個案報告 Anaphylaxis to Intravenous Alteplase: A Case Report

Anaphylaxis to Intravenous Alteplase: A Case Report

Yi-Hsien Tu1, Pi-Shan Sung1, 2, Wei-Pin Hong1, Yu-Ming Chang1
1
Department of Neurology, National Cheng Kung University Hospital, College of Medicine,
National Cheng Kung University, Tainan, Taiwan.
2
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

ABSTRACT
Background: In the hyperacute phase of ischemic stroke with the use of a thrombolytic agent,
angioedema and other allergic reaction to recombinant tissue plasminogen activator (rt-PA) was an
uncommon but potentially fatal complication. Here we report a case of anaphylactic reaction to rt-PA who
had a favorable outcome.
Case report: A 80-year-old female man with underlying diseases of asthma and cardiomegaly
experienced sudden right hemiparesis, right side facial palsy, and speech arrest. After self-paid standard-
dose rt-PA using, the patient developed dyspnea, blood pressure drop, and loss of consciousness. With the
discontinuation of rt-PA, emergent intubation, and vasopressors use, the patient regained stable vital signs.
The patient was discharged 9 days later with intact language function and full muscle power.
Conclusion: Anaphylaxis to alteplase is extremely rare but potentially fatal. Physicians should
closely monitor vital signs during alteplase infusion and stop the alteplase infusion immediately if clinical
symptoms or signs indicating anaphylaxis are observed.

Keywords: alteplase, anaphylaxis, anaphylactic shock, allergy.

BACKGROUND CASE REPORT

Anaphylaxis of recombinant tissue
plasminogen activator (rt-PA) was extremely rare.
The mechanism of anaphylactic reaction from rt-
PA was not fully elucidated. Previous studies had
shown that activation of the complement and kinin
1
cascades, with histamine- and bradykinin-related
1-3
mechanisms play an important role.
reported a case of an acute anaphylactic reaction
during rt-PA infusion.
An 80-year-old female had underlying
diseases of asthma and cardiomegaly but she
had no known record of angiotensin-converting
enzyme (ACE) inhibitors using. According to her
family, the patient developed sudden onset of right
hemiparesis, right side facial palsy, and speech
Here we arrest at home. The patient and her family arrived
at emergency room (ER) for help within one hour
after symptoms onset.
On arrival, her initial blood pressure was 134

Corresponding author: Dr. Yu-Ming Chang, Department of Neurology, National Cheng Kung University Hospital, Tainan,
Taiwan.
E-mail: cornworldmirror@hotmail.com
DOI: 10.6318/FJS.202109_3(3).0006

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 Anaphylaxis to Intravenous Alteplase: A Case Report

/101 mmHg. The patient’s family reported that
she had partial improvement of her speech but
right hemiparesis remained the same. The initial
National Institutes of Health Stroke Scale (NIHSS)
score was 2.
There was a high possibility of large vessel
occlusion due to the presence of aphasia initially.
We further arranged multiphase Computed
Tomography angiography (CTA) and Computed
Tomography perfusion (CTP) (Figure 1, Figure
2). The images showed left middle cerebral artery
(MCA) territory penumbra but with no obvious

Fig. 1. Computed Tomography Angiography (CTA) revealed no obvious proximal large vessel occlusion
(M1-M2).

Fig. 2. CT perfusion revealed that cerebral blood flow and cerebral blood volume were both decreased at the
left frontotemporal lobe, but mean transit time and time to peak were both increased, which suggested
a small penumbra without the ischemic core.

