Intrinsic Coagulation Activation and the Risk of Arterial

Intrinsic Coagulation Activation and the Risk of Arterial
Thrombosis in Young Women
Results From the Risk of Arterial Thrombosis in Relation to Oral
Contraceptives (RATIO) Case-Control Study
B. Siegerink, MSc; J.W.P. Govers-Riemslag, PhD; F.R. Rosendaal, MD, PhD;
H. ten Cate, MD, PhD; A. Algra, MD, PhD
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
Background—Classically, intrinsic coagulation proteins are thought to have a minor role in hemostasis. Recently, these
proteins, especially FXII, were implicated as possible key players in the pathogenesis of arterial thrombosis. This study
aims to determine the risks of arterial thrombosis conferred by increased activation of intrinsic coagulation proteins in
young women and the effect of oral contraceptive use on this association.
Methods and Results—The Risk of Arterial Thrombosis In relation to Oral contraceptives (RATIO) study is a
population-based case-control study including young women (age 18 to 50 years) with myocardial infarction (n⫽205)
and ischemic stroke (n⫽175) and 638 healthy controls. Intrinsic coagulation protein activation was determined by
measuring activated protein-inhibitor complexes. This complex is with C1 esterase inhibitor (FXIIa-C1-INH,
FXIa-C1-INH, Kallikrein-C1-INH) or antitrypsin inhibitor (FXIa-AT-INH). Odds ratios (ORs) and corresponding
confidence intervals (95% CIs) were calculated with logistic regression. High levels of protein activation (⬎90th
percentile of controls) showed an increased risk of ischemic stroke: FXIIa-C1-INH (OR, 2.1; 95% CI, 1.3 to 3.5),
FXIa-C1-INH (OR, 2.8; 95% CI, 1.6 to 4.7), FXIa-AT-INH (OR, 2.3; 95% CI, 1.4 to 4.0), and Kallikrein-C1 (OR, 4.3;
95% CI, 2.6 to 7.2). If anything, myocardial infarction risk was only increased by Kallikrein-C1-INH (OR, 1.5; 95%
CI, 0.9 to 2.5). Oral contraceptive use further increased the risks.
Conclusions—High levels of activated proteins of the intrinsic coagulation system are associated with arterial thrombosis,
whereas the strength of these associations differs for myocardial infarction and ischemic stroke. This contradicts similar
analyses among men in the Northwick Park Heart Study. Together with the finding that oral contraceptive use further
increases the risks, the question of whether the role of intrinsic coagulation proteins in the pathogenesis of arterial
thrombosis is sex-specific is raised. (Circulation. 2010;122:1854-1861.)
Key Words: thrombosis, arterial 䡲 coagulation, intrinsic 䡲 activation 䡲 women
A
rterial thrombosis occurs when an artery is occluded by
a thrombus. Classical risk factors are diabetes mellitus,
hypercholesterolemia, hypertension, smoking, obesity, and
oral contraceptive use. The most common manifestations are
peripheral arterial disease, myocardial infarction (MI), and
ischemic stroke (IS). Arterial thrombosis is common among
the elderly and the most common cause of death in highincome countries.1
intrinsic coagulation pathway consists of the serine proteases
coagulation factor XII (FXII), coagulation factor XI (FXI),
and prekallikrein (PK). It further includes 1 nonenzymatic
protein, high-molecular-weight kininogen.2
FXII has the capacity of autoactivation on binding on
negatively charged surfaces.3 After activation, activated FXII
(FXIIa) activates both FXI into activated factor XI (FXIa) and
PK into its active form kallikrein (KAL). High-molecularweight kininogen acts as a cofactor in both steps, during
which the potent vasodilator bradykinin is released. FXIa
further activates coagulation factor IX which forms, together
with cofactor VIIIa, Ca2⫹ ions and phospholipids, the tenase
complex thereby activating the common pathway of the
Clinical Perspective on p 1861
A thrombus is formed on activation of the coagulation
system. Historically, this system has been characterized by 2
separate activating pathways: the extrinsic and intrinsic. The
Received February 17, 2010; accepted August 13, 2010.
From the Department of Clinical Epidemiology (B.S., F.R.R., A.A.), Einthoven Laboratory for Vascular Medicine (B.S., F.R.R.), and Department of
Thrombosis and Hemostasis (F.R.R.), Leiden University Medical Center, Leiden; Laboratory for Clinical Thrombosis and Hemostasis, Department of
Internal Medicine, and Cardiovascular Research Institute Maastricht (J.W.P.G.-R., H.t.C.), Maastricht University Medical Center, Maastricht; and Julius
Center for Health Sciences and Primary Care (A.A.) and Department of Neurology (A.A.), University Medical Center Utrecht, Utrecht, the Netherlands.
Correspondence to Dr Ale Algra, Professor of Clinical Epidemiology, Department of Clinical Epidemiology, LUMC, PO Box 9600, 2300 RC Leiden,
the Netherlands. E-mail [email protected]
© 2010 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.110.943738
1854
Siegerink et al
Intrinsic Coagulation and Arterial Thrombosis Risk
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
coagulation cascade.4 A subform of FXIIa is also known to
activate coagulation factor VII, thus stimulating the common
pathway by priming the extrinsic pathway.5 The intrinsic
coagulation proteins are also involved in other biological
processes, such as fibrinolysis (activation of plasminogen by
FXIIa, FXIa, and KAL), vasoconstriction, and blood pressure
control (KAL and bradykinin). On activation, the serine
proteases of the intrinsic coagulation pathway are quickly
bound by an inhibitor such as the C1-esterase inhibitor, thus
forming an inhibitor complex that lacks the serine protease
function.6,7 An excess of these inhibitors is readily available
in plasma, thus the availability of activated intrinsic coagulation proteins forms the limiting step in the formation of
these inhibitor complexes. This makes these inhibitor complexes a good measure of the level of activated proteins.
