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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2149-2157
REVIEW ARTICLE
Antiprothrombin Antibodies: Detection and Clinical Significance in
the Antiphospholipid Syndrome
By
Monica Galli and
Tiziano Barbui
From Divisione di Ematologia, Ospedali Riuniti, Bergamo, Italy.
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ANTIPHOSPHOLIPID SYNDROME |
ANTIPHOSPHOLIPID antibodies have
been associated with a variety of clinical phenomena, including
arterial and venous thrombosis, thrombocytopenia, and obstetric
complications. The term "antiphospholipid syndrome"1
is used to link a variety of thromboembolic events to antibodies
against specific proteins involved in blood coagulation. Thrombotic
events are reported in approximately 30% of patients with
antiphospholipid antibodies,2,3 with an overall incidence
of 2.5% patients/yr.4 Deep vein thrombosis of the legs
and/or pulmonary embolism account for about two thirds of the
thrombotic events, and cerebral arterial thrombosis are the most common
arterial complications.2,3 Obstetric complications include
recurrent spontaneous miscarriages, fetal deaths, or fetal growth
retardations.5 Women with antiphospholipid antibodies are
particularly prone to second or early third trimester fetal deaths.6 Hypoxia secondary to spiral arterial vasculopathy is considered to be the cause of the obstetric events.7 A
variable degree of thrombocytopenia is reported in as many as 20% to
25% of patients.8 Thrombocytopenia is generally mild and
seldom associated with bleeding complications; only 5% to 10% of
patients are severely thrombocytopenic (<50 × 109
platelets/L).8
Less commonly, hemolytic anemia, livedo reticularis, skin necrosis,
dementia or neuropsychiatric events, and the so-called "catastrophic" antiphospholipid syndrome are included in this picture.8 Two types of antiphospholipid syndrome have been described: the "primary" syndrome, which occurs in the absence of
an underlying disease,9 and the "secondary" syndrome,
which is related to systemic lupus erythematosus, other autoimmune or neoplastic diseases, or other pathological conditions.10
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ANTIPHOSPHOLIPID ANTIBODIES |
Since the beginning of this decade it has been increasingly appreciated
that antiphospholipid antibodies are a large and heterogeneous family
of immunoglobulins which, despite their name, do not bind to
phospholipids, but are directed at plasma proteins with affinity for
anionic (phospholipid) surfaces. Some of the antigenic targets of these
antibodies include  2-glycoprotein I,11-13
prothrombin,14 high- and low-molecular-weight
kininogens,15 annexin V,16 (activated) protein
C,17,18 and protein S.17,18
Since most of the antigens are involved in blood coagulation, some
antiphospholipid antibodies may hamper the regulation of blood
coagulation, thus providing an explanation of the high rate of
thrombosis in patients with the antiphospholipid syndrome. Most
biological and clinical studies have dealt with anti-2-glycoprotein I and antiprothrombin antibodies, which are the best known
antiphospholipid antibodies. In this report we will focus on
antiprothrombin antibodies, particularly their prevalence,
immunological and functional properties, clinical significance, and treatment.
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HISTORICAL BACKGROUND |
In 1959 Loeliger19 described a case whose lupus
anticoagulant activity was more pronounced in a mixture of the
patient's plasma with normal plasma than in the patient's own plasma.
The patient's plasma prothrombin was low. Elegant adsorption
experiments of patient's plasma with BaSO4 led the
investigator to suggest prothrombin was the necessary cofactor for the
expression of this lupus anticoagulant activity. One year later,
Rapaport et al20 reported a case of systemic lupus
erythematosus whose lupus anticoagulant was associated with profound
acquired hypoprothrombinemia. The patient's severe bleeding
complications were fully described and discussed in relation with
reported cases; the investigators concluded that the plasma coagulation
disturbances of systemic lupus erythematosus usually resulted from a
combination of an inhibitor impeding the activity of the prothrombin
activator complex and acquired hypoprothrombinemia. In the subsequent
15 years, many patients were reported with systemic lupus
erythematosus, who showed bleeding complications associated with a
lupus anticoagulant and acquired hypoprothrombinemia.21-25 In none of these cases did the circulating inhibitor neutralize the
coagulant activity of prothrombin added to the plasma. In 1972 Feinstein and Rapaport26 reviewed the
acquired inhibitors of blood coagulation and concluded that although
the lupus anticoagulants impaired clotting in vitro, abnormal bleeding
was only seen in cases of severe hypoprothrombinemia and/or
thrombocytopenia. Lechner25 and Natelson et
al27 provided evidence that the hypoprothrombinemia associated with lupus anticoagulants involved a reduction of both prothrombin activity and prothrombin antigen.
During the 1980s more work was performed to clarify the
hypoprothrombinemia of patients with lupus anticoagulants. Bajaj et al28 provided the first evidence that the plasma of
patients with lupus anticoagulants and severe hypoprothrombinemia
contained nonneutralizing antibodies, which bound prothrombin without
inhibiting its conversion to thrombin in the reaction mixtures used to
measure plasma prothrombin activity. The investigators postulated that hypoprothrombinemia results from the rapid clearance of
prothrombin-antiprothrombin antibody complexes from the circulation.
In 1984 Edson et al29 showed the presence of
antiprothrombin antibodies in the plasma of patients with lupus
anticoagulants but without severe hypoprothrombinemia in prothrombin
crossed immunoelectrophoresis experiments. Using a similar laboratory approach, these findings were confirmed and extended by Fleck et
al,30 who found antiprothrombin antibodies in 31 of 42 lupus anticoagulant-positive patients (74%), 15 of whom had prolonged prothrombin time. Adsorption of patients' plasma with insoluble prothrombin reduced both the immune complexes and the anticoagulant activity. Finally, eluates of the insoluble prothrombin contained IgG
that displayed lupus anticoagulant activity. The investigators concluded that these lupus anticoagulant antibodies were polyspecific, because they reacted with negatively charged phospholipids and prothrombin.
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DETECTION METHODS AND IMMUNOLOGICAL PROPERTIES |
Double immunodiffusion and crossed-immunoelectrophoresis were the first
techniques used for screening antiprothrombin
antibodies.28-31 Their main advantage lay in the
possibility of detecting prothrombin/antiprothrombin immune complexes.
This in vitro finding makes it reasonable to assume that such complexes
are also present in plasma in vivo, which may be of biologic
significance. However, their main disadvantage is that these methods do
not provide a quantitative estimate of the antibody. Moreover, in some
cases the titer or the affinity of antiprothrombin antibodies is too
low to give unequivocal precipitin lines.
Other techniques are based on the impairment of prothrombin activation
by antiprothrombin antibodies14,17 (see below). The need
for isolated antiprothrombin antibodies and purified cogulation
factors, however, makes these methods unsuitable for the routine
evaluation of large numbers of patients with antiphospholipid antibodies.
