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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3401-3407
Ongoing Prothrombotic State in Patients With Antiphospholipid
Antibodies: A Role for Increased Lipid Peroxidation
By
Domenico Praticò,
Domenico Ferro,
Luigi Iuliano,
Joshua Rokach,
Fabrizio Conti,
Guido Valesini,
Garret A. FitzGerald, and
Francesco Violi
From the Institute of Clinical Medicine I, University "La
Sapienza," Rome, Italy; and the Center for Experimental
Therapeutics, University of Pennsylvania, Philadelphia, PA.
 |
ABSTRACT |
We measured the urinary excretion of Isoprostane
F2 -III and Isoprostane-F2-VI, two markers
of in vivo lipid peroxidation, and the circulating levels of the
prothrombin fragment F1+2, a marker of thrombin generation, in 18 antiphospholipid antibodies-positive patients, in 18 antiphospholipid
antibodies-negative patients with systemic lupus erythematosus, and in
20 healthy subjects. Furthermore, 12 patients positive for
antiphospholipid antibodies were treated with (n = 7) or without (n
= 5) antioxidant vitamins (vitamin E at 900 IU/d and vitamin C at
2,000 mg/d) for 4 weeks. Compared with antiphospholipid
antibodies-negative patients, antiphospholipid antibodies-positive
patients had higher urinary values of Isoprostane-F2-III
(P = .0001), Isoprostane-F2-VI (P = .006), and plasma levels of the prothrombin fragment F1+2 (P
= .0001). In antiphospholipid-positive patients, F1+2 significantly correlated with Isoprostane-F2-III (Rho = .56, P = .017) and Isoprostane-F2-VI (Rho
= .61, P = .008). After 4 weeks of supplementation with
antioxidant vitamins, we found a significant decrease in F1+2 levels
(P < .005) concomitantly with a significant reduction of both
Isoprostane-F2-III (P = .007) and
Isoprostane-F2-VI (P < .005). No change of these variables was observed in patients not receiving antioxidant treatment. This study suggests that lipid peroxidation might contribute to the activation of clotting system in patients positive for antiphospholipid antibodies.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
THE ANTIPHOSPHOLIPID syndrome (APS)
identifies patients with circulating antiphospholipid antibodies (aPL)
and episodes of venous and/or arterial thrombosis.1 Even if
aPL have been found prevalently in patients with autoimmune
diseases,1 aPL may be observed in other clinical conditions
such as atherosclerosis. Thus, a significant association between
anticardiolipin antibodies and myocardial infarction has been
reported.2,3
Several mechanisms have been proposed for explaining the
pathophysiological events that may potentially account for thrombosis in aPL-positive patients. The majority of these studies focused on the
possibility that these antibodies per se induce thrombosis by affecting
the activity of several cell lines such as endothelial cell, monocyte,
and platelets or interfering with the clotting system.4-6
Experiments in animal models gave support to this hypothesis, because
in a mouse model, the injection of human monoclonal anticardiolipin
antibody was associated with a thrombogenic effect.7 However, the demonstration that aPL per se are thrombogenic in the
human syndrome is still lacking.
In the present study we explore an alternative possibility, which is
based on two previous findings. It has been reported that aPL-positive
patients have an ongoing prothrombotic state, as indicated by high
circulating levels of the prothrombin fragment F1+2, a marker of
thrombin generation in vivo.8,9 Furthermore, following the
study of Horkko et al,10 which reported that antibodies against cardiolipin bind exclusively to peroxidized phospholipids, our
group has demonstrated that, in patients positive for aPL, there is a
close association between lipid peroxidation and aPL.11
To study lipid peroxidation, we measured two distinct isoprostanes
deriving from arachidonic acid oxidation
(Fig 1), namely 8-iso-Prostaglandin-F2 and
Isoprostane-F2-I, now known as
Isoprostane-F2-III and
Isoprostane-F2-VI.12
Isoprostane-F2-III was used as a marker of lipid
peroxidation, because it is elevated in clinical settings associated
with in vivo oxidant stress13,14 and is generated during
low density lipoprotein (LDL) oxidation in vitro in
coincidence with lipid peroxides formation.15,16 Isoprostane-F2-III may also be generated as a by-product of COX enzyme,16,17 but this pathway appears to have a
trivial contribution on the overall biosynthesis of the compound, as
reflected by its excretion in urine even in syndromes of COX
activation.14 Furthermore, we found a significant increase
of a distinct isoprostane, Isoprostane-F2-VI, formation
of which in vivo and in vitro is totally independent of
COX activity.18 Urinary levels of the isoprostanes were
highly correlated, suggesting a common mechanism of
formation.11
The aim of the present study was to investigate if there is a
relationship between lipid peroxidation and clotting activation in
patients with aPL.
| |
MATERIALS AND METHODS |
Study population.
