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Clinical Case Report

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Is intravenous thrombolysis safe for acute
ischemic stroke patients taking warfarin with
INR 1.9?
A case report
Zhaokun Li, MSa, Jing Su, MSb, Shanshan Zhang, BSa, Hongcai Du, BSa, Yufeng Tang, MSa,
∗
Jingfeng Duan, BSa, Zhonglun Chen, MSa,
Abstract
Introduction: Intravenous thrombolysis is not suitable for patients undergoing oral anticoagulants therapy, with INR > 1.7 or PT >

15 s. We described a case of intravenous thrombolysis in a patient with INR 1.9.

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Patient concerns: A 66-year-old female patient was diagnosed with acute appendicitis complicated with atrial fibrillation. Seven
days after admission, the patient suffered mixed aphasia with right limb asthenia. The NIHSS score was 11 points. and early infarction
and hemorrhagic manifestations were not found in the emergency head CT. Thirty minutes after the onset of symptoms, NIHSS of
patient increased from 11 to 14, but the INR was 1.92.
Diagnosis: Acute ischemic stroke.
Interventions: The IT therapy was recommended and all the therapy related risks were explained to the patient’s parents. Briefly,

the patient was given rTPA 38.5 mg. In addition to intravenous thrombolysis, VitK1 40 mg was simultaneously administered.
Outcome: The patient’s symptoms of drowsiness were improved. After 24 hours, all symptoms were stabilized with NIHSS of 2

points, there was a slight language obstruction, and no hemorrhagic transformation in head CT. Three months later, the review
showed MRS score of 0, and the patient could take care of herself in daily life.
Conclusion: The clinical guidelines are still the main reference for guiding clinical practice, and the main thrombolytic standards and
contraindications for treatment still need to be conformed. On this basis, for individualized patients, clinicians must accurately judge
the cause of acute stroke, to make optimal choice, reduce disability and mortality, and improve quality of life of patients.
Abbreviations: AIS = acute ischemic stroke, IT = intravenous thrombolysis, rtPA = recombinant tissue plasminogen activator.
Keywords: acute ischemic stroke, International normalized ratio, intravenous thrombolysis, Vitamin K

the stroke onset. Nevertheless, this type of therapy can cause
several adverse reactions, such as intracranial hemorrhage,
allergic reactions, and potentially fatal intracranial symptomatic
bleeding. Therefore, the use of IT requires a rigorous assessment
of risk and benefit before it can be approved. According to the
Guidelines for acute ischemic stroke (AIS) (2018) and AHA/ASA
guidelines, this therapy is not suitable for patients undergoing
oral anticoagulants therapy, with INR > 1.7 or PT > 15 s.[1] If the
patients is prescribed VitK1 antagonists (such as warfarin) to
maintain an INR > 1.7 or PT > 15 s, the treatment options are
very limited. Herein, we reported a single case of a patient with
the INR of 1.9 who was taking warfarin and was treated with IT.

1. Introduction
Intravenous thrombolysis (IT) with recombinant tissue plasminogen activator (rtPA) is the only pharmacological therapy that is
approved for treatment of the ischemic stroke within 4.5 hours of
Editor: N/A.
†These authors contributed equally to this work.
The study was funded by the Sichuan Science and Technology Department’s
support project.
The authors have no conflicts of interest to disclose.
a

Department of Neurology, b Department of Hematology, Mianyang Central
Hospital, Mianyang, China.

∗

Correspondence: Zhonglun Chen, Department of Neurology, Mianyang Central
Hospital, Mianyang 621000, China (e-mail: mchczl@163.com).