In the last few years, several groups of investigators have developed
enzyme-linked immunosorbent assay (ELISA) methods, which are by now the
most commonly used techniques. They give a quick determination of the
titer and the isotype of antiprothrombin antibodies. Interestingly, the
mode of presentation of prothrombin in immunoassays greatly influences
its recognition (Table 1). Antiprothrombin
antibodies bind to prothrombin coated on  -irradiated32 or high-activated polyvinylchloride (PVC),18,33 but not on plain polystyrene ELISA plates.18,32,33 IgG and/or IgM
antibodies to human prothrombin in solid phase have been reported in
approximately half of the patients with antiphospholipid
antibodies.18,32,33 Antiprothrombin antibodies recognize
both human and bovine prothrombin, although the human molecule is a
better antigen.32,34 Prothrombin is recognized more
efficiently when the protein is bound to phosphatidylserine-coated ELISA plates using calcium ions: the prevalence of positive samples increases up to 90%.33 This may be explained in different
ways. Firstly, unlike PVC-bound prothrombin, prothrombin complexed to phosphatidylserine is not likely to be restricted in its lateral movements: this would allow clustering and proper orientation, offering
better binding conditions for the antibodies. Alternatively, the ELISA
with phosphatidylserine in solid phase may, through the calcium ions,
capture the circulating prothrombin-antiprothrombin immune complexes
present in some samples. Finally, antiprothrombin antibodies might
react with neoepitopes that prothrombin makes available only when bound
to phosphatidylserine through calcium ions.
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Table 1.
The Mode of Presentation of Prothrombin
Influences Its Recognition by Antiprothrombin Antibodies in ELISA
Systems
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Recent evidence from Rauch35 indicates that antiprothrombin
antibodies recognize prothrombin also when bound to hexagonal (II)
phase phosphatidylethanolamine, and that the plasma lupus anticoagulant
activity is specifically neutralized by the prothrombin/hexagonal (II)
phase phosphatidylethanolamine complex. Phosphatidylethanolamine is a
neutral phospholipid that can assume nonbilayer configurations under
appropriate thermodinamic conditions.36 The hexagonal (II)
phase consists of hexagonally packed cylinders of lipid surrounding central aqueous channels toward which the polar head groups are oriented.37 Immunization of mice with hexagonal (II) phase
phosphatidylethanolamine induced antiphospholipid antibodies that
displayed lupus anticoagulant activity.38 Experiments
performed in our laboratory basically confirm these findings. Staclot
LA (Stago, Asnieres, France) and bovine brain
phosphatidylethanolamine used as source of hexagonal II phase and
lamellar phosphatidylethanolamine, respectivelywere coated on ELISA
plates, assuming that they maintain their conformational structures in
solid phase. Prothrombin bound to Staclot LA, but not to bovine brain
phosphatidylethanolamine, in a calcium-dependent fashion (Table
2). The presence of IgG antibodies reacting
with the calcium-mediated prothrombin/Staclot LA complex was
investigated by ELISA in 59 patients with lupus anticoagulants: 41 of
them (69%) recognized the complex (Fig 1).
The binding was strictly prothrombin and calcium dependent, because in
their absence only a minority of samples reacted with Staclot LA coated
on the plate (Fig 1).
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Table 2.
Human Prothrombin and 2-Glycoprotein I Binding to
Phospholipids Depends on Phospholipid Charge and Conformation
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| Fig 1.
IgG antiphospholipid antibodies binding to
phosphatidylethanolamine (PE). When lamellar PE (from bovine brain) was
used as the solid-phase antigen in ELISA, only 5 of 59 plasma samples
had an absorbance exceeding 2 SD the mean of controls. When hexagonal
II PE (Staclot LA) was used as the solid phase antigen, only two
samples reacted. When the solid-phase antigen in ELISA plates was
represented by the calcium-mediated complex of hexagonal II PE and
human prothrombin, 41 samples (69%) had an absorbance exceeding 2 SD
the mean of controls. Horizontal lines represent the upper
limit of 20 normal controls (ie, mean + 2 SD). *Values represent
the mean ± SD of patients' group.
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The general behavior of antiprothrombin antibodies in ELISA closely
resembles that of anticardiolipin antibodies: these antibodies recognize 2-glycoprotein I only when bound to anionic phospholipids or to -irradiated polystyrene or high-activated PVC ELISA
plates.11-13 The requirements for binding are probably due
to the relatively low affinity of anti-cardiolipin antibodies for
2-glycoprotein I; the apparent kd ranges from 10 6 to
105.39,40 Kinetic studies have
shown that some anticardiolipin antibodies with
anticoagulant activity cause a 30- to 40-fold enhancement of
2-glycoprotein I binding to membranes containing 20%
phosphatidylserine.41 Furthermore, -irradiated ELISA
plates increase the surface density of 2-glycoprotein I about 1.5 times39 and induce its conformational change.42
The antineoepitope(s) or low-affinity nature of anti-2-glycoprotein
I antibodies remains to be clarified.
Similarly, experimental evidence does not clearly establish whether and
which antiprothrombin antibodies are antineoepitope(s) or low-affinity
antibodies. With respect to the former possibility, human prothrombin
has been shown to undergo a conformational change upon binding to
phosphatidylserine-containing surfaces in the presence of calcium
ions.43 However, Bajaj et al28 reported rather
high values for affinity of antiprothrombin antibodies for human
prothrombinapproximately 1010 to
109in lupus anticoagulant-positive patients with
hypoprothrombinemia. In patients with normal antigenic levels of
prothrombin one might theoretically expect lower-affinity antibodies.
This was indirectly suggested by Fleck et al,30 who
reported a patient whose plasma prothrombin was essentially free, not
bound to IgG, despite the presence of antiprothrombin antibodies, which
could be removed by repeated adsorption with insoluble prothrombin.
However, the kd of this type of antibody has not yet been formally
determined. Cakir et al44 reported binding of
antiprothrombin antibodies to covalently cross-linked prothrombin
dimers and multimers coated on an ELISA plate. Cross-linked prothrombin
dimers and multimers facilitate bivalent, high-avidity binding of
intrinsically low-affinity antibodies. These findings point toward the
low affinity, rather than antineoepitope nature of antiprothrombin antibodies.
Antiprothrombin antibodies, like anti-2-glycoprotein I antibodies,
reduce the kd of prothrombin to an artificial anionic phospholipid
surface 2.5 to 5.0 times (from 822 ± 150 nmol/L to 184 to 341 nmol/L).45 Table 3 summarizes
the main properties of antiprothrombin and anticardiolipin antibodies.
