Relationship between control of ventricular rate in atrial fibrillation and systemic coagulation activation in patients with mitral stenosis.

Abstract

Systemic thromboembolism is a major complication in patients with mitral stenosis (MS), especially in those who have atrial fibrillation (AF). It has been suggested that systemic coagulation activity may be increased in these patients. The study aim was to investigate the relationship between control of ventricular rate and systemic coagulation factors in patients with MS and AF by measuring plasma levels of prothrombin fragment (PF) 1+2, thrombin-antithrombin III complex (TAT) and plasminogen activator inhibitor-1.
Fifty-four consecutive patients with moderate to severe MS and AF were included in the study. Patients with resting heart rates < 100 beats per min were considered as having a controlled ventricular response rate (group A; n = 28) and those with > 100 beats per min as an uncontrolled ventricular response rate (group B; n = 26).
Group A patients had a lower mean mitral gradient and pulmonary artery pressure than group B patients (11 +/- 6 versus 15 +/- 5 and 35 +/- 7 versus 39 +/- 8; p < 0.05, respectively). Plasma concentrations of PF 1+2 (4.17 +/- 2.1 versus 2.95 +/- 1.21; p < 0.01) and TAT III (4.61 +/- 1.75 versus 3.12 +/- 1.01; p < 0.01) were elevated in group B compared with group A. Similarly, group B patients had higher plasminogen activator inhibitor-1 levels than group A patients (7.87 +/- 3.8 versus 5.8 +/- 2.9; p < 0.05). A significant correlation was found between heart rate and plasma PF 1+2 and TAT levels. Multiple logistic regression analysis revealed that heart rate and mean mitral gradient were independent predictors of systemic coagulation activation.
Besides contributing towards hemodynamic and symptomatic relief, the control of AF rate in MS patients induces a drastic decline in coagulation activation, and may also reduce the incidence of thromboembolism.

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Relationship between Control of Ventricular Rate in
Atrial Fibrillation and Systemic Coagulation Activation
in Patients with Mitral Stenosis
Ramazan Atak, Hasan Turhan, Kubilay Senen, Kenan Yalta, Selime Ayaz,1Omer Alyan, Nurcan
Basar, Deniz Demirkan
Departments of Cardiology and 1Biochemistry, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey
Systemic thromboembolism is a serious complica-
tion in patients with valvular heart disease,
particularly in those with mitral stenosis (MS) (1-8).
Mitral stenosis is a well-known risk factor for stroke,
especially in patients with atrial fibrillation (AF) (3-
5,7,8), left atrial spontaneous echo contrast (LASEC)
(9,10), enlarged left atrium (5,8), age >40 years (3,5)
and reduced cardiac output (4,6,8). In explaining the
mechanisms responsible for the pre-thrombotic state in
these patients, previous studies on platelet, coagula-
tion and fibrinolytic systems have revealed hemostatic
abnormalities indicating the presence of a hypercoagu-
lable state in MS (11-18). In MS which coexists with AF
- when the patient is unlikely to remain in sinus
rhythm - it is essential to control the heart rate in order
to obtain any hemodynamic improvement and symp-
tomatic relief.
Recent studies have revealed that ventricular rate
control is as crucial as rhythm control for the preven-
tion of cardiovascular mortality and morbidity in
non-valvular chronic AF (19,20). However, in pub-
lished reports the link between rate control and
systemic coagulation has been neglected, despite
improvements in hemodynamic parameters and
symptomatic relief having long been recognized as the
leading cause(s) for rate control. The aim of the present
study was to identify any relationship between the
control of ventricular rate and systemic coagulation
factors in patients with MS and AF.
