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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Reduced incidence of ischemic stroke in patients with severe factor XI deficiency
Ophira Salomon,1 David M. Steinberg,2 Nira Koren-Morag,3 David Tanne,4 and Uri Seligsohn1
1The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv; 2Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv; 3Division of
Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; and 4Stroke Unit, Department of Neurology, Sheba Medical
Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Inherited disorders of hemostasis are
natural models for investigating mechanisms of thrombosis and development of
antithrombotic therapy. Because mice
with total factor XI deficiency are protected against ischemic stroke and do not
manifest excessive bleeding, we investigated the incidence of ischemic stroke in
patients with severe inherited factor XI
deficiency. Incidence of ischemic stroke
in 115 patients aged 45 years or more with
severe factor XI deficiency (activity less
than 15 U/dL) was compared with inci-
dence in the Israeli population as estimated from a stroke survey of 1528 patients. Adjustment for major risk factors
of stroke (hypertension, diabetes mellitus, hypercholesterolemia, current smoking) was based on comparison of their
prevalence in the stroke survey to an
Israeli health survey of 9509 subjects.
Incidence of myocardial infarction in the
factor XI cohort was also recorded. After
adjustment for the 4 major risk factors of
ischemic stroke, the expected incidence
of ischemic stroke was 8.56 compared
with one observed (P ⴝ .003). The reduced 1:115 incidence of ischemic stroke
contrasted with a 19:115 incidence of
myocardial infarction, similar to the expected incidence. Thus, severe factor XI
deficiency probably is protective against
ischemic stroke but not against acute
myocardial infarction. (Blood. 2008;111:
4113-4117)
© 2008 by The American Society of Hematology
Introduction
Severe inherited disorders of hemostasis in humans or animals
serve as models for investigating the mechanisms of thrombosis
and atherosclerosis or as paradigms for development of new
antithrombotic drugs. Recent studies in patients with severe
hemophilia A or B, type 3 von Willebrand disease, and Glanzmann
thrombasthenia have demonstrated that these profound hemostatic
defects confer no or minimal protection against atherosclerosis.1-3
Nevertheless, longitudinal studies have shown that severe hemophilia A or B are associated with decreased incidence of myocardial
infarction, suggesting that low coagulability protects afflicted
patients against arterial thrombotic occlusions.4,5
Severe factor XI (FXI) deficiency is another potential protector
against thrombosis because it is associated with reduced thrombin
generation and augmented fibrinolysis related to decreased activation of thrombin activatable fibrinolysis inhibitor (TAFI).6 Indeed,
FXI deficiency induced in animals by specific antibodies or gene
targeting exerts an antithrombotic effect in arterial or venous
models of thrombosis without compromising hemostasis; the tail
bleeding time in mice lacking FXI is normal.7-14 Contrasting these
models, patients with severe FXI deficiency present with acute
myocardial infarction at an incidence similar to that expected in the
general population.15 Whether or not patients with severe FXI
deficiency are protected against venous thrombosis or ischemic
stroke is unknown. The rather low incidence of unprovoked venous
thromboembolism in different age groups of the general population
(1:300-1:1000) and the relatively small number of patients with
severe FXI deficiency make it hard to assess whether FXI
deficiency is protective or not. Regarding stroke, mice with total
FXI deficiency are protected against ischemic brain injury in an
experimental stroke model.14 This finding prompted us to investigate the incidence of ischemic stroke in patients with severe FXI
deficiency in comparison to the incidence in the general population.
Methods
We compared stroke incidence in 2 populations: a relatively small
clinical cohort of patients with severe FXI deficiency and the entire
population of Israel.
Patients with FXI deficiency
The FXI-deficient group consisted of unrelated patients whose plasma FXI
activity was less than 15 U/dL and who were consecutively referred to our
Center during the last 8 years because of a prolonged activated partial
thromboplastin time (aPTT) or a bleeding tendency that led to the diagnosis.
We limit attention here to the 115 patients who were aged 45 years or older.