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EPITOPE MAPPING |
The epitope(s) recognized by antiprothrombin antibodies have not yet
been fully defined. Bajaj et al28 reported two cases with
lupus anticoagulants and severe hypoprothrombinemia, showing that the
plasma of one patient reacted not only with prothrombin, but also with
prethrombin 1 (the carboxy-terminal segment of prothrombin) and
DIP- -thrombin (the carboxy-terminal segment of prethrombin 1). No
reactivity was seen against fragment 1 (the amino-terminal segment of
prothrombin) or fragment 2 (the amino-terminal segment of prethrombin
1) (Fig 2).
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| Fig 2.
Different pathways of prothrombin activation. (*)
Indicates active site exposure. Inverted "Y" indicates
-carboxyglutamic acid.
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Later, the binding of 14 lupus anticoagulant-positive IgG preparations
to prothrombin, prethrombin 1, fragment 1, and thrombin coating ELISA
plates was studied45: 11 IgG bound to prothrombin and 8 of
them also to prethrombin 1 and fragment 1. None reacted with
immobilized thrombin. These data were confirmed by Malia et
al,46 who found that antiprothrombin antibodies reacted
with prothrombin and its fragment 1-2, but not with the descarboxylated molecule. Finally, Fleck et al30 could not detect binding
to purified prothrombin by Western blot, implying that denaturation of
prothrombin by sodium dodecyl sulfate (SDS) disrupts essential discontinuous epitopes that are dependent on the tertiary structure of
the molecule. However, these investigators did demonstrate that at
least some antiprothrombin antibodies bind to epitopes that persist in
prothrombin in citrated plasma, regardless of how the three-dimensional
structure of prothrombin changes with the markedly reduced availability
of calcium ions in citrated plasma. These findings suggest that the
majority of antiprothrombin antibodies are of a poly- or oligo-clonal nature.
Because the amino-terminal region of prothrombin shares homology with
other vitamin K-dependent proteins, it was suggested that
antiprothrombin antibodies recognize a common epitope on this region of
prothrombin as well as of protein C and protein S.18 This
seems unlikely, in the light of experiments by Rao et al,45
who analyzed the binding of 14 IgG fractions from lupus anticoagulant-positive patients to phosphatidylserine in the presence of prothrombin, protein C, or protein S: only prothrombin supported the
binding of the IgG preparations to the anionic phospholipids. These
investigators obtained similar results when the neutral phospholipid
phosphatidylethanolamine was substituted for phosphatidylserine.
Puurunen et al47 reported that antiprothrombin antibodies
cross-react with plasminogen in patients with myocardial infarction. Inhibition studies showed that antibody binding to prothrombin was
prevented by soluble prothrombin, plasminogen, and synthetic peptides
of 20 amino acids from plasminogen kringle 5 and from prothrombin
kringle 2.47 This cross-reactivity was confirmed by
immunizing mice with either human prothrombin or human plasminogen. All
plasma samples from 16 mice immunized with prothrombin had antiprothrombin antibodies and 13 cross-reacted with plasminogen. All
plasma samples from 12 mice immunized with plasminogen contained antibodies to plasminogen and 8 cross-reacted with
prothrombin.48 It can be hypothesized that antiprothrombin
antibodies that cross-react with plasminogen interfere with the
fibrinolytic pathway.
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ANTICOAGULANT PROPERTIES |
In 1991 our group characterized the lupus anticoagulant activity of two
patients with phospholipid-dependent inhibitors of coagulation14: purified IgG antibodies hampered prothrombin activation by coagulation factors Xa and Va on a negatively charged phospholipid surface in the presence of calcium ions. The anticoagulant activity was exerted on human but not on bovine prothrombin and was
independent of the source (human or bovine) of factors Xa and Va;
anionic phospholipids were an absolute requirement for the expression
of this anticoagulant activity. We concluded that antibodies directed
at the prothrombin/phospholipid complex were responsible for the lupus
anticoagulant activity. Antiprothrombin antibodies also hamper the
conversion of factor X by coagulation factors IXa and VIII, provided
prothrombin, anionic phospholipids, and calcium are
present.49 A schematic representation of the sites of
action of antiprothrombin and anticardiolipin, ie,
anti-2-glycoprotein I, antibodies along the coagulation cascade is
shown in Fig 3. The anticoagulant activity
of antiprothrombin antibodies is expressed mainly, though not
exclusively, against prothrombin of human, but not animal,
origin.14,49 The reason(s) for this species-specificity are
not known.
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| Fig 3.
Sites of action of antiprothrombin and anticardiolipin
antibodies along the blood coagulation cascade: antiprothrombin
antibodies inhibit the activation of factor X and prothrombin;
anticardiolipin antibodies inhibit prothrombin but not factor X
activation. Dashed lines indicate inhibitory effect.
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Although most antiprothrombin antibodies behave in vitro as acquired
phospholipid-dependent inhibitors of coagulation, some have no
anticoagulant activity and can therefore be revealed only by ELISA
tests, using prothrombin on high-activated PVC ELISA plates or
complexed to phosphatidylserine.33,50 Again, the behavior
of antiprothrombin antibodies in coagulation tests resembles that of
anticardiolipin antibodies.51 So far, the reason(s) for the
generation of antiphospholipid antibodies either with or without
anticoagulant properties have not been explained.
Although antiprothrombin and anticardiolipin antibodies display lupus
anticoagulant activity, they affect phospholipid-dependent coagulation
tests differently (Table 4). The
synergistic effect of antiprothrombin antibodies on two consecutive
phospholipid-dependent coagulation reactions is shown mainly by overall
clotting tests, such as kaolin clotting time (KCT)52 or
colloidal silica clotting time (CSCT),53 which proceed
through the generation of factor Xa and activation of prothrombin.
Phospholipid-dependent tests like the dilute Russell's viper venom
time (dRVVT), that selectively evaluates the conversion of prothrombin
to thrombin, are less sensitive to the anticoagulant activity of these
antibodies.
Anticardiolipin antibodies hamper prothrombin activation in a strictly
2-glycoprotein I-dependent fashion,51 but not that of
factor X54; consequently, their presence affects the dRVVT
more than the KCT or other overall clotting assays.52 Our
group reported that the lupus anticoagulant activity caused by
antiprothrombin antibodies can be distinguished from that due to
anticardiolipin antibodies by use of specific coagulation profiles
generated by comparison of the ratios of the KCT and the
dRVVT52: if the ratio of the KCT exceeds that of the dRVVT,
it is considered a coagulation profile associated with antiprothrombin
antibodies; if the relationship is reversed it is considered a
"dRVVT" coagulation profile that may be associated with
anticardiolipin antibodies. However, both inhibitors may simultaneously
contribute to the phospholipid-dependent anticoagulant activity of
individual plasmas. Indeed, their high prevalence suggests that both
antiprothrombin and anticardiolipin antibodies are often present when a
lupus anticoagulant is detected. This is sustained by the recent
findings of Horbach et al50 in 28 patients with lupus
anticoagulants: the anticoagulant activity was totally dependent on
antiprothrombin or on anti-2-glycoprotein I antibodies in four and
seven cases, respectively, whereas in the majority of the plasmas
(n = 17) both antibodies contributed to the phospholipid-dependent
anticoagulant activity. These findings lead us to suggest that when
both inhibitors are present, the stronger one is responsible for the
final allocation of the plasma to either the dRVVT or the KCT
coagulation profile.
