586
Hemorrhagic Infarcts
ROBERT G. HART, M.D.,
MORE THAN A HUNDRED YEARS AGO, John
Lidell observed that "red softening commences after
24—48 hours, dating from the apoplectiform attack" of
cerebral embolism.1 While his pathological descrip-
tions are arguably ambiguous, Lidell's observations
surely are among the earliest descriptions of hemor-
rhagic infarct (HI). Our clinical-pathological concepts
of His then lay relatively dormant until 1951, when
Fisher and Adams emphasized the association of HI
and embolism and proposed their well-known hypoth-
esis about the mechanism of hemorrhagic transforma-
tion.2 HI remained an autopsy diagnosis until comput-
ed tomography (CT) and magnetic resonance imaging
(MRI) permitted diagnosis during life. Recent studies,
including two in this issue of STROKE, 3 ' * have refined
our clinical concepts of HI.5"10 Treatment of acute
stroke patients with thrombolytic agents and antico-
agulants, both having secondary brain hemorrhage as
their most feared complication, has rekindled interest
in the occurrence and mechanisms of hemorrhagic in-
farction." 15
Hemorrhagic infarction describes multifocal, secon-
dary bleeding into brain infarcts. Innumerable foci of
capillary and venular extravasation either remain as
discrete petechiae or merge to form confluent purpura
(fig. 1). Pathologically, the distinction between pale
and hemorrhagic infarcts is arbitrary in mild cases.
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Most recent infarcts show a few scattered petechiae,
along their margins. Most pathologists do not desig-
nate an infarct as hemorrhagic unless a large part is
involved with petechiae or unless petechiae are conflu-
ent.2- 17
Autopsy studies report that about 30% (range
18-42%) of recent brain infarcts are hemorrhagic, with
the wide range in prevalence largely explained by
varying definitions of mild HI and by ill-defined inter-
vals from stroke to death. 2 ' 3 - "-20 Autopsy studies em-
phasize a high prevalence of HI associated with embol-
ic stroke: His occur in 51-71% of "embolic" strokes
compared to 2 - 2 1 % of "nonembolic" strokes. 2 ' 3i " In
most cases, the inability to diagnose embolic stroke
with certainty, even at autopsy, clouds the interpreta-
tion of both autopsy and clinical data.
CT and autopsy studies convincingly link HI with
infarct size.3 V7> l4 ' 2I Lodder and colleagues in this is-
sue question whether the association of HI and car-
dioembolic stroke at autopsy is explained by infarct
size rather than by the stroke mechanism. 3 If cardioem-
bolic strokes are unduely large, HI could be a marker
of large infarcts rather than the stroke mechanism per
se. Earlier autopsy studies of HI did not report the
From the Department of Medicine (Neurology), University of Texas
Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas,
USA 78284.
Address correspondence to Drs. Hart& Easton, Department of Medi-
cine (Neurology), University of Texas Health Science Center, Floyd
Curl Drive, San Antonio, Texas 78284.
Received May 14, 1986; accepted May 21, 1986.
AND J. DONALD EASTON, M.D.
interval from stroke to death, the cause of death, or the
correlation of infarct size with HI, thus confounding
analysis of the relationship of HI to infarct size inde-
pendent of stroke mechanism. 2 ' 17 ' l9 Using brain herni-
ation to reflect infarct size, Lodder and colleagues
conclude that "in the cases dying from brain herni-
ation, HI was equally frequent in the group with a
cardiac embolic cause of stroke, as it was in the group
without such cause." 3 However, alternative interpreta-
tion of these data yields a different conclusion. We
would not consider the few petechiae termed "small
HI" by Lodder and colleagues (their fig. 2, indicated
by arrows) as HI. Considering only confluent pete-
chiae (the unequivocal HI in their fig. 1), His were
present in 42% (6 of 14) patients with cardioembolic
sources who herniated compared with 15% (2 of 13) of
patients without cardioembolic sources who herniated.
It is our view that these important data of Lodder et al
support the notion that cardioembolic strokes have a
special, but certainly not exclusive, propensity for
hemorrhagic transformation. Relatively dense His that
occur deep within the distribution of the affected vessel
are most often associated with a cardioembolic mecha-
nism.