2. Case presentation

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

This study was approved by the Human Ethics Committee of
Mianyang central hospital. Informed written consent was
obtained from the patient for publication of this case report
and accompanying images. A 66-year-old female patient, who
was experiencing metastatic right abdominal pain for 2+ days,
was admitted to our hospital and was consequently diagnosed
with acute appendicitis. The patient had a history of rheumatic
heart disease complicated with atrial fibrillation. In addition, she
was previously prescribed oral warfarin, had INR of 1.7 to 2.5,

How to cite this article: Li Z, Su J, Zhang S, Du H, Tang Y, Duan J, Chen Z. Is
intravenous thrombolysis safe for acute ischemic stroke patients taking warfarin
with INR 1.9? A case report. Medicine 2020;99:10(e19358).
Received: 9 May 2019 / Received in final form: 19 December 2019 / Accepted:
29 January 2020
http://dx.doi.org/10.1097/MD.0000000000019358

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Figure 2. After 24 hours, DWI stimulated acute infarction in the left basal
ganglia.

Figure 1. the local lumen in the M3 segment of the left arteriae cerebri media
was embolismic.

society and families. Nevertheless, among patients with AIS who
are eligible for IT, less than 3% are suitable candidates for the IT
therapy. Due to various contraindications such as thrombocytopenia and INR prolongation occurring in the very limited time
window in which the therapy can be applied, patients are unable
to receive intravenous thrombolysis, thus missing a valuable
treatment, and potentially facing the disability. Nevertheless,
previous studies have suggested that the reduction of thrombolysis restrictions can increase the thrombolytic proportion in
emergency patients.[3] Hence, expanding the indications for
intravenous thrombolysis is important for increasing the
proportion of IT.
It is uncertain whether thrombolytic therapy is safe in patients
with AIS treated with warfarin. IT may increase the risk of
symptomatic intracranial hemorrhage and can even lead to death;
therefore, it is not recommended for patients with INR >1.7.[1,2]
Thus, the risks such as severe consequences due to stroke or
intracranial hemorrhage due to thrombolysis, as well as benefits
should be adequately considered in the evaluation of patients
with thrombolysis and elevated INR. Nevertheless, this does not
mean that IT therapy cannot be implemented in patients with
extended INR. Mazya et al have found that IT is safe and effective
in patients receiving oral warfarin. They also found that a
recanalization rate was significantly higher in patients with INR
< 1.7 compared to the control group.[4] Yet, it remains unclear
whether the safety of intravenous thrombolysis in patients with
INR > 1.7 can be reduced. Italo et al have reported on 2 acute
cardiogenic stroke patients receiving warfarin who had INR >
1.7 and 1.9, respectively, and were consequently treated with
intra-arterial thrombolysis. Both patients recovered well and did
not develop any intracranial hemorrhage.[5] Furthermore, a study
based on SITI registration in Europe demonstrated that among
212 patients who received oral anticoagulant drugs in combination with IT, 45 patients had an INR > 1.7. After adjusting the
independent predictors, these patients did not show significant
differences in terms of symptomatic intracranial hemorrhage
rate, 3-month mortality and prognosis compared with patients
who did not take anticoagulant drugs.[6] Moreover, Frank et al[7]
have found that among 2755 thrombolysis patients enrolled in
large clinical studies based on VISTA data, 138 cases had an INR
>1.7, and the increase in INR in 14 patients was due to oral
warfarin. The results showed that patients receiving oral warfarin
did not develop intracranial symptomatic hemorrhage, and only
7 of 138 patients developed intracranial symptomatic hemorrhage. After adjusting for age and NIHSS baseline score, the
patients with an INR > 1.7 showed a slightly higher probability
of good prognosis than the control group; nevertheless, the

