Activation of Clotting Factors XI and IX in Patients With
Acute Myocardial Infarction
M.C. Minnema, R.J.G. Peters, R. de Winter, Y.P.T. Lubbers, S. Barzegar, K.A. Bauer,
R.D. Rosenberg, C.E. Hack, H. ten Cate
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Abstract—In acute coronary events, plaque rupture and the subsequent formation of the catalytic tissue factor–factor VIIa
complex is considered to initiate coagulation. It is unknown whether clotting factors XI and IX are activated in acute coronary
events. Therefore, we prospectively investigated the activation of clotting factors XI and IX as well as activation of the contact
system and the common pathway in 50 patients with acute myocardial infarction (AMI), in 50 patients with unstable angina
pectoris (UAP), and in 50 patients with stable angina pectoris (SAP). Factor XIa–C1 inhibitor complexes, which reflect acute
activation of factor XI, were detected in 24% of the patients with AMI, 8% of the patients with UAP, and 4% of the patients
with SAP (P⬍0.05), whereas factor XIa–␣1-antitrypsin complexes, which reflect chronic activation, were observed equally
in all 3 study groups. Factor IX peptide levels were significantly higher in the patients with AMI and UAP compared with
the patients with SAP (P⬍0.01). No differences regarding markers of the common pathway were demonstrated.
Fibrinopeptide A levels were elevated in patients with AMI compared with patients with UAP and those with SAP (P⬍0.01).
Factor XIIa– or kallikrein–C1 inhibitor complexes were not increased. In conclusion, this is the first demonstration of the
activation of clotting factors XI and IX in patients with acute coronary syndromes. Because these clotting factors are
considered to be important for continuous thrombin generation and clot stability, their activation might have clinical and
therapeutic consequences. (Arterioscler Thromb Vasc Biol. 2000;20:2489-2493.)
Key Words: coagulation 䡲 thrombosis 䡲 myocardial infarction 䡲 cardiovascular disease
T
XII–independent activation of factor XI. Thrombindependent activation of factor XI constitutes an amplification
pathway, because activation of factor XI leads, via the
activation of factors IX and X, to the formation of additional
thrombin.12 This additional thrombin may be important for
the activation of a carboxypeptidase B, called thrombinactivatable fibrinolysis inhibitor (TAFI), resulting in the
attenuation of fibrinolysis.13–15 Hence, thrombin-dependent
activation of factor XI may be a critical element in the onset
of acute coronary syndromes.
To study the role of factor XI in coronary vascular disease, we
used sensitive assays for detecting the activation of factor XI,
factor IX, and the contact system in patients with AMI or UAP
compared with patients with stable angina pectoris (SAP).
hrombus formation on a fissured coronary atherosclerotic plaque plays a fundamental role in the onset of
acute coronary events, such as unstable angina pectoris
(UAP) and acute myocardial infarction (AMI).1 In addition to
activated platelets, fibrin contributes significantly to thrombus formation, and reperfusion with fibrinolytic agents reduces the mortality associated with myocardial infarction.2
Fibrin formation is thought to be triggered by the formation
of tissue factor (TF)–factor VIIa complexes. TF is found in
the atherosclerotic plaque itself, and expression of TF after
plaque rupture facilitates the formation of the catalytic
TF–factor VIIa complex.3–5 On exposure to blood, this
complex activates clotting factors X and IX, leading to the
generation of thrombin and formation of fibrin.6
The role of the contact system is less defined in this
process. Although activation of the contact system, ie, factor
XII and prekallikrein, has been suggested to occur in acute
coronary syndromes, direct evidence (such as obtained by
specific activation markers) is lacking.7–9
In 1991, it was demonstrated that thrombin is capable of
activating factor XI in vitro,10,11 and this would imply a factor
Methods
Patients
Consecutive patients with characteristic chest pain within the last 12
hours before presentation at the emergency room were eligible for
the present study.
Received May 1, 2000; revision accepted June 26, 2000.