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 Anaphylaxis to Intravenous Alteplase: A Case Report
ischemic core or proximal large vessel occlusion
but M3-4 segment MCA stenosis or partial
occlusion.
Endovascular therapy was not indicated due
to distal segment of MCA lesion. After discussing
with her family about intravenous (IV) rt-PA for
potential benefits and risks, self-paid standard-dose
rt-PA was injected.
After IV rt-PA dripping for 3 minutes,
the patient developed dyspnea with wheezing.
Desaturation, blood pressure drop (SBP 70-
80 mmHg), and consciousness change were
noted at the same time. Rt-PA was discontinued
immediately. The total amount of rt-PA infusion at
that time was 8.5 mg.
Instant neurological examination showed
that consciousness level deteriorated (E4V1M4)
but pupil size remained the same and four limbs
muscle power was above 3 in Medical Research
Council grade.
Emergent intubation was done due to shock
and desaturation status. No laryngeal edema
was witnessed during the intubating process.
The patient regained stable vital signs soon
after intubation and aggressive intravenous fluid
resuscitation with further norepinephrine injection
for shock condition. The differential diagnosis of
her consciousness change and desaturation was
Fig. 3. Timeline figure illustrated each time points of progression. Blood pressure drop soon after rt-PA
injection and surged rapidly after stopping rt-PA injection and norepinephrine administration.
diverse. Intracerebral hemorrhage secondary to rt-
PA use was considered first but emergent brain CT
showed no hemorrhage. Allergic reaction to rt-
PA was highly suspected on the other hand. The
patient was then admitted to the stroke intensive
care unit (ICU) for further care and treatment
under the impression of anaphylactic shock to rt-
PA. (Figure 3).
In the following course in the ICU and
general ward, her neurologic signs and vital signs
remained stable and kept improving. 24 hours
brain non-contrast-enhanced CT showed no
ICH. Clopidogrel was added and the patient was
extubated smoothly two days after the episode.
Brain magnetic resonance imaging revealed left
frontal scattered infarct (Figure 4).
She had newly diagnosed atrial fibrillation
and had been prescribed Apixaban 2.5 mg twice
daily on the 5th day after onset. The patient was
discharged on the 9th day after onset with intact
language function and full muscle power.
DISCUSSION
In this article, we reported a case with
anaphylaxis to rt-PA during the infusion period
for acute ischemic stroke, although the history
of allergy was denied. Her vital sign was
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 Anaphylaxis to Intravenous Alteplase: A Case Report
Fig. 4. Brain magnetic resonance imaging revealed several hyperintensities at the left frontal area in diffusion-
weighted imaging, indicating several recent infarctions.
stabilized after the timely intubation, the use
of norepinephrine, and, most importantly, the
discontinuation of alteplase.
A review of the literature indicates that the
incidence of anaphylaxis to alteplase was extremely
rare, ranging from 0.0004% to 1.9%. 4, 5 For
Taiwanese patients, a multi-center stroke registry
study in Taiwan over a 12-year period collected
559 patients who had received IV rt-PA. Five
patients developed orolingual angioedema after
rt-PA administration. The incidence of orolingual
angioedema was 0.89% (95% confidence interval
0.29%-2.09%), which was lower than the incidence
obtained by meta-analysis (1.9%).6 Moreover, the
incidence of alteplase-related angioedema was less
than 0.02% of patients given alteplase for acute
5
myocardial infarction. The above-mentioned
Taiwanese study also found ACE inhibitors were
found to have the highest relative risk for rt-
PA-related orolingual angioedema (17.1; 95%
6
confidence interval 3.0-96.9). We had summarized
the important information in the case reports
we had reviewed in the Table, including their
demographic data, previous ACE inhibitor drug
history, neurologic deficits, presentation of allergic
reaction and the following management of allergy
2, 4, 5, 6, 7
episodes.
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The mechanism of anaphylaxis of alteplase
was not fully understood. The postulation was
diverse, including activation of the complement
and kinin cascades,1 histamine- and bradykinin-
related mechanisms,7 and type 1 hypersensitivity
reactions.4
To date, the guideline for the management
of anaphylaxis to alteplase was lacking. 8 In a
systematic review, the Adverse Event Reporting
System database of the US Food and Drug
Administration was searched. 7 A total of 12
cases of adverse allergic reaction was directly
attributable to IV thrombolytics, including
angioedema, urticaria, hypotension, anaphylactic
shock, and death. Most reactions resolved
with the withdrawal of medication as well as
diphenhydramine, steroids, and/or epinephrine,
which were also noted in other case reports.2, 4, 5
Since most treatment options were empirical, we
are hopeful that future research will provide an
evidence-based recommendation.
CONCLUSION
The incidence of anaphylaxis to alteplase is
extremely low and the underlying mechanism may
be multi-causative. Since the history of allergy
 Table. Demographic and clinical characteristics of patients with allergic reaction to rt-PA
Case Episode Age/Gender Underlying Previous Clinical presentation NIHSS Presentation of allergy Management of allergy Authors
diseases use of ACE of stroke
inhibitor
#1 #1 61/female CAD, HT Lisinopril right facial weakness, 4 Hypotension, extremities Fluid resuscitation, Zarar et al.7
and hemisensory loss hypoperfused diphenhydramine
#1 #2 63/female CAD, HT Lisinopril right hemiparesis, 3 Hypotension Fluid resuscitation, Zarar et al.7
and hemisensory loss diphenhydramine,
epinephrine
#2 #1 74/female HT Lsinopril left hemiparesis 17 Left orolingual Epinephrine, Fugate et al.2
angioedema, hives on her dexamethasone,
upper extremities diphenhydramine
#3 #1 70/female HT Nil right hemiparesis unknown Sinus tachycardia, Catecholamines, Rudolf et al.4
hypotension, cyanosis, antihistamines;
loss of consciousness
#4 #1 74/female CAD, DM, HT, Nil globally aphasic, 24 Urticarial rash, bilateral Hydrocortisone, Hill et al.5
congestive heart right homonymous oropharyngeal swelling, diphenhydramine,
failure hemianopia, gaze hypotension ranitidine, crystalloid
to the left, right
hemiplegia and loss
of painful sensation
#5 #1 76/female AF, CAD, Yes right-gaze preference, 18 Left orolingual Methylprednisolone Hill et al.5
HT, revious left hemiplegia, angioedema diphenhydramine,
transient hemispatial neglect, ranitidine
ischemic attack emianopia, visual
neglect, and altered
sensation
#6 #1 82/female AF, HT Nil Aphasia, right 20 Whole tongue swelling, Diphenhydramine, Lin et al.6
hemiparesis urticaria and flushing over hydrocortisone
trunk
Anaphylaxis to Intravenous Alteplase: A Case Report

