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: cmolina@vhebron.net

& 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