Patients were interviewed regarding their clinical history, cerebrovascular
or cardiovascular events, and major atherosclerotic risk factors (ie, hypertension, diabetes mellitus, hypercholesterolemia, current smoking, and medications). Medical records of the patients were also reviewed. Follow-up for
each patient with FXI is from birth to the end of 2006, when data on all
patients were updated for cerebrovascular events. Criteria for acute
myocardial infarction (AMI) were adapted from the Cardiovascular Health
Study16 and were defined by chest pain, increased biochemical markers, and
typical electrocardiographic changes. The Institutional Review Board of
Sheba Medical Center approved the study, and informed consent was
obtained from each patient in accordance with the Declaration of Helsinki.
Submitted October 24, 2007; accepted February 6, 2008. Prepublished online
as Blood First Edition paper, February 11, 2008; DOI 10.1182/blood-2007-10120139.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
The publication costs of this article were defrayed in part by page charge
© 2008 by The American Society of Hematology
BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
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BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
SALOMON et al
Table 1. Clinical and genotypic data on unrelated patients with severe FXI deficiency
N
No. affected by
ischemic stroke
No. affected by
myocardial
infarction
II/II
II/III
III/III
Other
Not tested
FXI genotype
Men
45 to 54 y
5
0
0
2
3
0
0
0
55 to 64 y
18
0
4
8
8
1
1*
0
65 to 74 y
13
0
4
7
5
1
0
0
Over 75 y
17
0
6
8
5
4
0
0
Total
53
0
14
25
21
6
1
0
45 to 54 y
17
0
0
5
6
4
1†
1
55 to 64 y
20
0
0
2
15
3
0
0
65 to 74 y
10
0
0
3
4
3
0
0
Over 75 y
15
1
5
5
5
4
1‡
0
Total
62
1
5
15
30
14
2
1
115
1
19
40
51
20
3
1
Women
Grand total
*Type I homozygote,20 FXI level less than 1 U/dL of normal.
†Type II/Tyr427Cys compound heterozygote,21 FXI level less than 1 U/dL.
‡Gly555Glu homozygote,22 FXI level less than 1 U/dL.
NASIS
For estimation of the expected number of strokes in the Israeli population,
the data from the National Acute Stroke Israeli Survey (NASIS) were
analyzed. This prospective survey included all consecutive patients with an
acute cerebrovascular event admitted to all 28 Israeli Medical Centers in
February and March 2004.17 Comprehensive information on demographic
features, risk factors, clinical manifestations, diagnosis, and management
were obtained. Of 2127 patients enrolled, 1528 had ischemic stroke, and
their data were used for analyses performed in this study. Patients with
transient ischemic attack (N ⫽ 372), intracerebral hemorrhage (N ⫽ 156),
or patients who did not undergo imaging (N ⫽ 71) were excluded.
INHIS-1
The Israel National Health Interview Survey (INHIS-1) was conducted as
part of the European Health Interview Survey (EUROHIS) performed in
33 countries whose objective was to develop a standard tool for international comparison of health measurements based on standardized methods.18 In Israel, the survey was conducted by Israel’s Center for Disease
Control between April 2003 and October 2004 and consisted of interviews
using the EUROHIS questionnaire as a template. Of 16 346 households
with individuals older than 21 years, 9509 (4028 men, 5481 women; 58.2%)
agreed to participate. The questionnaire included demographic characteristics, health-related behavior, health status, use of health services, and
medications. Participants reported on current smoking and on family
physician diagnoses of hypertension, hypercholesterolemia, and diabetes
mellitus. The variables were presented in the final INHIS-1 report by age
and sex.18
Laboratory tests
FXI activity was determined by an aPTT-based assay. The common
mutations causing FXI deficiency in Israel were determined by polymerase
chain reaction (PCR) and restriction enzyme analysis.19
Statistical analyses
The statistical analysis used the standardized incidence ratio (SIR) to
compare the incidence of ischemic strokes in the FXI-deficient cohort to the
expected incidence. The expected number of ischemic strokes was computed from sex-specific incidence in 5-year age groups, as computed by
dividing the annualized NASIS counts by population totals from the Israel
Central Bureau of Statistics.17 Patients with FXI contribute person-years of
exposure until the age of ischemic stroke incidence or the end of follow-up
if they were stroke-free. A further analysis controlled for major risk factors
for ischemic stroke in computing the expected number of strokes.
Risk factor adjustment. The prevalence of major ischemic stroke risk
factors in the FXI-deficient cohort and the patients with first ischemic stroke
(from NASIS) was compared with the prevalence in the Israeli population
at large (from INHIS) by age groups and sex. The NASIS-to-INHIS
comparison was used to estimate odds ratios for ischemic stroke incidence.