FXI deficiency causes mild bleeding in patients, whereas
FXII, KAL, and high-molecular-weight kininogen deficiencies do not.2 These observations led to the traditional view
that the intrinsic coagulation proteins do not play a major role
in hemostasis and thus are not likely to be a risk factor for
thrombosis. However, recent evidence, both laboratory and
clinical, indicate that these proteins might play a role in
thrombus formation. Murine studies with FXII and FXI
knockout mice show that initiation of clot forming is not
FXII-dependent, but that propagation of clot formation is.8,9
FXI-deficient patients showed, in addition to their mild
bleeding diathesis, a decrease in stroke incidence, but this
decrease is not observed for MI.10,11 In middle-aged men,
high levels of FXI and low levels of FXII increased the risk
of MI.12 An Austrian record-linkage study suggested that low
FXII levels were associated with reduced overall death
rates.13 In the Northwick Park Heart Study, which included
middle-aged men, low levels of activation from selected
intrinsic coagulation proteins caused an increase in risk for
both MI and IS.14 Because estrogens could have an impact on
transcription levels of coagulation proteins, especially FXII
because of an estrogen receptive element in the promoter of
the F12 gene, the relation between (intrinsic) coagulation
proteins and the risk of arterial thrombosis is potentially
different in women.3,15
It is unknown to what extent intrinsic coagulation proteins
are involved in the pathophysiological processes that lead to
the different forms of arterial thrombosis, especially in young
women. This patient group is of particular interest because of
their use of estrogen-containing medication (ie, oral contraceptives). We therefore set out to determine whether high
levels of activation of the intrinsic coagulation system are
associated with different forms of arterial thrombosis in
young women and whether oral contraceptive use further
increases this risk.
Methods
Study Design
The Risk of Arterial Thrombosis In relation to Oral contraceptives
(RATIO) study is a multicenter population-based case-control study.
The study consists of 3 substudies, including patients with confirmed
MI, IS, or peripheral arterial disease. One control group was matched
to all 3 case groups. The study was initiated to evaluate the risk of
1855
arterial thrombosis due to the changing composition of oral contraceptive pills (1990 –1995).16 –18 Blood and DNA were collected
during the second phase of the study (1998 –2002). Informed consent
was obtained from all participants, and the study was approved by
the medical ethics committees of the participating hospitals. For the
current study we report data from the MI and IS substudies.
Participants
Patient selection has been described in detail previously.16,17,19 In
short, all women 18 to 50 years of age who presented with a first
event of MI or IS to 1 of the 16 participating hospitals in the
Netherlands between 1990 and 1995 were eligible and approached
for study participation. Diagnosis was made on the basis of clinical
symptoms and confirmed by appropriate tests. MI was diagnosed by
the presence of clinical symptoms, elevated cardiac enzyme levels,
and electrocardiographic changes. Clinical symptoms of IS were
confirmed by either computed tomography or magnetic resonance
imaging. Women were approached to participate as a control subject
by random digit dialing and were matched according to age, area of
residence, and year of event. A standardized questionnaire on patient
characteristics and possible cardiovascular risk factors such as
(familial) medical history, use of oral contraceptives, and smoking
habits was filled in by both cases and controls. Some of these
questions were targeted to the year before diagnosis (cases) or the
matched index year (controls). All participants were re-approached
to donate blood or buccal swab for DNA analyses during the second
phase of the study. Blood samples, together with a questionnaire on
patient characteristics, were collected after a median of 69 months
(range, 38 to 117 months) for MI and 95 months (range, 23 to 146
months) for IS cases, thereby ensuring blood was drawn after the
acute phase.
Assays
We determined inhibitor complexes of the serine proteases of the
intrinsic coagulation system as a measure of enzyme activation in
citrated plasma. The inhibitor could either be a C1-esterase inhibitor
for FXIIa, FXIa of kallikrein (FXIIa-C1-INH, FXIa-C1-INH, KALC1-INH), or antitrypsin inhibitor (FXIa-AT-INH). These complexes
were measured by an ELISA, as described earlier.14 In short, for the
FXIIa-C1-INH ELISA we used monoclonal antibody (mAb) KOK
12, which is specific for complexed C1-inhibitor as antigen, and
mAb F3, which recognizes FXII as well as ␣-FXIIa and ␤-FXIIa
subsequently as conjugate. The KAL-C1-INH assay uses the same
antigen, but uses mAb K15, which is directed against prekallikrein
and kallikrein as conjugate.20,21 The FXIa inhibitor assays both use
the XI-5 mAb as antigen, which recognizes both the native and
activated FXI form of FXI.22 R11 mAb, which binds to native,
complexed, and inactive C1-inhibitor, was used as conjugate for
the FXIa-C1-INH assay; mAb AT-15, which is directed against
complexed AT, was used as conjugate in the FXIa-AT-INH assay. 23,24 All conjugates were biotinylated with EZLink
N-hydroxysuccinimide ester-biotin according to instructions from
the manufacturer (Pierce, Rockford, Ill). Absorbance was read at 450
nm on an EL 808 Ultra microplate reader (Bio-tek Instruments Inc.,
Winooski, Vt).
Results were expressed as a proportion of fully activated normal
pooled plasma; activation was performed by adding an equal volume
of 0.2 mg mL–1 of dextran sulfate (Mr 500 000; Sigma Chemical
Co., St Louis, Mo) in the FXIIa-C1-INH and KAL-C1-INH assay.
Normal pooled plasma for the FXIa inhibitor assays was fully
activated by adding kaolin (final concentration 5 mg mL–1). Activation was stopped by adding 3 volumes of phosphate-buffered saline
containing 0.1 mg mL–1 of soybean trypsin inhibitor (Sigma Chemical Co.) and 0.05% (wt/vol) polybrene (Sigma Chemical Co.).
Kaolin was removed by centrifuging the reaction mixture for 5
minutes at 13 000⫻g. No signal was detected in FXII-, FXI- or
kallikrein-deficient plasmas as a control for the specific ELISA.
1856
Circulation
November 2, 2010
Table 1.
Characteristics of the RATIO Participants
Myocardial Infarction
(n⫽205)
Ischemic Stroke
(n⫽175)
Control (n⫽638)
Mean age, y
43
39
39
White, n (%)
195 (95)
167 (97)
602 (94)
Hypertension
53 (26)
50 (29)
40 (6)
Diabetes mellitus
10 (5)
7 (4)
10 (2)
Hypercholesterolemia
21 (10)
14 (8)
19 (3)
History of,* n (%)
Oral contraceptives use*
81 (40)
92 (53)
213 (33)
169 (82)
101 (58)
270 (42)
FXIIa-C1-INH, median (Q1–Q3)†
0.23 (0.13–0.33)
0.28 (0.15–0.45)
0.24 (0.12–0.33)
FXIa-C1-INH, median (Q1–Q3)†
0.23 (0.14–0.60)
0.37 (0.18–0.76)
0.23 (0.15–0.52)
FXIa-AT-INH, median (Q1–Q3)†
0.24 (0.20–0.29)
0.29 (0.22–0.42)
0.25 (0.21–0.31)
KAL-C1-INH, median (Q1–Q3)†
0.05 (0.03–0.13)
0.11 (0.03–0.27)
0.04 (0.03–0.12)
Smoking*
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
Q1–Q3 indicates range of first and third quartile.