Between October 1996 and March 1998, we studied 18 consecutive
outpatients (16 women and 2 men; 19 to 53 years of age) considered positive for aPL, recruited in the Rheumatology and Thrombosis Units of
the Institute of I Clinica Medica. In particular, 17 subjects showed
positivity for anticardiolipin antibodies (aCL), with a titer ranging
from 20 to 110 GPL or MPL; among these, 9 were also positive for lupus
anticoagulant (LA). Only 1 patient was positive for LA but not for aCL.
Eight of 18 aPL-positive patients were affected by primary
antiphospholipid syndrome (PAPS),19 having a history of
arterial and/or venous thrombosis in the previous 13 to 31 months: 5 had had an episode of arterial thrombosis (3 thromboembolic stroke, 1 myocardial infarction, and 1 retinal thrombosis), 2 had a deep venous
thrombosis, and 1 had a deep venous thrombosis and recurrent fetal
loss. The remaining 10 patients suffered from systemic lupus
erythematosus (SLE), diagnosed in accordance with the criteria of the
American College of Rheumatology, formerly the American Rheumatism
Association20; among these subjects, 2 had had a
thromboembolic stroke and 1 had a deep venous thrombosis in the
previous 13 to 27 months.
In the same period, we also selected 18 patients (17 women and 1 man;
17 to 50 years of age) suffering from SLE but negative for aPL. Among
these subjects, 5 experienced arterial and/or venous thrombosis in the
previous 14 to 24 months: 3 had had an episode of arterial thrombosis
(2 myocardial infarctions and 1 thromboembolic stroke) and 2 had a deep
venous thrombosis.
At the time of the study, all patients with a previous episode of
arterial thrombosis were treated with aspirin (100 mg/d). The 6 patients who had had an episode of venous thrombosis in the previous 16 to 27 months discontinued the anticoagulant treatment at least 6 months
before the inclusion in the study.
Twenty healthy subjects (19 women and 1 man; 18 to 50 years of age)
negative for aPL were also studied as controls.
The duration of disease in patients suffering from SLE averaged 8 ± 4 years (range, 1 to 16 years). Nineteen patients (8 positive and 11 negative for aPL) were being treated with corticosteroids (prednisone
at 5 to 25 mg/d or methylprednisolone at 4 to 24 mg/d) and/or
methotrexate (0.25 to 0.30 mg/kg intravenously once weekly). No patient
with PAPS was on treatment with corticosteroids or methotrexate.
Neither patients nor controls received vitamin supplementation 1 month
before the study.
Serum levels of C3 and C4, C-reactive protein, and clottable
fibrinogen, all acute-phase reactants, were measured as previously described.6 No patient had had active infections, trauma,
surgery, liver diseases, or alcohol or acetaminophen abuse in the
previous 3 months.
Among healthy subjects, none had cardiovascular risk factors, but 3 were smokers (6 cigarettes per day).
Study design.
In a first study, a cross-sectional comparison of the two isoprostane
levels and prothrombin fragment F1+2 (F1+2) between patients and
controls was performed. In the same day, a blood sample to measure the
clotting parameter and 12 hours of urine collection to measure
isoprostanes were taken from patients who had fasted for at least 12 hours. In a second study, we sought to investigate if antioxidant
treatment affected the circulating levels of F1+2 as well as the
urinary level of Isoprostane-F2-III and
Isoprostane-F2-VI. To this purpose, 12 aPL-positive
patients who had at least one isoprostane higher than the cut-off
point, ie, mean + 2 SD of controls, were randomly treated with (group A, n = 7) or without (group B, n = 5) antioxidant supplementation (vitamin E at 900 IU/d, vitamin C at 2,000 mg/d). Isoprostanes and F1+2
were measured before and after 4 weeks of treatment. Three patients of
group A and 2 of group B were also treated with corticosteroids
(prednisone at 5 to 25 mg/d or methylprednisolone at 4 to 24 mg/d). The
remaining patients, 4 of group A and 3 of group B, had PAPS.
Laboratory tests.
After overnight fasting and supine rest for at least 10 minutes, blood
samples were taken into tubes containing 3.8% trisodium citrate and
centrifuged at 5,000g for 10 minutes to obtain plasma. The
plasma was used immediately for measurement of fibrinogen. Blood
samples were also taken to measure plasma F1+2, vitamin E, vitamin C,
serum anticardiolipin antibodies, C-reactive protein, the complement
components C3 and C4, and tumor necrosis factor  (TNF).
