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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Levels of intrinsic coagulation factors and the risk of myocardial infarction among
men: opposite and synergistic effects of factors XI and XII
Carine J. M. Doggen, Frits R. Rosendaal, and Joost C. M. Meijers
The role of the intrinsic coagulation system on the risk of myocardial infarction is
unclear. In the Study of Myocardial Infarctions Leiden (SMILE) that included 560
men younger than age 70 with a first
myocardial infarction and 646 control subjects, we investigated the risk of myocardial infarction for levels of factor XI (factor XIc) and factor XII (factor XIIc).
Furthermore, the risks for factor VIII activity (factor VIIIc) and factor IX activity
(factor IXc) were assessed. Factor XIc
was 113.0% in patients compared with
109.8% in control subjects (difference,
3.2%; 95% CI, 1.1%-5.4%). The risk of
myocardial infarction adjusted for age for
men in the highest quintile compared
with those in the lowest quintile was
1.8-fold increased (ORadj, 1.8; 95% CI,
1.2-2.7). In contrast, factor XIIc among
patients with myocardial infarction was
lower than in control subjects, respectively, 93.0% and 98.6% (difference, 5.6%;
95% CI, 3.3%-7.9%). The odds ratio of
myocardial infarction for men in the highest quintile versus those in the lowest
quintile was 0.4 (ORadj, 0.4; 95% CI, 0.20.5). The highest risk was found among
men with both high factor XIc and low
factor XIIc (analyses in tertiles: ORadj,
6.4; 95% CI, 2.2-18.0). Factor VIIIc increased the risk of myocardial infarction
although not dose dependently. Factor
IXc increased the risk; odds ratio of myocardial infarction for men in the highest
quintile versus those in the lowest quintile was 3.2 (ORadj, 3.2; 95% CI, 2.0-5.1).
Thus, factors XIc and XIIc have opposite
and synergistic effects on the risk of
myocardial infarction in men; factor VIIIc
and factor IXc increase the risk. (Blood.
2006;108:4045-4051)
© 2006 by The American Society of Hematology
Introduction
Myocardial infarction occurs when a thrombus evolves on a ruptured
atherosclerotic plaque followed by vessel occlusion.1 This exposes
tissue factor to blood which triggers the extrinsic system of thrombin
generation by the formation of tissue factor (TF)–factor VIIa complex
and induces platelet adhesion, activation, and aggregation. The TFfactor VIIa complex activates factor X and factor IX, leading to the
generation of thrombin and formation of fibrin.2 Once thrombin is
formed, further thrombin is generated by activation of factor V, factor
VIII, and factor XI.3 Thrombin generation also leads to activation of
thrombin activatable fibrinolysis inhibitor (TAFI) resulting in downregulation of fibrinolysis.4,5 Inhibition of factor XI in an experimental
thrombosis model in rabbits leads to enhanced thrombolysis, thereby
showing an antifibrinolytic effect of factor XIa.6 Factor XI inhibition in
baboons does not prevent thrombus initiation, but it does seem to reduce
thrombus growth rate, overall thrombus mass, and thrombo-occlusion,
thereby leading to more favorable outcomes.7 Additionally, factor
XI-deficient mice were protective from an induced arterial occlusion,
suggesting that therapeutic inhibition of factor XI may be a reasonable
strategy for treating or preventing thrombus formation.8 Thus, factor XI
acts as a procoagulant and an antifibrinolytic factor, and dysregulation
may increase the risk of thrombosis. However, factor XI deficiency does
not confer protection against myocardial infarction.9 Elevated levels
may even increase the risk,10 similarly to the increased risk of venous
thrombosis.11
Factor XI is part of the intrinsic coagulation system and can be
activated by factor XII (Hageman factor) independently from
thrombin.12 The traditional view is that low levels of factor XII
increase the risk of venous thrombosis. Indeed, in one study factor
XII levels were lower in patients who had a venous thrombosis
compared with healthy blood donors,13 although in a large casecontrol study we found no relation between factor XII levels and
venous thrombosis.14 Several case reports pointed out the occurrence of myocardial infarction in persons with factor XII deficiency.15,16 However, the few studies investigating the risk of
myocardial infarction in persons with decreased levels gave
conflicting results.10,17 Although coagulation factors such as fibrinogen and factor VII have been investigated intensively, the role of
the intrinsic system in the development of thrombosis, including
myocardial infarction, remains unclear.
In the Study of Myocardial Infarctions Leiden (SMILE) we
investigated factor XI and factor XII coagulant activity in 560 men
with a nonfatal myocardial infarction and 646 control subjects from
the Netherlands and calculated risks of myocardial infarction with
increasing quintiles of activity. Additionally, the roles of factor VIII
and factor IX have been investigated as well. We extensively
assessed the relationship of factor XI and factor XII with other
markers of risk and adjusted the risk of myocardial infarction for
cardiovascular risk factors that were found to be associated with
these factors.
