Endovascular

Treatment of Deep Cerebral
Venous Thrombosis by Local
Infusion of Tissue
Plasminogen Activator
Bakhtiar Yamini, M.D., R. Loch Macdonald, M.D., Ph.D., and Jordan Rosenblum, M.D.*
Section of Neurosurgery, Department of Surgery and *Department of Radiology, Pritzker
School of Medicine and The University of Chicago, Chicago, Illinois

Yamini B, Macdonald RL, Rosenblum J. Treatment of deep cerebral venous thrombosis by local infusion of tissue plasminogen
activator. Surg Neurol 2001;55:340 – 6.
BACKGROUND

Treatment of extensive intracranial venous sinus thrombosis with thrombolytic drugs is described, although the
indications for and most efficacious technique for achieving thrombolysis remain uncertain. We report the successful lysis of superficial and deep venous system
thrombosis by infusion of recombinant human tissuetype plasminogen activator (rt-PA) into the anterior superior sagittal sinus.
CASE DESCRIPTION

A 34-year-old man presented with headaches followed by
decreased level of consciousness and left hemiplegia.
Angiography showed thrombosis of the superior sagittal
and both transverse and straight sinuses with extension
into the internal cerebral veins. The superior sagittal
sinus was catheterized via a transfemoral route and rt-PA,
25 mg, was infused. There was no significant change in
the thrombosis. The catheter was left in place and rt-PA
was infused at 1 mg/minute for 19 hours. Repeat angiography showed resolution of the thrombosis. The patient
was placed on heparin and then coumadin. He recovered
completely.
CONCLUSIONS

This report suggests that superselective infusion of
thrombolytics into thrombosed intracranial venous sinuses can lyse intracranial venous sinus thrombosis. The
thrombolytic agent must be infused for hours. The apparent successful lysis of clot in the deep venous system
when infusion was into the superior sagittal sinus might
be related to diffusion of rt-PA throughout the intracranial
venous system or to improved venous outflow caused by
lysis of clot in superficial dural sinuses. © 2001 by
Elsevier Science Inc.
KEY WORDS

Dural sinus thrombosis, thrombolytic therapy, plasminogen
activator, tissue type, venous thrombosis.
Address reprint requests to: Dr. R. Loch Macdonald, Section of Neurosurgery, MC3026, University of Chicago Hospital, 5841 South Maryland
Avenue, Chicago, IL 60637.
Received July 12, 2000; accepted February 27, 2001.
0090-3019/01/$–see front matter
PII S0090-3019(01)00471-2

lthough the treatment of cerebral venous
thrombosis by superselective infusion of recombinant tissue plasminogen activator (rt-PA) directly into the thrombosed sinuses has been reported in the literature [11,16,18,22], the successful
management of deep cerebral venous thrombosis
with rt-PA has not been as completely demonstrated [16]. More patients have been described
with cerebral venous thrombosis who have been
treated with superselective venous infusions of
urokinase, although most have had superficial venous sinus thrombosis only [2,5,7,12,14,15,17,19,21,
24,26]. We present a patient with extensive dural
sinus and cerebral venous thrombosis who was
treated with superselective infusion of rt-PA into
the superior sagittal sinus. This resulted in resolution of thrombosis in the superficial and deep venous systems and in complete recovery of the
patient.

A

Case Report
A 34-year-old right-handed man awoke with leftsided periorbital headache. He was seen in the
emergency department where a cranial computed
tomographic (CT) scan was interpreted as normal.
He left against the advice of his physicians before a
diagnosis was made but returned to the hospital 12
hours later and 24 hours after the onset of the
headache with progressively decreasing level of
consciousness, emesis, and left-sided hemiparesis.
He had no significant medical history. A brother
had suffered a stroke and was found to have transient thrombocytosis and his mother had a history
of embolic arterial occlusive disease of the lower
extremity.
On examination the patient slept when left alone
© 2001 by Elsevier Science Inc.
655 Avenue of the Americas, New York, NY 10010

tPA for Venous Thrombosis

Surg Neurol 341
2001;55:340 –6

Axial cranial CT scans of the patient on admission to the hospital showing hyperdensity in the superior sagittal
sinus and straight sinus (left, wide arrows) and linear hyperdensities in the internal cerebral veins (right, narrow
arrows). The findings are consistent with thrombosis of these structures.