From the Department of Vascular Medicine (M.C.M., H.t.C.) and the Department of Cardiology (R.J.G.P., R.d.W.), Academic Medical Center,
Amsterdam, the Netherlands; the Central Laboratory of the Red Cross Blood Transfusion Service (M.C.M., Y.P.T.L., C.E.H.), Laboratory for Clinical
and Experimental Immunology, Amsterdam, the Netherlands; the Department of Veterans Affairs Medical Center (S.B., K.A.B.), West Roxbury, Mass;
Beth Israel Deaconess Medical Center (R.D.R.), Molecular Medicine Unit, Boston, and the Department of Biology (R.D.R.), MIT, Cambridge, Mass; and
the Department of Internal Medicine (H.t.C.), Slotervaart Hospital, Amsterdam, the Netherlands.
Presented in part at the XVII Congress of the International Society on Thrombosis and Haemostasis, Washington, DC, August 14 –18, 1999.
Correspondence to Monique C. Minnema, MD, Department of Vascular Medicine, F4-159.2, AMC, Meibergdreef 9, PO Box 22700, 1100 DE
Amsterdam, Netherlands. E-mail [email protected]
© 2000 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
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Arterioscler Thromb Vasc Biol.
November 2000
UAP was defined by the presence of at least 1 episode of ischemic
pain during rest (Braunwald IIIB classification, “primary” UAP),16
accompanied by diagnostic ST-segment shift or T-wave changes, but
without enzymatic evidence of AMI (creatine kinase-MB levels less
than twice the upper limit of normal). AMI was defined as the
combination of characteristic chest pain, ECG changes, and creatine
kinase-MB levels twice the upper limit of normal. Patients with
chronic SAP from the outpatient clinic, characterized by exerciseinduced ischemic chest pain or proven coronary artery disease on
angiogram, without changes in symptoms in the previous 3 months,
served as a control group.
Exclusion criteria were the use of heparin or fibrinolytic therapy
before blood sampling, thrombotic diseases, or surgery in the past 3
months or oral anticoagulant medication. Use of aspirin was not an
exclusion criterion.
The study was approved by the institutional review board of the
Academic Medical Center, and written informed consent was obtained from all patients.
Blood Sampling and Assays
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On admission, venous blood samples for the determination of
prothrombin fragment 1⫹2 (F1⫹2) were collected with minimal
stasis in sodium citrate (0.105 mol/L) Vacutainer tubes (Becton
Dickinson), and those for fibrinopeptide A (FPA) were collected in
siliconized Vacutainer tubes (Becton Dickinson) containing the
provided anticoagulant mixtures provided in the kits. Plasmas for the
factor XIa, factor XIIa, and kallikrein complex assays were collected
in siliconized Vacutainer tubes containing EDTA 0.34 mol/L (Becton Dickinson), to which a solution of Polybrene (0.05% [wt/vol]
final concentration, Janssen Chimica) and benzamidine (100 mmol/L
final concentration, Acros) was added. The factor IX and factor X
activation peptides were assessed from blood collected in siliconized
Vacutainer tubes containing the following anticoagulant: 38 mmol/L
citric acid, 75 mmol/L sodium citrate, 136 mmol/L dextrose,
6 mmol/L EDTA, 6 mmol/L adenosine, and 25 U/mL heparin.
Platelet-poor plasma was obtained by centrifuging at 1600g for 30
minutes at room temperature. Plasma samples were immediately
frozen on dry ice and stored at ⫺70°C until assayed.
Activation of factor XI in the samples was measured by assessing
levels of factor XIa–C1 inhibitor and factor XIa–␣1-antitrypsin
complexes as described.17 In these sandwich-type ELISAs, microtiter plates are coated with monoclonal antibody (mAb) XI-5, directed
against the heavy chain of factor XI. Complexes between factor XIa
and C1 inhibitor or ␣1-antitrypsin, present in the plasma samples to
be tested, are detected with mAbs against C1 inhibitor or ␣1antitrypsin, respectively. In the plasma of normal volunteers, levels
of these complexes are below the detection limit of 10 pmol/L for
these assays.