Clinical material and methods
Patients
Fifty-four consecutive patients (39 women, 15 men;
mean age 29.2 ± 7.3 years; range: 18 to 45 years) with
Address for correspondence:
Ramazan Atak MD, Naci Cakir Mahallesi, 5. Sokak, Mimar Sinan
Sitesi, A Blok, 7/20, Dikmen, Ankara, Zip Code 06460, Turkey
e-mail: hratak@yahoo.com
© Copyright by ICR Publishers 2004
Background and aim of the study: Systemic throm-
boembolism is a major complication in patients with
mitral stenosis (MS), especially in those who have
atrial fibrillation (AF). It has been suggested that sys-
temic coagulation activity may be increased in these
patients. The study aim was to investigate the rela-
tionship between control of ventricular rate and
systemic coagulation factors in patients with MS and
AF by measuring plasma levels of prothrombin frag-
ment (PF) 1+2, thrombin-antithrombin III complex
(TAT) and plasminogen activator inhibitor-1.
Methods: Fifty-four consecutive patients with moder-
ate to severe MS and AF were included in the study.
Patients with resting heart rates <100 beats per min
were considered as having a controlled ventricular
response rate (group A; n = 28) and those with >100
beats per min as an uncontrolled ventricular
response rate (group B; n = 26).
Results: Group A patients had a lower mean mitral
gradient and pulmonary artery pressure than group B
patients (11 ± 6 versus 15 ± 5 and 35 ± 7 versus 39 ± 8;
p <0.05, respectively). Plasma concentrations of PF
1+2 (4.17 ± 2.1 versus 2.95 ± 1.21; p <0.01) and TAT III
(4.61 ± 1.75 versus 3.12 ± 1.01; p <0.01) were elevated
in group B compared with group A. Similarly, group
B patients had higher plasminogen activator
inhibitor-1 levels than group A patients (7.87 ± 3.8
versus 5.8 ± 2.9; p <0.05). A significant correlation
was found between heart rate and plasma PF 1+2 and
TAT levels. Multiple logistic regression analysis
revealed that heart rate and mean mitral gradient
were independent predictors of systemic coagulation
activation.
Conclusion: Besides contributing towards hemody-
namic and symptomatic relief, the control of AF rate
in MS patients induces a drastic decline in coagula-
tion activation, and may also reduce the incidence of
thromboembolism.
The Journal of Heart Valve Disease 2004;13:159-164

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moderate to severe MS and AF (NYHAclasses II to IV)
were included in the study. All patients had undergone
cardiac catheterization due to the presence of a dis-
crepancy between clinical and echocardiographic
findings, to exclude coronary artery disease, and for
evaluation before percutaneous mitral balloon valvu-
loplasty. Twenty age- and gender-adjusted healthy
subjects served as the control group. Exclusion criteria
were significant mitral regurgitation, aortic stenosis or
regurgitation, tricuspid valve disease, left atrial (LA)
thrombus detected by transesophageal echocardiogra-
phy (TEE), and coexistent left ventricular (LV)
dysfunction. Other exclusion criteria were pregnancy,
prolonged activated partial thromboplastin time
(aPTT) or international normalized ratio (INR), artifi-
cial activation of hemostatic parameters, antiplatelet or
anticoagulant therapy, diabetes mellitus, renal and
hepatic dysfunction, overt malignancy, chronic inflam-
matory disease, history of systemic embolism, deep
vein thrombosis or pulmonary embolism.
The study protocol was approved by the ethics com-
mittee of the authors’ institution, and informed con-
sent was acquired from each individual included in the
study.
Hemodynamic investigations
All patients underwent transthoracic echocardiogra-
phy using ultrasound equipment (GE Vingmed
System Five) fitted with a commercially available 2.5-
MHz transducer to measure LA diameter and
fractional shortening by M-mode in the parasternal
long-axis view, and to calculate mitral valve area
(MVA) using Doppler pressure half-time and planime-
try methods. Mean transmitral diastolic gradients and
pulmonary artery pressure (PAP) were also measured
by Doppler studies. TEE was the second step for all
patients in order to rule out the presence of LA throm-
bus and LASEC. LA thrombus was excluded by the
absence of a clearly defined intracavitary mass that
was acoustically distinct from the underlying endo-
cardium. LASEC was diagnosed on the basis of
dynamic smoke-like echoes within the LA cavity or
160 Ventricular rate and coagulation activation in MS
R. Atak et al.
J Heart Valve Dis
Vol. 13. No. 2
March 2004
Table I: Clinical, hematological and echocardiographic characteristics of patients with controlled and uncontrolled heart rate.