From the Department of Clinical Epidemiology, Leiden University Medical
Center; the Thrombosis and Haemostasis Research Center, Leiden University
Medical Center; and the Department of Vascular Medicine, Academic Medical
Center, University of Amsterdam, The Netherlands.
Blood First Edition Paper, August 24, 2006; DOI 10.1182/blood-2005-12-023697.
Submitted December 21, 2005; accepted August 3, 2006. Prepublished online as
© 2006 by The American Society of Hematology
BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
Materials and methods
Details of the Study of Myocardial Infarctions Leiden (SMILE) have been
described elsewhere.18 Briefly, patients were men younger than age 70 with
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
4045
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4046
BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
DOGGEN et al
a first myocardial infarction that occurred between January 1990 and
January 1996. The control group also consisted of men without a history of
myocardial infarction and was frequency matched on age to the patients.
Both patients and control subjects were born in the Netherlands. They
completed a questionnaire and an interview took place prior to blood draw
(see next paragraph). Questions referred to (former) smoking habits and
alcohol use, diabetes, and current use of medications. In addition, for
patients, diabetes and medication use prior to myocardial infarction was
retrieved from discharge letters. A person was classified as having
hypertension or hypercholesterolemia if he was taking prescription drugs
for these conditions. Blood pressure was measured after a rest of at least 10
minutes with the person sitting in an upright position. The quetelet index
was derived by dividing weight (in kilograms) by squared height (in
meters), and obesity was defined as an index of 30 kg/m2 or above. All
participants gave informed consent, and the study protocol was approved by
the Institutional Review Board of the Leiden University Medical Center.
Fasting blood samples were drawn from the antecubital vein in Sarstedt
Monovette tubes (Sarstedt, Nümbrecht, Germany) and obtained between
July 1994 and February 1997. Blood in the first tube was allowed to clot,
and the serum was used for measuring total cholesterol, high-density
lipoprotein (HDL)–cholesterol, and triglyceride levels. Total cholesterol
and triglyceride concentrations were measured using enzymatic assays
adapted to a Hitachi 747 (Boehringer Mannheim, Mannheim, Germany),
and HDL-cholesterol concentration was measured on a Hitachi 911
(Boehringer Mannheim). Blood taken in 0.109 mol/L trisodium citrate was
centrifuged for 10 minutes at 3000g at room temperature. The citrated
plasma was divided into aliquots in multiple tubes and immediately stored
at ⫺80°C. Factor XI activity (XIc), factor XII activity (XIIc), and factor IX
activity (IXc) were measured in one-stage coagulation assays on a Behring
Coagulation System (Dade Behring, Marburg, Germany) with protocols
and reagents from the manufacturer. The factor XI and XII coagulant assays
were standardized using commercial plasma (Standard Human Plasma from
Dade Behring). The assigned values of the manufacturer were used,
because at the time of analysis an international standard for either factor
was not available. The factor IX coagulant assay was standardized with
pooled plasma from more than 150 healthy hospital workers that was
calibrated with 2 international standards (NIBSC 99/826 and NIBSC
01/618). Intra-assay variations for the coagulation assays were 6%, 6%, and
5% for factor XIc, XIIc, and IXc, respectively. In 6 patients and 6 control
subjects factor IXc was not measured. For the analyses on factor IX levels,
persons using oral anticoagulation medication were excluded (134 patients). Factor VIII (VIIIc) was measured in 2 dilutions by a one-stage
clotting assay with factor VIII-deficient plasma and automated activated
partial thromboplastin time (Organon Teknika, Boxtel, The Netherlands) on
a STA (Diagnostic Stago; Boehringer Mannheim). Levels are expressed as
IU/dL. Pooled normal plasma, calibrated against the WHO standard factor
VIIIc (91/666) was used as a reference. In one control subject factor VIIIc
was not measured. The median time between myocardial infarction and
blood collection was 2.6 years, with a minimum of 6 months. To evaluate
whether coagulation factors decreased after myocardial infarction in our
study, we stratified the elapsed time since myocardial infarction into 1-year
categories. Elapsed time since myocardial infarction did not relate to any
coagulation factor (data not shown).
Means were calculated with standard deviations (SDs) and the appropriate 95% confidence intervals (CIs). Differences between mean values were
tested by means of analysis of variance (ANOVA). Quintiles of coagulation
factors were defined on the basis of the distribution among control subjects.
The lowest quintile was used as a reference category for calculating odds
ratios (ORs). Odds ratios were calculated as an approximation of relative
risks. Unconditional logistic regression was used to adjust for age (ORadj)
and other cardiovascular risk factors. The 95% confidence intervals (95%
CIs) of odds ratios were calculated based on the standard errors from the
logistic model. Quintiles of total cholesterol, HDL-cholesterol, and triglyceride levels were also defined on the basis of the distribution among control
subjects. However, in the logistic regression model the 3 lipid levels were
included as continuous variables. Triglyceride levels used in the model
were 10log-transformed. SPSS for Windows version 12.0.1 (SPSS, Chicago, IL) was used for all statistical analyses.