Complexes between factor XIIa and kallikrein with C1 inhibitor
were measured with ELISAs, which were modified from radioimmunoassays.18 In short, microtiter plates were coated with a mAb
against complexed C1 inhibitor and incubated with the samples to be
tested. Bound complexes were detected with biotinylated mAbs
against factor XII or kallikrein. These assays are specific and able to
detect 0.02% activation of the plasma concentration of the respective
zymogens. As an in-house standard, dextran sulfate–activated EDTA
plasma, which was calibrated against purified factor XIIa– or
kallikrein–C1 inhibitor complexes, was used. Normal values are ⬍60
pmol/L for factor XIIa–C1 inhibitor complexes and ⬍350 pmol/L for
kallikrein–C1 inhibitor complexes.
The factor IX and factor X peptide were assayed with doubleantibody radioimmunoassays as described.19,20 These assays measure the fragment that is liberated from factor IX and factor X during
activation. F1⫹2 fragment was measured by use of a commercially
available kit according to the manufacturer’s instructions (Enzygnost
F1⫹2, Behringwerke). FPA levels were measured with a doubleantibody radioimmunoassay (Byk-Santec).
Statistical Analysis
Patient characteristics are given as mean⫾SD; differences between
groups were analyzed by ␹2 tests. Results of the measured coagulation parameters are presented as median (range), and differences
between the individual study groups were analyzed by the Mann-
TABLE 1.
Patient Characteristics
AMI (n⫽50)
UAP (n⫽50)
SAP (n⫽50)
Age, y
63⫾13
63⫾12
64⫾11
Males, n (%)
36 (72)
29 (58)
32 (64)
UAP
2 (4)
10 (20)
8 (16)
AMI
10 (20)
18 (36)
33 (66)
2 (4)
11 (22)
20 (40)
Cholesterol, mmol/L
5.78⫾1.04
5.76⫾0.94
5.75⫾1.2
Family history, n (%)
19 (39)
26 (52)
23 (46)
6 (12)
7 (14)
7 (14)
Hypertension, n (%)
18 (37)
24 (48)
17 (34)
Smoking, n (%)
22 (44)
13 (26)
21 (42)
History of CAD, n (%)
CABG
Risk factors
Diabetes, n (%)
Medication, n (%)
Oral nitrates
9 (18)
17 (34)
15 (30)
Calcium antagonists
12 (24)
15 (30)
28 (56)
␤-Blockers
11 (22)
27 (54)
24 (48)
7 (14)
7 (14)
9 (18)
10 (20)
23 (46)
36 (72)
ACE inhibitors
Aspirin
Values are mean⫾SD or as indicated. CAD indicates coronary artery
disease; CABG, coronary artery bypass grafting; and ACE, angiotensinconverting enzyme.
Whitney U test. Factor IX and X peptides are also presented as
median (range) but were analyzed, after logarithmic transformation,
by the Student t test. Correlations between observations were
analyzed by the Spearman rank correlation test and are presented as
correlation coefficients (r values). A 2-sided value of P⬍0.05 was
considered statistically significant.
Results
Patients
In total, 50 patients with AMI and 50 patients with UAP were
included in the study. The control group consisted of 50
patients with SAP. Table 1 shows the clinical characteristics
of the patients. The groups were similar in age, sex, and risk
factors for atherosclerosis, such as family history, cholesterol
levels, diabetes, and hypertension. Smoking was more common in the SAP and AMI groups compared with the UAP
group (P⬍0.05). As can be expected, antianginal medication
on admission was different between the groups, as was prior
cardiology history, with a higher frequency of previous
myocardial infarction or coronary bypass surgery in patients
with SAP than in patients with UAP or AMI. The use of
aspirin was not an exclusion criteria because a direct effect of
aspirin on the levels of coagulation markers has not been
demonstrated (H. ten Cate, K.A. Bauer, R.D. Rosenberg,
unpublished data, 1989). By use of the Spearman rank
correlation test, no correlation between factor XIa–C1 inhibitor levels and aspirin use was found (r⫽0.06, P⫽NS).
