Journal of Critical Care 60 (2020) 106–110

Contents lists available at ScienceDirect

Journal of Critical Care
journal homepage: www.journals.elsevier.com/journal-of-critical-care

Severe arterial thromboembolism in patients with Covid- 19
Joost R.C. Lameijer, MD a,⁎, Joris van Houte, MD b, Marijn M.G. van Berckel, MD c,
Leo R. Canta, MD d, Lonneke S.F. Yo, MD a, Marten R. Nijziel, MD PhD e, G.M. Krietemeijer, MD a,
Stephanie A.M. Troquay, MD a, Marc P. Buise, MD PhD b, Joris Hendriks, MD a
a

Department of Radiology, Catharina Hospital Eindhoven, the Netherlands
Department of Anesthesiology and Intensive Care, Catharina Hospital Eindhoven, the Netherlands
Department of Surgery, Catharina Hospital Eindhoven, the Netherlands
d
Department of Neurology, Catharina Hospital Eindhoven, the Netherlands
e
Department of Haematology, Catharina Hospital Eindhoven, the Netherlands
b
c

a r t i c l e

i n f o

Available online xxxx

Keywords:
Thrombosis
COVID-19
Disseminated intravascular coagulation
Anti-coagulant therapy
Coagulopathy
Imaging

a b s t r a c t
Introduction: The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has emerged early December 2019 and was recently confirmed by the World Health Organization (WHO) to be a public health emergency of international concern. Earlier reports have shown coagulopathy in patients with severe coronavirus
disease 2019 (Covid-19).
Main symptoms and important clinical findings: We present four critically ill Covid-19 patients, who were admitted
to our hospital. They were treated with supportive care, oral chloroquine, and standard 2500 or 5000 International Units (IU) of dalteparine subcutaneously once daily. Two patients died during the course of their stay as
a consequence of severe large vessel arterial thromboembolism. The other two patients survived but symptoms
of paralysis and aphasia persisted after cerebral ischemia due to large vessel arterial thromboembolism. Patients
showed no signs of overt disseminated intravascular coagulation (DIC) in their laboratory analysis.
Conclusion: This case series suggest that even in absence of overt DIC, arterial thromboembolic complications
occur in critically ill patients with Covid-19. Further studies are needed to determine which parameters are useful
in monitoring coagulopathy and which dose of anti-thrombotic therapy in Covid-19 patients is adequate, even
when overt DIC is not present.
© 2020 Elsevier Inc. All rights reserved.

1. Introduction
The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) emerged in Wuhan, the capital city of the Hubei province in
China at the end of 2019 [1,2]. Infection with SARS-CoV-2 results in coronavirus disease 2019 (Covid-19). In the United States alone over
2,000,000 patients were already diagnosed with Covid-19, and the
World Health Organization has declared Covid-19 a public health emergency of international concern [3,4].
Recent reports and studies suggest that Covid-19 can cause coagulopathy in severe cases, which has a negative prognostic factor for survival. The majority of non-survivors with Covid-19 show signs of
disseminated intravascular coagulation (DIC) [5-7]. Recent studies
mainly focus on pulmonary thromboembolism and small arterial vessel
disease. [8-11] Only small patient series are available on systemic arterial thromboembolic disease of the larger vessels. [12-14]
⁎ Corresponding author at: Catharina Hospital Eindhoven, PO Box 1350, 5602 ZA
Eindhoven, The Netherlands.
E-mail address: joost.lameijer@catharinaziekenhuis.nl (J.R.C. Lameijer).

We present four cases of Covid-19 patients, who presented with
large vessel arterial thromboembolic disease, without showing signs
of overt DIC. These cases highlight the importance of recognizing signs
of arterial thromboembolism in critically ill Covid-19 patients. It also
emphasizes the importance of monitoring the presence of
hypercoagulopathy, which may have implications for adjustment of
anti-coagulant treatment regimens in these critically ill patients.
2. Patients
2.1. Patient 1
A 58-year-old male was admitted to our hospital on March 27, 2020.
He had a history of psoriasis and psoriatic arthritis for which he used
methotrexate from 2011 until 2016. He presented to the ER with
cough, fever and malaise which had started 12 days earlier. His chest radiograph showed signs of peripheral consolidations, and real-time
reverse-transcriptase–polymerase-chain-reaction (rRT-PCR) proved
positive for SARS-CoV-2. A summary is provided in Table 1. He received
daily subcutaneous injections of 2500 IU of dalteparin (body weight