*In the year before event/index year.
†Levels are expressed as a proportion of fully activated normal pooled plasma.
Statistical Analysis
With the 90th percentile of the controls as a predefined cutoff point,
we applied a logistic regression model to obtain odds ratios (ORs) as
measures of the risk of arterial thrombosis associated with high
levels of activation of the intrinsic coagulation factors. All ORs were
adjusted for the frequency matching factors of area of residence, year
of event, and age. Further adjustments were made for the potential
confounders (diabetes mellitus, hypertension and hypercholesterolemia, and smoking) in a fully adjusted model. To assess the intrinsic
coagulation protein system as a whole, a dummy variable was
created, which counted the number of proteins with high activation
levels. Interaction of all intrinsic coagulation proteins with oral
contraceptive use in the year before the event was assessed by
comparing the risk in those with either or both exposures with those
with no exposures.
Results
The first phase of the RATIO study included 248 cases with
MI, 203 cases with IS, and 925 controls. During the recruitment of the second phase of, 30 cases with MI, 63 cases with
IS, and 158 controls either could not be traced or refused to
participate. With 50 additional IS cases, 218 cases with MI,
190 with IS, and 767 controls were included in the second
phase of the study. Blood was successfully collected from
203 MI cases, 175 IS cases, and 638 controls.
Table 1 displays the baseline characteristics of the study
participants. As expected, cases had more cardiovascular risk
factors such as smoking, hypercholesterolemia, diabetes mellitus, and hypertension than controls. The median levels of
activated inhibitor complexes of the intrinsic coagulation
proteins are displayed in Table 1. The Figure shows the
distribution of the 4 inhibitor complexes for cases and
controls separately.
The odds ratios of arterial thrombosis and high levels of
activated intrinsic coagulation protein levels, as well as the
corresponding cutoffs, are displayed in Table 2. By our
definition, 10% of controls have high levels of inhibitor
complexes. No association between MI and FXIIa-C1-INH
was found (10% of cases exposed; OR, 0.82; 95% confidence
interval [CI], 0.46 to 1.47). Also, FXIa-C1-INH (9%; OR,
0.96; 95% CI, 0.54 to 1.71) and FXIa-AT-INH (9%; OR,
0.94; 95% CI, 0.53 to 1.68) were not associated with MI.
KAL-C1-INH slightly increased the risk of MI (15%; OR,
1.50; 95% CI, 0.91 to 2.47). In IS patients, high levels of
FXIIa-C1-INH were more frequent than in controls (23%
exposed; OR, 2.10; 95% CI, 1.27 to 3.48). Also, high levels
of FXIa-C1-INH (21%; OR, 2.77; 95% CI, 1.63 to 4.73) and
FXIa-AT-INH (20%; OR, 2.33; 95% CI, 1.37 to 3.96) were
more frequent. KAL-C1-INH conferred a 4-fold increase in
ischemic stroke (28%; OR, 4.34; 95% CI, 2.62 to 7.18).
Further adjustments for hypertension, diabetes mellitus, hypercholesterolemia, and smoking did not change the overall
pattern, as is displayed in Table 2 (“fully adjusted” ORs).
The use of an oral contraceptive in the year before the
event roughly doubled the risk of both MI (OR, 2.3; 95% CI,
1.6 to 3.4) and IS (OR, 2.8; 95% CI, 1.8 to 4.2).16,17 The risk
of ischemic stroke conferred by a combination of high levels
of intrinsic coagulation protein activation (ie, ⬎p90) and
prior oral contraceptive use was higher than could be expected by the separate effects, as can be seen in Table 3. The
risk of MI was not further increased by the combination of
high levels of intrinsic coagulation protein activation and oral
contraceptives, except for KAL-C1-INH. The combination of
high levels of KAL-C1-INH and oral contraceptives use
when compared with women who had neither risk factor
increased the risk of MI 6-fold (OR, 6.1; 95% CI, 2.5 to 15).
This combined effect was also present in the IS analysis:
women with both high levels of KAL-C1-INH and oral
contraceptive use had a 17-fold increase in IS risk (OR, 17;
95% CI, 7.4 to 41). Further adjustments for potential confounders (hypertension, diabetes, hypercholesterolemia, and
smoking) did not change the overall pattern, as is displayed in
Table 2 (“fully adjusted” ORs).
Table 4 shows the ORs per number of proteins with high
levels of activation. For each additional high level of activated protein inhibitor complex, the risk of IS is increased
2-fold (OR, 2.11; 95% CI, 1.31 to 3.38), whereas the risk for
Siegerink et al
Intrinsic Coagulation and Arterial Thrombosis Risk
1857
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
Figure. Levels of activated intrinsic coagulation proteins. Individual levels of protein activation are expressed as a proportion of fully
activated normal pooled plasma. Medians are displayed with horizontal bars. MI patients are depicted with open squares (〫), ischemic
stroke patients with triangles (Œ), and controls with circles (F). AU indicates arbitrary units; CON, controls.
MI was not affected (OR, 1.14; 95% CI, 0.75 to 1.73). When
compared with those without a high level of intrinsic coagulation protein activation, people with ⱖ2 high levels had a
4-fold increase in risk for IS (OR, 4.39; 95% CI, 2.44 to 7.90),
but no such association was found between multiple high
levels and MI (OR, 1.30; 95% CI, 0.66 to 2.57).
In total, 19 MI and 21 IS patients were on anticoagulants.
The results of the analyses when restricted to those patients
who did not take oral anticoagulant therapy at the time of
blood drawing did not change. Therefore, oral anticoagulant
therapy does not change our results. The associations of
FXIa-C1-INH, FXIa-AT-INH, and KAL-C1-INH persist in
IS patients whose blood was sampled years (⬎7) after the
event (data not shown). The association of FXIIa-C1-INH
appeared to attenuate with increasing time between event and
blood drawing. However, absence of association cannot be
established because of the broad CIs.
