Thrombolytic therapy is the only available medical treatment for acute ischemic stroke that has been proven to be effective. Intravenously administered recombinant tissue plasminogen activator (rtPA) has been shown to improve the long-term functional outcome and is recommended for the treatment of eligible acute stroke patients. However, due to the risk of major bleeding, particularly in the brain, patients need to be carefully selected on the basis of eligibility criteria. These have been largely adopted from the inclusion and exclusion criteria used in the randomized clinical trials.

1. Stroke IV thrombolysis beyond limitations; case
series and review of literature

2. Review Article
Stroke IV thrombolysis beyond limitations; case
series and review of literature
Mukesh Sharma a,
*, Mudgerikar Sucheta a
, Andani Naresh b
a
Senior Consultant, Department of Neurology, Apollo Hospital, Ahmedabad, India
b
Junior Registrar, Department of Neurology, Apollo Hospital, Ahmedabad, India
a r t i c l e i n f o
Article history:
Received 5 August 2013
Accepted 7 August 2013
Available online 12 September 2013
Keywords:
Thrombolytic therapy
Intravenous recombinant tissue-
type plasminogen activator (IV rtPA)
Alteplase
Ischemic stroke
Hyperglycemia
a b s t r a c t
Background: Thrombolytic therapy with intravenous alteplase for ischemic stroke is
restricted by guidelines, because of the risk of hemorrhage, especially in the brain, and only
a small number of selected patients are being treated. Findings from meta analyses and
post licensing experience suggest that more subjects, who otherwise have a poor predicted
outcome without treatment, might benefit from intravenous.
Methods: We retrospectively assessed clinical safety of the IV stroke thrombolysis beyond
guidelines in 20 patients out of 140 total patients thrombolysed by IV rtPA in our depart-
ment. Patient eligible for thrombolysis within 3 h were selected by CT or MRI and beyond
3 h only by MRI brain. Imaging study was done at the time of presentation and after 24 h to
rule out symptomatic ICH.
Finding: We have not recorded any symptomatic ICH in any patients which we thrombo-
lysed beyond guideline. Two patients had asymptomatic hemorrhagic transformation.
Conclusion: This document does not intend to change the guidelines but reviews the liter-
ature on the use of intravenous alteplase for stroke beyond guidelines and in particular
conditions which help in more and more patients can be benefited by stroke thrombolysis.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Thrombolytic therapy is the only available medical treatment
for acute ischemic stroke that has been proven to be effective.
Intravenously administered recombinant tissue plasminogen
activator (rtPA) has been shown to improve the long-term
functional outcome1,2
and is recommended for the treatment
of eligible acute stroke patients.3e5
However, due to the risk of
major bleeding, particularly in the brain, patients need to be
carefully selected on the basis of eligibility criteria. These have
been largely adopted from the inclusion and exclusion criteria
used in the randomized clinical trials.6,7
There is increasing
evidence that the commonly used intravenous recombinant
tissue-type plasminogen activator (IV rtPA) eligibility criteria
are sometimes too restrictive and limit the use of thrombolysis
in acute stroke. A number of recent studies have reported that
treatment of patients with common IV rtPA exclusion criteria
does not result in an increased complication rate or in worse
outcome.8,9
The purpose of this review is to gather the available
literature on the use of intravenous alteplase for stroke beyond
the guidelines and in situations not well covered by the
guidelines and put forth our experience in this matter.
* Corresponding author.
E-mail address: drmukeshneuro@rediffmail.com (M. Sharma).
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 1 1 e2 1 6
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.08.004

