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Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage

Stephan A. Mayer, MD

Background—Intracerebral hemorrhage (ICH) causes higher morbidity and mortality than other forms of stroke and has
no proven effective treatment. Hematoma volume is a powerful predictor of outcome after ICH.
Summary of Review—Historically, ICH bleeding was considered to be a monophasic event that stopped quickly as a result
of clotting and tamponade by surrounding brain tissue. More recently, prospective and retrospective CT-based studies
have demonstrated that hematoma growth occurs in up to 38% of patients initially scanned within 3 hours of onset and
in 16% scanned between 3 and 6 hours, even in the absence of coagulopathy. Progressive bleeding of this type has been
associated with contrast extravasation on CT angiography and poor outcome after early (⬍4 hours) surgical clot
evacuation. On the basis of these observations, it is plausible that ultra-early hemostatic therapy given in the emergency
setting might reduce ICH volume in some patients and improve outcome. Among candidate agents for this indication,
the most promising is recombinant activated factor VIIa, which promotes local hemostasis at sites of vascular injury in
both coagulopathic and normal patients.
Conclusions—Ultra-early hemostatic therapy, given within 3 to 4 hours of onset, may potentially arrest ongoing bleeding
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and minimize hematoma growth after ICH. Given the current lack of effective therapy for ICH, clinical trials testing this
treatment approach are justified. (Stroke. 2003;34:224-229.)
Key Words: cerebral hemorrhage 䡲 factor VIIa 䡲 hemostasis 䡲 stroke management

I ntracerebral hemorrhage (ICH), defined as spontaneous

bleeding into the brain, is the deadliest, most disabling, and
least treatable form of stroke. Compared with ischemic stroke
reduction after ICH remains untested, and clinical trials of
dexamethasone7,8 and glycerol9 therapy have failed to show a
benefit. The role of surgical hematoma evacuation remains
and subarachnoid hemorrhage, victims of ICH suffer higher controversial as well. In the most comprehensive meta-anal-
mortality and are left with more severe deficits.1 Of the nearly ysis to date, 530 ICH patients randomly assigned in 7 trials to
40 000 Americans who experienced an ICH in 1997, 35% to surgical or medical management showed a nonsignificant
52% were dead within 1 month, and only 20% were living trend toward increased death or dependency after surgery.10
independently at 6 months.2 The hospital mortality rate of Recent studies have demonstrated the feasibility of CT-
ICH victims who are comatose and mechanically ventilated is guided stereotaxic thrombolysis and clot aspiration for small
60%.3,4 deep hematomas11 and intraventricular local thrombolytic
ICH constitutes 15% of all strokes in the United States and therapy for hastening the removal of intraventricular hemor-
Europe and 20% to 30% in Asian populations.1 Advancing rhage,12,13 but definitive trials of these interventions have yet
age and hypertension are the most important risk factors for to be performed. According to a recent American Heart
ICH. Degeneration and rupture of small arteries or arterioles Association Scientific Statement, “treatment studies of ICH
due to sustained hypertension is the most common cause of are urgently needed. . . . We hypothesize that ultra-early
ICH, accounting for more than 60% of cases.5,6 Cerebral treatment will be critical for patients with ICH.”2
amyloid angiopathy has become increasingly recognized as a
cause of lobar ICH in the elderly, accounting for approxi- CT Studies of Early Hematoma Growth
mately 10% of cases.1,5 In recent years, attention has shifted to early hematoma
growth as an important cause of early neurological deterio-
Current Therapy of ICH ration after ICH. Historically, bleeding in ICH was thought to
In contrast to advances in the acute management of subarach- be completed within minutes of onset, and neurological
noid hemorrhage and ischemic stroke, effective therapies for deterioration during the first day was attributed to cerebral
ICH are not available, treatment is primarily supportive, and edema and mass effect around the hemorrhage.14 In the
outcomes remain poor. Blood pressure reduction and osmo- 1980s, several case series described early growth of ICH on
therapy are usually given in the acute setting, but the effect of repeated CT scans in the absence of coagulopathy.15–18 More
these interventions is unclear.2,5 The impact of blood pressure recent prospective and retrospective studies indicate that

Received June 5, 2002; final revision received July 22, 2002; accepted August 2, 2002.
From the Division of Critical Care Neurology, Departments of Neurology and Neurosurgery, Columbia University College of Physicians and Surgeons,
New York, NY.
Reprint requests to Stephan A. Mayer, MD, Neurological Institute, 710 W 168th St, Unit 39, New York, NY 10032. E-mail
© 2003 American Heart Association, Inc.
Stroke is available at DOI: 10.1161/01.STR.0000046458.67968.E4