Discussion
Our study shows that high levels of activated proteins of the
intrinsic coagulation system are associated with IS, and are
not or are to a lesser extent associated with MI, in young
women. In general, high levels increased the risk of ischemic
stroke 2.5-fold, whereas the risk of MI was hardly affected.
The increased risk for IS was further increased by oral
contraceptive use. When the intrinsic coagulation proteins
were assessed as a whole, high levels were more frequent in
IS when compared with myocardial infarction.
The rate-limiting step in the formation of the inhibitor
complexes is the availability of activated coagulation proteins, because the inhibitors are present in excess in plasma.
The cause of the elevated complexes is not clear. It could
either be a relative increase in which the absolute levels of
zymogens remain stable with an increased activation rate, or
it could be an absolute increase of zymogens with a stable
activation rate.
Our study has some limitations; because of the case-control
study design, blood was collected after the event in the case
groups. This might have led to reverse causation, a process in
which a consequence of an event is mistaken for the cause of
the event. Because blood sampling in the RATIO study is
several months after the event, we can safely rule out the
1858
Circulation
Table 2.
November 2, 2010
Risk of Arterial Thrombosis Due to High Levels of Activated Intrinsic Coagulation
ⱕ90th Percentile
⬎90th Percentile
OR (95% CI)
ORfully adjusted (95% CI)
Control
568 (90)
63 (10)
1 关ref兴
1 关ref兴
Myocardial infarction
182 (90)
21 (10)
0.82 (0.46–1.47)
0.74 (0.38–1.46)
Ischemic stroke
130 (75)
39 (23)
2.10 (1.27–3.48)
1.87 (1.07–3.26)
Control
568 (90)
63 (10)
1 关ref兴
1 关ref兴
Myocardial infarction
184 (91)
19 (9)
0.96 (0.54–1.71)
1.13 (0.60–2.15)
Ischemic stroke
133 (79)
35 (21)
2.77 (1.63–4.73)
2.92 (1.63–5.22)
Control
568 (90)
63 (10)
1 关ref兴
1 关ref兴
Myocardial infarction
185 (91)
18 (9)
0.94 (0.53–1.68)
0.94 (0.49–1.82)
Ischemic stroke
134 (80)
34 (20)
2.33 (1.37–3.96)
2.18 (1.22–3.87)
Control
570 (90)
63 (10)
1 关ref兴
1 关ref兴
Myocardial infarction
174 (85)
30 (15)
1.50 (0.91–2.47)
2.12 (1.18–3.81)
Ischemic stroke
123 (72)
47 (28)
4.34 (2.62–7.18)
5.14 (2.93–9.00)
FXIIa-C1-INH, n (%)
FXIa-C1-INH, n (%)
FXIa-AT-INH, n (%)
KAL-C1-INH, n (%)
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
Odds ratios are obtained from logistic regression and are adjusted for the stratification factors age, area of
residence, and year of event. Odds ratios depicted as “fully adjusted” are additionally adjusted for diabetes mellitus,
hypertension and hypercholesterolemia, and smoking.
ref indicates reference.
possibility that our findings directly reflect the transient
effects of the acute phase, which lasts days to weeks.
However, slowly subsiding effects that are induced by IS
could explain some of the relation between FXIIa-C1-INH
and IS. Nontransient effects (or chronic effect) can still be the
cause of reverse causation in our study and can only be ruled
out in a prospective study.
Furthermore, the necessity of a blood sample after the
event implicates that our results are only valid for nonfatal
arterial thrombosis. Although our study can be considered
to be of reasonable size, or even relative large because of
the rare nature of cardiovascular disease in young women,
the RATIO study lacks power to detect small effects. Lack
of precision, which is reflected in the wide CIs, sometimes
hampers definite interpretation of our results. This is most
clear when the intrinsic coagulation system is assessed as
a whole; only few patients and controls are positive on 3 or
all 4 assays, making it difficult to interpret the ORs for
these strata. However, the pattern is clear: the risk increase
found for ischemic stroke is higher for each additionally
elevated activated protein inhibitor complex, whereas this
pattern is absent for MI. This observation suggests that the
pathogenic role of the intrinsic coagulation proteins is not
similar for all manifestations of arterial thrombosis.
Our results indicate that the risks conferred by high
levels of intrinsic coagulation proteins were further increased by oral contraceptive use. This raises the question
of whether women who want to start with oral contraceptive use perhaps should be screened. The highest risk, after
adjustment for potential confounders, was found in women
who both had high levels of activated prekallikrein (⬎p90
of controls) and used oral contraceptives: a 23-fold increase in risk compared with women with neither risk
factor (fully adjusted model). Even with this relative risk,
a total of 15 686 women have to be screened for their
kallikrein activation levels before the start of oral contraceptives. If the 10% of these women with the highest
kallikrein activation levels do not start to use oral contraceptives, 1 IS case will be prevented per year. Although a
formal cost-benefit analyses could show a different number, these calculations show that screening is clearly not
desirable, mainly because of the low incidence of IS in this
population. This is even more clear when one considers the
beneficial effects of oral contraceptive use in this population, such as a reduction of pregnancy-associated morbidity and mortality and ovarian and endometrial cancer.
A nested case-control study in the second Northwick Park
Heart Study (NPHS II) also assessed the relationship between
the inhibitor complexes of intrinsic coagulation proteins and
the risk of coronary heart disease (CHD, n⫽231) and stroke
(n⫽56, of which 12 were hemorrhagic). CHD was defined as
definite MI (fatal and nonfatal), possible MI (fatal), angina
pectoris, or coronary angiographic findings requiring intervention and ECG changes at 5 years of follow-up. Strokes
were diagnosed and categorized on the basis of clinical
presentation, computed tomography, lumbar puncture, and
autopsy findings.
CHD risk was decreased in the second tertile of FXIIa-C1INH; if anything, the third tertile also showed a decrease in
risk, but to a lesser extent, thus resulting in a U-shaped
relation. Other inhibitor complexes (FXI-C1-INH, FXI-ATINH, KAL-C1-INH) did not seem to alter CHD risk. A
similar U-shaped pattern was observed for the relation between KAL-C1-INH complexes and stroke. These results are
essentially similar after reanalysis with the 90th percentile as
a cutoff (analyses done in collaboration with the NPHS II
Siegerink et al
Table 3.