Results
Detailed characteristics of patients and control subjects have been
described before.18 The mean age of patients was 56.2 years (SD,
9.0 years) and of control subjects 57.3 years (SD, 10.8 years). Risk
factors as smoking, obesity, diabetes, hypertension, and hypercholesterolemia were more often found in patients than in control
subjects, with the most striking contrasts in younger persons (Table 1).
Mean factor XIc among patients with myocardial infarction was
113.0% (CI, 111.5%-114.4%) and varied between 55% and 160%.
For control subjects mean factor XIc was 109.8% (CI, 108.2%111.3%), with a corresponding range between 56% and 194%.
Factor XIc in patients was 3.2% (CI, 1.1%-5.4%) higher compared
with control subjects. A 10% increase in factor XIc was associated
with a 1.09-fold increased in risk of myocardial infarction (ORadj,
1.09; 95% CI, 1.02-1.15). The distribution of patients and control
subjects by quintiles of factor XIc is shown in Table 2. The risk of
myocardial infarction was increased for each quintile of factor XI
compared with the lowest quintile (levels equal or below 94%). In
other words, the risk was decreased for men in the lowest quintile
compared with those with higher levels. The risk of myocardial
infarction adjusted for age for men in the highest quintile compared
with those in the lowest quintile was 1.8-fold increased (ORadj,
1.8; 95% CI, 1.2-2.7). For men younger than age 50 even higher
risks were found, 3- to 4-fold increased compared with the lowest
quintile. Further adjustment for cardiovascular risk factors and
factor XIIc increased the odds ratios. Excluding persons who were
using aspirin at time of blood draw (128 patients and 36 control
subjects) in our overall analyses did not materially change the
results, the difference in factor XIc between patients and control
subjects remained the same (3.2% [CI, 0.9%-5.5%]). Excluding
134 patients who were using anticoagulants at the time of blood
draw increased the difference between patients and control subjects
to 5.6% (CI, 3.2%-7.9%). Consequently, the relative risk of
myocardial infarction became even more pronounced for each
quintile increase of factor XI compared with the lowest quintile and
showed a dose-response relationship.
Mean factor XIIc among patients with myocardial infarction
was lower than in control subjects, respectively, 93.0% (CI,
91.3%-94.6%) and 98.6% (CI, 97.0%-100.2%), with a difference
of 5.6% (CI, 3.3%-7.9%). The range among patients varied from
23% to 139%, whereas the range among control subjects varied
from 37% to 164%. A 10% increase in factor XIIc was associated
with a 0.87-fold decreased risk of myocardial infarction (ORadj,
0.87; 95% CI, 0.82-0.92). The risk of myocardial infarction was
decreased for men with factor XIIc levels in the upper 2 quintiles
each with levels above 107% (Table 2). The odds ratio of
myocardial infarction for men in the highest quintile versus those in
the lowest quintile was 0.4 (ORadj, 0.4; 95% CI, 0.2-0.5). Among
men younger than age 50 the risk seemed to be decreased only in
those with factor XIIc of 119% or more (ORadj, 0.7; 95% CI,
0.4-1.5). Further adjustment for cardiovascular risk factors and
factor XIc slightly changed the odds ratios. Excluding persons who
were using aspirin at the time of blood draw in our overall analyses
did not materially change the results, the difference in factor XIc
between patients and control subjects remained the same (5.5 [CI,
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BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
INTRINSIC COAGULATION AND MYOCARDIAL INFARCTION
4047
Table 1. Characteristics of patients and control subjects
Overall
Characteristic
Patients
N
Mean age, y (SD)
Younger than 50 y
Control subjects
Patients
560
646
154
56.2 (9.0)
57.3 (10.8)
44.4 (4.2)
Control subjects
160
42.5 (6.9)
Smoking tobacco use, no. (%)
No
211 (37.7)
431 (67.7)
35 (22.7)
94 (58.8)
Yes
349 (62.3)
215 (33.3)*
119 (77.3)
66 (41.3)*
Alcohol use, no. (%)
Never
86 (15.4)
64 (9.9)
13 (8.4)
Occasionally
24 (4.3)
21 (3.3)
4 (2.6)
5 (3.1)
450 (80.4)
561 (86.6)*
137 (89.0)
140 (87.5)
Regularly
15 (9.4)
Quetelet index,† no. (%)
Less than 20 kg/m2
5 (0.9)
10 (1.6)
3 (1.9)
4 (2.5)
Between 20 and 25 kg/m2
153 (27.4)
186 (28.8)
37 (24.0)
57 (35.6)
Between 25 and 30 kg/m2
305 (54.6)
343 (53.2)
80 (51.9)
78 (48.8)
96 (17.2)
106 (16.4)
34 (22.1)
21 (13.1)*
Absent
534 (95.4)
624 (96.6)
147 (95.5)
157 (98.1)
Present
26 (4.6)
22 (3.4)
7 (4.5)
3 (1.9)
At least 30 kg/m2
Diabetes, no. (%)
Hypertension, no. (%)
Absent
454 (81.1)
539 (83.4)
143 (92.9)
153 (95.6)
Present
106 (18.9)
107 (16.6)
11 (7.1)
7 (4.4)
Absent
548 (97.9)
635 (98.3)
151 (98.1)
159 (99.4)
Present
12 (2.1)
11 (1.7)
3 (1.9)
1 (0.6)
Hypercholesterolemia, no. (%)
Data for patients refer to the period prior to myocardial infarction, apart from quetelet index.