ParameterGroup A
(n = 28)
Group B
(n = 26)
Resting heart rate (bpm)
Age (years)
Male:female ratio
NYHA functional class
Resting heart rate (bpm)
Medication(for heart rate control)
Digitalis
β-blocker
Calcium-channel blocker
Digitalis +β-blocker
Digitalis + Ca-channel blocker
No medication
<100>100
30.1 ± 9.5
9:19
2.5 ± 0.6
79.8 ± 12.1*
28.5 ± 7.8
6:20
2.6 ± 0.7
119.6 ± 13.7
13 (47)
6 (21)
4 (14)
4 (14)
1 (4)
0
11 (42)
5 (20)
4 (15)
2 (8)
0
4 (15)
Hematological variables
INR
APTT (s)
Platelet count (×10-9/l)
Fibrinogen (g/l)
0.87 ± 0.25
27.4 ± 6.0
270 ± 45
3.4 ± 1.1
0.78 ± 0.21
30.5 ± 5.5
255 ± 51
3.7 ± 1.0
Echocardiographic variables
Fractional shortening (%)
LA diameter (cm)
Mitral valve area (PHT, cm2)
Mean diastolic gradient (mmHg)
Systolic PAP (mmHg)
LASEC (n)
31 ± 3
4.8 ± 1.0
1.3 ± 0.56
11 ± 6†
35 ± 7†
18 (64)
29 ± 2
5.0 ± 1.1
1.4 ± 0.44
15 ± 5
39 ± 8
19 (73)
Values in parentheses are percentages.
*p <0.001 versus group B; †p <0.05 versus group B.
APTT: Activated partial thromboplastin time; INR: International normalized ratio; LA: Left atrial;
LASEC: Left atrial spontaneous echo contrast; PAP: Pulmonary artery pressure; PHT: Pressure half-time.

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appendage, with a characteristic swirling motion dis-
tinct from noise artifact. Just before blood sampling, all
patients underwent electrocardiographic examination
after at least 30-60 min resting states. Patients with a
resting heart rate <100 beats per min were considered
as having a controlled ventricular response rate (group
A; n = 28), and those with a heart rate >100 beats per
min as an uncontrolled ventricular response rate
(group B; n = 26).
Hematological investigations
Simple hematological parameters, including platelet
count, fibrinogen concentration, INR and aPTT were
tested routinely at hospital admission. Peripheral
venous blood samples of patients for measuring levels
of plasma coagulation parameters, including pro-
thrombin fragment (PF 1+2), thrombin-antithrombin
III complex (TAT) and plasminogen activator inhibitor-
1 (PAI-1) were drawn at hospital admission between
08:00 and 10:00. Samples were taken using 21-G vacu-
um tube phlebotomy needles into 3.8% 1:9 trisodium
citrate-containing tubes, without venous stasis. The
plasma was immediately separated by centrifugation
of the blood (3,000 g for 15 min), and then stored in
several aliquots at -70°C until used for assay.
Plasma PF 1+2 (Enzygnost PF 1+2 microenzyme
immune assay; Behringwerke AG, Germany) and plas-
ma TAT (Enzygnost TAT microenzyme immune assay;
Behringwerke AG) concentrations as markers of in-
vivo thrombin generation were measured using the
solid-phase sandwich, enzyme-linked immunosorbent
assay method. Specific measurement of PAI-1 levels
reflecting fibrinolytic activity was performed with an
immunofunctional assay as described previously.
Statistical analysis
All data were reported as mean ± SD. For continuous
variables, differences between two groups were tested
with an independent sample t-test. Associations
between two categorical variables were tested with a
chi-square test. All patients with MS and either con-
trolled or uncontrolled heart rate, in addition to control
subjects, were compared for PF 1+2, TAT and PAI-1
levels using the Mann-Whitney U-test. The correlation
between heart rate and plasma coagulation parameters
was assessed by the Pearson correlation test.