Mayer Ultra-Early Hemostatic Therapy for ICH 225

TABLE 1. Frequency of Early Hematoma Growth

Prospective Retrospective

Interval from symptom onset Brott et al,19 1997 Fujitsu et al,22 1990 Fujii et al,21 1998 Kazui et al,23 1996
to CT (h) (n⫽103) (n⫽107) (n⫽627) (n⫽204)
0 –3 38% (39/103) NA 18% (78/422) 36% (27/74)
3.1–6.0 NA NA 8% (8/97) 16% (7/45)

0–6 NA 21% (23/107) 17% (86/519) 29% (34/119)

6.1–24.0 NA NA 2% (2/108) 10% (7/67)
NA indicates data not available. Hematoma growth was defined as a ⬎33% increase in volume by Brott et al, a ⬎50% or 20-ml
increase by Fujii et al, and a ⬎40% or 12.5-ml increase in volume Kazui et al. A definition was not specified by Fujitsu et al.

early hematoma growth occurs in 18% to 38% of ICH Supportive Evidence: CT Angiography and
patients scanned within 3 hours of onset and is highly Ultra-Early Surgery
correlated with early neurological deterioration (Table Further evidence that ongoing bleeding can occur for several
1).19 –24 hours after the onset of ICH comes from CT angiographic
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In the only prospective study of this phenomenon, Brott et studies that have demonstrated contrast extravasation into the
al19 performed a baseline CT scan within 3 hours of onset in hematoma. In these studies contrast extravasation occurred in
103 patients with ICH and found a substantial increase in the 30%25 and 46%26 of patients scanned on average within 6
volume of parenchymal hemorrhage (⬎33%) in 26% of hours of onset, was more likely to occur with earlier scan-
patients when rescanned 1 hour later. An additional 12% of ning,25,26 and was associated with increased mortality26 and
patients had hematoma growth between the 1- and 20-hour subsequent hematoma enlargement.25 The clinical signifi-
cance of early rebleeding after ICH was emphasized in a pilot
CT scans. Overall, ICH growth occurred in 38% of patients
study of ultra-early surgical ICH evacuation performed
scanned within 3 hours of symptom onset, and this figure was
within 4 hours of onset. This study was aborted after fatal
believed to be an underestimate because several patients who
postoperative rebleeding occurred in 3 of the first 11 patients
were moribund or who went to surgery did not have a
(27%) treated in this fashion.27 In an earlier study of 100 ICH
follow-up scan. Hemorrhage growth between the baseline and
patients treated with surgical evacuation within 7 hours of
1-hour CT scans was associated with concurrent neurological onset, the investigators concluded that “the most common
worsening, as measured by changes in Glasgow Coma Scale cause of a poor outcome . . . is incomplete hemostasis
score and National Institutes of Health Stroke Scale scores. resulting in reaccumulation of the hematoma.”28
No baseline clinical or CT variables were predictive of
hemorrhage growth, including blood pressure, baseline he- Pathophysiology of Early Hematoma Growth
matoma size, and admission Glasgow Coma Scale scores. The pathogenesis of early hematoma growth is poorly under-
Patients with hematoma growth had higher mortality (44% stood. There is no animal model for early hematoma growth,
versus 34%) and worse disability scores 30 days after onset, nor is it likely that one can be developed that can faithfully
but these differences did not reach significance. recreate the complex and dynamic nature of human ICH. The
Retrospective studies have confirmed that ICH growth is reasonable and conventional notion is that hematoma growth
relatively common within 6 hours of onset and much less results from persistent bleeding or rebleeding from a single
frequent thereafter (Table 1).21–23 These studies have also site of arterial or arteriolar rupture. Although this may be true
linked hematoma growth to early neurological deterioration in many cases, several lines of evidence suggest that early
and increased mortality. Kazui et al,23,24 for instance, reported hematoma enlargement may also result from secondary
an increased frequency of early clinical deterioration (66% bleeding into perilesional tissue in the periphery of the clot.
versus 14%) as well as ICH-related mortality (29% versus
TABLE 2. Relationship of ICH Location to Frequency of
3%) in patients with hematoma growth compared with those
Hematoma Enlargement
without. The only consistently identified risk factor for early
hematoma growth is the interval between symptom onset and Brott et al,19 1997 Kazui et al,23 1996 Fujii et al,20 1994
the initial CT: the earlier the scan, the more likely it is that a Initial CT time (h) 0–3 0–24 0–24
follow-up CT will show enlargement.21,24 Other risk factors Putamen, % 61 (23/38) 14 (10/70) 19 (28/149)
that have been identified include liver disease,24 a history of Thalamus, % 50 (15/30) 19 (13/67) 10 (16/156)
cerebral infarction,24 hypertension (systolic blood pressure Lobar, % 32 (6/19) 26 (9/34) 6 (2/35)
⬎200 mm Hg) in the setting of hyperglycemia,24 irregular Cerebellar, % 0 (0/4) 20 (2/10) 12 (5/42)
hematoma shape,24 depressed level of consciousness,21 alco-
Pons, % 40 (2/5) 36 (4/11) 28 (8/29)
hol use,21 and reduced fibrinogen levels,21 but these have yet
Other, % 43 (3/7) 25 (3/12) 13 (1/7)
to be confirmed. There appears to be no impact of ICH
Total, % 38 (39/103) 22 (41/204) 14 (60/359)
location on the frequency of hematoma growth (Table 2).
226 Stroke January 2003