#7 #1 78/male DM, HT, prior Ramipril Poor response, 5 Right side tongue swelling Diphenhydramine, Lin et al.6
stroke urinary incontinence Hydrocortisone,
epinephrine
#8 #1 71/female HT, prior stroke Nil Mute, impaired 9 Right side tongue rt-PA interruption, Lin et al.6
comprehension swelling, stridor diphenhydramine,
hydrocortisone,
epinephrine
#9 #1 58/male HT Enalapril Dysarthria, right 9 Right side tongue swelling Hydrocortisone Lin et al.6
Prior stroke hemiparesis
#10 #1 73/female CAD, Mitral Nil left hemiparesis 6 Right side tongue Epinephrine, Lin et al.6
valvuloplasty, swelling, tachycardia, diphenhydramine,
AF, DM, HT desaturation, wheezing hydrocortisone
Abbreviation: AF: atrial fibrillation; CAD: coronary artery disease; DM: diabetes mellitus; HT: hypertension.

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 Anaphylaxis to Intravenous Alteplase: A Case Report
to rt-PA was often unavailable for most patients,
neurologists or physicians should closely monitor
vital signs and any clinical change, especially
allergic reactions like angioedema, during alteplase
infusion. Alteplase must be stopped immediately if
clinical symptoms or signs indicate anaphylaxis.
REFERENCE
1. Bennett WR, Yawn DH, Migliore PJ, et al.
Activation of the complement system by
recombinant tissue plasminogen activator. J Am
Coll Cardiol 1987;10:627-632. DOI: 10.1016/
s0735-1097(87)80206-1.
2. Fugate JE, Kalimullah EA, Wijdicks EF.
Angioedema after tPA: what neurointensivists
should know. Neurocrit Care 2012;16:440-443.
DOI: 10.1007/s12028-012-9678-0.
3. Molinaro G, Gervais N, Adam A. Biochemical
basis of angioedema associated with
recombinant tissue plasminogen activator
treatment: an in vitro experimental approach.
Stroke 2002;33:1712-1716. DOI: 10.1161/01.
str.0000017284.77838.87.
4. Rudolf J, Grond M, Prince WS, et al. Evidence
164
of anaphylaxy after alteplase infusion. Stroke
1999;30:1142-1143. DOI: 10.1161/01.str.30.5.1142.
5. Hill MD, Barber PA, Takahashi J, et al.
Anaphylactoid reactions and angioedema during
alteplase treatment of acute ischemic stroke.
CMAJ 2000;162:1281-1284.
6. Lin SY, Tang SC, Tsai LK, et al. Orolingual
angioedema after alteplase therapy of acute
ischaemic stroke: incidence and risk of prior
angiotensin-converting enzyme inhibitor
use. Eur J Neurol 2014;21:1285-1291. DOI:
10.1111/ene.12472.
7. Z a r a r A , K h a n A A , A d i l M M , e t a l .
Anaphylactic shock associated with intravenous
thrombolytics. Am J Emerg Med 2014;32:e113-
115. DOI: 10.1016/j.ajem.2013.08.046.
8. Powers WJ, Rabinstein AA, Ackerson T, et al.
Guidelines for the early management of patients
with acute ischemic stroke: 2019 Update to
the 2018 Guidelines for the early management
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Stroke 2019;50:e344-e418. 2019/10/31. DOI:
10.1161/str.0000000000000211.
 Anaphylaxis to Intravenous Alteplase: A Case Report

Alteplase致過敏性休克：一個案報告

杜宜憲 1、宋碧姍 1, 2、洪煒斌 1、張育銘 1

1
國立成功大學附設醫院 神經內科
2
國立成功大學醫學院 臨床醫學研究所

摘　要
背景：在中風急性期使用血栓溶解劑治療時，對於組織型蛋白酶原活化因子引起的血管水腫和
其餘過敏反應，雖然不常見但仍可能致命。我們報告一例對於靜脈輸注組織型蛋白酶原活化因子產
生過敏反應的個案，病人在停止藥物輸注和緊急插管加護病房之後達到良好的預後。
病例報告：一位具有氣喘和心肌病變病史的80歲女性，出現急性右側偏癱、右側中樞型顏面神
經麻痺，以及失語症狀。病人在接受組織型蛋白酶原活化因子時，產生呼吸困難、血壓下降及意識
喪失。經過緊急停藥、氣管內管置放、升壓藥物使用後，回復生命徵象，並在九天後出院，病人出
院時達到完好語言功能以及四肢肌力。
結論：對於組織型蛋白酶原活化因子的過敏反應雖然罕見，但仍有致命的風險。醫師在血栓
溶解劑滴注階段必須密切監測生命徵象，若是出現過敏的臨床症狀，必須立即停止血栓溶解劑的使
用。

關鍵詞：蛋白酉每 原活化因子、過敏反應、過敏性休克、過敏

通訊作者：張育銘醫師　國立成功大學附設醫院神經內科
E-mail: cornworldmirror@hotmail.com

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