Determinants of systemic coagulation activation were
evaluated with the use of multivariate logistic regres-
sion analysis. The independent variables evaluated
were heart rate, mean diastolic transmitral gradient,
PAP, MVA and LA diameter. A p-value ≤0.05 was con-
sidered to be statistically significant.
Results
Clinical and echocardiographic variables of the
Ventricular rate and coagulation activation in MS
R. Atak et al.
161
J Heart Valve Dis
Vol. 13. No. 2
March 2004
Table II: Hemostatic variables in patients with controlled and uncontrolled heart rate, and in control subjects.
Variable Group A
(n = 28)
Group B
(n = 26)
Controls
(n = 20)
PF 1+2 (nmol/l)
TAT (ng/l)
PAI-1 (ng/l)
2.95 ± 1.21
3.12 ± 1.01
5.8 ± 2.9
4.17 ± 2.1*
4.61 ± 1.75*
7.87 ± 3.8†
2.02 ± 0.48
2.65 ± 1.21
5.35 ± 3.2
Values are mean ± SD.
*p <0.01 versus group A;†p <0.05 versus group A.
PAI-1: Plasminogen activator inhibitor; PF 1+2: Prothrombin fragment 1+2; TAT: Thrombin-antithrombin III complex.
Table III: Multivariate logistic regression analysis of echocardiographic and hemodynamic measures related to increased sys-
temic coagulation activation.
Parameter PF 1+2 TAT
__________________________________________
p-valueOdds ratio
__________________________________________
p-valueOdds ratio95% CI95% CI
Heart rate
Mean mitral gradient
SPAP
MVA
LA diameter
0.01
0.04
0.18
0.091
0.11
3.45
1.87
0.86
0.93
1.02
1.33-7.05
0.75-4.23
0.24-2.88
0.33-2.97
0.45-3.34
0.02
0.067
0.34
0.22
0.31
2.85
1.24
0.76
0.82
0.65
1.12-5.05
0.43-3.04
0.18-1.99
0.27-2.03
0.12-1.87
CI: Confidence interval; LA: Left atrial; MVA: Mitral valve area; PF 1+2: Prothrombin fragment 1+2; SPAP: Systolic pulmonary
artery pressure; TAT: Thrombin-antithrombin III complex.

Page 4

patient groups are listed in Table I. Ten patients had
mild mitral regurgitation, and eight had mild aortic
regurgitation. There was no statistically significant dif-
ference between groups A and B with regard to age,
gender, NYHA functional class, medication, LA diam-
eter, MVA, ejection fraction, presence of LASEC,
fibrinogen levels, INR and aPTT (Table I). The mean
heart rate in group Apatients was 79.8 ± 12.1 beats per
min, compared with 119.9 ± 13.7 beats per min in
group B (p <0.001). Group Apatients had a lower mean
mitral gradient and PAPs than group B. The mean
plasma concentrations of PF 1+2, TAT and PAI-1 were
elevated in group B patients compared with both
group A patients and control subjects. No significant
differences were found between plasma levels of PF
1+2, TAT and PAI-1 in group Apatients compared with
control subjects (p >0.05 for all cases) (Table II). A sig-
nificant correlation was found between heart rate and
plasma PF 1+2 and TAT levels (r = 0.443, p <0.01; r =
0.640, p <0.01, respectively), but no such correlation
was found between heart rate and plasma PAI-1 levels
(r = 1.98, p >0.05). Multiple logistic regression analysis
revealed that heart rate and mean mitral gradient were
independent predictors of systemic coagulation activa-
tion in patients with MS (Table III).
Discussion
The results of the present study indicated that coag-
ulation activity was increased in patients with rapid
ventricular responses (resting heart rate >100 beats per
min) compared to those with an optimal heart rate
(resting, <100 beats per min) in patients with MS and
AF. In addition, the mean mitral gradient and PAP
were also higher in the group with rapid heart rates.