and no history of stroke and TIA. The patient was also fully
capable of taking care of herself in daily life. After admission, she
was prescribed anti-infective and fluid replacement therapy, and
continued to orally take 2.5 mg warfarin, while receiving diuresis.
In addition, she underwent routine checkup of the heart rate.
After admission, her INR was 1.18, and the patient’s clinical
symptoms were improved and abdominal pain was alleviated.
Seven days after admission, the patient suffered mixed aphasia
with right limb asthenia, which occurred during dinner time. The
NIHSS score was 11 points, and early infarction and hemorrhagic manifestations were not found in the emergency head CT.
Thirty minutes after the onset of symptoms, her symptoms
continued, and she experienced binocular vision and lethargy,
while NIHSS increased from 11 to 14. Next, we evaluated her
vascular condition, and the head CTA revealed severe stenosis at
the beginning of the M2 segment of the left arteriae cerebri media.
Meanwhile, the local lumen in the M3 segment of the left arteriae
cerebri media was not developed, which suggested the presence of
embolism (Fig. 1). Re-examination showed that platelets were
normal, but the INR was 1.92. Consequently, the IT therapy was
recommended and all the therapy related risks were explained to
the patient’s parents. Briefly, the patient was given rTPA 38.5 mg
(0.9 mg/Kg) in combination with intravenous thrombolysis at
18:05. Subsequently, the patient’s symptoms of drowsiness were
improved. In addition to intravenous thrombolysis, VitK1 40 mg
was simultaneously administered using another channel. Intravenous thrombolysis was administered 34 minutes from the onset
of the symptoms.
Three hours after therapy, the INR was 1.77. After 6 hours, the
patient’s clinical symptoms were relieved; she was conscious, her
speaking ability was partially recovered, she experienced
incomplete aphemia, recovery of right limb muscle strength
and NIHSS of 6 points. After 24 hours, all symptoms were
stabilized with NIHSS of 2 points, there was a slight language
obstruction, and no hemorrhagic transformation in head CT.
DWI stimulated acute infarction in the left basal ganglia (Fig. 2).
At discharge, NIHSS was 1 point, while the MRS was 1 point.
Three months later, the review showed MRS score of 0, and the
patient could take care of herself in daily life. She continued oral
warfarin treatment.

3. Discussion
In China, the incidence of ischemic stroke is increasing year by
year, and the fatality/ disability rate is 34.5% to 37.1%,[2] which
exerts huge medical economic burden and spiritual burden to
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full communication with the family again. Subsequently, the
patient was given IT therapy. In the meantime, in order to rapidly
neutralize the elevation of INR caused by warfarin, 40 mg VitK1
was synchronously infused.
Recently, Kefas et al[14] have reported a case with INR 1.9 due
to warfarin, who was treated with IT. Nonetheless, the patient
was confirmed with cardiogenic stroke, and was not given drugs
(such as PCC, warfarin and FFP etc.) to reverse INR before and
during intravenous thrombolysis. According to our knowledge,
this was the first case report in which intravenous thrombolysis
was given at an INR of 1.9 due to warfarin, and Vit k1 was
simultaneously given to reverse the warfarin-induced INR
elevation. Although it is a case study, it may also be a
breakthrough window. Previous studies were not specifically
designed for stroke patients with INR > 1.7. Purely extracting
part of the population from these studies will inevitably cause
some defects in terms of sample size, assessment method before
thrombolysis and intervention strategies. Therefore, it is
necessary to perform large-sample clinical studies on implementing thrombolysis in patients with INR > 1.7, to re-evaluate the
effectiveness and safety of thrombolysis, as well as to evaluate the
effect of drugs for reversal of INR on thrombolysis.
In clinical practice, not every stroke patient with an INR > 1.7
can be treated with IT. Currently, the clinical guidelines are still
the main reference for guiding clinical practice, and the main
thrombolytic standards and contraindications for treatment still
need to be conformed. On this basis, for individualized patients,
clinicians must accurately judge the cause of acute stroke, to
make optimal choice, reduce disability and mortality, and
improve quality of life of patients.