His are observed on less than 5% of initial CTs of
patients with acute ischemic stroke 7 - n but in an addi-
tional 10% if CT is repeated in the subsequent
weeks. 6 ' 823 " 23 Hemorrhagic transformation visible on
CT is delayed for variable intervals following stroke;
early hemorrhagic transformation (within 48 hours of
stroke onset) appears to be particularly frequent with
presumed cardioembolic strokes. 4 ' 6 - 8 - 92 * Horning et
al performed serial CTs over a four week interval in 65
patients with acute ischemic stroke and reported hem-
orrhagic transformation in 17% within the first week
after stroke, an additional 23% in the second week, 3%
in the third week, and none in the fourth week. 6 The
overall 43% prevalence of HI is considerably higher
than other clinical series of serial CTs8 and even ex-
ceeds the autopsy prevalence, suggesting patient popu-
lation differences or potentiation of HI by their use of
osmotic agents and low-dose heparin.6
In one small series, enhancement of acute (within 28
hours) infarcts on CTs performed three hours after
high-dose intravenous contrast infusion was predictive
of later development of HI. 23 HI are readily detected by
MRI, but systematic comparison with CT has not yet
been undertaken. Surprisingly, HI has not been associ-
ated with acute or chronic hypertension in most clinical
and autopsy studies. 3 -'• l7 - 18 - 27
Given the dynamic nature of secondary hemorrhagic
transformations and their relationship to large infarcts,
it is difficult to directly compare prevalences of HI
between CT and autopsy studies. Large infarcts would
be over-represented in autopsy studies of recent stroke
and postmortem examination would detect HI with
greater sensitivity than CT; hence HI should occur
more frequently in autopsy studies. On the other hand,
 HEMORRHAGIC INFARCTS/tfa/7 and Easton
FIGURE 1. Variable degrees of hemorrhagic infarction. A) Scattered petachaie in a "watershed" infarct. B) Dense, confluent
purpura in a cardioembolic stroke (from Escourille and Poirier, with permission).16 Different degrees/patterns may have
implications for stroke mechanism.
late-developing HI may especially occur in stroke sur-
vivors and result in higher CT detection rates.
About half (range 29-73%) of all His in clinical-CT
studies are associated with presumed cardioembolic
strokes. 4 ' 6 ' 7i 1 0 '" Of patients with presumed acute car-
dioembolic stroke, HI will be present on only 5% of
CTs performed within the first 24 hours6' M- a - N but in
about 20% (range 8-62%) of CTs performed 1-2
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weeks after s t r o k e . 6 1 0 1 4 2 4 3 0 Hemorrhagic transfor-
mation is delayed for 6-12 hours after cardioembolic
stroke, but usually occurs within 48 hours in nonanti-
coagulated patients. 4 9 3 1 This relatively early hemor-
rhagic transformation (within 48 hours) associated
with presumed cardioembolic strokes compared to
non-embolic infarcts partly explains why studies of
early CT or of autopsies with early stroke deaths report
a particularly high association of HI with cardioem-
bolic stroke.
Serial CT studies of HI in patients with presumed
cardioembolic stroke have yielded two additional
clinical correlations: (1) most hemorrhagic transforma-
tions in nonanticoagulated patients are not associated
with clinical worsening and (2) anticoagulation regu-
larly accentuates the degree of HI, often with clinical
deterioration. In one large collection of nonanticoagu-
lated patients with presumed cardioembolic stroke and
evolving HI documented by serial CTs, only 17% (2 of
12) experienced clinical deterioration associated with
hemorrhagic transformation. 5 ' 9 Hemorrhagic transfor-
mation never occurred in the initial six hours after
stroke onset, but the majority were present between
24—48 hours.31 Among anticoagulated patients with
hemorrhagic transformation documented by serial CT,
56% (15 of 27) deteriorated.9 Severe secondary hemor-
rhage, resembling confluent hematoma, occurred in
41% (11 of 27) of anticoagulated patients but only 8%
(1 of 12) of nonanticoagulated patients.9 Other clinical
and autopsy studies have confirmed that anticoagula-
tion during the period of hemorrhagic transformation
587
accentuates the degree of secondary hemorrhage, often
with clinical worsening, in patients with presumed car-
dioembolic stroke.4'17 Anticoagulation does not appear
to increase the likelihood of hemorrhagic infarction,
but appears to accentuate the degree of hemor-
rhage.14'26 The period of active bleeding is transient
and anticoagulants administered after the appearance
of HI on CT do not usually result in clinical or radio-
graphic worsening. 424
What mechanism(s) allows blood to leak into some
infarcts, but not into others? In mild-moderate His,
hemorrhage is believed to result from diapedesis
through ischemic endothelium, usually without vessel
rupture. An ischemic insult of sufficient degree to in-
duce a transient abnormality in vascular permeability
appears to be a necessary substrate for HI. The extent
of disruption of endothelial junctions and capillary
rupture are related to the duration and degree of ische-
mia in primates with transient middle cerebral artery
occlusion.32 A second essential condition is postulated
to be restoration of circulation to the injured capillary
bed during the interval of increased permeability, ei-
ther by re-opening of the initial site of occlusion or by
establishment of collateral circulation. 2 ' l9
In other patients, variable degrees of necrosis of the
vessel walls are present and the severe secondary hem-
orrhage appears unifocal, with mass effect and intra-
ventricular extension.3' '• "• 33 The bleeding in these pa-
tients clinically resembles intracerebral hemorrhage
from a single focus, and some clinicians have suggest-
ed two distinct syndromes of hemorrhagic transforma-
tion: (1) multifocal hemorrhagic infarction and (2) sec-
ondary hematoma (apparently unifocal) within an
infarct.3'6- "• M We suspect that, pathologically and
mechanistically, the difference is of degree rather than
of kind: Both are points along a spectrum of vascular
injury, transiently increased permeability and secon-
dary hemorrhage.