During thrombin generation, the amino-terminal
portion of the prothrombin molecule is released as the
inactive PF 1+2 fragment. Once evolved, thrombin
converts fibrinogen to fibrin, thereby releasing fib-
rinopeptide A and B; alternatively, it can be inhibited
by the endogenous heparin sulfate-antithrombin III
mechanism to form TAT, a stable enzyme-inhibitor
complex. PF 1+2 fragment, fibrinopeptide A and TAT
can thus be used as indices of thrombin generation in
vivo. Several studies have revealed significantly
increased amounts of these peptide molecules in the
sera of patients with MS and AF (12-15,18).
In the present study, in addition to measuring plas-
ma levels of PF 1+2 and TAT as markers of coagulation
activity, plasma levels of PAI-1 were also measured.
PAI-1 is regarded as a major determinant of fibrinolyt-
ic activity in human plasma, and high levels have been
found in conditions associated with increased throm-
boembolic risk, such as recurrent deep vein
thrombosis, postoperative period, malignant tumors,
septicemia and coronary artery disease (21,22).
Increased PAI-1 levels in patients with an uncontrolled
heart rate (group B) represent decreased fibrinolytic
activity and contribute to the pre-thrombotic state in
these patients.
The presence of LA thrombus in MS is accompanied
by increased systemic levels of peptide byproducts of
the coagulation cascade, including PF 1+2, fibrinopep-
tide A and TAT. For this reason, thrombus in LA was
accepted as an exclusion criterion. Other factors that
have been reported to predispose to thromboembolism
in MS include the presence of LASEC (9,10), age >40
years (3,5), increasing severity of the valvular stenosis
(5,8), LA dilatation (5,8) and reduced cardiac output
(4,6,8). No significant differences were found in the
present patients in terms of the parameters described
above.
Many hypotheses have been proposed to explain the
pre-thrombotic state in MS, including turbulence in
and around a stenotic mitral valve and blood stasis in
the LA or pulmonary circulation with subsequent
platelet activation and initiation of thrombus forma-
tion (23). Coagulation activation, platelet activation
and endothelial dysfunction may add to the mechani-
cal effects of valvular stenosis and stasis, and thus may
promote thromboembolism in these patients. When
the heart rate increases, the interval of LV diastole
shortens more than that of LV systole, and this results
in an increase in the transmitral gradient, LA pressure
and consequent blood stasis in the left atrium. These
subsequent events seem to be the causal factors
explaining the higher risk of coagulation activation in
the uncontrolled heart rate group. In the present study,
both heart rate and mean diastolic mitral gradient
were found to be independent factors affecting coagu-
lation activation. It is well known that mean mitral
gradient is affected by volume status in addition to the
heart rate; therefore, the mean diastolic mitral gradient
may affect coagulation activation, independently of
the heart rate.
The heart rate affects not only mean diastolic mitral
gradient and LA pressure, but also LA appendage
velocity. The LA appendage velocity of the long RR
period was found to be higher than that of the short RR
period in patients with AF (24). On this basis, it can be
concluded that LA appendage velocity is expected to
be lower in patients with higher heart rates. LA
appendage velocity and LA thrombus formation have
been found to be closely interrelated in previous stud-
ies, which explains the higher incidence of
thromboembolic complications
appendage velocities (25-27). In the present study, the
LA appendage velocity of each patient was measured
using TEE, though the values were ignored owing to
the presence of stress-induced tachycardia in both
in lower LA
162 Ventricular rate and coagulation activation in MS
R. Atak et al.
J Heart Valve Dis
Vol. 13. No. 2
March 2004

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groups.
Percutaneous mitral balloon valvuloplasty has been
proved to ameliorate not only hemodynamic parame-
ters but also endothelial function and coagulation
abnormalities (28-30). Likewise, systemic coagulation
potential seemed to abate as hemodynamic condition
flourished in the study group, indicating the signifi-
cance of rate control in obviating the hazardous
thromboembolic complications.
Besides contributing towards hemodynamic and
symptomatic relief, the control of AF rate in MS cases
induces a drastic decline in coagulation activation, and
may also reduce the incidence of thromboembolism.
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