Figure 2. Estimated effect of the interval between CT scan and

treatment on the probability of interval hematoma expansion
when the initial CT scan is performed on average 90 minutes
Figure 1. Early hematoma growth in a 71-year-old woman with after ICH onset. Data are extrapolated from Brott et al, 1997.19
left putaminal hemorrhage. The ICH volume increased by 80%,
from 15 mL at 2.5 hours to 26 mL at 11.5 hours. Concurrent
Rationale for Ultra-Early Hemostatic Therapy
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single-photon emission CT images indicate that that the

enlargement resulted from the addition of discrete hemorrhages for ICH
within the no-flow zone around the existing clot (yellow arrows). The 3 most consistently identified predictors of poor outcome
Modified from Mayer et al, 1998,30 with permission.
after ICH are hematoma volume, the presence of intraven-
tricular hemorrhage, and depressed level of conscious-
First, careful pathological studies of brain tissue in the ness.48 –51 Of these, hematoma volume has been identified as
periphery of fatal hemorrhages have revealed multiple micro- the single most powerful predictor of 30-day mortality after
scopic and macroscopic hemorrhages believed to represent ICH.51 Given the evidence that ongoing bleeding can occur
ruptured arterioles or venules.29 Second, simultaneous CT for several hours after onset, it is plausible that ultra-early
and single-photon emission CT studies have demonstrated hemostatic therapy might minimize hematoma volume and
instances in which ICH growth results from the addition of improve outcome. In this paradigm, ultra-early hemostatic
multiple confluent hemorrhages to the periphery of an exist- therapy for ICH could be used as the counterpart to
ing clot in the perilesional low-flow zone (Figure 1).30 Third, thrombolytic intervention for acute ischemic stroke. Although
a team of investigators found an association between early the challenges of stroke treatment within a narrow time
hematoma growth and irregular clot morphology, which is window are well established, the feasibility of this approach
presumably the result of multifocal bleeding.24 Fourth, simul- is supported by the fact that ICH patients present to emer-
taneous bleeding from multiple lenticulostriate arteries has gency departments earlier than ischemic stroke patients.52
been demonstrated angiographically immediately after Arrest of hematoma growth might reduce the frequency of
ICH.31–35 neurological deterioration by preventing early worsening
These clinical data suggest that early hematoma growth related to hematoma growth, as well as late deterioration
may result in some cases from bleeding into a “penumbra” of (⬎12 hours after onset) related to perihematomal edema and
damaged and congested brain tissue immediately surrounding mass effect, which is most often a problem once a large
a hematoma. Although human positron emission tomography hemorrhage has been established.53 If effective, ultra-early
and diffusion-weighted imaging studies have failed to dem- hemostatic therapy might also make early surgical hematoma
onstrate ischemia in the low-flow zone surrounding a hema- evacuation safe enough to become a feasible treatment
toma beyond 5 hours of onset,36,37 pathological and experi-
As is the case with all stroke treatments, hematostatic
mental studies have shown that a thin rim of ischemic damage
therapy must be given as soon as possible after the onset of
develops in the hyperacute stage of ICH.38,39 Secondary
ICH to be effective. By extrapolating the data that Brott et al19
bleeding from arterioles and venules may initially result from
collected on patients initially scanned within 3 hours of onset
increased intravascular hydrostatic pressure and may progress
(mean, 89 minutes), if one assumes that early rebleeding
because of regional mechanical, ischemic, or plasma-
occurs midway between a linear and exponential rate during
mediated inflammatory tissue damage. As a clotted hema- the next 60 minutes, even if a hemostatic intervention is
toma forms, plasma rich in thrombin, fibrin degradation completely effective, hematoma enlargement would be ex-
products, and plasmin quickly seeps into the surrounding pected in 10%, 17%, or 22% of patients after a 15-, 30-, or
brain tissue.40 These coagulation end products may cause 45-minute treatment delay following the baseline scan (Fig-
inflammation,41– 44 local metalloprotease induction,45 changes ure 2).
in blood-brain barrier permeability,38,46 or a local coagulo-
pathic environment.47 However, the time course and possible Hemostatic Agents: Therapeutic Options
relevance of these processes to early hematoma growth Replacement therapies such as fresh frozen plasma, pro-
remain unclear. thrombin complex concentrate,54 and factor IX concentrate55
Mayer Ultra-Early Hemostatic Therapy for ICH 227