Logistic regression models with main effects for the 4 risk factors were
fitted to the data for each sex and age group combination. Additional models
were run to check for the possibility of interactions between pairs of risk
factors. Results from the main effects models were used to compute
sex- and age group–specific estimates of the odds ratio for first ischemic
stroke incidence for each of the 16 (24) possible combinations of risk
factors. The odds ratios were then used to estimate, for each sex, adjusted
annual incidence for each combination of risk factors.
Comparison of groups. A 2-sided Poisson test was used to compare the
FXI prevalence to the expected prevalence. The test is based on the fact
that, under the hypothesis of equal incidence, the observed number of
incident ischemic stroke cases in the FXI-deficient cohort will have a
Poisson distribution whose mean is the expected incidence. Results were
considered statistically significant if P values were less than .05. The
Poisson distribution was used to compute 95% confidence intervals for
the SIR.
Results
The incidence of ischemic stroke and AMI in the FXI-deficient
cohort
The FXI-deficient cohort consisted of 53 men (mean age,
68.4 years) and 62 women (mean age, 62.8 years). Only one case of
ischemic stroke was recorded in a woman who is currently 80 years
old. At the age of 61 years she experienced an AMI and was found
to have hypertension and hypercholesterolemia. In the subsequent
years she had several episodes of atrial fibrillation, with one
occurring at the time of presentation of ischemic stroke at the age
of 63 years.
In a previous study of 96 FXI-deficient patients we recorded
16 patients who had AMI.15 An update of the incidence of AMI
revealed a proportion of 19:115 among the currently studied
patients. The prevalence of AMI was slightly higher than the
expected, based on population incidence,15 in striking contrast with
the low incidence of ischemic stroke (Table 1).
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BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
FACTOR XI DEFICIENCY AND ISCHEMIC STROKE
4115
Table 2. The prevalence of stroke risk factors in the FXI-deficient cohort, patients of the INHIS (stroke) study, and subjects of NASIS (health
survey)
Smoking, %
Age groups
Diabetes, %
FXI
INHIS
Hypertension, %
NASIS
FXI
INHIS
Hypercholesterolemia, %
FXI
INHIS
NASIS
NASIS
FXI
INHIS
NASIS
45 to 54 y
20.0
34.2
55.1
0
6.9
38.9
0
14.8
48.9
20.0
20.1
46.6
55 to 64 y
27.8
25.3
41.6
16.7
14.8
42.4
27.8
28.6
71.3
33.3
32.7
55.8
65 to 74 y
25.0
18.0
26.7
8.3
20.4
47.0
83.3
41.2
68.3
25.0
36.3
45.4
Over 75 y
29.0
9.3
13.1
0
17.3
32.2
64.7
38.8
70.6
17.6
25.2
34.2
45 to 54 y
41.2
23.5
38.6
0
5.5
20.0
17.6
17.5
55.8
17.6
19.4
41.9
55 to 64 y
15.0
16.9
19.3
0
12.5
57.1
15.0
30.6
71.4
15.0
35.7
59.0
65 to 74 y
12.5
10.8
7.4
0
15.3
46.7
30.0
47.7
83.4
30.0
44.7
59.6
Over 75 y
13.3
7.0
1.8
6.7
10.9
34.1
53.3
52.4
82.7
26.9
44.9
40.7
Men
Women
Distribution of FXI mutations in the FXI-deficient cohort
The 2 common mutations causing FXI deficiency in Ashkenazi
Jews are the Glu117stop null mutation and the Phe283Leu missense mutation.19 The genotypes in 111 of the 115 patients
comprised 40 homozygotes for Glu117stop, 20 homozygotes for
Phe283Leu, and 51 compound heterozygotes for Glu117stop and
Phe283Leu (Table 1). As expected, mean plus or minus standard
deviation FXI levels differed significantly among patients harboring these genotypes. In homozygotes for Glu117stop, the FXI level
was 0.69 plus or minus 0.57 U/dL; in homozygotes for Phe283Leu,
the FXI level was 8.0 plus or minus 3.04 U/dL; and in compound
heterozygotes for Glu117stop and Phe283Leu, the FXI level was
3.29 plus or minus 1.77 U/dL. In the remaining 4 patients, FXI
levels were less than 1 U/dL; the genotypes in 3 of the 4 patients are
depicted in Table 1.