Intrinsic Coagulation and Arterial Thrombosis Risk
1859
Risk of Arterial Thrombosis Due to High Levels of Activated Intrinsic Coagulation Protein and Prior Oral Contraceptives
Myocardial Infarction
High Level
(⬎90th Percentile)
Ischemic Stroke
OC
Use
Controls, n
MI Cases, n
–
–
376
107
–
⫹
192
75
⫹
–
47
16
0.9 (0.4–1.7)
0.8 (0.4–1.7)
18
1.8 (0.9–3.6)
1.6 (0.7–3.3)
⫹
⫹
16
5
2.4 (0.7–7.7)
1.8 (0.5–7.2)
21
8.7 (3.7–21)
8.1 (3.1–21)
–
–
382
111
1 关ref兴
1 关ref兴
60
1 关ref兴
1 关ref兴
–
⫹
186
73
2.5 (1.7–3.7)
2.2 (1.4–3.5)
73
3.2 (2.0–5.1)
3.4 (2.0–5.7)
⫹
–
40
12
1.1 (0.5–2.3)
1.5 (0.7–3.2)
20
3.8 (1.9–7.7)
4.7 (2.1–10)
⫹
⫹
23
7
1.8 (0.7–4.7)
1.5 (0.5–4.4)
15
6.1 (2.5–14)
5.5 (2.2–14)
–
–
383
112
1 关ref兴
1 关ref兴
65
1 关ref兴
1 关ref兴
–
⫹
185
73
2.5 (1.6–3.7)
2.2 (1.4–3.5)
69
3.1 (1.9–4.9)
3.1 (1.9–5.3)
⫹
–
39
11
1.0 (0.5–2.2)
1.2 (0.5–2.8)
15
3.2 (1.5–6.6)
3.3 (1.4–7.3)
⫹
⫹
24
7
1.9 (0.7–4.8)
1.3 (0.4–3.8)
19
4.8 (2.1–11)
4.1 (1.7–9.8)
–
–
377
106
1 关ref兴
1 关ref兴
62
1 关ref兴
1 关ref兴
OR (95% CI)
ORfully adjusted (95% CI)
IS Cases, n
OR (95% CI)
ORfully adjusted (95% CI)
1 关ref兴
1 关ref兴
62
1 关ref兴
1 关ref兴
2.4 (1.6–3.5)
2.0 (1.3–3.2)
68
2.8 (1.8–4.5)
2.7 (1.6–4.5)
FXIIa-C1-INH
FXIa-C1-INH
FXIa-AT-INH
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
KAL-C1-INH
–
⫹
193
68
2.2 (1.5–3.3)
1.9 (1.2–3.0)
61
2.7 (1.7–4.4)
2.6 (1.5–4.5)
⫹
–
46
17
1.2 (0.6–2.2)
1.6 (0.8–3.4)
19
3.7 (1.9–7.4)
4.2 (1.9–9.0)
⫹
⫹
17
13
6.1 (2.5–15)
6.8 (2.5–18)
28
17 (7.4–41)
23 (9.2–59)
Relative risks are stratified to oral contraceptive use before the event or index year (–/⫹), high levels of protein activation (⫹/–), or both (⫹/⫹) with the –/– category
as reference. Odds ratios are obtained from logistic regression and are adjusted for the stratification factors age, area of residence, and year of event. “Fully adjusted”
odds ratios are additionally adjusted for diabetes mellitus, hypertension and hypercholesterolemia, and smoking.
OC indicates oral contraceptive; ref, reference.
investigators; results not shown here). There are several
possible explanations for the discrepant findings in the
RATIO and the NPHS II analyses. First, the differences
might be due to chance. Second, the NPHS II is a nested
case-control study, so blood draw was before the event.
Although reverse causation in the RATIO study is not a likely
explanation for our results, because of the timing of blood
draw and the different effects for MI and IS, it cannot be ruled
out. Third, the case definitions in the RATIO study were
more stringent when compared with those in the NPHS. In the
NPHS, ischemic and hemorrhagic strokes were combined,
and CHD also included possible MI. Fourth, the largest
difference between the studies is found in the sex and age
of the participants: NPHS included only middle-aged men,
Table 4.
whereas the RATIO study included only relatively young
women. This difference is of particular interest because
FXII transcription is estrogen sensitive, because of an
estrogen-responsive element in the promoter region of the
F12 gene.3 Furthermore, a recent murine study suggests
that estrogens influence the transcription of more coagulation proteins.15
The mechanism(s) by which these proteins are involved
in the pathogenesis of IS in young women still have to be
established. Perhaps such an increased activity of these
proteins results in an imbalance of the several systems in
which the intrinsic coagulation proteins are involved (eg,
coagulation, fibrinolysis, and inflammation). Ultimately,
this imbalance then leads to a hypercoagulable state, which
Risk of Arterial Thrombosis With Increasing Numbers of High Levels of Activated Intrinsic Coagulation Proteins
Myocardial Infarction
Ischemic Stroke
No. of High
Levels
Controls
n (%)
n (%)
OR (95% CI)
ORfully adjusted (95% CI)
n (%)
OR (95% CI)
ORfully adjusted (95% CI)
0
454 (72)
137 (69)
1 关ref兴
1 关ref兴
84 (50)
1 关ref兴
1 关ref兴
1
117 (19)
44 (23)
1.14 (0.75–1.73)
1.16 (0.72–1.88)
44 (26)
2.11 (1.31–3.38)
2.10 (1.125–3.53)
2
42 (6.5)
16 (7.5)
1.27 (0.67–2.43)
1.42 (0.68–3.00)
17 (11)
3.00 (1.50–6.00)
3.57 (1.72–7.43)
3
13 (2)
2 (1)
0.44 (0.08–2.33)
0.58 (0.10–3.47)
15 (8)
4.67 (1.88–12)
5.41 (2.00–14)
1 (0.5)
1.10 (0.08–15)
3.84 (0.29–51)
7 (5)
12.6 (2.7–58)
8.09 (1.5–42)
4
3 (0.5)
Odds ratios are obtained from logistic regression and are adjusted for the stratification factors age, area of residence, and year of event. Odds ratios depicted as
“fully adjusted” are additionally adjusted for diabetes mellitus, hypertension and hypercholesterolemia, and smoking.
ref indicates reference.