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CLINICAL RELEVANCE |
A number of retrospective, cross-sectional and prospective clinical
studies have established that the presence of lupus anticoagulants constitutes a risk factor for arterial and venous
thrombosis.55 The prevalence of patients with thrombosis
was found to be retrospectively associated with anticardiolipin
antibodies and the related dRVVT coagulation profile rather than with
antiprothrombin antibodies and the KCT profile in 25 patients with
phospholipid-dependent inhibitors of coagulation52 (Table
5).
These findings have been confirmed and extended by a prospective
clinical study performed on 100 patients with lupus anticoagulants classified according to their coagulation profile at diagnosis: 44 of
them displayed the KCT coagulation profile, and the other 56 the dRVVT
profile.56 Fourteen patients developed 18 thrombotic events
during a median follow-up of 37.5 months, with an overall rate of
thrombosis of 4.2% patients/yr. Twelve of them had the dRVVT
coagulation profile, and the other two the KCT profile
(P = .03). Compared with the KCT profile, the dRVVT
coagulation profile gave an odds ratio of thrombosis of 5.25 (95%
confidence interval, 1.17 to 23.50). Ten of the 14 patients who
developed thrombosis during follow-up had already experienced
thrombosis: a previous thrombotic event caused an odds ratio of
recurrence of 2.72 (95% confidence interval, 0.85 to 8.73)
(P = .09).
Therefore, the possibility of distinguishing a patient's thrombotic
risk on the basis of the coagulation profile appears clinically relevant. Care must be exercized when extrapolating these data to
current clinical practice, because the reagents and techniques used in
the KCT and the dRVVT may greatly influence the predictive value of the
coagulation profiles. In this respect, we reported that the CSCT could
be used in place of the KCT without loss of the ability to distinguish
patients with lupus anticoagulants at different risk of
thrombosis.53 Unlike our in-house dRVVT assay system, a
commercially available dRVVT kit failed to generate coagulation
profiles that identified the thrombotic risk of lupus anticoagulant-positive patients.57 Similar results were
reported by Callahan et al.58 Because of the uncertainties
about the reproducibility and potential clinical relevance of these
coagulation profiles, the ability of several commercially available
dRVVT kits to generate coagulation profiles that identify lupus
anticoagulant-positive patients at increased risk of thrombosis is
presently being investigated by a collaborative study.
The question whether antiprothrombin antibodies increase the risk of
thromboembolic events remains unanswered. Horbach et al59
studied a large population of patients with systemic lupus erythematosus, showing that IgG and IgM antiprothrombin antibodies (measured by ELISA) were risk factors for venous thrombosis (odds ratio, 2.53 and 2.72; 95% confidence intervals, 1.1 to 5.81 and 1.09 to 6.79 for IgG and IgM antibodies, respectively) but not for arterial
thrombosis. However, when multivariate analysis was performed,
antiprothrombin antibodies failed to increase the risk of venous
thrombosis.59 Association between antiprothrombin antibodies and thrombosis in patients with systemic lupus erythematosus has been confirmed by another retrospective study by univariate analysis.60 Funke et al61 reported that IgG and
IgM antibodies directed against the calcium-mediated
prothrombin/phosphatidylserine complex conferred an odds ratio of 2.8 (95% confidence intervals, 1.1 to 7.6) for venous thrombosis and an
odds ratio of 4.1 (95% confidence intervals, 1.6 to 10.5) for arterial
thrombosis in patients suffering from systemic lupus erythematosus. In
clinical conditions other than systemic lupus erythematosus a
"nested" case-control study estimated that high levels of
antiprothrombin antibodies gave an odds ratio of 6.54 (95% confidence
intervals, 1.73 to 25.0) of deep vein thrombosis/pulmonary embolism to
middle-aged men.62 Other retrospective studies failed to
show that antiprothrombin antibodies represent a risk factor for
thromboembolic events.18,32,33
The retrospective nature of these studies prevents from drawing
definite conclusions. Only one prospective study has been performed
that confirmed the association between high titers of antiprothrombin
antibodies and an increased risk of developing myocardial
infarction,63 which is not one of the typical features of
the antiphospholipid syndrome. Therefore, more "cross-sectional" or prospective clinical studies are warranted to establish the clinical
relevance of antiprothrombin antibodies.
This uncertainty also holds true at the pathophysiological level.
Despite their behavior as lupus anticoagulants in coagulation tests in
vitro, antiprothrombin antibodies increase thrombin generation on an
endothelial cell surface45 and in a flow
system.64 These findings, obtained with a very limited
number of Ig samples, are probably due to the stabilizing effect of
antiprothrombin antibodies on the binding of prothrombin to a
phospholipid surface mentioned above and suggest that antiprothrombin
antibodies with lupus anticoagulant activity have a prothrombotic
effect. However, in another, rather complex experimental
system,65 antiprothrombin antibodies did not show this
behavior. Conflicting results have been reported on the effect of
antiprothrombin antibodies on the anticoagulant activity of the protein
C system. Our group showed that anticardiolipin (ie,
anti-2-glycoprotein I), but not antiprothrombin antibodies hampered
the anticoagulant activity of the protein C system.66 On
the other hand, Horbach et al67 found a significant
impairment of protein C activity by antiprothrombin antibodies in the
presence of human prothrombin.
Finally, other additional congenital or acquired factors (ie, factor V
"Leiden," prothrombin gene mutation, hyperhomocysteinemia, increased plasma levels of prothrombin, factor VIII, von Willebrand factor, and decreased protein C and protein S plasma activities) may
contribute to the final thrombotic risk regardless of the type of
phospholipid-dependent inhibitor of coagulation in some lupus
anticoagulant-positive patients.
Regarding the other manifestations of the antiphospholipid syndrome
(ie, thrombocytopenia and recurrent miscarriages), the KCT coagulation
profile appeared to be retrospectively associated with an unexplained
moderate thrombocytopenia (platelet count, 50 to
150 × 109/L) (P = .005).56 We
cannot exclude the possibility that antiprothrombin antibodies bind to
platelets and cause thrombocytopenia, but we detected antibodies
directed to specific platelet glycoproteins in a proportion of patients
with antiphospholipid antibodies similar to that reported for patients
with idiopathic thrombocytopenic purpura.68 Moreover,
antiglycoprotein, but not antiphospholipid, antibodies could be eluted
from patients' platelet. These data suggest that the cause of
thrombocytopenia in patients with antiphospholipid antibodies is
similar to the cause of idiopathic thrombocytopenic purpura.