There was no difference in time between the first symptoms of chest pain and time of admission (ie, collection of
blood samples) between the AMI and UAP group (295⫾233
minutes and 287⫾210 minutes, respectively; P⫽NS).
Activation of Factor XI
There were significantly more patients with elevated factor
XIa–C1 inhibitor complexes in the AMI group than in the
Minnema et al
Activation of Factors XI and IX in AMI
2491
and 1 patient in the SAP group. In each group, 24% to 30%
of the patients had one or both complexes elevated compared
with normal upper limits.
One patient with SAP had relatively high levels of factor
XIa–C1 inhibitor and factor XIa–␣1-antitrypsin complexes of
53.4 and 51.2 pmol/L, respectively, which was confirmed in
a second blood sample taken 3 months later. This was a
female patient (aged 48 years) who had experienced an AMI
3 years before, had 2-vessel disease on coronary angiogram,
and had smoking as a risk factor.
Activation of Factor IX
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The median levels of the factor IX peptide were 354.4 pmol/L
in the AMI group, 316.5 pmol/L in the UAP group, and 259.2
pmol/L in the SAP group (Table 2). Although the differences
in the AMI and UAP groups were not statistically different,
both groups had significantly higher levels of the activation
peptide factor IX compared with the levels in the SAP group
(P⬍0.01). No significant correlations with factor XIa–C1
inhibitor or factor XIa–␣1-antitrypsin complexes were
observed.
Activation of the Contact System
Factor XIa (FXIa)–C1 inhibitor (C1inh) and FXIa–␣1-antitrypsin
(␣1AT) complexes in patients with AMI, UAP, or SAP. In 50
patients with AMI and in 50 patients with UAP, who presented
at the emergency room, blood samples were collected before
any therapy was given. Fifty patients with SAP served as a control group. FXIa-inhibitor complexes were measured by ELISA.
Normal value of both assays is ⱕ10 pmol/L.
UAP (P⫽0.02) and SAP (P⫽0.006) groups (Figure). Twelve
patients in the AMI group (24%) had levels above the normal
value of 10 pmol/L for this assay. Five patients in the UAP
(10%) group and 2 patients in the SAP group also had
elevated levels of factor XIa–C1 inhibitor complexes
(P⫽NS).
The levels of factor XIa–␣1-antitrypsin complexes did not
differ between the study groups. Nine patients with AMI
(18%) had levels above the normal value of 10 pmol/L, which
was the case for 10 and 14 of the patients in the UAP and SAP
groups, respectively (Figure). Both complexes were elevated
for 6 patients in the AMI group, 2 patients in the UAP group,
In 3 patients with AMI and in 2 patients with UAP, factor
XIIa–C1 inhibitor complexes were above the normal value of
60 pmol/L. Factor XIIa–C1 inhibitor complex levels in these
patients were 61, 94, and 372 pmol/L for the 3 AMI patients
and 81 and 100 pmol/L for the 2 UAP patients. None of the
patients with SAP had detectable factor XIIa–C1 inhibitor
complexes (P⫽NS, results not shown).
Kallikrein–C1 inhibitor complexes were detectable in 2
patients with AMI (64 and 85 pmol/L), in 3 patients with
UAP (60, 70, and 90 pmol/L), and in 1 patient with SAP (68
pmol/L; P⫽NS, results not shown). Because the normal value
of these complexes is ⬍350 pmol/L, none of the patients had
elevated kallikrein–C1 inhibitor complexes.
