with COVID-19 disease due to increased usage of sedation and paralytics to manage respiratory failure that may mask neurological deficits. Additionally, due to concerns of exposure and transmission involved with transporting these patients, there may be underutilization of neurological consultation, neuroimaging and electroencephalography (EEG) leading to confounding factors that prevent estimation of the true prevalence of cerebrovascular disease burden in these patients. The timing and mechanisms of cerebrovascular disease during the course of illness are not well known. In some patients, neurological manifestations may be the only presenting symptom. We report a series of 3 patients with COVID-19 presenting with acute ischemic stroke.

Case 1

A 73-year-old female with a history of hypertension and diabetes mellitus (DM) working at a local nursing home presented with the chief complaint of altered mental status. Her symptoms began 3 weeks prior to presentation with family describing the patient as being lethargic and intermittently confused. These symptoms progressed to being found unresponsive at her workplace on the day of admission. Neurological exam was significant for generalized weakness and severe expressive aphasia leading to a National Institutes of Health Stroke Scale (NIHSS) score of 15. Computerized tomography (CT) of the brain revealed hypodensities within the left parietal lobe and right cerebellum suggestive of ischemic stroke. She was not a candidate for intravenous thrombolysis due to presentation outside of the time window. Pertinent laboratory results obtained on admission to the hospital are summarized in Table 1. They included elevated BUN and creatinine, thrombocytopenia, elevated D-dimer, fibrinogen and activated plasma thromboplastin time. Continuous electroencephalography monitoring for 24 hours demonstrated generalized slowing without epileptiform discharges or seizures. Magnetic resonance imaging (MRI) of the brain with gadolinium contrast confirmed multifocal acute-subacute infarctions located both supratentorial and infratentorial including left inferior parietal lobule, left temporal and occipital lobes, bilateral cerebellar hemisphere and scattered throughout the subcortical white matter bilaterally (Figure 1A-1D). There was no evidence of intracranial vessel stenosis or occlusion. Her electrocardiogram was unremarkable and her telemetry throughout the hospital stay did not show any arrhythmia. Twenty-four hours after admission she developed a fever of 38.9°C. Although she had no respiratory symptoms, given fever and history of COVID-19 exposure at her workplace, COVID-19 nasopharyngeal polymerase chain reaction (PCR) was tested and returned positive. Her stroke mechanism was thought to be secondary to the hypercoagulable state from COVID-19 infection with early disseminated intravascular coagulation. She was treated with aspirin and atorvastatin for secondary stroke prevention. The patient remained mildly encephalopathic and ultimately discharged to a skilled nursing facility for further rehabilitation.

Table 1.

Characteristics of Patients With Acute Ischemic Infarction and COVID-19 Disease.

	Case 1	Case 2	Case 3
Demographics
Age (years)/Sex	73/Female	43/Female	51/Male
COVID-19 exposure	Healthcare related	Healthcare related	Unknown
Clinical history and course
Comorbidities	HTN, Type 2 DM, CKD stage 3	None	Type 2 DM
Fever during hospitalization	present	present	present
Respiratory symptoms	No	No	Yes
Neurological symptoms	Encephalopathy, Quadriparesis, aphasia	Right-sided hemiplegia, aphasia, gaze preference	Encephalopathy, left-sided hemiplegia, aphasia
Initial NIHSS (range 0-42)	15	27	22
Stroke symptom onset since infection (days)	21	7-10	8
Systemic thromboembolism	No	Pulmonary embolism	Pulmonary embolism
Stroke mechanism	Hypercoagulability	Hypercoagulability	Hypercoagulability
Thrombolysis	No	Yes	No
Recanalization grade (thrombolysis in cerebral ischemia grade)	NA	TICI 3	TICI 2B
Intensive care unit length of stay (days)	1	2	13
Intubation (yes/no)	no	yes	yes
Days on mechanical ventilation	0	1	8
Neuroimaging findings
Ischemic stroke	Multifocal, anterior and posterior circulation	Left striatocapsular infarction, anterior circulation	Multifocal, anterior circulation
Large artery atherosclerosis on angiography	No	No	No
Hemorrhagic conversion	No	No	No
Large vessel occlusion	No	Yes	Yes
Discharge
Discharge NIHSS	12	6	27
Discharge disposition	Skilled nursing facility	home	Long term acute care facility
COVID-19 viremia clearance at discharge on repeat testing	No (positive at discharge)	Unknown	No (positive on day 4;14 and negative on days 12; 13)