Plasma levels of prothrombin fragment F1+2 were assayed by an enzyme
immunoassay based on the sandwich principle (Enzygnost F1+2;
Behringwerke, Marburg, Germany; reference value, 0.6 ± 0.2 nmol/L;
range, 0.3 to 1.2 nmol/L). Intra-assay and interassay coefficients of
variation were 8% and 9%, respectively.6
Plasma vitamin E and vitamin C were assayed by high performance liquid
chromatography with UV detection21 and electrochemical detection,22 respectively.
Serum TNF was assayed in duplicate by an enzyme immunoassay (Biokine
TNF test kit; T Cell Diagnostics Inc, Cambridge, MA). The detection
limit was calculated to be 10 pg/mL. Intra-assay and interassay
coefficients of variation were 8% and 9%, respectively. Among 25 healthy subjects, 2 showed detectable TNF serum levels (median <10
pg/mL; range, <10 to 34 pg/mL).
LA was measured in platelet-poor plasma centrifuged twice at
5,000g using four different coagulation tests: activated
partial thromboplastin time (aPTT), kaolin clotting time (KCT), dilute Russel's viper venom time (dRVVT), and dilute aPTT, as previously described.23 Patients were considered positive for LA if
they had at least two abnormal (prolonged) clotting tests, which
returned to normal values after adding 0.05 mmol/L
phosphatidylcholine-phosphatidylserine liposomes (confirmatory
test).23 An enzyme-linked immunoadsorbent assay, validated
in an international workshop, was used for measurement of aCL. IgG or
IgM aCL were considered positive when the serum concentration was
greater than 10 GPL or 10 MPL units, respectively.24 Patients were considered positive for aPL if LA and/or aCL were detected in two separate occasions at least 2 months apart.
Urinary Isoprostane-F2-III and
Isoprostane-F2-VI were measured by GC/MS assayed as
previously described.7,18 The internal standards used were
[18O2]Isoprostane-F2-III and
[2H4]Isoprostane-F2-VI. The
intra-assay and interassay variability in urine obtained from healthy
volunteers is ±3% and ±4% for
Isoprostane-F2-III and ±4% and ± 5% for
Isoprostane-F2-VI, respectively.
Statistical analysis.
Statistical analysis was performed by  2 statistic or
Fisher's exact test (if n < 5) for independence and by appropriate
t-test. When necessary, appropriate nonparametric tests were
used. Correlation analysis was performed by Spearman test. Data were
presented as the mean ± SD. Median and range are given for TNF,
Isoprostane-F2-III, and
Isoprostane-F2-VI, because they show appreciably skewed distribution. Only P values less than .05 were regarded as
statistically significant. All calculations were made with the computer
program STAT-View II (Abacus Concepts, Berkley, CA).25
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RESULTS |
Table 1 reports on clinical and laboratory
characteristics of aPL-positive patients and SLE patients who were
negative for aPL. No significant differences in urinary
Isoprostane-F2-III and Isoprostane-F2-VI
were noticed as a function of sex, age, or cardiovascular risk factors,
such as hypertension, dyslipidemia, or smoking. They did not show
differences in renal function or acute-phase reactant proteins, such as
C-reactive protein, C3, C4, and fibrinogen (not shown). Conversely,
aPL-positive patients had higher values of
Isoprostane-F2-III (P = .0001),
Isoprostane-F2-VI (P = .006), and prothrombin
fragment F1+2 (P = .0001) than SLE patients negative for aPL
(Table 1 and Fig 2). Similar findings were
observed when aPL-positive patients were compared with healthy subjects
(Fig 2).
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Table 1.
Clinical and Laboratory Characteristics of Patients
Positive for aPL and of SLE Patients Negative for aPL
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| Fig 2.
Urinary levels of Isoprostane-F2-III
(upper panel) and Isoprostane-F2-VI (middle panel) and
plasma prothrombin fragment F1+2 (lower panel) in patients positive
for antiphospholipid antibodies (aPL+), in patients with systemic
lupus erythematosus negative for the antiphospholipid antibodies (SLE
aPL ), and in healthy subjects (HS). Statistical analysis was
performed by Mann-Whitney-U test.
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SLE patients negative for aPL had similar values of prothrombin
fragment F1+2 (1.02 ± 0.38 nmol/L v 0.69 ± 0.26 nmol/L,
P > .05), but higher levels of
Isoprostane-F2-III (median, 135 pg/mg [range, 80 to 210 pg/mg] v 87 pg/mg [range, 26 to 161 pg/mg] creatinine;
P = .002) and Isoprostane-F2-VI (median, 1,057 pg/mg [range, 449 to 1780] v 655 pg/mg [range, 505 to 690 pg/mg] creatinine; P = .003) compared with controls (Fig
2).
