Conversely, apoptosis-blocking agents could protect
oligodendrocytes from FasL-expressing T cells or
macrophages. Recent clinical trials suggest that
other TNF family molecules play a predominant role
in the immunoregulation of MS. TNF and lympho-
toxin alpha (LT␣) have long been considered prime
candidates for the mediators of oligodendroglial death
in MS. Nevertheless, administration of a TNF receptor
antibody designed to block both TNF and LT␣ activity
resulted in an unexpected worsening of disease.6 Stud-
ies using experimental autoimmune encephalomyelitis
(EAE), an animal model of MS, highlight the dichoto-
mous role of Fas in autoimmune demyelination. De-
pending on the mouse strain used, Fas deficiency can
either suppress or exacerbate EAE.7-8 The therapeutic
usefulness of Fas- and TRAIL-modulating reagents in
MS will ultimately depend on the balance of their ef-
fects on the facilitators and targets of the abnormal
immune response which, as the current articles also
suggest, may vary based on the stage and category of
disease.
Editorial
What causes intracerebral hemorrhage
during warfarin therapy?
Robert G. Hart, MD
It is a cruel irony that the use of warfarin, given to
prevent ischemic stroke, increases the risk of severe
hemorrhagic stroke as its most devastating complica-
tion. Conventional intensities of anticoagulation in-
crease the risk of intracerebral hemorrhage 5 to 10
times, by absolute rates of 1% per year or more for
many stroke-prone patients. The increased intrace-
rebral bleeding associated with warfarin therapy off-
sets its benefits in certain patient populations.
Although warfarin and related oral vitamin K antag-
onists have been used for stroke prevention for 50
years, more cases of anticoagulant-associated intra-
cerebral bleeding are now reported— up to one per
month at some tertiary referral hospitals,1 most oc-
curring when the international normalized ratio
(INR) is within the therapeutic range.1,2 Recent use
of lower intensities of anticoagulation and monitor-
See also page 947
From the Department of Medicine, University of Texas Health Science Center, San Antonio.
Address correspondence to Dr. Robert G. Hart, Professor of Medicine (Neurology), University of Texas Health Science Center, MSC: 7883, 7703 Floyd Curl
Drive, San Antonio, TX 78229-3900; e-mail: hartr@uthscsa.edu
References
1. Huang W-X, Huang P, Gomes A, Hillert J. Apoptosis mediators
FasL and TRAIL are upregulated in peripheral blood mononu-
clear cells in MS. Neurology 2000;55:928 –934.
2. Comi C, Leone M, Bonisonni S, et al. Defective T cell Fas
function in patients with multiple sclerosis. Neurology 2000;55:
921–927.
3. Zipp F, Weller M, Calabresi P, et al. Increased serum levels of
soluble CD95 (APO-1/Fas) in relapsing-remitting multiple scle-
rosis. Ann Neurol 1998;43116 –120.
4. Dowling P, Shang G, Raval S, Menonna J, Cook S, Husar W.
Involvement of the CD95 (APO-1/ Fas) receptor / ligand system
in multiple sclerosis brain. J Exp Med 1996;184:1513–1518.
5. Pouly S, Becher B, Blain M, Antel JP. Interferon-g modulates
human oligodendroglial susceptibility to Fas-mediated apopto-
sis. J Neuropathol Exp Neurol 2000;59:280 –286.
6. The Lenercept Multiple Sclerosis Study Group, The University
of British Columbia MS/MRI Analysis Group. TNF neutraliza-
tion in MS. Neurology 1999;53:457– 465.
7. Sabelko KA, Kelly KA, Nahm MH, Cross AH, Russell JH. Fas
and Fas ligand enhance the pathogenesis of experimental auto-
immune encephalomyelitis, but are not essential for immune
privilege in the central nervous system. J Immunol 1997;159:
3096 –3099.
8. Suvannavejh GC, Dal Canto MC, Matis LA, Miller SD. Fas-
mediated apoptosis in clinical remissions of relapsing experi-
mental autoimmune encephalomyelitis. J Clin Invest 2000;105:
223–231.
Neurology 2000;55:907–908
ing by INR and anticoagulation clinics makes antico-
agulation safer, but these advantages are offset by
wider use of anticoagulation in the elderly popula-
tion, who are at increased risk for serious bleeding.
The risk/benefit ratio of anticoagulant therapy for
stroke prevention often hinges on differences in in-
tracerebral hemorrhage rates of 1 to 2% per year3—
relatively small differences that are difficult, yet
crucial, to predict accurately for individual patients. It
is clear that warfarin-associated intracerebral hemor-
rhage is associated with advancing age, cerebrovascu-
lar disease, and the intensity of anticoagulation.2-5 The
presence and severity of hypertension is an additional
likely, if less well documented, independent contributor
to risk. Thus, the threshold INR prolongation that im-
portantly increases the rate of intracerebral bleeding is
not a single value, but rather depends on the patient’s
Copyright © 2000 by AAN Enterprises, Inc. 907
age and other features.5 Antiplatelet therapy with aspi-
rin also increases (by 50 to 75%) the risk of intracere-
bral hemorrhage, but to a lesser degree than seen with
efficacious doses of warfarin.6,7
It is not obvious how antithrombotic therapies in-
crease intracerebral bleeding. They do not appear to
promote vascular injury, inhibit vascular repair, or
induce, directly or indirectly, arterial rupture. It has
been postulated that antithrombotic agents unmask
subclinical bleeding that occurs with increasing fre-
quency in the elderly population, especially in those
individuals with hypertension and cerebrovascular
disease.4
In this context, three recent articles in Neurology
provide major new insights into the pathogenesis of
anticoagulation-associated intracerebral hemor-
rhage. In this issue, Rosand et al.1 studied the rela-
tionship between cerebral amyloid angiopathy and
warfarin-associated lobar intracerebral bleeding by
assessing the APOE type 2 allele in a case-control
study, supplemented by autopsy observations in a
subset. A strong, convincing association of amyloid
angiopathy with lobar, but not deep hemispheric,
hemorrhage emerged. In a thoughtful discussion of
their results, the authors conclude that amyloid an-
giopathy is an important contributor to warfarin-
associated lobar hemorrhage, but that genotype
screening is not currently useful to stratify risk of
anticoagulation, as it is an insufficiently sensitive
and specific indicator of amyloid angiopathy.1
Gorter,5 for the Stroke Prevention in Reversible
Ischemia Trial and European Atrial Fibrillation
Trial investigators, reported that anticoagulation in-
tensity averaging an INR of 3 increased intracere-
bral bleeding to intolerable rates in patients with
recent ischemic stroke or TIA due to presumed pri-
mary cerebrovascular mechanisms.3,5 In sharp con-
trast, patients with atrial fibrillation who have had
recent cerebral ischemia handle it well. The presence
of “leukoariosis” on CT scans was the strongest inde-
pendent predictor of intracerebral bleeding in pa-
tients with cerebrovascular disease.5 Additional
studies are needed to confirm this observation, using
criteria for leukoariosis that can be reproducibly ap-
plied before application to patient management.