Figure 1.

Neuroimaging findings in patients with COVID-19 disease and acute ischemic infarction. Images A-D: Magnetic resonance diffusion-weighted imaging sequence (MR-DWI) showing bilateral supratentorial and infratentorial infarcts. Images E-F: Computerized tomography of the brain axial sections showing left striatocapsular infarction (white arrows). Images G-J: MR-DWI showing bilateral anterior cerebral artery and right middle cerebral artery territory and borderzone infarction.

Case 2

A 43-year-old female nursing home manager without medical history presented to the emergency department (ED) with the chief complaint of right-sided weakness, aphasia and left gaze preference and a NIHSS of 27. CT-brain showed a hyperdense left middle cerebral artery sign. CT angiography (CTA) of the head and neck demonstrated tandem occlusions of the left internal carotid artery and left middle cerebral artery (MCA) M1 and M2 segments). Incidentally the CTA also demonstrated a saddle pulmonary embolism (PE) but oxygen saturation was normal on room air without signs of respiratory distress. Intravenous thrombolysis with tissue plasminogen activator (IV-TPA) was administered. The patient was electively intubated prior to mechanical thrombectomy. Complete recanalization was achieved on the first pass of the mechanical thrombectomy (TICI 3). Given her recent exposure to COVID-19 patients at her workplace and a subjective history of fever, she was tested for COVID-19 and returned positive. A Point of care Echocardiogram did not show any right heart strain and her ejection fraction was normal. Laboratory results on admission are listed in Table 1, results included mild thrombocytopenia, hypercoagulable panel and antiphospholipid antibodies results showed decreased protein C, plasminogen activity and equivocal cardiolipin IgM level. Follow up CT-brain showed left basal ganglia infarction (Figure 1). She was started on an intravenous heparin infusion for PE and later transitioned to rivaroxaban. Her electrocardiogram was unremarkable, and no arrhythmias were observed during her stay. The stroke mechanism was hypothesized due to hypercoagulability given the simultaneous arterial and venous thromboembolism. On day 3, her symptoms improved significantly with residual mild right-sided weakness, dysarthria and anomia (NIHSS 5). She was discharged home to self-quarantine for 2 weeks with close neurology follow up appointments.

Case 3

A 51-year-old male with a history of type 2 DM presented to an outside hospital with abdominal pain and myalgia. During hospitalization, he developed acute respiratory failure and encephalopathy requiring intubation for airway protection and hypoxemia. COVID-19 PCR testing was positive. Laboratory values are mentioned in Table 1. They were significant for lymphopenia, elevated acute phase reactants like c reactive protein, ferritin levels. Coagulation profile was abnormal with elevated fibrinogen and d-dimer levels on admission. Antiphospholipid antibody panel was unremarkable. On day 8, he developed left sided hemiplegia and aphasia and his NIHSS was 22. CT-brain was unremarkable, but CTA-head and neck showed occlusion of the supraclinoid ICA and right anterior cerebral artery. He was transferred to our facility for mechanical thrombectomy and additionally intra-arterial tirofiban infusion was administered for residual thrombus. Emergent carotid angioplasty and stenting was also performed due to critical ICA stenosis. His follow up MRI-brain showed bilateral ACA and right MCA infarctions with petechial hemorrhage (Figure 1). He was extubated to nasal cannula oxygen on day 10. On day 14, he developed recurrent acute hypoxemic respiratory failure due to aspiration pneumonia and bilateral subsegmental pulmonary embolism requiring reintubation and was extubated on day 18. He was subsequently discharged to a long-term acute care hospital on day 20 with residual quadriparesis and severe aphasia.