1

and was confused when awakened. He obeyed commands with the right extremities. There was no
papilledema. He had right-sided gaze preference
with dense left hemiparesis and hemisensory loss
that progressed to hemiplegia within 2 hours. Partial thromboplastin time was slightly less than normal at 17.9 seconds (normal range; 22.7 to 37.1
seconds). Other routine hematological and blood
chemistry tests were normal. Platelet count was
424,000.
An unenhanced CT scan of the head showed hyperdensities along the superior sagittal sinus, both
transverse sinuses, the straight sinus, the vein of
Galen, and both internal cerebral veins (Figure 1).
There was no intraparenchymal hypodensity or
hemorrhage. The patient was given heparin, 1000 IU
per hour by vein, without a loading dose. A cerebral
angiogram was obtained immediately and revealed
extensive dural sinus and deep cerebral venous
system thrombosis as suggested by the CT scan
(Figure 2). The decision was then made to attempt
clot lysis and, via femoral vein cannulation, a 5
French Weinberg catheter was passed until its tip
was in the proximal left sigmoid sinus. A Tracker威
18 catheter (Target Therapeutics, Fremont, CA) was
used to selectively catheterize the superior sagittal

sinus, and 25 mg of rt-PA was infused as 2 mg
boluses at each centimeter along the thrombosed
portion of the superior sagittal sinus. An immediate
post-infusion angiogram showed no significant
change in the degree of thrombosis. The catheter
was advanced again to the junction of the anterior
and middle thirds of the superior sagittal sinus and
left at that site. It was connected to an infusion
pump and rt-PA was infused continuously at 1 mg
per hour for 19 hours. The heparin was continued at
1000 IU per hour and prothrombin and partial
thromboplastin times and fibrinogen levels were
measured every 4 hours. Prothrombin time and fibrinogen levels remained normal. Thrombin time
was always greater than 100. The partial thromboplastin time ranged from 36 to 80 seconds.
The following morning an angiogram was performed by transfemoral catheterization of the internal carotid arteries. The venous phase showed almost complete resolution of the thrombosis (Figure
3). The rt-PA was discontinued and all catheters
were removed. Over the next several days the patient’s neurologic exam improved so that he could
be discharged home after 7 days. He was continued
on oral coumadin therapy. Further evaluation for
hematologic disease including antithrombin III, pro-

342 Surg Neurol
2001;55:340 –6

Yamini et al

Lateral (left) and anteroposterior (right) venous phase cerebral angiogram of right internal carotid artery
injection taken upon admission of the patient to hospital. There is absence of filling of the posterior two thirds
of the superior sagittal sinus, both transverse sinuses, the straight sinus, the vein of Galen, and the internal cerebral
veins. The findings are consistent with thrombosis of these veins.

2

tein C and S, and factor V Leiden assay were negative. A work-up for autoimmune disease including a
search for anticardiolipin antibodies and lupus anticoagulant was negative. Plasma homocysteine,
anti ␤2 glycoprotein, serology for syphilis, and polymerase chain reaction analysis of factor 2 were all
normal. The patient was a professional musician
and neurological function recovered such that he
was able to resume playing the piano with the same
dexterity as before his illness.

Discussion
The management of patients with cerebral venous
thrombosis is intravenous heparin. We report a patient who presented with altered consciousness
and hemiplegia that lasted for 24 hours but from
which the patient was able to recover completely.
Although such a recovery seems likely to have been
brought about by the superselective intrasinus infusion of rt-PA, the controversy regarding optimal
management of such patients stems in part from the
great variability in the natural history of the disease
and the potentially serious risks associated with
systemic or superselective fibrinolytic therapies.
The natural history of patients with cerebral ve-

nous thrombosis is highly variable. Early reports
noted mortality rates of 30% to 50%, whereas more
recent reviews quote a mortality rate of 10% [20].
Several factors may account for this difference, including improved general medical care and management of intracranial hypertension, diagnosis of
milder cases because of heightened awareness of
the condition and more sensitive diagnostic tests,
and possibly more widespread use of intravenous
anticoagulation with heparin and coumadin in the
acute stage. In survivors, the long-term outlook is
good, with 86% of patients having no neurological
sequelae, 12% developing second episodes of cerebral venous thrombosis, and 14% having recurrent
seizures [20]. Factors that may be associated with
worse prognosis include advanced age, coma, presence of hemorrhagic infarction, extensive deep cerebral venous thrombosis, infectious or malignant
etiology, increased intracranial pressure, uncontrolled seizures, and associated pulmonary embolism [1–3]. Other series have not confirmed these
prognostic factors [2]. The outlook in any given
case remains variable and the possibility of good
outcome even in comatose patients makes prediction of outcome in individual cases difficult.
There are more than 50 cases of deep cerebral