Activation of the Common Pathway
The concentration of the factor X peptide was not different
between the 3 study groups; furthermore, no significant
difference was observed in the levels of F1⫹2 between the
groups (Table 2). In contrast, FPA levels differed significantly between patients with AMI and UAP (P⫽0.002) and
between patients with AMI and SAP (P⬍0.0001). The FPA
TABLE 2. Levels of Factor IX and X Peptides, F1ⴙ2, and FPA in Patients With
AMI, UAP, or SAP
AMI
UAP
SAP
Factor IX peptide, pmol/L
354.4 (136–886.8)
316.5 (135.7–924.9)
259.2 (102.8–597)
Factor X peptide, pmol/L
92 (42.5–219.2)
97.7 (45.6–262.9)
94.9 (56.7–213)
F1⫹2, nmol/L
1.2 (0.5–10)
1.1 (0.5–10)
1.3 (0.6–10)
11.8 (1.7–40)
6.2 (1.1–40)
3.8 (0.7–40)
FPA, ␮g/L
Values are median (range). Factor IX and IX peptide, F1⫹2, and FPA levels were measured as
described in Methods. Differences between groups were analyzed by Student t test (factor IX and X
peptide) or Mann-Whitney U test (F1⫹2 and FPA). Factor X peptide and F1⫹2 levels were not
significantly different; factor IX peptide levels were higher in the AMI and UAP groups compared with
the SAP group (P⬍0.01). FPA levels were significantly higher in the AMI group compared with the UAP
(P⫽0.002) and SAP (P⬍0.001) groups. Levels of FPA were also significantly different between UAP
and SAP groups (P⫽0.002).
2492
Arterioscler Thromb Vasc Biol.
November 2000
levels between patients with UAP and SAP were also
significantly different (P⫽0.002).
There was no significant correlation between the factor
XIa–C1 inhibitor or factor XIa–␣1-antitrypsin complexes and
F1⫹2, factor X peptide, or FPA levels. Factor X peptide and
F1⫹2 correlated with the factor IX peptide levels in all
groups, with r⫽0.63 (P⬍0.001) and r⫽0.35 (P⬍0.001),
respectively.
Discussion
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The development of coronary thrombosis in response to the
rupture of atherosclerotic plaques is the primary determinant
of the evolution of stable atherosclerotic disease to UAP and
AMI.21 The exposure of TF and subsequent activation of the
extrinsic pathway of coagulation leads to the generation of
thrombin and formation of fibrin. However, the extrinsic
pathway is rapidly inhibited by TF pathway inhibitor, and
continuation of thrombin formation is dependent on the
feedback activation by thrombin of the clotting factors V,
VIII, and (probably also) factor XI.6 We investigated whether
activation of factors XI and IX would be detectable in acute
coronary events.
Activated factor XI was measured as a complex with the
C1 inhibitor as its major inhibitor17 and was indeed detected
in 24% of the patients with AMI, which was significantly
greater than the percentage found in patients with UAP or
SAP. Thus, the formation of a coronary thrombus may be
reflected by relatively high levels of factor XI activation in
some patients, apparent as factor XIa–C1 inhibitor complexes. However, factor XIa–C1 inhibitor complexes were
not more elevated in patients with UAP compared with the
control group. This likely reflects the well-known clinical
variability of this syndrome, with (despite strict inclusion
criteria) difficulty in assessing the beginning of the “instability.” No difference in factor XIa–␣1-antitrypsin complexes
was demonstrated among the study groups. Factor XIa–␣1antitrypsin complexes are cleared at a much slower rate than
are factor XIa–C1 inhibitor complexes; thus, they are more
easily detectable.22 Complexes between factor XIa and its
dominant inhibitor (the C1 inhibitor) can only be measured
within hours after the initiation of clotting activation.22
Indeed, factor XIa–␣1-antitrypsin complexes have been demonstrated in patients 7 to 10 days after a myocardial infarction
and in patients with coronary artery disease.22,23 The lack of
difference in levels of factor XIa–␣1-antitrypsin complexes
between the study groups might be caused by the relationship
between the extent of coronary atherosclerosis and clotting
activity.23,24
The present study clearly demonstrates, for the first time,
the involvement of clotting factor IX in acute coronary
syndromes. Although a correlation between factor XI and
factor IX activation was not observed, it is likely that factor