Discussion

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causing Coronavirus 2019 disease first discovered in Wuhan China in 2019. Although the point of viral entry is via the respiratory epithelium and the first described cases involved pneumonia with severe acute respiratory distress syndrome (ARDS), as more manifestations of the disease are being reported there is mounting evidence demonstrating that the virus has multi-system effects.¹

The central nervous system (CNS) manifestations of COVID-19 disease have been documented in reports of neurological symptoms including focal neurological deficits, seizures, headaches and dizziness initially in a retrospective cohort of patients from Wuhan, China.² Acute cerebrovascular complications and moderate to severe encephalopathy were seen in 5.7% and 14.7% in the severe disease cohort respectively.² Li et al., in their retrospective observational cohort of 221 patients, reported 5% incidence of acute ischemic stroke, with a mortality of 54.5% in the stroke cohort.³ Ischemic strokes as a manifestation of the related thrombotic events in these patients may be related to the increased inflammatory response to the virus and an overall state of hypercoagulability. A Dutch cohort of intensive care unit patients with COVID-19 disease reported a 31% incidence of thrombotic events including both arterial and venous thromboembolic events.⁴ Additionally, a case series of young patients in New York with COVID-19 disease and ischemic stroke secondary to large vessel occlusion adds to the observational studies which hypothesize that strokes in this patient population may be related to mechanisms of hypercoagulability and endothelial dysfunction induced by SARS-CoV-2 infection.⁵

Our case series describes 3 patients with both arterial ischemic strokes and 2 of these patients with concomitant arterial and venous thromboembolism (pulmonary embolism and ischemic strokes) highlighting the association with thromboembolic disease and Sars-CoV-2 infection. The mechanisms for ischemic stroke in COVID-19 disease are likely multifactorial. In addition to thromboembolism, hypercoagulability from low-grade disseminated intravascular coagulopathy, endothelial and platelet activation from neurotropism and systemic inflammatory response may play a significant role.⁴ Coagulopathy associated with severe COVID 19 disease and sepsis has been reported, likely with endothelial dysfunction and microthrombosis. Endothelial dysfunction induced by severe infection leads to a hypercoagulable state by increasing thrombin generation and decreasing fibrinolysis.⁶ This can be reflected in lab results of patients with features of sepsis induced coagulopathy including thrombocytopenia with elevated D-dimer, fibrinogen levels and prolonged prothrombin times.⁷ In our patients several of them had features of sepsis induced coagulopathy including elevated fibrinogen and D-dimer levels, abnormal coagulation profiles and all 3 had borderline thrombocytopenia (Table 2). Another observation series of patients from the United Kingdom also demonstrated 6 cases of large vessel occlusion strokes in their group with COVID-19 disease who also had markedly elevated D-dimer levels.⁸

Table 2.

Laboratory Tests and Coagulation Profile of Patients With COVID-19 Disease and Acute Ischemic Infarction.