are used to treat bleeding in coagulopathic ICH patients, such ing reversible enzyme-inhibitor complexes.57 By inhibiting
as those treated with warfarin, but would not be expected to kallikrein, aprotinin indirectly inhibits the formation of acti-
enhance hemostasis in patients with normal coagulation. vated factor XII, which disrupts coagulation. Aprotinin pri-
Human and recombinant factors VIII and IX are used as marily inhibits the initiation of both coagulation and fibrino-
replacement therapy for patients with hemophilia A or B, lysis induced by contact of blood with a foreign surface, but
respectively, but, similarly, a strong procoagulant effect in it has no effect on platelet function.57 Its main indication is for
patients with normal levels of these factors would not be reducing perioperative bleeding, including cardiac surgery75
expected. Cryoprecipitate is specifically used to enhance and orthotopic liver transplantation,76 rather than the treat-
hemostasis in patients with hypofibrinogenemia, and desmo- ment of spontaneous internal bleeding. Aprotinin can cause
pressin diacetate arginine vasopressin (DDAVP) is used in hypersensitivity reactions and arterial or venous thrombosis
patients with primary or acquired platelet disorders.56 In but has not been found to increase the frequency of throm-
patients with normal coagulation, the most feasible hemo- botic complications in controlled surgical trials.57
static agents for ultra-early ICH therapy include the antifi-
brinolytic amino acids aminocaproic acid and tranexamic Future Directions
acid, aprotinin, and activated recombinant factor VII At present, published clinical trials for ICH have been
(rFVIIa).57,58 focused on surgical removal of the clot or treatment of
Our present understanding of the pathophysiology of early cerebral edema with dexamethasone or glycerol. In the recent
ICH growth suggests that rFVIIa may be well suited for past, several investigators have explored the feasibility of
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limiting early hematoma growth in acute ICH. FVIIa is an ultra-early hemostatic therapy for ICH with aminocaproic
important natural initiator of hemostasis and exerts its pri- acid (M. Diringer, MD, and J. Grotta, MD, oral personal
mary effects locally in regions of endothelial disruption and communication). Two dose-escalation phase IIA studies are
vascular injury.58,59 When vessel rupture occurs, tissue factor currently in progress to determine whether rFVIIa is a safe
is exposed in the subendothelial layers of the vessel wall, and and feasible treatment for ICH patients scanned within 3
local platelet aggregation occurs.60 Factor VII, of which only hours of onset. A larger phase IIB dose-ranging “proof-of-
1% normally circulates in the active form, forms a complex concept” study that will compare the efficacy of 3 different
with exposed tissue factor, activating the hemostatic mecha- doses of rFVIIa for reducing the frequency of CT-
nism locally to form a hemostatic plug.58,61 The FVIIa–tissue documented early hematoma expansion is planned. This
factor complex initiates the conversion of factor X to Xa, study will test the hypothesis that ultra-early hemostatic
which in turn converts prothrombin to thrombin.62 Pharma- therapy can limit ongoing bleeding in acute ICH and, if
cological doses of rFVIIa amplify this process and also positive, may provide justification for a definitive phase III
catalyze the conversion of factor X to Xa on the surface of trial.
activated platelets in the absence of tissue factor.61 In 6 years
of clinical use for the treatment of hemophilic patients with Acknowledgments
inhibitors, rFVIIa has been associated with a low risk of Drs J.P. Mohr, Thomas Brott, Ulla Hedner, and Nicolai Brun
systemic coagulation or thromboembolic complications58,63 provided important advice and support regarding this project.
and has a good record for treating intracranial hemor-
rhage.64 – 66 Preliminary clinical trials indicate that rFVIIa also References
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Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage
Stephan A. Mayer

Stroke. 2003;34:224-229; originally published online December 12, 2002;

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doi: 10.1161/01.STR.0000046458.67968.E4
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