Neither coagulation profiles predict the risk of recurrent
miscarriages, probably because of the small number of patients with
poor obstetric outcome included in the study.56 Rand et al
showed that IgG fractions from patients with antiphospholipid antibodies reduced both the expression of annexin V on cultured trophoblasts69 and the binding of annexin V to anionic
phospholipid bilayers, frozen thawed washed platelets, activated
partial thromboplastin time reagent, and prothrombin time
reagent.70 This effect was 2-glycoprotein
I-dependent.70 The investigators postulated that, at least
in some cases, anticardiolipin antibodies with sufficiently high
affinity for 2-glycoprotein I hamper the anticoagulant effect of
annexin, thus accelerating coagulation reactions on a phospholipid
surface. Although attractive, this model needs further confirmation on
a larger number of patients to establish whether anticardiolipin
antibodies play a pathophysiological role in the development of
recurrent miscarriages or fetal losses. Unfortunately, the effect of
antiprothrombin antibodies in this system was not investigated.
The data suggest it is reasonable not to treat patients with
antiprothrombin antibodies unless they have severe hypoprothrombinemia with bleeding. Conditions that may prompt treatment are the
perioperative state and the bleeding of skin, gums, nose, and
urothelium. Corticosteroids are the treatment of
choice.71,72 Successful regimens consist of
methylprednisolone, 30 mg/kg per day administered intravenously for 3 days, followed by prednisone, 2 mg/kg daily for 14 days72 and of 1 g of cyclophosphamide administered intravenously on the first
day combined with prednisone, 1 mg/kg daily for 1 month.71 Patients who fail to improve have been treated with
danazol,73 high-dose intravenous
gammaglobulins,74 or cyclophosphamide,73 with
variable success.
Treatment of the thrombotic complications of the antiphospholipid
syndrome raises two questions in patients with antiprothrombin antibodies. Heparin, oral anticoagulants, or antiplatelet agents may
increase the risk of bleeding caused by hypoprothrombinemia. In fact,
even though the risk of thrombosis in lupus anticoagulant-positive patients with the KCT coagulation profile seems lower than with the
dRVVT profile,52,56 approximately 20% of those with the KCT profile nevertheless have a history of arterial and/or venous thrombosis, with an estimated rate of thrombosis of about 1.2% patients/yr.56 Therefore, care must be exercised when
administering antithrombotic drugs. The optimal duration and intensity
of oral anticoagulant treatment in these patients is likely to be
indicated by the WAPS (Warfarin in the Anti-Phospholipid Syndrome)
study, an international randomized trial proposed under the auspices of
the SSC Subcommittee for the Standardization of Lupus
Anticoagulants/Phospholipid-Binding Antibodies75: patients
with arterial and/or venous thrombosis in the last 5 years are
randomized either to long-term, high-intensity warfarin treatment (PT
International Normalized Ratio, INR, 3.0 to 4.5) or to standard
treatment. The study has already recruited more than 100 patients. The
estimated date for its completion is December 2000.
The other aspect relates to the monitoring of oral anticoagulation,
which is still an unsolved issue in patients with antiphospholipid antibodies. Laboratory control of oral anticoagulant therapy with the
PT INR might be inappropriate in lupus anticoagulant-positive patients
with hypoprothrombinemia, because the INR may not reflect the true
level of anticoagulation. Some groups reported widely varying PT INR
values in the plasma of lupus anticoagulant-positive patients under
oral anticoagulants, ranging from 2.0 up to 10.0.76-78 This
is probably due to the different responsiveness of commercial thromboplastin reagents to the various phospholipid-dependent inhibitors of coagulation.79 Since the studies so far do
not provide conclusive information, a multicenter cross-sectional study
has been proposed in the setting of the SSC Subcommittee for the
Standardization of Lupus Anticoagulants/Phospholipid-Binding Antibodies, to investigate the effect of lupus anticoagulants on the PT
INR measured with the most widely used thromboplastins.
| |
CONCLUSIONS AND FUTURE |
In conclusion, antiprothrombin antibodies are frequently found in
patients with antiphospholipid antibodies. Their immunological and
functional properties vary widely, mainly depending on their affinity
for human prothrombin. Despite increasing knowledge about their
mechanism(s) of action, the clinical relevance of these antibodies has
not yet been established, also because their presence has been reported
in a number of conditions other than the antiphospholipid syndrome.80 Taking into account the reported association
between the KCT coagulation profile (that reflects, at least in part, the in vitro anticoagulant activity of antiprothrombin antibodies) and
thrombocytopenia, future work will be aimed at defining whether these
antibodies play any role in the pathogenesis of this common complication of the antiphospholipid syndrome. It is even more compelling to distinguish clearly between the contributions of anticardiolipin (ie, anti-2-glycoprotein I) and antiprothrombin antibodies in the development of arterial and venous thromboembolic events.
| |
ACKNOWLEDGMENT |
We thank Drs G. Beretta, G. Brembilla, and G. Bonandrini, and S. Marziali and C. Zanotti for their excellent technical assistance. We
are also grateful to J. Baggott for editorial assistance.
| |
FOOTNOTES |
Submitted May 11, 1998; accepted December 9, 1998.
Address reprint requests to Monica Galli, MD, PhD, Divisione di
Ematologia, Ospedali Riuniti, L.go Barozzi, 1, 24128 Bergamo, Italy;
e-mail: ematologia{at}cyberg.it.
| |
REFERENCES |
1.
Harris EN, Gharavi AE, Hughes GRV:
Anti-phospholipid syndrome.
Clin Rheum Dis
11:591, 1985[Medline]
[Order article via Infotrieve]
2.
Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJW:
Lupus anticoagulant: An analysis of the clinical and laboratory features of 219 cases.
Am J Hematol
19:265, 1985[Medline]
[Order article via Infotrieve]
3.
Lechner K, Pabinger-Fasching I:
Lupus anticoagulant and thrombosis. A study of 25 cases and review of the literature.
Haemostasis
15:254, 1985[Medline]
[Order article via Infotrieve]
4.
Finazzi G, Brancaccio V, Moia M, Ciavarella N, Mazzucconi MG, Schinco PC, Ruggeri M, Pogliani EM, Gamba G, Rossi E, Baudo F, Manotti C, D'Angelo A, Palareti D, De Stefano V, Berrettini M, Barbui T:
Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: A four-year prospective study from the Italian Registry.
Am J Med
100:530, 1996[Medline]
[Order article via Infotrieve]
5.
Branch DW:
Thoughts on the mechanism of pregnancy loss associated with the antiphospholipid syndrome.
Lupus
3:275, 1994[Free Full Text]
6.
Branch DW, Silver RM:
Criteria for antiphospholipid syndrome: Early pregnancy loss, fetal loss or recurrent pregnancy loss?