Hypothetically, the propensity of large infarcts to
 STROKE VOL 17, No 4, JULY-AUGUST 1986

undergo hemorrhagic transformation may be a reflec-

tion of the probability that the ischemia is sufficient to
alter vascular permeability. In watershed infarcts,
which may be large in volume and in which early
reperfusion would be expected to occur, ischemia may
be insufficient to substantially alter vascular integrity
and dense HI is uncommon.1735 HI is present in about
one-third of patients with brain infarction due to vaso-
spasm secondary to subarachnoid hemorrhage, with
onset during remission of vasospasm.36
In cardioembolic infarcts, hemorrhagic transforma-
tion is postulated to occur when distal migration of the
embolic fragment from its initial site of arterial ob-
struction allows reperfusion of the damaged vascular
bed (fig. 2).2' l7~19 The relationship between re-opening
of the site of occlusion and hemorrhagic transforma-
tion is strongly supported by both radiographic and
pathologic data.2'IOi l7> l8'38> 39 However, persistent
proximal occlusions have been found in 11-17% of
His associated with cardioembolic stroke, implicat-
ing other routes of reperfusion as well.10'17' '9 The role
of collateral circulation-reperfusion in hemorrhagic
transformation has not been thoroughly studied except
in experimental models.
Do strokes resulting from artery-to-artery embolism
have the same predisposition for and mechanism of HI
as those due to cardiogenic emboli? There are few
clinical or pathologic data addressing this issue, due to
the difficulty of defining this mechanism with certain- FIGURE 3. Subcortical hemorrhagic transformation may be
ty. We speculate that artery-to-artery embolism un- particularly associated with presumed cardioembolic stroke.
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commonly results in sufficient ischemia to derange
vascular permeability. However, with particularly
large artery-to-artery emboli, the situation may well be
analogous to cardioembolic stroke.4
From analysis of these data, including those present-
ed in this issue of STROKE, we conclude that car-
dioembolic strokes do indeed have a special propensity
for hemorrhagic transformation, independent of infarct
size. Further, the early re-opening due to distal migra-
tion of embolic fragments appears to result in a recog-
nizable pattern of early (within 48 hours) hemorrhagic
transformation with central or globular and relatively
dense HI (fig. 3).2> 8 Development of collateral circula-
Brain surface
Pressure restored
\ Hemorrhagic infarction
None of these four patients with presumed cardioembolic stroke
received anticoagulation, one (upper right) deteriorated associ-
ated with hemorrhagic transformation. From the case collec-
tion of the Cerebral Embolism Study Group.9- 21
tion may be important in late hemorrhagic transforma-
tion (after one week); these His tend to be scattered or
gyral in pattern, near the infarct periphery and have
little predictive value for stroke mechanism. These
generalizations are not absolute. Many exceptions are
known and may be explained by variations in the tim-
ing of re-opening of embolic occlusions and of devel-
opment of the collateral circulation.
It appears that the mechanism of secondary hemor-
rhagic transformation is a remarkably complex and
dynamic process, involving a combination of vascular
injury with altered permeability and reperfusion, inte-
grated over time. Standing on the shoulders of giants' •2
with the aid of CT and MRI imaging, clinicians now
have new concepts about HI to consider, assimilate
and further define.

Anemic Infarction References

Embolism breaks up.
goes into one branch
FIGURE 2. Hemorrhagic transformation in embolic stroke.
Re-perfusion during the initial days due to distal migration of
emboli from the initial site of occlusion may be a key factor in
hemorrhagic transformation. From Toole, Cerebrovascular
Disorders, with permission.37
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