XI generation contributed to factor IX conversion, as shown
in a study in primates.25 Moreover, discordant plasma halflife times between factor XIa–C1 inhibitor complexes and the
factor IX peptide22,26 and the activation of factor IX directly
via the TF–factor VIIa complex influence the plasma levels
of the factor IX peptide. Also, under experimental conditions,
such as the controlled administration of tumor necrosis factor
to normal subjects, temporal dissociation in the activation of
coagulation markers has been demonstrated.27
In the patients with SAP, the IX peptide levels were
slightly higher (geometric mean 267.7 pmol/L) compared
with levels found in another study in 654 men (geometric
mean 204.4 pmol/L) without a history of unstable angina
pectoris or myocardial infarction but with a high risk of fatal
coronary heart disease.28
In contrast to the enhanced factor XI and factor IX
activation in patients with acute coronary events, activation
markers of the common pathway of coagulation, ie, the factor
X peptide and F1⫹2, were in the same range in all 3 study
groups. FPA, a marker of thrombin activity, was significantly
higher in AMI and UAP patients than in the control group.
This confirms the results of other studies, indicating that FPA
is a sensitive marker of acute coronary thrombosis.29,30 The
lack of difference in markers of factor Xa and thrombin
generation may reflect a difference in assay sensitivity.
In the revised model of coagulation, factor XI is activated
by thrombin, whereas factor XII is believed to have a
profibrinolytic function rather than initiating coagulation via
the intrinsic pathway. This is illustrated by several case
reports, linking a deficiency of factor XII with myocardial
infarction and depression of factor XII– dependent fibrinolytic activity with risk of reinfarction.31–34 We could not
detect any significant activation of factor XII or prekallikrein
in either study group, suggesting no role for factor XII in the
activation of factor XI in patients with coronary artery
disease. Using another, very sensitive, assay for factor XIIa,
Coppola et al35 also did not detect enhanced activation of
factor XII in 58 patients with myocardial infarction and 28
patients with UAP compared with an age-matched control
group. Our results seem to be in contrast with those of
Hoffmeister et al,9 who demonstrated activation of the contact
system in patients with UAP. However, patients in that study
were included after recurrent symptoms of angina pectoris at
rest, and 98% of the patients were already being treated with
drugs, indicating that these patients were more likely to be in
a postacute than in an acute phase of their disease.
In conclusion, the present study demonstrates increased
activation of factor XI and factor IX in a subset of patients
with AMI and UAP. This activation can have important
implications, inasmuch as activation of factors XI and IX may
have a function in the consolidation of clot formation.6,12,36
Continuous generation of thrombin not only leads to fibrin
formation but also contributes to enhanced stability of the
fibrin clot via activation of TAFI.14,15 Recently, Klement et
al37 have demonstrated that inhibition of TAFI activity is
capable of significantly potentiating tissue plasminogen activator–induced lysis of an arterial thrombus in a rabbit model,
an important finding with possible clinical implications in the
future.
Furthermore, inasmuch as clot-bound thrombin contributes
to the activation of factor XI,15 these results underline the
importance of therapeutic strategies that inhibit the activity of
clot-bound thrombin in the management of patients with
acute coronary events.38,39
Acknowledgments
M.C.M. is supported by a grant from the Netherlands Heart Foundation. H.t.C. is an established investigator of the Netherlands
Heart Foundation.
Minnema et al
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Activation of Clotting Factors XI and IX in Patients With Acute Myocardial Infarction
M. C. Minnema, R. J. G. Peters, R. de Winter, Y. P. T. Lubbers, S. Barzegar, K. A. Bauer, R. D.
Rosenberg, C. E. Hack and H. ten Cate
Arterioscler Thromb Vasc Biol. 2000;20:2489-2493
doi: 10.1161/01.ATV.20.11.2489
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