Leading opinion
Hemorrhagic transformation: a foe that could be a friend?
Carlos A. Molina
Early pharmacologically or mechanically
induced reperfusion is the most effective
treatment for acute ischemic stroke when
given within the first hours of stroke onset.
The beneficial effect obtained by thrombo-
lysis-induced recanalization may be coun-
teracted by an increased risk of clinically
relevant hemorrhagic transformation
(HT). HT of cerebral infarction is consid-
ered a drawback and generally assumed to
be a major concern after thrombolytic
therapy for acute stroke. However, the
history of HT of cerebral infarction is very
misleading and leads to misconceptions,
and even nowadays many clinicians would
feel relieved if they observe no hemorrhage
but see a large infarction on follow-up
computed tomography (CT) 24 h after
thrombolysis, considering that the treat-
ment although ineffective was at least ‘safe.’
The term HT designates a variety of
bleedings degree with different pathophy-
siology and clinical significance. There-
fore, distinction between symptomatic
and asymptomatic hemorrhage repre-
sents a useful tool for thrombolytic and
other reperfusion trials. Initial definition
of symptomatic intracranial bleeding as
‘any bleeding related to clinical worsen-
ing’ currently seems obsolete, useless,
and, most importantly, it does not accu-
rately reflect the pathophysiological me-
chanisms of neurological worsening in
stroke thrombolysis. Clinical deteriora-
tion during the acute phase of stroke and,
particularly, in the setting of thrombolysis
may respond to a variety of causes in-
cluding brain edema with mass effect,
drop of regional perfusion pressure,
stroke progression or early recurrence,
increased temperature, etc. The link be-
tween HT and clinical worsening should
be established based on whether the
amount, location and timing of hemor-
rhage could reasonably be considered the
cause of clinical worsening.
The European Cooperative Acute
Stroke Study (ECASS) investigators dis-
trusted the concept of symptomatic he-
morrhage and categorized HT according
to radiographic criteria (1). On CT the
extent of HT varies widely, ranging from
petechial HI to large parenchymal hema-
toma (PH) with mass effect. Neither the
presence of hemorrhagic infarctions (HI)
nor the presence of small PHs without a
prominent space occupying effect (PH1)
influenced the risks of early deterioration,
disability, or death at 3 months (2, 3).
Only PHs with substantial space-occupy-
ing effect are clearly associated with an
increased risk of early deterioration, dis-
ability, and death. In patients suffering
PH2, both ischemic brain edema and a
large hematoma volume may contribute
to the space-occupying effect and clinical
deterioration (4).
The phenomenon of reperfusion he-
morrhage as a result of clot lysis and
recirculation into an ischemic and abnor-
mally permeable vascular bed has been
thought to be one of the mechanisms of
HT after brain embolism (5). The timing
of arterial recanalization has been shown
to be an important determinant of the
risk of HT in animal models of acute
stroke, (6, 7), in which delayed recanali-
zation has been associated with the pre-
sence of HT at 24 h. We demonstrated in
human stroke that delayed spontaneous
recanalization occurring for 46 h of on-
set is associated with an increased risk of
HT (8). Unlike spontaneous recanaliza-
tion, early reperfusion is a common event
after thrombolysis, occurring in up to
66% of rtPA-treated patients (9, 10),
which eventually leads to reperfusion
hemorrhage into areas of irreversible da-
mage. This is supported by diffusion-
weighted and perfusion-weighted ima-
ging studies in which thrombolysis-in-
duced HT appeared earlier than that
which occurs spontaneously (11, 12).
In a prospective study (13), we demon-
strated in stroke patients with proximal
MCA occlusion that although the occur-
rence of HTof any type is unrelated to the
time point of recanalization, distribution
of HT subtypes differs significantly, de-
pending on the time to reperfusion. HI1–
HI2 represents a marker of early successful
recanalization, which leads to a reduced
infarct size and improved clinical out-
come. Conversely, delayed recanalization
(46 h) was associated with an increased
risk of PH.
It has been hypothesized that the differ-
ence between symptomatic and asympto-
matic hemorrhage may be related more to
the degree of bleeding than to differences
in pathophysiology (14, 15). The amount
of hemorrhage after reperfusion may re-
flect the degree of blood–brain barrier
breakdown. Early successful recanaliza-
tion reestablishes brain perfusion and
may rescue still viable ischemic tissue
despite the development of some pete-
chial hemorrhages into a relatively small
core of irreversible brain damage. Con-
versely, after several hours of persistent
occlusion, the severity and extent of
a blood–brain barrier disruption yields
to a large hemorrhage after reperfusion,
which grows enough to counteract the
beneficial effect of reperfusion, which
leads to clinical worsening.
The underlying mechanism and clin-
ical meaning of HI may differ, depending
on whether it appears within the first few
Correspondence: Carlos A. Molina MD, PhD
Neurovascular Unit, Hospital Vall D’Hebron
Passeig Vall D’Hebron 119-129,
08035, Barcelona, Spain.
E-mail: [email protected]
& 2006 The Author.226 Journal compilation & 2006 International Journal of Stroke Vol 1, November 2006, 226–227
days or later after stroke. Early (o36 h)
HI may indicate that recanalization oc-
curred when the ischemic tissue was still
at least partially viable. In contrast, HI
detected later but not in the early stage
may reflect persisting arterial occlusion
with reperfusion via collateral flow or
very delayed recanalization, both of
which have been associated with larger
infarction and worse clinical outcome.
Should hemorrhagic infarction still be
considered a treatment-related complica-
tion in thrombolytic trials? Most stroke
trials include the term ‘any hemorrhage’
seen on follow-up CT or magnetic reso-
nance imaging as a safety end-point.
From the safety standpoint only PHs
with substantial space-occupying effect
detected on CT at 24–36 h should be
regarded as primary safety parameter in
reperfusion trials, as it consistently de-
monstrated to be associated with an in-
creased risk of early deterioration,
disability, and death. Other types of HT
including HI and PH1 simply indicate
that recanalization and reperfusion over
an ischemic core has occurred. The pre-
sence of petechial or more confluent HI
would represent a good prognostic sign
and a marker of early reperfusion, re-
duced infarct size and good clinical out-
come particularly in patients with
proximal MCA occlusion treated with
i.v. tPA o3 h. However, HI detected on
CTat later time points (436 h) but not in
the early stage may reflect late reperfusion
via collateral flow or very delayed recana-
lization, larger infarction and worse clin-
ical outcome. In this later case, HI is only
a ‘guilty by association’ as pointed out by
Pessin 25 years ago (16).
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& 2006 The Author.Journal compilation & 2006 International Journal of Stroke Vol 1, November 2006, 226–227 227
C. A. Molina Leading opinion