Expected and observed incidence of ischemic stroke
The expected number of individuals with an ischemic stroke in the
FXI-deficient cohort (regardless of stroke risk factors) was 5.52 in
men, 2.55 in women, and 8.07 in the entire cohort. The observed
count of one ischemic stroke is significantly lower (P ⫽ .005). The
standardized incidence ratio is 0.124 (95% confidence interval,
0.030-0.690).
The prevalence of ischemic stroke risk factors in the
FXI-deficient cohort, the general population, and ischemic
stroke patients
Table 2 compares the prevalence of current smoking, diabetes
mellitus, hypertension, and hypercholesterolemia in men and
women of the FXI-deficient cohort, INHIS, and NASIS. As
expected, the prevalence of these risk factors was remarkably
higher in patients with ischemic stroke (NASIS) than in the general
population (INHIS). In FXI-deficient men, the prevalence of
hypertension in the older age groups was higher than in the
population (INHIS), the prevalence of diabetes mellitus was lower,
and the prevalence of smoking and hypercholesterolemia similar.
In FXI-deficient women, the prevalence of smoking, hypertension,
and hypercholesterolemia were comparable with those of INHIS.
However, only one FXI-deficient woman had diabetes mellitus,
while its rate in the population was about 10%. When the incidence
of ischemic stroke was adjusted for the 16 combinations of risk
factors, the expected number of strokes was 6.68 among men and
1.88 among women, for an overall expected number of
8.56 ischemic strokes among patients with severe FXI deficiency. The observed count of only one patient with ischemic
stroke is significantly lower (P ⫽ .003). The risk factor–adjusted
standardized incidence ratio is 0.117 (95% confidence interval,
0.028-0.651).
Discussion
The major finding of this study was a remarkably reduced
incidence of ischemic stroke in patients with severe FXI deficiency
compared with the expected number based on incidence in the
general Israeli population. The apparent protection against ischemic stroke that was conferred by severe FXI deficiency included
patients with plasma FXI levels ranging from less than 1 U/dL to
14 U/dL, which corresponded with their genotypes (Table 1).
To understand the reduced incidence of ischemic stroke in the
FXI-deficient cohort, we evaluated whether the frequency distribution of risk factors for ischemic stroke was for some reason
diminished in the FXI-deficient cohort. A total of 2 large reference
groups were available for comparison of the frequency of risk
factors, 9509 representatives of the Israeli population (the INHIS
study), and 1528 patients with ischemic stroke (the NASIS study).
The comparison indicated that by and large, the frequency of the
4 major risk factors of ischemic stroke (current smoking, hypertension, diabetes mellitus, and hypercholesterolemia) in the FXIdeficient cohort was similar to the frequency in the general
population except for a lower frequency of diabetes mellitus in
women and a higher frequency of hypertension in men older than
65 years (Table 2). A more detailed analysis of stroke incidence for
the 16 possible combinations of the 4 risk factors showed that the
overall expected number of patients with ischemic stroke in the
FXI deficient cohort was 8.56, whereas only one case was observed
(P ⫽ .003).
There are 2 limitations to our findings to consider. First, one
could argue that our FXI-deficient cohort may have missed some
individuals who had a fatal stroke. However, more than 30 years of
follow-up of numerous FXI-deficient patients who were diagnosed
at a young age by one of the authors (U.S.) has not revealed any
case of ischemic stroke. Second, because 112 of the 115 patients
with severe FXI deficiency are Ashkenazi Jewish, one could argue
that perhaps Ashkenazi Jews in general have a reduced incidence of
ischemic stroke compared with other ethnic groups in Israel. No
data are available on such a potential difference, yet even if there
would be an ethnic variability in the incidence of ischemic stroke,
this is likely to be small and cannot account for the strikingly low
incidence of ischemic stroke in the FXI-deficient cohort.
FXI displays both procoagulant and antifibrinolytic activities.6,7
Thrombin, initially formed by the tissue factor–FVIIa pathway,
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BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
SALOMON et al
activates FXI leading through additional reactions to further
thrombin generation, which is followed by fibrin clot formation.