1860
Circulation
November 2, 2010
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
could further increase the risk of ischemic stroke. According to this hypothesis, some event, such as a plaque rupture
or changes in blood flow, acts as a trigger of the start of
coagulation. The extent of the following thrombus formation is dependent on the tendency to clot: Patients suffering
from a hypercoagulable state are more likely to form an
occlusive thrombus with clinical effects than those without
such a predisposition. This mechanism predicts that a
dose-dependent effect should be observed: the greater the
imbalance, the larger the tendency to coagulate, the greater
the risk of ischemic stroke. Not all forms of arterial
thrombosis need to be subject to this hypothesized mechanism. Possibly, exposure of the highly thrombogenic
surface after rupture of a coronary plaque inevitably will
start clot formation, whether the patient is more prone to
coagulation or not. Although the formation of a thrombus
in itself is involved in the pathogenesis of both MI and IS,
we hypothesize that the tendency to start a clot is an
important risk factor for IS, but not for MI.
Conclusions
Results from the RATIO study showed that increased levels
of activated intrinsic coagulation proteins are associated with
IS, but not MI, in young women. These risks are further
increased by oral contraceptive use. These results differ from
an earlier study in middle-aged men (NPHS II). This raises 2
questions: Why are the effects of intrinsic coagulation proteins different for MI and IS in young patients, and are these
effects sex-specific?
Answers to these questions could come from both basic
and epidemiological research. Basic research is needed to
further unravel the function of activated intrinsic coagulation
proteins and perhaps identify different mechanisms for different forms of arterial thrombosis. Epidemiological research
could also provide more insight in the potentially different
mechanisms for MI and IS; for example, by specifying the
associations per stroke subtype. Furthermore, epidemiological research could provide more insight on the possible
sex-specific effects by including both male and female
patients. A prospective study design could also diminish the
risk of reverse causation, but the low incidence of arterial
thrombosis in the young would make such a study very
inefficient.
Acknowledgments
The authors wish to thank the participants and the earlier contributors
to the RATIO study. We are indebted to H. Ghafouri, who assisted
with the measurements. A special thanks to Dr J.A. Cooper from the
NPHS for providing the additional analyses.
Sources of Funding
This study was supported by grants from the Netherlands Heart
Foundation (grant 2001.069) and the Leducq Foundation, Paris,
France, for the development of Transatlantic Networks of Excellence
in Cardiovascular Research (grant 04 CVD 02).
Disclosures
None.
References
1. World Health Organization. The Top 10 Causes of Death: Fact Sheet 310.
Geneva, Switzerland: World Health Organization; 2008.
2. Kaplan AP, Silverberg M. The coagulation-kinin pathway of human
plasma. Blood. 1987;70:1–15.
3. Farsetti A, Misiti S, Citarella F, Felici A, Andreoli M, Fantoni A,
Sacchi A, Pontecorvi A. Molecular basis of estrogen regulation of
Hageman factor XII gene expression. Endocrinology. 1995;136:
5076 –5083.
4. van Dieijen G, Tans G, Rosing J, Hemker HC. The role of phospholipid
and factor VIIIa in the activation of bovine factor X. J Biol Chem.
1981;256:3433–3442.
5. Radcliffe R, Bagdasarian A, Colman R, Nemerson Y. Activation of
bovine factor VII by hageman factor fragments. Blood. 1977;50:
611– 617.
6. Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood. 1997;90:3819 –3843.
7. Schmaier AH. Assembly, activation, and physiologic influence of the
plasma kallikrein/kinin system. Int Immunopharmacol. 2008;8:
161–165.
8. Renne T, Pozgajova M, Gruner S, Schuh K, Pauer HU, Burfeind P,
Gailani D, Nieswandt B. Defective thrombus formation in mice lacking
coagulation factor XII. J Exp Med. 2005;202:271–281.
9. Gailani D, Renne T. Intrinsic pathway of coagulation and arterial
thrombosis. Arterioscler Thromb Vasc Biol. 2007;27:2507–2513.
10. Salomon O, Steinberg DM, Dardik R, Rosenberg N, Zivelin A, Tamarin
I, Ravid B, Berliner S, Seligsohn U. Inherited factor XI deficiency confers
no protection against acute myocardial infarction. J Thromb Haemost.
2003;1:658 – 661.
11. Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U.
Reduced incidence of ischemic stroke in patients with severe factor XI
deficiency. Blood. 2008;111:4113– 4117.
12. Doggen CJ, Rosendaal FR, Meijers JC. Levels of intrinsic coagulation
factors and the risk of myocardial infarction among men: Opposite
and synergistic effects of factors XI and XII. Blood. 2006;108:
4045– 4051.
13. Endler G, Marsik C, Jilma B, Schickbauer T, Quehenberger P,
Mannhalter C. Evidence of a U-shaped association between factor
XII activity and overall survival. J Thromb Haemost. 2007;5:
1143–1148.
14. Govers-Riemslag JW, Smid M, Cooper JA, Bauer KA, Rosenberg RD,
Hack CE, Hamulyak K, Spronk HM, Miller GJ, Ten CH. The plasma
kallikrein-kinin system and risk of cardiovascular disease in men.
J Thromb Haemost. 2007;5:1896 –1903.
15. Cleuren ACA, van der Linden IK, de Visser YP, Wagenaar GTM,
Reitsma PH, van Vlijmen BJM. 17alpha-Ethinylestradiol rapidly alters
transcript levels of murine coagulation genes via estrogen receptor alpha.
J Thromb Haemost. 2010;8:1838 –1846.
16. Kemmeren JM, Tanis BC, van den Bosch MA, Bollen EL, Helmerhorst
FM, van der Graaf Y, Rosendaal FR, Algra A. Risk of Arterial
Thrombosis in Relation to Oral Contraceptives (RATIO) study: oral
contraceptives and the risk of ischemic stroke. Stroke. 2002;33:
1202–1208.
17. Tanis BC, van den Bosch MA, Kemmeren JM, Manger Cats V,
Helmerhorst FM, Algra A, van der Graaf Y, Rosendaal FR. Oral contraceptives and the risk of myocardial infarction. N Engl J Med. 2001;345:
1787–1793.