White matter abnormalities are pathologically heter-
ogeneous, and these findings may not directly apply
to other patient populations. Nevertheless, the dem-
onstration that white matter abnormalities detected
by neuroimaging are strong, independent predictors
of anticoagulation-associated intracerebral bleeding
should eventually lead to useful clinical tools for
stratifying risk.
Finally, Roob et al.8 used gradient-echo MRI to
seek small hemosiderin deposits (indicative of
asymptomatic “microbleeds”) in 280 people without
clinical neurologic disease. Microbleeds were found
in 6% of these individuals, and were associated with
advancing age, hypertension, and leukoariosis. Hy-
pertension was more strongly associated with deep
hemispheric deposits than with lobar locations.
908 NEUROLOGY 55 October (1 of 2) 2000
Taken together, these three studies provide
compelling evidence that amyloid angiopathy is an
important factor in warfarin-associated lobar hem-
orrhage, whereas cerebrovascular disease and leu-
koariosis predict deep hemispheric bleeding during
anticoagulation. Asymptomatic microbleeds are reg-
ularly seen with both types of vasculopathy.9 Indeed,
warfarin-associated intracerebral hemorrhage repre-
sents an unmasking of several distinct underlying
cerebral vasculopathies that cause subclinical hem-
orrhages in the absence of anticoagulation. These
vascular disorders appear to be the same as those
causing spontaneous intracerebral hemorrhage, with
the thermostat turned up by antithrombotic therapy.
Consequently, the risk of warfarin-associated intra-
cerebral bleeding reflects the intrinsic risk of sponta-
neous intracerebral hemorrhage, both symptomatic
and microbleeds, multiplied by a factor determined
by the intensity of anticoagulation.
Can the risk of warfarin-associated intracerebral
hemorrhage be predicted accurately for individual
patients? Those who are over age 75 years or who
have a history of cerebrovascular disease will have a
rate of intracerebral bleeding of about 1% per year if
treated with anticoagulants to an INR between 2 and
3. The presence and extent of white matter abnormali-
ties and asymptomatic microbleeding by neuroimaging
may further contribute to risk stratification when more
is known. Large, ongoing clinical trials testing war-
farin in patients with cerebrovascular disease
(WARSS, ESPRIT, WASID) should contribute valu-
able data, shedding new light on this increasingly
important entity.
References
1. Rosand J, Hylek EM, O’Donnell HC, Greenberg SM. Warfarin-
associated hemorrhage and cerebral amyloid angiopathy: a
genetic and pathologic study. Neurology 2000;55:947–951.
2. Hylek EM, Singer DE. Risk factors for intracranial hemor-
rhage in outpatients taking warfarin. Ann Intern Med 1994;
120:897–902.
3. Stroke Prevention in Reversible Ischemia Trial Study Group.
A randomized trial of anticoagulants versus aspirin after cere-
bral ischemia of presumed arterial origin. Ann Neurol 1997;
42:857– 865.
4. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and
intracranial hemorrhage. Facts and hypotheses. Stroke 1995;
26:1471–1477.
5. Gorter JW. Major bleeding during anticoagulation after cere-
bral ischemia: patterns and risk factors. Stroke Prevention in
Reversible Ischemia Trial (SPIRIT). European Atrial Fibrilla-
tion Trial (EAFT) study groups. Neurology 1999,53:1319 –
1327.
6. Hart RG, Halperin JL, McBride R, Benavente O, Man-Son-
Hing M, Kronmal RA. Aspirin for the primary prevention of
stroke and other major vascular events. Arch Neurol 2000;57:
326 –332.
7. He J, Whelton RK, Vu B, Klag MJ. Aspirin and risk of hemor-
rhagic stroke. JAMA 1998;280:1930 –1935.
8. Roob G, Schmidt R, Kapellar P, Lechner A, Hartung HP,
Fazekas F. MRI evidence of past cerebral microbleeds in a
healthy elderly population. Neurology 1999;52:991–994.
9. Greenberg SM, O’Donnell HC, Schaefer PW, Kraft E. MRI
detection of new hemorrhages: potential marker of progres-
sion in cerebral amyloid angiopathy. Neurology 1999;53:1135–
1138.
 What causes intracerebral hemorrhage during warfarin therapy?
Robert G. Hart
Neurology 2000;55;907-908
DOI 10.1212/WNL.55.7.907

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