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Surg Neurol 343
2001;55:340 –6

Lateral (left) and anteroposterior (right) venous phase cerebral angiogram of right internal carotid artery
injection taken approximately 24 hours after the initiation of rt-PA infusion into the anterior portion of the superior
sagittal sinus. There is now good filling of the posterior two thirds of the superior sagittal sinus, both transverse
sinuses, the straight sinus, the vein of Galen (wide arrows), and the internal cerebral vein (narrow arrows). There has
been nearly complete lysis of thrombus in these veins.

3

venous thrombosis reported in the literature [4,6].
A review of 110 patients with cerebral venous
thrombosis found nine cases involving the deep
venous system [1]. The clinical presentation of patients with thrombosis of the deep venous system
classically includes acute coma, decerebration,
hemiparesis, and extrapyramidal hypertonia. When
dural sinus thrombosis occurs signs and symptoms
of raised intracranial pressure may also be apparent. Crawford et al compared 28 patients with deep
cerebral venous thrombosis to 38 patients with superficial dural sinus thrombosis and noted that
deep cerebral venous thrombosis was more common in women and more likely to present with
acute neurological deterioration and coma [6]. The
outcome was worse with death in 36% of patients
with deep but only 11% of patients with superficial
thrombosis.
Treatment of intracranial venous thrombosis
may include surgery to place an intracranial pressure monitor, drain the ventricles, or remove a hematoma. Medical treatment includes anticonvulsants and therapies to reduce intracranial pressure
if necessary. Heparin or low molecular weight heparin followed by coumadin may be indicated. Einhäupl et al randomly allocated 20 patients with

sinus venous thrombosis to treatment with placebo
(n ⫽ 10) or intravenous heparin (n ⫽ 10) [10]. After
3 months, eight patients treated with heparin were
normal and two had minor neurological deficits,
whereas three patients treated with placebo died,
six had severe neurological sequelae, and one recovered fully. This study included a different type of
patient from those that are usually treated with
superselective intracranial thrombolytics in that
patients started treatment on average 1 month after
onset of symptoms. Intracranial hemorrhage was
present at time of treatment in 30% of heparintreated and 20% of placebo patients. Patients
treated with heparin did not have further intracranial bleeding, whereas two patients who were given
placebo did. A double-blind, randomized trial of the
low-molecular weight heparin, nadroparin, versus
placebo was conducted in 60 patients [8]. There
was no significant difference in outcome between
groups with poor outcome after 12 weeks in 13% of
nadroparin- and 21% of placebo-treated patients.
Nadroparin treatment did not cause new intracranial bleeding or increased hemorrhage in 15 patients who had hemorrhagic lesions before treatment. These studies do not show robust beneficial
effects of anticoagulation, although the risks seem

344 Surg Neurol
2001;55:340 –6

small. Combined analysis of these two studies suggested that there was a modest, clinically important
but statistically insignificant beneficial effect of anticoagulation [3,8]. As a result, many authorities
recommend anticoagulation for most patients with
cerebral venous thrombosis.
Fibrinolytic agents administered systemically for
cerebral venous thrombosis probably do not produce enough fibrinolysis to lyse intracranial venous
clots without producing substantial systemic fibrinolysis that may predispose to dangerous complications such as intracranial hemorrhage [9]. Superselective intracranial administration of urokinase
or rt-PA has been reported in selected patients with
intracranial venous thrombosis. There are at least
42 reported cases of urokinase treatment [2,5,7,12–
15,17,19,21,23–26]. There was no obvious gender
predilection with about 50% of patients being female. The average age was 33 (range: newborn to 75
years old) and 15 (36%) presented with varying
degrees of altered consciousness. Twelve cases
(29%) had thrombus in the straight sinus, vein of
Galen, and/or internal cerebral veins. Prolonged infusions of urokinase were undertaken in all but 12
cases with the average duration of treatment being
84 hours (range: 12 hours to 10 days) in the cases
with prolonged infusion. The average dose of urokinase was 4.6 million units (range in adult patients:
200,000 to 19 million units). Complications included
two intracranial hemorrhages not requiring surgery, one episode of neurological deterioration, one
puncture-site infection, two infections, and six systemic bleeding episodes (total: 29%). Outcome was
good in 39 cases, with only one death and two
patients left with severe disability.
We treated our patient with rt-PA because of limited availability of urokinase. Theoretical advantages of rt-PA over other fibrinolytics are that it may
activate fibrinolysis only in the blood clot, that it
has a very short half life (6 to 8 minutes), and that
it is not antigenic. There are now 24 such cases
reported [11,16,18,22]. The average age is 34 years
(range: 20 to 55 years old). Thirteen (54%) presented with varying degrees of altered consciousness. Only three cases (12%) had thrombus in the
straight sinus and ours is the first case involving
deeper veins. Two patients were treated with rt-PA
at a single sitting using 3.2 million IU heparin and 35
mg tPA. Prolonged infusions of an average of 84 mg
(range: 10 to 300 mg) were used in all other cases
with the average duration of treatment of 23 hours
(range: 8 to 77 hours). Complications included
bleeding at a femoral puncture site in two cases,
retroperitoneal hemorrhage requiring transfusion
in one, and worsening of intracranial hemorrhage in