18. van den Bosch MA, Kemmeren JM, Tanis BC, Mali WP, Helmerhorst
FM, Rosendaal FR, Algra A, van der Graaf Y. The RATIO study: oral
contraceptives and the risk of peripheral arterial disease in young women.
J Thromb Haemost. 2003;1:439 – 444.
19. Pruissen DM, Slooter AJ, Rosendaal FR, van der Graaf Y, Algra A.
Coagulation factor XIII gene variation, oral contraceptives, and risk of
ischemic stroke. Blood. 2008;111:1282–1286.
20. Nuijens JH, Huijbregts CC, Eerenberg-Belmer AJ, Abbink JJ, Strack van
Schijndel RJ, Felt-Bersma RJ, Thijs LG, Hack CE. Quantification of
plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(-)-inhibitor complexes in sepsis. Blood. 1988;72:1841–1848.
Siegerink et al
Intrinsic Coagulation and Arterial Thrombosis Risk
21. Nuijens JH, Huijbregts CC, Eerenberg-Belmer AJ, Meijers JC, Bouma
BN, Hack CE. Activation of the contact system of coagulation by a
monoclonal antibody directed against a neodeterminant in the heavy
chain region of human coagulation factor XII (Hageman factor). J Biol
Chem. 1989;264:12941–12949.
22. Wuillemin WA, Minnema M, Meijers JC, Roem D, Eerenberg AJ,
Nuijens JH, Ten CH, Hack CE. Inactivation of factor XIa in human
plasma assessed by measuring factor XIa-protease inhibitor complexes:
major role for C1-inhibitor. Blood. 1995;85:1517–1526.
1861
23. Nuijens JH, Huijbregts CC, van Mierlo GM, Hack CE. Inactivation of C-1
inhibitor by proteases: demonstration by a monoclonal antibody of a neodeterminant on inactivated, non-complexed C-1 inhibitor. Immunology. 1987;
61:387–389.
24. Abbink JJ, Kamp AM, Swaak AJ, Hack CE. Production of monoclonal
antibodies against inactivated alpha 1-antitrypsin: cross-reactivity with
complexed alpha 1-antitrypsin and application in an assay to determine
inactivated and complexed alpha 1-antitrypsin in biological fluids.
J Immunol Methods. 1991;143:197–208.
CLINICAL PERSPECTIVE
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
Arterial forms of thrombosis are leading causes of death and disability in the Western world. The Risk of Arterial
Thrombosis in Relation to Oral Contraceptives (RATIO) study is a population-based case-control study that focuses on
arterial thrombosis in young women (18 to 50 years of age) and has a unique opportunity to identify risk factors that are
difficult to identify in older patients because they could be obscured by age-related comorbidities. The identification of
these new risk factors could aid in the prevention and treatment of arterial thrombosis in all age groups. This study
investigated whether proteins of the intrinsic coagulation pathways are risk factors for arterial thrombosis. Historically, the
role of some of these factors was thought to be minor. However, both animal and clinical studies have implicated these
proteins in pathophysiological thrombus formation. Furthermore, these proteins also play a role in other relevant biological
systems, such as inflammation. Inhibitor complexes of coagulation factors XIIa, Xia, and kallikrein were determined as a
measure of protein activation. It was found that these complexes were higher in ischemic stroke cases, but were not higher
in myocardial infarction cases, when compared with matched controls. The risk of stroke was further increased (up to
23-fold) among users of oral contraceptives. However, because of the low incidence of arterial thrombosis in young
women, screening for these factors before the start of arterial thrombosis does not seem to be warranted. Further studies
should be performed to investigate the exact pathophysiological mechanism and whether these mechanisms are different
for the subtypes of arterial thrombosis, especially for subtypes of ischemic stroke.
Intrinsic Coagulation Activation and the Risk of Arterial Thrombosis in Young Women:
Results From the Risk of Arterial Thrombosis in Relation to Oral Contraceptives
(RATIO) Case-Control Study
B. Siegerink, J.W.P. Govers-Riemslag, F.R. Rosendaal, H. ten Cate and A. Algra
Downloaded from http://circ.ahajournals.org/ by guest on February 16, 2017
Circulation. 2010;122:1854-1861; originally published online October 18, 2010;
doi: 10.1161/CIRCULATIONAHA.110.943738
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2010 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/122/18/1854
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2013/10/17/CIRCULATIONAHA.110.943738.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/
Page 295
Résumés d’articles
295
Conclusions—Bien qu’un an d’entraînement physique intense n’ait pas semblé avoir d’influence bénéfique sur la rigidité cardiaque
des séniors sédentaires, cela a néanmoins induit un remodelage VG physiologique et a amélioré la fonction artérielle et la
capacité d’effort aérobie. (Traduit de l’anglais : Cardiovascular Effects of 1 Year of Progressive and Vigorous Exercise Training in
Previously Sedentary Individuals Older Than 65 Years of Age. Circulation. 2010;122:1797–1805.)
Mots clés : diastole 䊏 activité physique 䊏 vieillissement 䊏 maladies cardiaques 䊏 hémodynamique
Dysfonction vasculaire chez la femme ayant des antécédents de
prééclampsie et de retard de croissance intra-utérin
Eléments d’appréciation du risque vasculaire à venir
Yoav Yinon, MD ; John C.P. Kingdom, MD ; Ayodele Odutayo, BSc ; Rahim Moineddin, PhD ;
Sascha Drewlo, PhD ; Vesta Lai, RN ; David Z.I. Cherney, MD, PhD ; Michelle A. Hladunewich, MD
Contexte—Les femmes ayant présenté une maladie placentaire sont exposées à un risque accru de développement d’une
affection vasculaire. On ignore toutefois si la préexistence d’une dysfonction endothéliale intervient dans la prédisposition aux
pathologies placentaires et dans la survenue ultérieure d’un trouble vasculaire. Cette étude avait donc pour objet d’évaluer la
fonction vasculaire chez des femmes en période de postpartum et d’établir si son altération différait selon le type d’affection
placentaire.