*Chi-square test; P ⬍ .05.
†For 1 patient and 1 control subject, quetelet index was missing.
Table 2. Risk of myocardial infarction with increasing quintile of factor XIc and factor XIIc overall and in men younger than age 50
Patients
Control subjects
560
646
OR (95% CI)*
OR (95% CI)†
OR (95% CI)‡
Factor XIc
Overall, N
55%-94%
69
133
1§
1§
1§
95%-103%
117
136
1.7 (1.1-2.4)
1.9 (1.3-2.7)
2.0 (1.0-3.8)
104%-112%
117
121
1.8 (1.2-2.7)
2.2 (1.5-3.4)
2.7 (1.4-5.3)
113%-126%
132
128
2.0 (1.3-2.9)
2.9 (1.9-4.4)
2.7 (1.4-5.3)
127%-194%
125
128
1.8 (1.2-2.7)
3.2 (2.1-4.9)
2.5 (1.2-5.1)
154
160
55%-94%
9
34
1§
1§
1§
95%-103%
31
31
3.4 (1.4-8.4)
4.2 (1.7-10.7)
12.7 (1.4-113.6)
104%-112%
39
31
4.1 (1.7-9.9)
5.5 (2.1-14.0)
19.5 (2.1-178.0)
113%-126%
30
29
3.3 (1.3-8.3)
4.4 (1.7-11.5)
14.8 (1.6-136.1)
127%-194%
45
35
4.4 (1.9-10.5)
6.6 (2.5-17.3)
19.0 (2.0-182.0)
560
646
Younger than 50 y, no.
Factor XIIc
Overall, N
23%-79%
144
132
1§
1§
1§
80%-95%
133
132
0.9 (0.6-1.3)
0.8 (0.5-1.1)
1.0 (0.6-1.8)
96%-106%
132
122
1.0 (0.7-1.4)
0.8 (0.5-1.1)
1.0 (0.6-1.7)
107%-118%
95
131
0.6 (0.4-0.9)
0.5 (0.3-0.7)
0.7 (0.4-1.3)
119%-164%
56
129
0.4 (0.2-0.5)
0.2 (0.1-0.4)
0.3 (0.1-0.6)
154
160
Younger than 50 y, no.
23%-79%
29
32
1§
1§
1§
80%-95%
38
33
1.2 (0.6-2.4)
1.1 (0.5-2.3)
0.7 (0.2-2.0)
96%-106%
33
28
1.3 (0.6-2.8)
1.1 (0.5-2.3)
0.9 (0.3-2.7)
107%-118%
30
31
1.1 (0.5-2.2)
0.8 (0.4-1.7)
1.0 (0.4-2.7)
119%-164%
24
36
0.7 (0.4-1.5)
0.4 (0.2-1.0)
0.3 (0.1-1.0)
*Adjusted for age.
†Adjusted for age and either factor XIIc or factor XIc, each as continuous factor.
‡Adjusted for age, either factor XIIc or factor XIc each as a continuous factor; total cholesterol, HDL-cholesterol, and triglyceride levels; quetelet index; smoking; alcohol
use; and diabetes, excluding persons having hypertension.
§Reference group.
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4048
BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
DOGGEN et al
Table 3. Risk of myocardial infarction with increasing quintile of factor VIIIc overall and factor IXc
Patients
Control subjects
560
645
OR (95% CI)*
OR (95% CI)†
OR (95% CI)‡
Factor VIIIc
Overall, N
50-93 IU/dL
86
137
1㛳
1㛳
1㛳
94-110 IU/dL
102
122
1.4 (0.9-2.0)
1.4 (0.9-2.1)
2.1 (1.1-3.9)
1.8 (1.0-3.5)
111-130 IU/dL
137
134
1.7 (1.2-2.4)
1.9 (1.3-2.9)
131-152 IU/dL
134
125
1.8 (1.3-2.7)
2.4 (1.6-3.6)
2.6 (1.3-5.0)
153-277 IU/dL
101
127
1.4 (0.9-2.0)
1.5 (1.0-2.4)
1.6 (0.8-3.4)
Younger than 50 y, no.