Laboratory tests (Numbers in parentheses shows the day on which the lab was drawn)
Admission White cell count (thousand/cmm)	7.65	9.18	5.00
Lymphopenia	present	NA	present
Nadir Platelet count (thousand/cmm) (normal range 182-369)	127 (6)	150 (2)	183 (1)
Peak blood urea nitrogen (mg/dl) (normal range 7-18)	31 (1)	12 (1)	26 (16)
Peak creatinine (mg/dl) (normal range 0.51-0.95)	1.79 (1)	0.9 (1)	1.04 (1)
Low density lipoprotein level (mg/dl) (normal range 0-99)	57	80	90
Triglyceride level (mg/dl) (normal range 0-149)	53	112	255
Hemoglobin A1c (normal range 4-5.6%)	7.5%	5.5%	12.2%
Peak C-reactive protein (mg/dl) (normal range 0-0.8)	NA	4.2 (1)	22.1 (18)
Peak Ferritin (ng/dl) (normal range 14.7-205.1)	NA	42.6 (2)	1650 (8)
Coagulation profile
Prothrombin time (seconds) (normal range 9.7-13 seconds)	NA	10.3 (1)	10.8 (13)
Activated thromboplastin time (seconds) (normal range 23-32.4 seconds)	38.7 (1)	24.2 (1)	21.9 (13)
Peak Fibrinogen (mg/dl)(normal range 200-400)	501 (3)	301 (1)	710 (16)
Peak D-dimer (ng/dl) (normal range <500)	1140 (3)	NA	8140 (8)
Hypercoagulable panel	NA	Decreased protein C and plasminogen activity (reflects thrombosis and thrombolytic use)	Borderline elevated protein C and plasminogen activity (possible acute phase response)
Antiphospholipid antibodies	NA	Cardiolipin antibody IgM elevated (12 MPL; 10-40 MPL Equivocal)	Cardiolipin antibody IgA and IgM elevated (15 APL and 16 MPL; 10-40 Equivocal)

Two of our patients also had antiphospholipid antibodies present in the form of elevated IgA and IgM anticardiolipin antibodies along with other markers of infection induced coagulopathy. Both of these patients also had pulmonary embolism along with their large vessel occlusion (LVO) ischemic strokes. The presence of these antibodies in the setting of acute infection should be interpreted with caution since they can be elevated transiently during critical illness or systemic infection without a diagnosis of antiphospholipid antibody syndrome.⁹ However the simultaneous presentation of both acute LVO ischemic strokes along with pulmonary embolism, along with typical laboratory markers of infection induced coagulopathy supports the hypothesis that SARS-CoV-2 infection may have been a contributor to the etiology of ischemic stroke in our case series.

One of the limitations of our case was the inability to obtain formal echocardiograms as a part of the evaluation of stroke etiology. These cases presented to our institution during the peak of the pandemic and as a result resources were limited for evaluation especially in the setting of hemodynamic stability and attempts to reduce exposure and conserve personal protective equipment. One of our cases which presented with a pattern of embolic strokes involving both anterior circulation and posterior circulation territories may have benefited from an echocardiogram to evaluate alternative etiologies to COVID-19 induced coagulopathy as a cause of the strokes. However, the presence of concomitant COVID-19 disease, abnormal coagulation markers and other markers of endothelial dysfunction provides us supporting evidence for our hypothesis.

Conclusion

Reports of arterial and venous thromboembolic events secondary to the hypercoagulability precipitated by COVID-19 infection continue to emerge. COVID-19 disease creates a pro-inflammatory and procoagulant state that has led to our series of patients developing both acute ischemic strokes and venous thromboembolic disease. At times these focal neurological symptoms may occur in isolation without typical respiratory symptoms. Therefore, COVID-19 testing may be warranted in patients presenting with stroke-like symptoms despite a paucity of respiratory symptoms or hypoxemia especially in areas with a high density of COVID-19 cases, as in our region and should also be considered at this time in patients with embolic strokes of unknown source. Despite their systemic inflammation and infection these patients can still respond to timely reperfusion techniques including intravenous thrombolysis and mechanical thrombectomy. Although there is a concern regarding transmission and minimizing invasive therapies in these patients; the decision to treat ischemic stroke should not be delayed or withheld while waiting for results of SARS-CoV-2 infection testing.

Our series also highlights the importance of recognizing the neurological effects of hypercoagulability in COVID-19 patients and timely intervention to provide reperfusion therapies. COVID-19 testing in patients presenting with stroke symptoms may be useful in communities with a high case burden or patients with a history of exposure.