Méthodes et résultats—Des patientes qui avaient respectivement des antécédents de prééclampsie de début précoce (n =15), de
prééclampsie de survenue tardive (n = 9) et de retard de croissance intra-utérin sans prééclampsie (n = 9) ont été suivies pendant
une durée de 6 à 24 mois après leur accouchement parallèlement à des femmes dont la grossesse s’était déroulée normalement
(n = 16). La vasodilatation médiée par le flux sanguin et celle indépendante de celui-ci (induite par la trinitrine) ont été étudiées
au niveau de l’artère humérale par écho-Doppler de haute résolution. La rigidité artérielle a été appréciée par analyse de l’onde
de pouls (indice d’augmentation). Le bilan biologique a porté sur les taux de facteurs angiogéniques circulants (facteur de
croissance de l’endothélium vasculaire, fms-like tyrosine kinase 1 soluble, facteur de croissance placentaire et endogline soluble).
La vasodilatation dépendante du flux est apparue significativement plus faible chez les femmes qui avaient des antécédents de
prééclampsie de début précoce et de retard de croissance intra-utérin que chez celles ayant antérieurement présenté une
prééclampsie de survenue tardive et que chez les témoins (respectivement, 3,2 ± 2,7 % et 2,1 ± 1,2 % contre 7,9 ± 3,8 % et
9,1 ± 3,5 % ; p <0,0001). La vasodilatation indépendante du flux a été comparable dans tous les groupes. De même, l’indice
d’augmentation de la pression artérielle radiale s’est révélé significativement majoré chez les femmes ayant des antécédents de
prééclampsie de début précoce et de retard de croissance intra-utérin, alors qu’il a été normal chez celles ayant présenté une
prééclampsie tardive et chez les témoins (p = 0,0105). Les taux de facteurs angiogéniques circulants ont été similaires dans tous
les groupes.
Conclusions—Seules les femmes ayant des antécédents de prééclampsie de survenue précoce et de retard de croissance intra-utérin
sans prééclampsie sont sujettes à une altération de leur fonction vasculaire, ce qui pourrait expliquer leur prédisposition aux
pathologies placentaires et leur propension supérieure à développer secondairement une affection vasculaire. (Traduit de
l’anglais : Vascular Dysfunction in Women With a History of Preeclampsia and Intrauterine Growth Restriction; Insights Into
Future Vascular Risk. Circulation. 2010;122:1846–1853.)
Mots clés : endothélium 䊏 prééclampsie 䊏 vasodilatation 䊏 femmes 䊏 maladies vasculaires 䊏
pathologies placentaires 䊏 femme en postpartum
Activation de la voie intrinsèque de la coagulation et risque de
thrombose artérielle chez la femme jeune
Résultats de l’étude cas-témoin Risk of Arterial Thrombosis in Relation
to Oral Contraceptives (RATIO)
B. Siegerink, MSc ; J.W.P. Govers-Riemslag, PhD ; F.R. Rosendaal, MD, PhD ;
H. ten Cate, MD, PhD ; A. Algra, MD, PhD
Contexte—L’opinion qui prévaut est que les protéines de la voie intrinsèque de la coagulation jouent un rôle mineur dans
l’hémostase. De récentes données suggèrent toutefois que ces protéines, et plus particulièrement le facteur XII, seraient des
acteurs clés dans la pathogenèse des thromboses artérielles. La présente étude a donc été entreprise pour évaluer les risques
14:01:09:06:11
Page 295
Page 296
296
Circulation
Juillet 2011
de thrombose artérielle associés à l’augmentation de l’activation de ces protéines chez la femme jeune et pour déterminer
l’influence exercée par la contraception orale sur cette association.
Méthodes et résultats—L’étude RATIO (Risk of Arterial Thrombosis in Relation to Oral Contraceptives [Risque de thrombose
artérielle associé à la prise de contraceptifs oraux]) est une étude de population cas-témoin menée chez des femmes jeunes
(âge compris entre 18 et 50 ans) ayant été victimes d’un infarctus du myocarde (n = 205) ou d’un accident vasculaire cérébral
ischémique (n =175) ainsi que chez 638 témoins sains. L’activation des facteurs de la voie intrinsèque de la coagulation a été
évaluée en dosant les taux de complexes protéine-inhibiteur activés. Ces complexes sont respectivement formés avec l’inhibiteur
de la C1 estérase (FXIIa-C1-INH, FXIa-C1-INH, kallicréine-C1-INH) ou l’inhibiteur de l’antitrypsine (FXIa-AT-INH). Les
odds ratios (OR) et leurs intervalles de confiance (IC) à 95 % ont été calculés à partir d’une analyse par régression logistique. Il
est ainsi apparu qu’un degré élevé d’activation de chacune de ces protéines (au-delà du 90ème percentile de la valeur mesurée
chez les témoins) avait contribué à augmenter le risque d’accident vasculaire cérébral ischémique : FXIIa-C1-INH (OR : 2,1 ; IC
à 95 % : 1,3 à 3,5), FXIa-C1-INH (OR : 2,8 ; IC à 95 % : 1,6 à 4,7), FXIa-AT-INH (OR : 2,3 ; IC à 95 % : 1,4 à 4,0) et kallicréineC1 (OR : 4,3 ; IC à 95 % : 2,6 à 7,2). En revanche, seul le complexe kallicréine-C1-INH a été associé à une augmentation
du risque d’infarctus du myocarde (OR : 1,5 ; IC à 95 % : 0,9 à 2,5). La prise de contraceptifs oraux a eu pour effet de majorer
les risques.
Conclusions—Des taux élevés de protéines activées de la voie intrinsèque de la coagulation favorisent les thromboses artérielles,
bien que la puissance de cette association diffère pour l’infarctus du myocarde et pour l’accident vasculaire cérébral ischémique.
Ces observations tranchent avec les résultats d’analyses similaires effectuées chez l’homme dans le cadre de la Northwick Park
Heart Study. Compte tenu du fait que les risques apparaissent majorés par la contraception orale, la question se pose de savoir si
le rôle joué par les facteurs de la voie intrinsèque de la coagulation dans la pathogenèse des thromboses artérielles serait propre
au sexe féminin. (Traduit de l’anglais. Intrinsic Coagulation Activation and the Risk of Arterial Thrombosis in Young Women;
Results From the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) Case-Control Study. Circulation :
2010;122:1854–1861.)
Mots clés : thrombose artérielle 䊏 coagulation, voie intrinsèque 䊏 activation 䊏 femme
14:01:09:06:11
Page 296