Yamini et al

two. Seven patients had intracranial hemorrhage
before thrombolytic therapy, and this worsened in
two (29%). There was no increase in intracranial
hemorrhage in 18 patients with intracranial hemorrhage among 40 treated with heparin [8,10].
The indications for superselective infusions of
urokinase or rt-PA remain ill-defined. Given the
risks of aggravating or precipitating intracranial
bleeding, most authorities have limited its use to
patients who continue to deteriorate despite medical management, who have substantial neurological deficits, and who probably do not have intracranial hemorrhage [11]. The outcome is better when
the thrombosed veins recanalize. This clearly can
be achieved more rapidly with superselective urokinase or rt-PA [3,11], but it may be at the expense of
an increased risk of intracranial bleeding, although
this has only been reported in patients who have
hemorrhage before treatment. All published reports are small series or case reports, and it is
difficult to draw any conclusions about efficacy, but
the overall outcome seems to be better than the
natural history in the general group of patients with
cerebral venous thrombosis.
We report that selective infusion of rt-PA into the
superior sagittal sinus resulted in thrombolysis of
clot in the internal cerebral veins. It also is possible
that the improved deep venous flow was not due
directly to clot lysis but to improved venous outflow secondary to lysis of clot in the area of the
torcula. In previous reports of infusion of urokinase
for straight sinus and internal cerebral vein thrombosis, patency was achieved in the deep venous
system in only 4 of 8 cases [12,15,19]. It was not
clear in most cases where the infusions were given.
Overall, complete patency was achieved in 32 of 59
patients (54%) treated with urokinase or rt-PA for
whom adequate information was available. Our
case shows that it may be possible to obtain adequate thrombolysis of the deep venous system even
with infusion into superficial sinuses.
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COMMENTARY

Yamini et al do an excellent job of concisely describing the current management schemes for superficial and deep cerebral sinus thrombosis. I
agree that aggressive management of this entity is
often necessary to avoid the sequelae of intraparenchymal hemorrhage or acute and chronic intracranial hypertension. Since urokinase and prourokinase are not currently available, Yamini et al
do us a service by describing their tPA dosage for
clearing the superficial and deep systems.
As an aside, we have found two other useful techniques for the management of sinus thrombosis.
The first is the aggressive movement of a curved
wire in the sinuses to macerate the clot before and
during drug instillation. This technique seems to
speed up the lysis, perhaps by exposing more surface area to the drug’s effects. The second is the use
of the Possis Angiojet, which is a device designed
for peripheral use but which can, with some difficulty, be advanced into the transverse and sagittal
sinuses to evacuate thrombus.
Michael Horowitz, M.D.
Department of Neurological Surgery
University of Pittsburgh
Pittsburgh, Pennsylvania
Intrasinus thrombolytic therapy can be very effective in the treatment of symptomatic dural sinus
thrombosis, as it was in the patient described in
this report. Several points merit discussion: (1) The
primary treatment is IV heparin, whether or not
venous hemorrhage is present. (2) MRI and MR
venography are important tools in the diagnosis
and management of these patients; the MRV can be
used as a baseline for noninvasive follow-up studies. (3) The timing of application of intrasinus
thrombolysis is controversial, but I would apply
this in patients failing heparin therapy who have at