J.R.C. Lameijer et al. / Journal of Critical Care 60 (2020) 106–110

107

Table 1
Characteristics and laboratory analysis of patients.
Characteristics

Patient 1

Patient 2

Patient 3

Patient 4

Age
Sex
Medical History
Symptoms at onset

58
Male
Psoriasis and psoriatic arthritis
Cough, fever and malaise

81
Male
MGUS
Back pain, malaise, and fever

48
Male
None
Cough, fever, malaise

Thoracic imaging

CT: Extensive bilateral ground
glass opacity and consolidations

Radiograph: extensive bilateral
consolidations

Medication on admission

Dalteparin 2500 s.c.
Second generation
cephalosporin i.v.
Chloroquine oral
94 (91–98)
Nnasal cannula, 4 L O2)
93 (87–101)

Dalteparin 2500 s.c.
Second generation
cephalosporin i.v.
Chloroquine oral
96 (95–98)
Nasal cannula, tube after
admission ICU
85 (76–129

58
Female
Hypertension, gout
Cough, fever,
malaise
Radiograph:
extensive bilateral
consolidations
Dalteparin 2500 s.
c.
Second generation
cephalosporin i.v.
95 (93–98)
Nasal cannula (4 L
O2)
85 (74–101)

Bilateral occlusion of carotid
arteries, middle cerebral arteries
and proximal anterior cerebral
arteries
3

Extensive bilateral ischemia in
territory of middle and posterior
cerebral artery and superior
cerebellar arteries
8

3

2

Normal ward

ICU

Normal ward

Normal ward

No

Yes, 2 days before arterial
thromboembolism, noradrenalin

No

Deceased

Deceased

Alive, right sided
paralysis and
global aphasia

Yes, last administration 6 days
before arterial
thromboembolism, noradrenalin
Alive, minimal left sided
paralysis of the arm and leg,
severe aphasia

7.4
12.6 (+)
0.5 (−)
570 (+)
210 (+)
11
8.1 (+)
781 (+)
9.3
–
2.2 (+)
Not available

6.6
12.8 (+)
0.34 (−)
170
84 (+)
25
1.2
699 (+)
9.4
15.3 (+)
>4 (+)
4

7.2
8.9
1.2
320
49
7
–
176
4.6
–
>4 (+)
Not available

6.2
12.7
2.2
830
57
–
1.1
354 (+)
5.8
19.4 (+)
>20 (+)
4

Oxygen saturation (%)
during admission, mean
(range)
MAP (mmHg), mean
(range)
Diagnosis of arterial
thromboembolism

SOFA-score at diagnosis of
arterial
thromboembolism
Department at time of
diagnosis of arterial
thromboembolism
Vasopression/inotropy
during admission
Outcome

Parameter

Reference

Hemoglobin
Leukocyte count
Lymphocyte count
Thrombocyte count
CRP
Troponin-T
Lactate
LD
Total Bilirubin
PT
D-dimer
DIC-score (ISTH)

8.5–11.0 mmol/L
4.0–10.0 × 109/L
1.0–3.5 × 109/L
150–400 × 109/L
<6.0 mg/L
<30 ng/L
<1.3 mmol/L
<250 U/L
< 17 μmol/L
12.0–14.5 s
<0.8 mg/L

65 kg). Treatment with chloroquine was started orally (start dose
600 mg, followed by 300 mg twice daily).
On March 31, 2020, he was found unresponsive, with extensor posturing, and gasping breath. Under suspicion of stroke or intracranial
haemorrhage, an unenhanced CT-scan of the brain was performed
which showed no signs of ischemia or haemorrhage. CT-angiography
of the aortic arch, carotids and circle of Willis (Fig. 1) showed bilateral
occlusion of the carotid arteries, the middle cerebral arteries, and proximal anterior cerebral arteries. Laboratory analysis showed markedly elevated D-dimer values (Table 1). Due to severe neurologic decline and
the extensiveness of thrombosis with no possibilities for further treatment, palliative sedation was started and the patient died several
hours later.
2.2. Patient 2
An 81-year-old male was admitted to our hospital on March 22,
2020. He had a medical history of stable IgG kappa monoclonal

Radiograph: extensive bilateral
consolidations
Dalteparin 5000 s.c.
Haloperidol

97 (92–99)
Tube during admission to ICU,
nasal cannula on ward
81 (63–107)