Lupus
5:409, 1996[Medline]
[Order article via Infotrieve]
7.
Out HJ, Kooijman CD, Bruinse HW, Derksen RHWM:
Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies.
Eur J Obstet Gynaecol Reprod Biol
341:179, 1991
8.
Galli M, Finazzi G, Barbui T:
Thrombocytopenia in the antiphospholipid syndrome.
Br J Haematol
93:1, 1996[Medline]
[Order article via Infotrieve]
9.
Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RHWM, Machin SJ, Barquinero J, Out HJ, Harris EN, Vilardell-Torres M, Hughes GRV:
The `primary' antiphospholipid syndrome: Major clinical and serological features.
Medicine
68:366, 1989[Medline]
[Order article via Infotrieve]
10.
Alarcon-Segovia D, Deleze M, Oria CV:
Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus: A review of 500 consecutive cases.
Medicine
68:353, 1989[Medline]
[Order article via Infotrieve]
11.
Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda Vriesman PJC, Zwaal RFA, Bevers EM:
Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor.
Lancet
335:1544, 1990[Medline]
[Order article via Infotrieve]
12.
McNeil HP, Simpson RJ, Chesterman CN, Krilis SA:
Anti-phospholipid antibodies are directed against a complex antigen that include a lipid-binding inhibitor of coagulation: 2-glycoprotein I (apolipoprotein H).
Proc Natl Acad Sci USA
87:4120, 1990[Abstract/Free Full Text]
13.
Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T:
Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease.
Lancet
336:177, 1990[Medline]
[Order article via Infotrieve]
14.
Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RFA:
Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin.
Thromb Haemost
66:629, 1991[Medline]
[Order article via Infotrieve]
15.
Sugi T, McIntyre JA:
Autoantibodies to phosphatidylethanolamine (PE) recognize a kininogen-PE complex.
Blood
86:3083, 1995[Abstract/Free Full Text]
16.
Matsuda J, Saitoh N, Goihci K:
Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody.
Am J Hematol
47:56, 1994[Medline]
[Order article via Infotrieve]
17.
Oosting JD, Derksen RHWM, Bobbink IWG, Hackeng TM, Bouma BN, de Groot PG:
Antiphospholipid antibodies directed against a combination of phospholipid with prothrombin, protein C or protein S: an explanation for their pathogenetic mechanism?
Blood
81:2618, 1993[Abstract/Free Full Text]
18.
Pengo V, Biasiolo A, Brocco T, Tonetto S, Ruffatti A:
Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies.
Thromb Haemost
75:721, 1996[Medline]
[Order article via Infotrieve]
19.
Loeliger A:
Prothrombin as co-factor of the circulating anticoagulant in systemic lupus erythematosus?
Thromb Diath Haemorrh
3:237, 1959
20.
Rapaport SI, Ames SB, Duval BJ:
A plasma coagulation defect in systemic lupus erythematosus arising from hypoprothrombinemia combined with antiprothrombinase activity.
Blood
15:212, 1960[Abstract/Free Full Text]
21.
Biggs R, Denson KWE:
The mode of action of a coagulation inhibitor of the blood of 2 patients with disseminated lupus erythematosus.
Br J Haematol
10:198, 1964
22.
Douglas AS, Clatanoff DV, McNicol GP, Bailey PAM:
An atypical circulating anticoagulant.
Scand J Haematol
3:49, 1966[Medline]
[Order article via Infotrieve]
23.
Gonyea L, Herdman R, Bridges RA:
The coagulation abnormalities in systemic lupus erythematosus.
Thromb Diath Haemorrh
20:457, 1968[Medline]
[Order article via Infotrieve]
24.
Corrigan JJ, Patterson JH, May NE:
Incoagulability of the blood in systemic lupus erythematosus. A case due to hypoprothrombinemia and a circulating anticoagulant.
Am J Dis Child
119:365, 1970[Abstract/Free Full Text]
25.
Lechner K:
Acquired inhibitors in nonhemophilic patients.
Hemostasis
3:65, 1974
26.
Feinstein DI, Rapaport SI:
Acquired inhibitors of blood coagulation, in
Spaet TH
(ed):
Progress in Hemostasis and Thrombosis, vol 1. New York, NY, Grune & Stratton, 1972, p 75.
27.
Natelson EA, Cyprus GS, Hettig RA:
Absent factor II in systemic lupus erythematosus. Immunologic studies and response to corticosteroid therapy.
Arthritis Rheum
19:79, 1976[Medline]
[Order article via Infotrieve]
28.
Bajaj SP, Rapaport SI, Fierer DS, Herbst KD, Schwartz DB:
A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome.
Blood
61:684, 1983[Abstract/Free Full Text]
29.
Edson JR, Vogt JM, Hasegawa DK:
Abnormal prothrombin crossed-immunoelecrophoresis in patients with lupus inhibitors.
Blood
64:807, 1984[Abstract/Free Full Text]
30.
Fleck RA, Rapaport SI, Rao LVM:
Anti-prothrombin antibodies and the lupus anticoagulant.
Blood
72:512, 1988[Abstract/Free Full Text]
31.
Bajaj SP, Rapaport SI, Barclav S, Herbst KD:
Acquired hypoprothrombinemia due to nonneutralizing antibodies to prothrombin: mechanism and management.
Blood
65:1538, 1985[Abstract/Free Full Text]
32.
Arvieux J, Darnige L, Reber G, Bensa JC, Colomb MG:
Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants.
Thromb Haemost
74:1120, 1995[Medline]
[Order article via Infotrieve]
33.
Galli M, Beretta G, Daldossi M, Bevers EM, Barbui T:
Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies.
Thromb Haemost
77:486, 1997[Medline]
[Order article via Infotrieve]
34.
Rao LVM, Hoang AD, Rapaport SI:
Differences in the interactions of lupus anticoagulant IgG with human prothrombin and bovine prothrombin.
Thromb Haemost
73:668, 1995[Medline]
[Order article via Infotrieve]
35.
Rauch J:
Lupus anticoagulant antibodies: Recognition of phospholipid-binding protein complexes.
Lupus
7:S29, 1998 (suppl 2)
36.
Allen TM, Hong K, Papahadjopoulos D:
Membrane contact, fusion, and hexagonal (HII) transitions in phosphatidylethanolamine liposomes.
Biochemistry
29:2976, 1990[Medline]
[Order article via Infotrieve]
37.
Rauch J, Tannenbaum M, Janoff AS:
Distinguishing plasma lupus anticoagulants from anti-factor antibodies using hexagonal (II) phase phospholipids.
Thromb Haemost
62:892, 1989[Medline]
[Order article via Infotrieve]
38.
Rauch J, Janoff AS:
Phospholipid in the hexagonal II phase is immunogenic: Evidence for immunorecognition of nonbilayer lipid phases in vivo.