3. 1.1. Beyond 4.5 h
We have thrombolysed three patients between 4.5 and 6 h on
the basis of diffusion and clinical mismatch. One patient
showed hemorrhagic transformation without symptomatic
worsening [Fig. 1]. Pooled analysis of data from the National
Institute of Neurological Disorders and Stroke (NINDS) trials
(parts 1 and 2, 3-h window),5
the 2 European Cooperative
Acute Stroke Study (ECASS) trials (6-h window),7,10
and the 2
Alteplase Thrombolysis for Acute Non-interventional Ther-
apy in Ischemic Stroke (ATLANTIS) trials (part A, 6-h window
and part B, 5-h window),6,11
suggest a potential benefit from
treatment beyond 3 h. The odds ratio for a favorable outcome
was 1.40 (95% CI, 1.05e1.85) for patients treated between 3
and 4.5 h, and 1.15 (0.90e1.47) for those treated between 4.5
and 6 h. What the pooled analysis clearly demonstrated is
that the sooner alteplase is given to stroke patients, the
greater the benefit, especially if started within 90 min. The
adage “time is brain”, which has now become widely familiar
in the medical community, should be further promoted in the
general public.
1.2. Age 80 or older
We have thrombolysed four patients above the age of 80 years
and none of them developed intracranial bleed. Because most
studies excluded patients above age 80, the risk of SICH (Se-
vere Intracerebral hemorrhage) in this population has not
been well studied. However, in the Canadian Alteplase for
Stroke Effectiveness Study, which was included in this review,
and 1 additional study which did not meet inclusion criteria
for this review, the rate of SICH in rtPA-treated patients older
than 80 years was not different from patients younger than
80.12
Moreover, in the NINDS tPA trial, which had no upper age
limit in the latter part of the study, no association between age
and SICH was found. In a recent systematic review that
compared stroke outcome after rtPA in older versus younger
patients no increased risk of SICH was found with advancing
age.13
These data suggest that acute stroke patients above 80
should not be excluded from treatment with tPA based on
their SICH risk.
1.3. Age 18 or less
The clinical trials did not enroll persons under the age of 18
years. We have thrombolysed one patient with RHD (Rheumatic
Heart Disease), AF below 18 years of age with consent without
any complication. Only a few cases, ranging in age from 12 to
16 years, have been reported to have received rtPA.14
There
were no complications and all had a good outcome.
1.4. Seizure at onset
As it may be difficult to differentiate ischemic stroke from
postictal Todd paralysis by clinical examination and brain CT
scan, current guidelines exclude patients with seizure at
stroke onset. MRI or angiography can be used to confirm the
diagnosis of an acute ischemic process in the presence of
concurrent seizures, and these patients can be treated. We
have treated two patients with stroke with seizure at onset
with intravenous rtPA with good results.
1.5. Hyperglycemia
Two patients came in window period with sugar level more than
400 mg/dl. We started insulin infusion before sending patient to
MRI and thrombolysed the patients after MRI brain without any
post thrombolysis hemorrhage. Hyperglycemia may not only
hamper the fibrinolytic process, delaying alteplase-induced
reperfusion of the ischemic penumbra, but treatment is also
associated with increased cerebral hemorrhage and worse
outcome. A retrospective analysis of 138 consecutive alteplase
treated patients showed that the rate of hemorrhage already
sharply increased above a glucose level >8.4 mmol/L. Levels
>11.1 mmol/L were associated with a 25% symptomatic hem-
orrhage rate.15
It remains to be determined whether aggressive
therapy for glycemic control before reperfusion may improve
the efficacy and safety of thrombolytic therapy in these patients.
1.6. Thrombocytopenia
One patient who perfectly fitted criteria for thrombolysis was
found to have platelets count 95,000/cmm. We checked PT and
Fig. 1 e Post thrombolysis asymptomatic hemorrhagic transformation in two patients.
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4. APTT which were normal and thrombolysed within 90 min
with excellent results. A very low platelet count (<100,000/
cmm) is a contraindication for the routine use of rtPA1
and
thrombolytic trials have generally excluded these patients.
Therefore, data are only available on patients with platelet
counts exceeding 100,000/cmm. One study identified lower
platelet counts as an independent risk factor for SICH.10
In the
other 2 studies no association was found in either univariate
or multivariate analyses.16,17
1.7. Deranged PT and APPT
We have done one case with INR 3 and APPT twice than the
control. In both cases thrombolysis was started very early,
within 30 min of onset of stroke. We got PT and APTT reports
when half the dose of alteplase had already been given. One of
the patients showed dense MCA sign which recovered 24 h
later on follow up CT scan. We have not found any literature
about thrombolysis beyond INR I.7 and deranged APTT [Figs. 2
and 3].
1.8. Severe stroke
Patients with severe strokes (National Institute of Health
Stroke Scale score >20) have a poor prognosis whether or not
they are treated with alteplase. Because the risk of hemor-
rhage is higher among this population, caution should be
exercised. However, these patients may still benefit from
treatment, as shown in a post hoc analysis of the NINDS,1
and
the pooled analysis of the NINDS, ECASS and ATLANTIS
Fig. 2 e Dense MCA sign in high PT patient.
Fig. 3 e Post IV rtPA dense MCA sign disappear.
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5. trials.7,11
Posterior circulation stroke mainly basilar artery
occlusion usually presented with more than 22 NIHHS score.
We have experience in two such patients who had complete
basilar block and recovered well after thrombolysis [Figs. 4
and 5].
1.9. Mild or rapidly improving symptoms
About one third of acute stroke patients with rapid
improvement of neurological deficit on arrival at the hospital
develop severe subsequent deterioration.28,29
In 19 patients
with rapidly improving symptoms, treatment with intrave-
nous alteplase was associated with good outcome. These
preliminary data suggest that withholding intravenous
thrombolysis because of mild or improving symptoms may
not always be justified. We have thrombolysed one patient
in whom motor deficit improved partially but sensory
aphasia persisted. There was complete improvement in
power post thrombolysis and speech improved well over
48 h. Another patient with right hemianopia and left P3
segment block improved completely post thrombolysis [Figs.
6 and 7].
1.10. Intracranial aneurysm
Uncomplicated thrombolysis with intravenous alteplase was
reported in 2 stroke patients with unruptured cerebral aneu-
rysms, and in another 2 patients with myocardial infarction
who had previously been treated for cerebral aneurysm (1
clipped and 1 coiled). Five cases have been described with an
intracranial aneurysm detected after intra-arterial thrombol-
ysis for stroke; 2 had a fatal intracranial hemorrhage. Our
patient was thrombolysed twice in 13 months without any
complications [Fig. 8].
Fig. 4 e Basilar A. blocked.
Fig. 5 e Post rtPA reopening of basilar artery and small infarct.
Fig. 6 e Left PCA blocked.
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6. 2. Conclusion
IV thrombolysis remains the only proven effective treatment for
acute ischemic stroke. Streamlining of treatment criteria might
substantially increase the number of patients selected for
treatment. It is imperative that this important aspect of IV
thrombolytic treatment be addressed and efforts made to define
common eligibility criteria for treatment with rtPA. Only in this
way we can safely and effectively increase the use of throm-
bolysis and achieve the ultimate goal of improved patient care.
Conflicts of interest
All authors have none to declare.
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