154
160
50-93 IU/dL
39
50
1㛳
1㛳
1㛳
94-110 IU/dL
37
29
1.7 (0.9-3.3)
1.6 (0.8-3.3)
1.7 (0.6-4.5)
111-130 IU/dL
33
42
1.1 (0.6-2.0)
1.1 (0.5-2.0)
0.8 (0.3-2.2)
131-152 IU/dL
26
19
1.8 (0.9-3.8)
1.9 (0.9-4.1)
2.1 (0.7-6.4)
153-277 IU/dL
19
20
1.2 (0.6-2.6)
1.0 (0.4-2.2)
0.8 (0.2-3.0)
Factor IXc§
Overall, N
420
640
12%-82%
40
130
1㛳
1㛳
1㛳
83%-91%
91
143
2.5 (1.6-3.9)
2.5 (1.6-3.9)
2.7 (1.4-5.3)
92%-97%
93
122
3.0 (1.9-4.8)
3.0 (1.9-4.9)
3.0 (1.5-6.2)
98%-104%
105
134
3.1 (2.0-4.9)
3.2 (2.0-5.1)
3.7 (1.8-7.8)
105%-135%
91
111
3.2 (2.0-5.1)
3.3 (2.0-5.4)
2.9 (1.3-6.8)
119
158
12%-82%
17
69
1㛳
1㛳
1㛳
83%-91%
22
32
2.6 (1.2-5.6)
2.6 (1.2-5.6)
2.0 (0.6-6.1)
92%-97%
26
23
4.1 (1.9-9.0)
4.8 (2.1-10.9)
5.5 (1.7-17.5)
98%-104%
32
17
7.0 (3.2-15.6)
9.2 (3.9-21.8)
9.5 (2.7-33.2)
105%-135%
22
17
5.0 (2.2-11.4)
6.2 (2.6-14.9)
3.1 (0.7-13.5)
Younger than 50 y, no.
*Adjusted for age.
†Adjusted for age and either factor IX (excluding anticoagulant users) or factor VIIIc, each as a continuous factor.
‡Adjusted for age, either factor IX (excluding anticoagulant users) or factor VIIIc each as a continuous factor; total cholesterol, HDL-cholesterol, and triglyceride levels;
quetelet index; smoking; alcohol use; and diabetes, excluding individuals having hypertension.
§Excludes anticoagulant users.
㛳Reference group.
3.0-8.1]). However, excluding anticoagulant users in our overall
analyses decreased the difference in factor XIIc between patients
and control subjects to 3.5% (CI 0.9%-6.0%). Persons with factor
XIIc in the highest quintile remained at a decreased risk of
myocardial infarction (ORadj, 0.5; 95% CI, 0.4-0.8).
Mean factor VIIIc among patients with myocardial infarction
was 126.3 IU/dL (CI, 123.6-129.1 IU/dL) and varied between 51
and 277 IU/dL. For control subjects mean factor VIIIc was 123.4
IU/dL (CI, 120.8-126.0 IU/dL), with a corresponding range between 53 and 273 IU/dL. Factor VIIIc in patients was 2.9 IU/dL
(CI, ⫺0.9 to 6.7 IU/dL) higher compared with control subjects. The
distribution of patients and control subjects by quintiles of factor
VIIIc is shown in Table 3. The risk of myocardial infarction
appeared to be increased for most quintiles compared with the
lowest quintile, and overall increased slightly after adjustment for
cardiovascular risk factors and factor IXc. Mean factor IXc among
patients with myocardial infarction was higher than in control
subjects, respectively, 96.6% (CI, 95.5%-97.7%) and 93.2% (CI,
92.2%-94.2%), with a difference of 3.4% (CI, 1.9%-4.9%). The
range among patients varied from 35% to 135%, whereas the range
among control subjects varied from 32% to 134%. The risk of
myocardial infarction was increased for men in each quintile
compared with the lowest quintile, and even more increased for
men younger than age 50 (Table 3). Overall, adjustment for
cardiovascular risk factors and factor VIIIc slightly changed the
odds ratios.
In control subjects no associations were found between
factor XIc and smoking, alcohol use, or diabetes (Table 4).
Obese persons with a quetelet index of 30 kg/m2 or above had
higher levels of factor XIc compared with lean persons with a
quetelet index below 20 kg/m2. No associations were found
between factor XIIc and any of these cardiovascular risk factors.
Systolic and diastolic blood pressures were not associated with
factor XIc or factor XIIc. Hypertension as determined by
medication use was not associated with clotting factor levels;
the difference in factor XIc between 107 men with hypertension
versus 539 without hypertension was ⫺2.2% (CI, ⫺6.4% to
1.9%) and in factor XIIc ⫺1.9% (CI, ⫺6.4% to 2.5%). Factor
XIc was associated with total cholesterol levels and with
triglyceride levels in control subjects (Table 5). Factor XIc
increased with every increase in quintile of total cholesterol and
triglyceride level. No associations were found with HDLcholesterol levels. Similar results were found for factor XIIc.
Hypercholesterolemia as determined by medication use was not
associated with levels; the difference in factor XIc between 11
men with hypercholesterolemia versus 635 men without hypercholesterolemia was 0.2% (CI, ⫺11.7% to 12.2%) and in factor
XIIc 8.2% (CI, ⫺4.6% to 20.9%).