difference was not statistically significant. In a clinical study
conducted in the United Kingdom, only 1 of the 115 stroke
patients with INR > 1.7 receiving warfarin developed intracranial symptomatic bleeding,[8] which suggests that IT may be
effective and relatively safe in stroke patients with an INR >1.7.
In clinical practice, for AIS patients with an INR > 1.7, IT
should reduce the risk of hemorrhage and improve the prognosis
rate. Using cardiogenic stroke animal models, Sun et al[9] have
attempted to reverse the increase in INR after taking warfarin
using PCC, followed by IT therapy with rTPA. The results
showed that PPC reduced the incidence of severe bleeding after IT
in rats with an INR of 2.0 to 3.0 caused by warfarin, which
suggested that IT therapy might be given after reversing INR with
PPC in patients receiving anticoagulation therapy. Based on this
important finding, Jalini et al[10] have reported a case that was
treated with IT following PCC to quickly reverse INR.
Symptomatic intracranial hemorrhage did not occur after
thrombolysis, and the NIHSS score was reduced from 24 points
at admission to 6 points at discharge; and was further reduced to
4 points after 8 weeks. However, since PCC contains coagulation
factors II, VII, IX, X, and proteins C and S, it may increase the risk
of thrombosis by 1% to 2% in patients with stroke. Hence, PCC
is not recommended for patients with AIS.[11,12] Meanwhile,
Vitamin K1 can activate the existing clotting factors in the body
without the need for synthesis or supplementation of new
proteins, and can reverse the abnormally elevated INR caused by
warfarin. It does not promote thrombosis under conventional
treatment, and intravenous injection can accelerate the effect of
reversing INR.[10–12] It is also used to reverse the increase in INR
caused by warfarin during the perioperative period of surgery, so
as to reduce the risk of bleeding in emergency surgery.[13] Invasive
emergency surgery should be performed at 6 to 12 hours after
intravenous administration of Vitk1 10 mg. However, for
patients receiving warfarin with an INR at the treatment window
(2.0–3.0) and below, the proportion of spontaneous bleeding is
very low. Thus, in the case of non-invasive conditions, VitK1
before thrombolysis may have a special effect on patients taking
warfarin who have an INR below the standard.[12]
In this case study, all the clinical examinations and preliminary
imaging evaluations were completed within 1 hour of the onset,
and no other intravenous thrombolysis contraindications were
found except INR, which led us to rethink the thrombolytic
indications. Initially, the IT therapy was rejected because it was
believed that the risk of bleeding was greater than its clinical
benefit would be due to an INR of 1.9. However, during the reevaluation, it was found that the patient was receiving warfarin,
and that she regularly underwent INR test, which was maintained
between 1.7 and 2.5. Before the visit, the patient did show
symptoms of ischemic stroke or TIA. In terms of the risk of
stroke, in addition to the common causes of arteriosclerosis, atrial
fibrillation, and heart valve disease, there are other rarely found
causes, such as inflammation, tumors, PFO, vascular malformations, and immunity. The patient in the present study was
admitted due to acute appendicitis. It was unclear whether the
stroke occurred due to the inflammatory response that activates
another coagulation pathway, or due to an abnormal embolism
of a small bacterial embolus. The CTA showed severe stenosis in
the left arteriae cerebri media, with partial occlusion at the distal
M3 segment, which indirectly suggests that the stroke may not be
caused by a cardiac arrest. With the continuation of the patient’s
clinical symptoms, the thrombotic mechanism was re-analyzed,
and risks and benefits were re-assessed, which prompted deep and

Author contributions
Conceptualization: Zhonglun Chen.
Data curation: Zhaokun Li.
Formal analysis: Zhaokun Li, Jing Su, Jingfeng Duan.
Investigation: Zhaokun Li, Jing Su, Shanshan Zhang, Yufeng
Tang.
Methodology: Zhaokun Li, Jing Su, Yufeng Tang.
Project administration: Yufeng Tang, Zhonglun Chen.
Resources: Shanshan Zhang, Zhonglun Chen.
Software: Jing Su, Shanshan Zhang, Hongcai Du, Jingfeng Duan.
Supervision: Shanshan Zhang, Hongcai Du, Jingfeng Duan.
Validation: Hongcai Du.
Visualization: Hongcai Du.
Writing – original draft: Zhaokun Li.
Writing – review & editing: Jing Su, Shanshan Zhang, Hongcai
Du, Yufeng Tang, Jingfeng Duan, Zhonglun Chen.

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