Patients with PAPS (n = 8) and aPL-positive SLE patients (n = 10) showed similar values for Isoprostane-F2-III
(median, 215 pg/mg [range, 90 to 390 pg/mg] v 245 pg/mg
[range, 72 to 405 pg/mg] creatinine; P > .05),
Isoprostane-F2-VI (median, 1,350 pg/mg [range, 940 to
1,690 pg/mg] v 1,800 pg/mg [range, 580 to 2,400 pg/mg]
creatinine; P > .05) and F1+2 (mean ± SD, 1.65 ± 0.37 nmol/L v ± 0.64 nmol/L; P > .05).
A further analysis was performed in all patients to assess the possible
effect of the history of thrombosis on lipid peroxidation and clotting
activation parameters. In aPL-positive patients, no difference in
isoprostanes and F1+2 was observed between subjects with and without
previous thrombosis; the same finding was observed in aPL-negative
patients (Table 2). In aPL-positive
patients, F1+2 correlated significantly with
Isoprostane-F2-VI (Rho = .61 P = .008) and
Isoprostane F2-III (Rho = .56, P = .017) levels,
whereas in SLE patients negative for aPL, the correlation was not
statistically significant (F1+2 v
Isoprostane-F2-VI, Rho = .20, P = .40; F1+2
v Isoprostane-F2-III, Rho = .22, P = .36; Fig 3). No correlation between either
isoprostane and F1+2 was observed in healthy subjects.
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Table 2.
Lipid Peroxidation and Clotting Activation Indexes in
aPL-Positive and aPL-Negative Patients With and Without Previous
Thrombosis
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| Fig 3.
Correlation analysis (Spearman test) of prothrombin
fragment F1+2 versus Isoprostane-F2-III ( ) and
versus Isoprostane-F2-VI ( ) in healthy subjects (HS),
in patients positive for antiphospholipid antibodies (aPL+), and in
patients with systemic lupus erythematosus negative for
antiphospholipid antibodies (SLE aPL).
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To assess if the antioxidant treatment affected the entity of lipid
peroxidation and the plasma levels of prothrombin fragment F1+2, 12 patients were treated with (group A, 6 women and 1 man; 22 to 49 years
of age) or without (group B, 5 women; 17 to 48 years of age)
antioxidant vitamins for 4 weeks. Baseline levels of isoprostanes and
F1+2 did not significantly differ between the two groups (P > .05). There was no difference in sex, age, and standard treatment
between the two groups; in particular, 3 of 7 patients in the group A
and 2 of 5 patients in the group B were on treatment with
corticosteroids. Patients of group A showed a significant decrease of
Isoprostane-F2-III (median, 190 [range, 116 to 370]
v 105 [range, 86 to 200]; P = .007),
Isoprostane-F2-VI (median, 1,200 [range, 870 to 1,780]
v 845 [range, 550 to 1,390]; P < .005), and
prothrombin fragment F1+2 (mean ± SD, 1.88 ± 0.43 v
1.17 ± 0.22; P < .005;
Fig 4). Conversely, no difference was observed in the group B between baseline and 4-week values of Isoprostane-F2-III (median, 150 [range, 60 to 405]
v 175 [range, 120 to 320]; P > .05),
Isoprostane-F2-VI (median, 1,350 [range,
580 to 2,245] v 1,280 [range, 1,380 to 2,000]; P > .05), and F1+2 (1.67 ± 0.91 v 1.90 ± 0.66 nmol/L;
P > .05). During the follow-up, the aPL positivity,
fibrinogen, and TNF did not significantly change in both groups
(Table 3). To assess the compliance to
antioxidant supplementation, vitamin E and C plasma levels were
measured before and after 4 weeks of treatment. Both vitamin E (mean ± SD, from 15.3 ± 5.3 to 38.3 ± 11.3 µmol/L; P < .05) and vitamin C (mean ± SD, from 17.8 ± 11.5 to 22.9 ± 9.4 µmol/L; P < .05)
significantly increased at the end of follow-up.
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| Fig 4.
Decrease of urinary Isoprostane-F2-III
(upper panel, P = .007) and Isoprostane-F2-VI
(middle panel, P < .005) and plasma prothrombin fragment
F1+2 (lower panel, P < .005) in patients positive for
antiphospholipid antibodies after 4 weeks of combination therapy with
vitamin E and vitamin C. Statistical analysis was performed by paired
t-test.