Among control subjects factor XIc was associated with
factor XIIc with every 1% increase in factor XIIc factor XIc
increased with 0.4% (95% CI, 0.3%-0.5%). To disentangle the
effect of factor XIIc from factor XIc, we looked at the effect of
each factor adjusted for the other. Because univariate effects
were opposite, and levels were associated in the same direction,
adjustment led to higher risk estimates, that is, 3-fold increased
risk (OR, 3.2; 95% CI, 2.1-4.9) for the highest quintile of factor
XI, and 80% reduced risk (OR, 0.2; 95% CI, 0.1-0.4) for the
highest quintile of factor XII (Table 2). Further adjustment for
total cholesterol, HDL-cholesterol, and triglyceride levels and
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BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
INTRINSIC COAGULATION AND MYOCARDIAL INFARCTION
4049
Table 4. Cardiovascular risk factors among control subjects and the association with factor XIc and factor XIIc
Risk factor
No. of subjects
Mean factor XIc, % (CI)
P*
Mean factor XIIc, % (CI)
P*
Smoking tobacco use
Never
117
107.0 (103.7-110.3)
98.4 (94.5-102.3)
Former
314
110.2 (107.9-112.5)
99.6 (97.2-101.9)
Current
215
110.6 (107.9-113.3)
.25
97.3 (94.4-100.3)
.5
Alcohol use
Never
64
106.1 (100.6-111.4)
98.3 (93.1-103.4)
Occasionally
21
109.0 (103.1-114.9)
96.2 (86.9-105.5)
561
110.0 (108.3-111.6)
Regularly
.65
98.7 (96.9-100.5)
.9
Quetelet index†
Less than 20 kg/m2
10
106.7 (92.0-121.4)
97.8 (86.0-109.6)
Between 20 and 25 kg/m2
186
104.0 (101.5-106.5)
96.3 (93.1-99.4)
Between 25 and 30 kg/m2
343
111.4 (109.3-113.6)
At least 30 kg/m2
106
114.3 (110.2-118.4)
Absent
624
109.7 (108.1-111.3)
Present
22
111.0 (101.1-120.8)
99.0 (96.7-101.3)
⬍ .001
101.2 (97.4-105.0)
.3
Diabetes
98.7 (97.0-100.3)
.78
96.6 (86.9-106.2)
.6
*P value of ANOVA.
†For 1 control subject quetelet index was missing.
quetelet index did not much affect the odds ratios, neither did
adjustment for factor IXc or factor VIIIc.
Tertiles were calculated based on the distribution among control
subjects. Overall, men in the highest tertile of factor XIc had a 1.5-fold
increased risk of myocardial infarction compared with men in the lowest
tertile (ORadj, 1.5; 95% CI, 1.1-2.0). In contrast, men in the highest
tertile of factor XIIc had a 60% decreased risk (ORadj, 0.4; 95% CI,
0.3-0.6) compared with those in the lowest tertile. The highest risk of
myocardial infarction was found among men in the highest tertile of
factor XIc and the lowest tertile of factor XIIc (ORadj, 6.4; 95% CI,
2.2-18.0) compared with men with the lowest factor XIc and highest
factor XIIc tertiles (Table 6). Further adjustment for cardiovascular risk
factors increased the odds ratios.
Discussion
Although positively associated, levels of factors XIc and XIIc had
opposite and synergistic effects on the risk of myocardial infarction. Higher factor XIc increased the risk, whereas higher factor
XIIc decreased the risk (ie, low factor XIIc increased the risk of
myocardial infarction). Additionally, factor VIIIc and factor IXc
increase the risk of myocardial infarction in men.
In our Study of Myocardial Infarctions Leiden (SMILE) high
factor XIc increased the risk of myocardial infarction, which is
in accordance with a Swiss case-control study that included 200
patients with a history of myocardial infarction.10 Factor XIc has
Table 5. Factor XIc and factor XIIc by quintile of total cholesterol, HDL cholesterol, and triglyceride levels among control subjects
No. of
subjects
Mean factor XIc, % (CI)
Less than 5.02
128
102.1 (99.0-105.1)
91.6 (88.2-95.0)
5.02-5.57
129
107.3 (104.1-110.5)
98.5 (95.1-102.0)
5.58-6.08
129
108.3 (104.9-111.6)
96.4 (92.6-100.2)
6.09-6.79
128
112.1 (108.6-115.8)
101.1 (97.3-104.9)
At least 6.80
131
118.6 (115.0-122.2)
105.0 (101.3-108.8)
⬍ .001
⬍ .001
Mean Factor XIIc, % (CI)
Total cholesterol level,* mM
P†
HDL cholesterol level,‡ mM
Less than 1.06
128
106.8 (103.3-110.3)
94.7 (91.0-98.4)
1.06-1.22
128
111.9 (108.0-115.7)
97.8 (94.3-101.4)
1.23-1.38
130
109.6 (106.2-113.0)
99.1 (95.5-102.7)
1.39-1.61
129
111.8 (108.7-115.0)
102.3 (98.5-106.2)
At least 1.62
128
108.6 (105.0-112.2)
98.9 (95.0-102.7)
.20
.08
P†
Triglyceride level,§ mM
Less than 0.83
125
105.9 (102.6-109.3)
96.1 (92.5-99.6)
0.83-1.09
131
106.4 (102.9-109.9)
95.3 (91.5-99.1)
1.10-1.41
131
109.4 (106.1-112.8)
98.0 (94.2-101.7)
1.42-2.03
128
111.3 (107.9-114.7)
101.3 (97.7-105.0)
At least 2.04
130
115.5 (111.8-119.1)
102.2 (98.3-105.8)
⬍ .001
.03
P†
*Cholesterol levels were missing for 1 control subject.