Bilateral ischemia in territory of
Occlusion of the
left middle cerebral middle and posterior cerebral
arteries.
artery

gammopathy of unknown significance (MGUS). He presented
with back pain, malaise, and fever for seven days. A summary is
provided in Table 1. A chest radiograph showed extensive bilateral
consolidations, and rRT-PCR proved positive for SARS-CoV-2.
He received daily subcutaneous injections of 2500 IU of dalteparin
(body weight 75 kg). Treatment with chloroquine was started orally
(start dose 600 mg, followed by 300 mg twice daily).
His condition deteriorated and 5 days after admission he was transferred to the ICU. He was intubated and ventilated due to respiratory insufficiency. Laboratory analysis is shown in Table 1. When a wake-up
call was carried out by stopping all sedatives, the patient remained unresponsive and showed an abnormal breathing pattern on mechanical
ventilation.
An unenhanced CT-scan of the brain was performed (Fig. 2), which
showed extensive bilateral ischemia with haemorrhagic transformation
and oedema in the vascular territory of both middle cerebral arteries,
the posterior cerebral artery and superior cerebellar arteries on both
sides The patient died the same day after discontinuation of treatment.

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J.R.C. Lameijer et al. / Journal of Critical Care 60 (2020) 106–110

Fig. 2. Unenhanced CT-scan of the brain showing bilateral, diffuse ischemia in multiple
vascular territories with haemorrhagic transformation of ischemic areas.

Patient 4 was a 48-year old male without relevant medical history
who presented with minimal left-sided paralysis of the arm and leg,
brisk reflexes on the left side and severe aphasia in the course of his
Covid-19. An unenhanced CT showed bilateral ischemia in vascular territories of the middle and posterior cerebral arteries. There were no options for intra-arterial treatment in this patient. The patient has largely
recovered from his Covid-19 and was discharged recently. At the time
of discharge, he still suffered from aphasia, but had largely recovered
from his minimal left sided paralysis.
Patient characteristics and laboratory analyses are shown in Table 1.
Fig. 1. CTA of the carotid arteries. On the upper left panel, maximum intensity projection
(MIP) of the left carotid bifurcation is shown, on the upper right panel a MIP of the right
carotid bifurcation. White arrows indicate decreased contrast opacification in the
internal carotid arteries, the actual thrombus could not be visualized. In the lower panel
an axial MIP of the circle of Willis. The arrows indicate near complete absence of
vascular enhancement in the vascular territories of the anterior and part of the medial
cerebral arteries due to diffuse arterial thrombosis.

2.3. Similar patients
In the period of March 2020 until April 2020, two other Covid-19 patients at our institution presented with cerebral ischemia.
Patient 3 was a 58-year old female. She was transferred from another institution with sudden apathy and right-sided paralysis. She
had a medical history of hypertension and gout. CT-angiography
showed occlusion of the left middle cerebral artery, and a successful
intra-arterial mechanic thrombectomy was performed. She recovered
from her Covid-19. She still suffers from right sided paralysis at the
time of writing, as well as a global aphasia, however some improvements were seen during admission.

3. Discussion
In this case series, we report four patients with severe Covid-19, who
developed severe thromboembolism of cerebral arteries. Of importance
is that these patients had no medical history of clinically significant atherosclerotic disease, cardiovascular disease, hypertension, stroke or coagulopathy. These cases highlight the importance of adequate
monitoring of coagulopathy in critically ill Covid-19 patients and vigilance for early signs of arterial thromboembolic disease even in patients
without overt cardiovascular risk profiles.
DIC is a well-established cause of coagulopathy in sepsis and septic
shock. In DIC, interleukin-6 (IL-6) and tumor necrosis factor (TNF)
play a central role in sepsis mediated coagulopathy and fibrin deposits
are caused by tissue-factor dependent thrombin generation. At the
same time, physiologic anticoagulant mechanisms (antithrombin, tissue factor pathway inhibitor (TFPI) and the protein C system) function
inappropriately. Furthermore, fibrinolysis is inactivated by high plasma
concentrations of plasminogen activator-inhibitor-1 (PAI-1) [15]. As a
consequence, DIC leads to thrombotic occlusion of small and middle
large arteries, but at the same time increases the risk of severe bleeding,
because of consumption of platelets and coagulation factors (i.e.