FXIa also promotes thrombin generation after a fibrin clot has
formed, which gives rise to activation of TAFI. TAFIa then
removes from fibrin lysine binding sites for plasminogen and tissue
plasminogen activator, thereby stabilizing the fibrin clot by making
it resistant to fibrinolysis.23 Consequently, when FXI is absent from
plasma, there is diminished fibrin clot formation and augmented
fibrinolysis demonstratable in vitro and in vivo.6,7,24 Interestingly,
increased plasma levels of FXI or TAFI have recently been
identified as risk factors of ischemic stroke.25-28 Together, these
observations suggest that the apparent protection against ischemic
stroke in patients with severe FXI deficiency is attributable to
reduced thrombin generation and augmented lysis of blood clots
formed or embolized into cerebral arteries.
If this is indeed the explanation for the beneficial effect of
severe FXI deficiency in preventing ischemic stroke, why is there
no protective effect against myocardial infarction (Table 1)? It has
long been recognized that there are vascular bed specificities which
can impart variable site-specific thrombotic events.29 These specificities stem from a substantial heterogeneity of structure and
function of the respective endothelial cells and their interactions
with cells and components of blood.30 One feature that characterizes the cerebral vasculature is the abundance of amyloid ␤ protein
precursor protein (A␤PP), unlike the heart, in which it is probably
absent.31 A␤PP is a type I transmembrane protein that upon
proteolytic processing by secretases yields amyloid ␤ protein that
promotes fibrinolytic activity,32 and is deposited in the brains of
patients with Alzheimer disease. There are 3 alternatively spliced
A␤PPs, of which the larger 2 isoforms with 751 or 770 amino acids
contain a 56-residue peptide functioning as a Kunitz protease
inhibitor, which is analogous to protease nexin 2 present in platelet
␣ granules.33 This inhibitor was shown to neutralize FXIa, FIXa,
and FXa,33-37 and was therefore termed “the cerebral anticoagulant.” Notably, a 2-fold overexpression of A␤PP in platelets of
transgenic mice caused marked inhibition of carotid artery thrombosis, while in A␤pp gene knock-out mice, thrombosis was more
pronounced than in wild-type mice.38 Although the relevance of
these in vitro and in vivo activities of A␤PP and amyloid ␤ protein
to the brain circulation in health and disease is yet to be defined, it
is tempting to speculate that the anticoagulant and profibrinolytic
effects of both A␤PP and FXI deficiency are responsible for the
specific protection against ischemic stroke in patients with severe
FXI deficiency.
Among several inherited disorders prevalent in Ashkenazi Jews
such as Gaucher, Tay Sachs, or Canavan diseases, FXI deficiency is
the most common; 1 in 11 individuals are heterozygotes for
Glu117stop or Phe283Leu.39 The remarkable frequency of all these
rare inherited disorders in Ashkenazi Jews has been attributed to
genetic drift, founder effects, and a phenomenal growth of this
population from 1500 until 1940.40 Notably, for each one of these
rare inherited disorders, more than one mutation was identified,
raising the possibility of evolutionary advantages conferred by the
mutant alleles. To date, however, no such advantages have been
discerned. Whether the apparent protective effect against ischemic
stroke in patients with severe FXI deficiency constitutes an
advantage is difficult to accept at this time because the estimated
frequency of severe FXI deficiency in Ashkenazi Jews is only 1 in
450.39 However, if heterozygotes for either of the 2 common FXI
mutations in whom there is partial FXI deficiency will also display
a low incidence of ischemic stroke, then it would be reasonable to
regard FXI deficiency as advantageous.
Authorship
Contribution: O.S. designed and performed the research; D.M.S.
developed the statistical analyses and wrote the paper; N.K. and
D.T. analyzed the data of the NASIS and INHIS studies; and U.S.
designed the study, analyzed the data, and wrote the paper.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Uri Seligsohn, The Amalia Biron Research
Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel
Hashomer 52621, Israel; e-mail: seligson@sheba.health.gov.il.
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From www.bloodjournal.org by guest on March 6, 2016. For personal use only.
2008 111: 4113-4117
doi:10.1182/blood-2007-10-120139 originally published
online February 11, 2008
Reduced incidence of ischemic stroke in patients with severe factor XI
deficiency
Ophira Salomon, David M. Steinberg, Nira Koren-Morag, David Tanne and Uri Seligsohn
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