†P value of ANOVA comparing factor XIc or factor XIIc by quintiles of each lipid.
‡HDL-cholesterol levels were missing for 3 control subjects.
§Triglyceride levels were missing for 1 control subject.
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4050
BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
DOGGEN et al
Table 6. Combined risk of myocardial infarction by tertiles of factor XIc and factor XIIc
FXIc/FXIIc
Patients
Control subjects
OR (95% CI)*
OR (95% CI)†
FXIc less than 100%
FXIIc more than 109%
5
26
1‡
1‡
FXIIc 91%–109%
44
72
3.3 (1.2-9.3)
4.5 (0.5-38.9)
FXIIc less than 91%
82
110
4.1 (1.5-11.1)
7.4 (0.9-61.4)
FXIIc more than 109%
28
76
1.9 (0.7-5.4)
2.5 (0.3-22.5)
FXIIc 91%–109%
84
85
5.3 (1.9-14.6)
15.0 (1.8-122.0)
114
62
9.9 (3.6-27.2)
17.6 (2.1-145.0)
7.4 (0.9-60.5)
FXIc 100%-116%
FXIIc less than 91%
FXIc more than 116%
FXIIc more than 109%
80
111
3.7 (1.4-10.1)
FXIIc 91%–109%
69
59
6.1 (2.2-17.0)
5.6 (0.6-47.9)
FXIIc less than 91%
54
45
6.4 (2.2-18.0)
11.6 (1.4-98.5)
For patients, N ⫽ 560; for control subjects, N ⫽ 646.
*Adjusted for age.
†Adjusted for age, total cholesterol, HDL-cholesterol, and triglyceride levels; quetelet index; smoking; alcohol use; and diabetes, excluding persons having hypertension.
‡Reference group.
procoagulant and antifibrinolytic effects; thus, an increased risk
of myocardial infarction in the presence of high factor XIc was
to be expected and is in line with studies on venous thrombosis.11 However, the results of a recently published case-control
study that included young women did not find a difference in
level between 200 women with a first myocardial infarction and
control subjects.19
High factor XIIc decreased the risk of myocardial infarction in our
study. In the second Northwick Park Heart Study among 1153 men aged
50 to 61 years in which only 104 coronary heart disease events occurred
during the 7.8 years of follow-up, plasma factor XIIa was an independent
risk factor. Men in the upper third had a higher risk compared with those in
the middle tertile, but also those in the lower third seemed to have a higher
risk.20 In a second analysis that included 1745 men high incidence rates
were only found for those with high factor XIIa, with similar rates in the
first and second third.21 In contrast, in the West of Scotland Coronary
Prevention Study factor XIIa antigen did not predict the risk of a coronary
event,22 neither did factor XIIc and antigen in other smaller studies.10,23
Our results could also be interpreted such that low factor XIIc increased
the risk of myocardial infarction, which is in correspondence to the lower
levels found in patients with venous thrombosis compared with healthy
blood donors,13 although some studies had different results.14
Factor VIIIc increased the risk of myocardial infarction about
1.4-fold or more, although not dose dependently. In the Risk of Arterial
Thrombosis In relation with Oral Contraceptive use (RATIO) study, in
which factor VIIIc was measured in the exact same way, the risk was
more clearly increased among young women. In that particular study the
risk decreased after adjustment for von Willebrand factor (VWF).19
Follow-up studies have also found associations between factor VIII and
ischemic heart disease in men24-26 and a risk which reduced after
adjustment for VWF.26 Factor IXc increased the risk of myocardial
infarction, even more strongly among young men. This finding is in line
with the results of the RATIO study among young women.19
The risk of myocardial infarction was highest for men with both high
factor XIc and low XIIc. This would suggest that the effect of factor XII
on risk is not by activation of factor XI, but by an alternative mechanism.
Previous studies have suggested that plasma levels of factor XIIa are
related to plasma levels of cholesterol and triglyceride,23,27,28 but not
HDL cholesterol.22 The present study corroborates these findings.