J.R.C. Lameijer et al. / Journal of Critical Care 60 (2020) 106–110

consumption coagulopathy). According to the International Society on
Thrombosis and Haemostasis (ISTH) criteria for DIC, low platelet counts,
increased prothrombin time (PT), decreased fibrinogen and high ddimer levels dictate the risk of overt DIC [16].
Recent reports have been published on coagulopathy in critically ill
Covid-19 patients, as well as large series which focused on pulmonary
thromboembolism [5,7,9,11]. In the majority of cases elevated levels of
D-dimer and prolonged PT are found in non-survivors compared to survivors, with the majority of non-survivors showing signs of overt DIC.
Coagulopathy is suggested to be a poor prognostic indicator of survival
in cases of Covid-19 [5]. In this case series we found markedly elevated
D-dimer levels in all patients as well, however there was no accompanying thrombocytopenia. Reports also show an increased risk of thrombosis in patients with a history of cardiovascular disease and stroke, as well
as hypertension and diabetes. Surprisingly, our patients had no such
medical history [14,17,18].
It has to be mentioned, that in the early months after SARS-CoV-2
emerged, chloroquine and hydroxychloroquine have been widely used
in the treatment of Covid-19 due to their in vitro Covid-19 inhibiting
properties. Also, at the time the patients in this case series were admitted to our hospital, treatment with hydroxychloroquine was standard
practice. In a more recent report, treatment with hydroxychloroquine
has not been proven beneficial in terms of intubation rate or survival.
[19] Nonetheless, procoagulant effects of hydroxychlorquine have not
been described. Rather, anti-coagulant effects have been shown in the
treatment of systemic lupus erythematosus (SLE). [20].
Although DIC-scores could not reliably be calculated according to
ISTH criteria in some of our patients because of missing values, available
laboratory results were not suggestive of overt DIC. Especially, normal
or elevated thrombocyte counts as found in all patients argue against
presence of overt DIC [16]. Our findings suggest that in absence of
overt DIC, arterial thromboembolic complications can still occur in critically ill patients with Covid-19.
Adequate thromboembolic prophylaxis is important in treating
Covid-19 patients and might be associated with decreased mortality in
patients [6]. Patients currently receive standard prophylactic doses of
low molecular weight heparin (LMWH) on admission in our hospital.
Up until now, no clear benefit of higher doses of LMWH has been
shown for septic patients with clinically relevant coagulopathy, including patients with DIC [21,22]. Specific features of critically ill Covid-19
patients (e.g. severe hypoxemia, hyper inflammatory status and ACE2
receptor mediated endothelial cell activation) might influence coagulopathy in different ways than expected based on current knowledge.
With emerging data on coagulopathy in critically ill Covid-19 patients, higher doses of LMWH might be indicated to prevent both venous and arterial thromboembolism. [12,14,23] Partly because of
these cases of cerebral artery thromboembolism we changed our regimen, and currently use dalteparin 5000 IU twice-daily for patients
above 80 kg, and 5000 IU once-daily for patients below 80 kg on admission to our ICU. On indication, this regimen might need to be extended
to Covid-19 patients admitted at nursing wards, supported by the fact
that patients 1 and 2 presented with arterial thromboembolism before
they were admitted to the ICU. Further studies are needed to determine
adequate treatment regimens in Covid-19 patients with coagulopathy
without overt signs of DIC. Also, the extensiveness of arterial thromboembolism related to Covid-19 should be evaluated in larger studies, in
order to estimate the prevalence of this serious complication. Most
likely, prevalence is underestimated as coagulopathy and thrombosis
might have been unrevealed in deceased Covid-19 patients.
There are some limitations in this case series. PT-values are not routinely tested at our institution, especially in patients admitted to the
nursing wards. At the time of diagnosis of stroke, limited knowledge
was available on large vessel arterial thrombosis in Covid-19 patients.
Therefore, routine blood sample analyses of Covid-19 patients only included a subset of coagulation parameters. This impeded calculation of

109

DIC-scores according to ISTH criteria, and also impeded analysis of
trends in coagulation parameters. Second, we did not perform
contrast-enhanced CT in patient 2. However, due to diffuse ischemia
in multiple vascular territories, it was concluded in consensus (by radiologists, neurologist and intensivist) that this resulted from diffuse large
vessel arterial thromboembolism.
We report the clinical course of four patients infected with SARSCoV-2, who presented with arterial thromboembolic events during
their admission to our hospital, despite a medical history which was
negative for diabetes, hypertension, cardiovascular disease, atrial fibrillation and stroke. Key aspects include the risk of hypercoagulopathy in
critically ill Covid-19 patients, which result in an increased risk for
large arterial vessel thromboembolism. Further studies are needed to
determine the prevalence of arterial thrombo-embolism in Covid-19
and to determine which parameters are useful in monitoring coagulopathy in different stages of their illness. Adjustment of anticoagulation
management regimens needs to be considered in order to prevent
Covid-19 patients from developing not only venous, but also severe arterial thrombotic complications.
Financial support
None.

Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence the work reported in this paper.
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