Proc Natl Acad Sci USA
87:4112, 1990[Abstract/Free Full Text]
39.
Roubey RAS, Eisenberg RA, Harper MF, Winfield JB:
"Anticardiolipin" autoantibodies recognize 2-glycoprotein I in the absence of phospholipid.
J Immunol
154:954, 1995[Abstract]
40.
Tincani A, Spatola L, Prati E, Allegri F, Ferremi P, Cattaneo R, Meroni PL, Balestrieri G:
The anti-2-glycoprotein I activity in human anti-phospholipid syndrome sera is due to monoreactive low-affinity autoantibodies directed to epitopes located on native 2-glycoprotein I and preserved during species evolution.
J Immunol
157:5732, 1996[Abstract]
41.
Willems GM, Janssen MP, Peslers MMAL, Comfurius P, Galli M, Zwaal RFA, Bevers EM:
Role of divalency in the high-affinity binding of anticardiolipin antibody-2-glycoprotein I complexes to lipid membranes.
Biochemistry
35:13833, 1996[Medline]
[Order article via Infotrieve]
42.
Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T:
Anticardiolipin antibodies recognize 2-glycoprotein I structure altered by interacting with an oxygen modified surface.
J Exp Med
179:457, 1994[Abstract/Free Full Text]
43.
Wu JR, Lenz BR:
Phospholipid-specific conformational changes in human prothrombin upon binding to procoagulant acid lipid membranes.
Thromb Haemost
71:596, 1994[Medline]
[Order article via Infotrieve]
44.
Cakir B, Rivadeneira AC, Hayes PM, Ortel TL, Petri M, Roubey RAS:
Anti-prothrombin autoantibodies: detection and characterization.
Lupus
7:S219, 1998 (abstr B67, suppl 2)
45.
Rao VM, Hoang AD, Rapaport SI:
Mechanism and effects of the binding of lupus anticoagulant IgG and prothrombin to surface phospholipid.
Blood
88:4173, 1996[Abstract/Free Full Text]
46.
Malia RG, Brooksfield C, Bulman L, Greaves M:
Prothrombin fragment F 1-2: The epitope for antiphospholipid antibody expression.XVIth Congress of the International Society of Thrombosis and Haemostasis, Florence, Italy, June 6-12, 1997. Thromb Haemost 171, 1997 (abstr 689, suppl)
47.
Puurunen M, Manttari M, Manninen V, Palosuo T, Vaarala O:
Antibodies to prothrombin crossreact with plasminogen in patients developing myocardial infarction.
Br J Haematol
100:374, 1998[Medline]
[Order article via Infotrieve]
48.
Puurunen M, Palosuo T, Vaarala O:
Cross-reactivity of humoral and cellular immunity to plasminogen and prothrombin.
Lupus
7:S209, 1998 (abstr B27, suppl 2)
49.
Permpikul P, Rao LVM, Rapaport SI:
Functional and binding studies of the roles of prothrombin and 2-glycoprotein I in the expression of lupus anticoagulant activity.
Blood
83:2878, 1994[Abstract/Free Full Text]
50.
Horbach DA, van Oort E, Derksen RHWM, de Groot PG:
The contribution of anti-prothrombin antibodies to lupus anticoagulant activity.
Thromb Haemost
79:790, 1998[Medline]
[Order article via Infotrieve]
51.
Galli M, Comfurius P, Barbui T, Zwaal RFA, Bevers EM:
Anticoagulant activity of 2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies.
Thromb Haemost
68:297, 1992[Medline]
[Order article via Infotrieve]
52.
Galli M, Finazzi G, Bevers EM, Barbui T:
Kaolin clotting time and dilute Russell's viper venom time distinguish between prothrombin- and 2-glycoprotein I-dependent antiphospholipid antibodies.
Blood
86:617, 1995[Abstract/Free Full Text]
53.
Norbis F, Barbui T, Galli M:
Dilute Russell's viper venom time and colloidal silica clotting time for the identification of the phospholipid-dependent inhibitors of coagulation.
Thromb Res
85:427, 1997[Medline]
[Order article via Infotrieve]
54.
Shi W, Chong BH, Hogg PJ, Chesterman CN:
Anticardiolipin antibodies block the inhibition by 2-glycoprotein I of the factor Xa generating activity of platelets.
Thromb Haemost
70:342, 1993[Medline]
[Order article via Infotrieve]
55.
Galli M, Finazzi G, Barbui T:
Antiphospholipid antibodies: Predictive value of laboratory tests.
Thromb Haemost
78:75, 1997[Medline]
[Order article via Infotrieve]
56. Galli M, Finazzi G, Norbis F, Marziali S, Marchioli R, Barbui T:
The different risk of thrombosis in patients with lupus anticoagulants
is predicted by their coagulation profile. Thromb Haemost 1999 (in
press)
57.
Norbis F, Barbui T, Galli M:
Comparison of two Russell's viper venom time (dRVVT) for distinguishing the phospholipid-dependent inhibitors of coagulation.XVIth Congress of the International Society of Thrombosis and Haemostasis, Florence, Italy, June 6-12, 1997. Thromb Haemost 331, 1997 (abstr 1356, suppl)
58.
Callahan JB, Manares CC, Moll S, Ortel TL:
Inability to distinguish between thrombotic and non-thrombotic antiphospholipid antibody positive patients with kaolin clotting time and dilute Russell's viper venom assay ratio.
Lupus
5:53, 1996 (abstr 111)
59.
Horbach DA, v Oort E, Donders RCJM, Derksen RHWM, de Groot PG:
Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus.
Thromb Haemost
76:916, 1996[Medline]
[Order article via Infotrieve]
60.
Bertolaccini ML, Atsumi T, Khamashta MA, Amengual O, Highes GRV:
Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus.
J Rheumatol
25:1104, 1998[Medline]
[Order article via Infotrieve]
61.
Funke A, Bertolaccini ML, Atsumi T, Amengual O, Khamashta MA, Hughes GRV:
Autoantibodies to prothrombin-phosphatidylserine complex: Clinical significance in systemic lupus erythematosus.
Lupus
7:S221, 1998 (abstr B74, suppl 2)
62.
Palosuo T, Virtamo J, Taylor PR, Aho K, Puurunen M, Vaarala O:
High antibody levels to prothrombin imply a risk of deep venous thrombosis and pulmonary embolism in middle-aged men.
Thromb Haemost
78:1178, 1997[Medline]
[Order article via Infotrieve]
63.
Vaarala O, Puurunen M, Manttari M, Manninen V, Aho K, Palosuo T:
Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men.
Thromb Haemost
75:456, 1996[Medline]
[Order article via Infotrieve]
64.
Hogg P, Chesterman CN:
Prothrombotic effect of anti-prothrombin antibodies.Presented at the SSC Subcommittee Meeting on Lupus Anticoagulants/Phospholipid-Dependent Antibodies. Florence, Italy, June 6, 1997.