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Table 3.
Laboratory Variables Before and After Treatment With
(Group A) or Without (Group B) Antioxidant Vitamins in Patients
Positive for aPL
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DISCUSSION |
The mechanism accounting for the formation of antibodies against
phospholipid in patients with primary or secondary antiphospholipid syndrome is still unclear.1
These autoantibodies are so named because they bind in vitro to
phospholipids, but the exact nature of the epitope(s) recognized remain
uncertain. Recently, Horkko et al26 have reported that at
least some aPL recognize neoepitopes of protein-phospholipid complexes
generated through a free radical mechanism: oxidation of phospholipids
generates breakdown products, such as aldehydes, which form covalent
adducts with aminoacidic residues of the associated protein. Whether
these neoepitopes of oxidized phospholipids have biological activity
linked to the thrombogenic mechanism remains to be investigated, but it
is plausible that these oxidation-generated epitopes occur in vivo and
possibly trigger synthesis of autoantibodies. This hypothesis is
corroborated by recent evidence that SLE patients with aPL have
enhanced lipid peroxidation in vivo, as documented by high urinary
excretion of isoprostanes, which is highly correlated to
anticardiolipin antibody titer.11 The suggestion that aPL positivity and lipid peroxidation are related is further supported by
the results of the current study, which reports that the urinary excretion of isoprostanes is also elevated in patients with PAPS.
In the present study, we tested whether lipid peroxidation and clotting
activation coexist in aPL-positive patients. We demonstrated that, in
aPL-positive patients, F2 Isoprostanes and F1+2 plasma levels were significantly correlated, suggesting that in vivo lipid
peroxidation and clotting activation are associated.
It is noteworthy that, in patients without aPL, the circulating levels
of prothrombin fragment F1+2 were within normal range and did not
correlate with F2 Isoprostanes. This further reinforces the
suggestion that, in patients with aPL, there is a relationship between
lipid peroxidation and clotting activation. The history of thrombosis
did not influence such behavior, because the increase of isoprostanes
and F1+2 was observed essentially in aPL-positive patients and was
similar in patients with and without previous thrombosis.
To further explore such an association, we investigated whether natural
antioxidants such as vitamin E and vitamin C could modulate the
increase in lipid peroxidation and the activation of clotting system.
We observed that, after vitamins supplementation, concomitantly with
the decrease in urinary levels of both F2-isoprostanes, the
circulating levels of the prothrombin fragment F1+2 were significantly reduced.
We have previously shown that, in SLE, lipid peroxidation and chronic
inflammation coexist, particularly in cases of aPL
positivity.11 In the present study we did not address the
question as to whether a similar mechanism may account for enhanced
lipid peroxidation in PAPS; therefore, further study is necessary to
explore this issue. However, after antioxidant treatment, no changes in
markers of acute inflammation were detected, suggesting that decrease of lipid peroxidation was not attributable to changes of disease activity.
Several lines of evidence suggest that oxygen free radicals contribute
to cell activation.27 Actually, antioxidants have been
reported to inhibit lipopolysaccharide-induced transcriptional and
posttranscriptional activation expression of macrophage tissue factor,28,29 a protein that stimulates the extrinsic
coagulation pathway by activating factor X to Xa.30
Furthermore, human monocytes exposed to copper-induced oxidant stress
had an enhanced expression of tissue factor, which was again inhibited
by antioxidants.31 These data lead to hypothesize that the
enhanced lipid peroxidation observed in aPL-positive patients could be
an important mechanism leading to clotting activation. It is
interesting to note that, in another clinical model associated with
thrombosis, such as diabetes mellitus, low antioxidant capacity was
inversely correlated with F1+2 plasma levels.32
In conclusion, this study is the first demonstration that, in patients
with aPL, there is a relationship between in vivo lipid peroxidation
and clotting activation. These data may open a new avenue to understand
the pathogenesis of thrombosis in this clinical setting and to develop
new therapeutic strategies for preventing thrombosis in these patients.
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ACKNOWLEDGMENT |
The authors are grateful to Dr Michael Maldonato for useful suggestions.
| |
FOOTNOTES |
Submitted July 27, 1998; accepted January 11, 1999.
Supported in part by Finanziamento Progetti di Ricerca 40% (to F.V.),
University "La Sapienza," Rome, Italy.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Francesco Violi, MD, Institute of Clinical
Medicine I, University La Sapienza, 00185 Rome, Italy; e-mail:
violi{at}uniroma1.it.
| |
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ABSTRACT
INTRODUCTION