However, we did not find any associations among factor XIIc and
obesity, smoking, alcohol use, diabetes, or blood pressure, which is in
contrast to a study among 2464 men aged 51 to 62 years in which
positive associations were found between factor XIIa with body mass
index, smoking, and blood pressure.27 Even though associations be-
tween factor XIIc and lipid levels clearly exist, the effect of factor XIIc
on the risk of myocardial infarction remained present for men in the
highest quintiles after adjusting for lipid levels and other cardiovascular
risk factors, indicating that factor XIIc itself seems to have an effect on
myocardial infarction.
Our results are in line with the current concept of coagulation
and that in contrast to factor XI, factor XII is not involved in
physiologic thrombin and fibrin formation. Patients deficient for
factor XII do not bleed, and, although factor XII is essential for
contact activation and the activated partial thromboplastin time, it
has been assumed that factor XII does not contribute to clot
formation. In contrast, factor XI is involved in normal thrombin
and fibrin formation, and elevated levels of factor XI have
previously been found to be associated with an increased risk of
venous thrombosis.11 Also, factor XI-deficient mice were protected
in models of arterial thrombosis.8
However, a recent report showed that factor XII–deficient
mice were protected in a model of lethal pulmonary embolism
and had a defective arterial thrombosis formation, suggesting
that factor XII also contributes to thrombin and fibrin formation.29 These results are in contradiction with our epidemiologic
findings, in which we found an increased risk of myocardial
infarction with low factor XIIc. One of the explanations might
be that humans have evolved to a different mechanism of
coagulation than mice. The presence of atherosclerosis plays an
important role in the occurrence of myocardial infarction in
humans, whereas vessels of the mice used in the models clearly
differ in this aspect. An alternative explanation is that the
potential functions of factor XII only become apparent at certain
concentrations of factor XII. In our epidemiologic study, the
concentration of factor XIIc in the subjects was not below 23%.
In the mouse study, only homozygote-deficient mice were
protected against arterial thrombosis. The heterozygote mice
showed similar results compared with mice containing normal
levels of factor XII, with nearly all vessels containing thrombi, a
slightly lower time to occlusion and slightly more platelets per
surface area.29 Because the used models were not designed or
sensitive for enhanced thrombus formation, it can therefore not
be excluded that heterozygote mice had enhanced thrombus
formation. Taken together and on the basis of our findings, we
can then speculate that lower levels of factor XII result in
enhanced thrombus formation by decreased fibrinolysis or
effects on inflammation and complement activation.30,31
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BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
By necessity we studied patients who survived the myocardial
infarction. It cannot be excluded that patients who died during the
acute phase of the myocardial infarction had higher or lower
coagulation levels. We think this is unlikely, however, because
survival of a person after myocardial infarction is influenced by
other factors, such as patient-induced delay and delay in providing
effective assistance, which affect the timeframe from onset of
symptoms to the start of interventions such as thrombolytic
therapy.32 Several other factors influencing 30-day mortality are the
level of systolic blood pressure, heart rate, Killip class, and
localization of myocardial infarction.33 It does not seem likely that
these 4 coagulation factors would play a role in this.
In conclusion, our results show that factors XIc and XIIc have
an opposite and synergistic effect on the risk of myocardial
infarction. If factor XIIc may be a new target for antithrombotic
therapies as suggested before29 remains to be established. Both
factor VIIIc and factor IXc increase the risk of myocardial
infarction among men.
Acknowledgments
We thank Dr T. Renné, University of Würzburg, Germany, for
sharing his data on the factor XII–deficient mice before
publication. We thank the cardiologists of the departments of
cardiology, Leiden University Medical Center; the general
hospital Diaconessenhuis Leiden and F. J. M. van der Meer,
INTRINSIC COAGULATION AND MYOCARDIAL INFARCTION
4051
head of the Leiden Anticoagulant Clinic, for their kind cooperation; and J. H. M. Souverijn for his assistance with the lipid
measurements. We thank T. Visser for drawing blood samples
and the personnel of the Department of Experimental Vascular
Medicine of the Academic Medical Center for performing the
laboratory measurements. We thank J. J. Schreijer and I. de
Jonge for their secretarial and administrative support. We also
express our gratitude to all individuals who participated in the
Study of Myocardial Infarctions Leiden.
This work was supported by the Netherlands Heart Foundation
(grant no. 92.345).
Authorship
Contribution: C.J.M.D. designed the overall study, performed the
data collection and statistical analyses, and drafted the manuscript;
J.C.M.M. designed the present study and was responsible for
execution of the assays and participated in the writing of the
manuscript; and F.R.R. designed the overall study and critically
reviewed the analyses and the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Carine J. M. Doggen, Department of Clinical
Epidemiology, Leiden University Medical Center, PO Box 9600,
2300 RC Leiden, The Netherlands; e-mail: [email protected].
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2006 108: 4045-4051
doi:10.1182/blood-2005-12-023697 originally published
online August 24, 2006
Levels of intrinsic coagulation factors and the risk of myocardial
infarction among men: opposite and synergistic effects of factors XI and
XII
Carine J. M. Doggen, Frits R. Rosendaal and Joost C. M. Meijers
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