65.
Hoffmann M, Monroe DM, Roubey RSA:
IgG from two patients with the antiphospholipid syndrome increase thrombin generation in an "in vitro" cell-based model of coagulation.XVIth Congress of the International Society of Thrombosis and Haemostasis, Florence, Italy, June 6-12, 1997. Thromb Haemost 1, 1997, (abstr 2, suppl)
66.
Galli M, Ruggeri L, Barbui T:
Differential effects of anti-2-glycoprotein I and antiprothrombin antibodies on the anticoagulant activity of activated protein C.
Blood
91:1999, 1998[Abstract/Free Full Text]
67.
Horbach DA, van Oort E, Derksen RHWM, de Groot Ph G:
Anti-prothrombin antibodies with LAC-activity inhibit tenase, prothrombinase and protein C activity by increasing the affinity of prothrombin to phospholipids.
Lupus
7:S208, 1998 (abstr B22, suppl 2)
68.
Galli M, Daldossi M, Barbui T:
Anti-glycoprotein Ib/IX and IIb/IIIa antibodies in patients with antiphospholipid antibodies.
Thromb Haemost
71:571, 1994[Medline]
[Order article via Infotrieve]
69.
Rand JH, Wu X-X, Andree HAM, Lockwood CJ, Guller S, Scher J, Harpel PC:
Pregnancy loss in the antiphospholipid-antibody syndrome. A possible thrombogenic mechanism.
N Engl J Med
337:154, 1997[Abstract/Free Full Text]
70.
Rand JH, Wu X-X, Andree HAM, Ross A, Rusinova E, Gascon-Lema MG, Calandri C, Harpel PC:
Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: A "lupus procoagulant" effect.
Blood
92:4652, 1998[Abstract/Free Full Text]
71.
Simel DL, St Clair EW, Adams J, Greenberg CS:
Correction of hypoprothrombinemia by immunosuppressive treatment of the lupus anticoagulant-hypoprothrombinemia syndrome.
Am J Med
83:563, 1987[Medline]
[Order article via Infotrieve]
72.
Bernini JC, Buchanan GR, Ashcraft J:
Hypoprothrombinemia and severe hemorrhage associated with a lupus anticoagulant.
J Pediatr
123:937, 1993[Medline]
[Order article via Infotrieve]
73.
Williams S, Linardic C, Wilson O, Comp P, Grainick HR:
Acquired hypoprothrombinemia: effects of Danazol treatment.
Am J Hematol
53:272, 1996[Medline]
[Order article via Infotrieve]
74.
Pernod G, Arvieux J, Carpentier PH, Mossuz P, Bosson JL, Polack B:
Successful treatment of lupus anticoagulant-hypoprothrombinemia syndrome using intravenous immunoglobulins.
Thromb Haemost
78:969, 1997[Medline]
[Order article via Infotrieve] (letter)
75.
Finazzi G, Barbui T, for the Provisional Steering Committee of the WAPS Study:
Feasibility of a randomized clinical trial for the prevention of recurrent thrombosis in the antiphospholipid syndrome: the WAPS project.
Ann Med Interne (Paris)
147:38, 1996 (suppl 1)
76.
Della Valle P, Crippa L, Safa O, Tomassini L, Pattarini E, Viganò-D'Angelo S, Sabbadini MG, D'Angelo A:
Potential failure of the International Normalized Ratio (INR) system in the monitoring of oral anticoagulation in patients with lupus anticoagulants.
Ann Med Interne (Paris)
147:10, 1996 (suppl 1)
77.
Moll S, Ortel TL:
Monitoring warfarin therapy in patients with lupus anticoagulants.
Ann Int Med
127:177, 1997[Abstract/Free Full Text]
78.
Laurie AS, Purdy G, Mackie IJ, Machin SJ:
Monitoring of oral anticoagulant therapy in lupus anticoagulant positive patients with the anti-phospholipid syndrome.
Br J Haematol
98:887, 1997[Medline]
[Order article via Infotrieve]
79.
Robert A, Le Querrec A, Delahousse B, Caron C, Houbouyan L, Boutière B, Horellou MH, Reber G, Sié P:
Control of oral anticoagulation in patients with the antiphospholipid syndromeInfluence of the lupus anticoagulant on International Normalized Ratio.
Thromb Haemost
80:99, 1998[Medline]
[Order article via Infotrieve]
80.
Guerin J, Smith O, White B, Sweetman G, Feighery C, Jackson J:
Antibodies to prothrombin in antiphospholipid syndrome and inflammatory disorders.
Br J Haematol
102:896, 1998[Medline]
[Order article via Infotrieve]
81.
McNeeley PA, Victoria EJ, Marquis D, Crisologo JF, Tuyay DC, Linnik MD:
APS patient' sera preferentially recognize the first domain of 2-glycoprotein I.
Lupus
7:S176, 1998 (abstr A15, suppl 2)
82.
Koike T, Ichikawa K, Kasahara H, Atsumi T, Tsutsumi A, Matsuura E:
Epitopes on 2-GPI recognized by anticardiolipin antibodies.
Lupus
7:S14, 1998 (suppl 2)
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|
|
P. Lieby, A. Soley, H. Levallois, B. Hugel, J.-M. Freyssinet, M. Cerutti, J.-L. Pasquali, and T. Martin
The clonal analysis of anticardiolipin antibodies in a single patient with primary antiphospholipid syndrome reveals an extreme antibody heterogeneity
Blood,
June 15, 2001;
97(12):
3820 - 3828.
[Abstract]
[Full Text]
[PDF]
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M. Galli and T. Barbui
Prevalence of Different Anti-Phospholipid Antibodies in Systemic Lupus Erythematosus and Their Relationship with the Antiphospholipid Syndrome
Clin. Chem.,
June 1, 2001;
47(6):
985 - 987.
[Full Text]
[PDF]
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J. Nojima, H. Kuratsune, E. Suehisa, Y. Futsukaichi, H. Yamanishi, T. Machii, Y. Iwatani, and Y. Kanakura
Association between the Prevalence of Antibodies to {beta}2-Glycoprotein I, Prothrombin, Protein C, Protein S, and Annexin V in Patients with Systemic Lupus Erythematosus and Thrombotic and Thrombocytopenic Complications
Clin. Chem.,
June 1, 2001;
47(6):
1008 - 1015.
[Abstract]
[Full Text]
[PDF]
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S. W. Reddel and S. A. Krilis
Testing for and Clinical Significance of Anticardiolipin Antibodies
Clin. Vaccine Immunol.,
November 1, 1999;
6(6):
775 - 782.
[Full Text]
[PDF]
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TOP
ANTIPHOSPHOLIPID SYNDROME
ANTIPHOSPHOLIPID ANTIBODIES