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Articles |
1
Central Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka 565-0871, Japan.
2
Department of Clinical Laboratory Science, School of
Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka
565-0871, Japan.
3
Department of Hematology and Oncology, Osaka University
Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
aAddress correspondence to this author at: Central Laboratory for Clinical Investigation, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka 565-0871, Japan. Fax 81-6-6879-6635; e-mail nojima{at}hp-lab.med.osaka-u.ac.jp.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We determined the prevalence of aPL Abs to various
phospholipid-binding plasma proteins in SLE patients with arterial
thrombosis (30 cases), venous thrombosis (19 cases), thrombocytopenia
(14 cases), fetal loss (14 cases), and patients without complications
(91 cases). The aPL Abs were measured by an ELISA system in which human
plasma proteins (ß2-GPI, prothrombin, protein C, protein
S, and annexin V) were immobilized on 
-irradiated or plain
polystyrene plates.
Results: All types of aPL Abs were frequently observed in the
patients with SLE when -irradiated polystyrene plates were used (51
of 168 cases positive for anti-ß2-GPI, 94 of 168 cases
positive for anti-prothrombin, 36 of 168 cases positive for
anti-protein C, 47 of 168 cases positive for anti-protein S, and 50 of
168 cases positive for anti-annexin V), whereas no Abs to these plasma
proteins were detected when plain polystyrene plates were used.
Multivariate analysis confirmed that both anti-ß2-GPI and
anti-prothrombin Abs were significant risk factors for arterial
thrombosis [odds ratios (ORs), 8.8 and 14.5, respectively; 95%
confidence intervals (CIs), 3.2–25 and 1.8–116, respectively] but
not for venous thrombosis. The presence of anti-protein S Abs was a
significant risk factor for venous thrombosis (OR, 30.4; CI, 3.3–281)
but not for arterial thrombosis. The only significant risk factor for
fetal loss was the presence of anti-annexin V Abs (OR, 5.9; CI,
1.4–14.8).
Conclusions: Patients with SLE frequently have some aPL Abs to ß2-GPI, prothrombin, protein C, protein S, and annexin V. Thrombotic complications in SLE may depend on the antigenic specificities of these Abs, alone or in combination.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SLE patients with both aCL and LA have a high prevalence of arterial and venous thrombosis and thrombocytopenia (21)(22), with an inverse correlation between platelet count and aCL concentrations in LA-positive patients (22). The IgG fraction purified from plasma from SLE patients containing both aCL and LA enhanced the platelet activation triggered by ADP, whereas IgG from plasma containing either aCL or LA had little or no effect (23). These findings suggest that aCL and LA may cooperate to promote platelet activation and participate in the pathogenesis of arterial thrombosis in patients with SLE.
In 1990, three groups of investigators reported simultaneously that aCL was not directed against anionic phospholipids, but it recognized plasma protein ß2-glycoprotein I (ß2-GPI) with an affinity for anionic phospholipid surfaces (24)(25)(26). The epitope for aCL expressed on ß2-GPI changed conformationally by interaction with negatively charged phospholipids or with an oxygen-substituted solid surface (27)(28)(29)(30)(31), whereas LA recognized human prothrombin bound to anionic phospholipids (32)(33)(34). Although ß2-GPI and prothrombin are accepted antigens of aPL Abs (35)(36)(37)(38), aPL Abs may also recognize different complexes of anionic phospholipids and a variety of plasma proteins, including protein C, protein S, and annexin V (39)(40).
In the present study, we examined the prevalence of IgG Abs against
phospholipid-binding plasma proteins (ß2-GPI,
prothrombin, protein C, protein S, and annexin V) in patients with SLE.
Recent studies have indicated that Abs to
ß2-GPI and prothrombin do not recognize the
native forms of ß2-GPI and prothrombin in
plasma, but they do recognize conformationally changed structures of
ß2-GPI and prothrombin after binding to
negatively charged phospholipids
(26)(27)(28)(32)(33)(40).
Moreover, the conformational changes of ß2-GPI
and prothrombin were recently found even when these proteins were bound
to the anionic surface of a -irradiated polystyrene plate in the
absence of phospholipids
(29)(31)(35)(40).
Therefore, we used an ELISA system specific for detecting the aPL Abs,
in which ß2-GPI, prothrombin, protein C,
protein S, and annexin V were directly immobilized on either
-irradiated polystyrene plates or plain polystyrene plates, and
we investigated the relationships between these Abs and thrombotic and
thrombocytopenic complications.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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detection of aCL and LA
aCL was measured by ELISA as reported previously
(21)(22). The cutoff for aCL Abs (398.0
milliabsorbance units) was reported previously
(21)(22). The LA activity was detected with both
the tissue thromboplastin inhibition test and a commercial reagent set
(STACLOT LA test; Diagnostica Stago) as described previously
(21)(22).
measurement of Abs to phospholipid-binding plasma
proteins
-Irradiated polystyrene plates (Maxi-Sorp Nunc-Immunoplates;
Kamstrup) or plain polystyrene plates (Immulon-1; Dynatec) were coated
overnight at 4 °C with 50 µL per well of
ß2-GPI, prothrombin, protein C, protein S
(Diagnostica Stago), or annexin V (Sigma), each suspended at a
concentration of 10 mg/L in Tris-buffered saline (TBS; 50 mmol/L
Tris-HCl, 0.1 mol/L NaCl, pH 7.4). The wells were blocked with 50 µL
of TBS containing 10 g/L bovine serum albumin (Sigma) for 60 min at
room temperature and then washed three times with TBS containing 1 mL/L
Tween 20. A 50-µL plasma sample (diluted 101-fold with 10 mL/L bovine
serum albumin in TBS containing 1 mL/L Tween 20) was added to each
well. After 60 min of incubation at room temperature, the wells were
washed with TBS-Tween. Horseradish peroxidase-conjugated goat
anti-human IgG (-chain specific; cat. no. A-2290) or IgM (µ-chain
specific; cat. no. A-4290) F(ab')2 fragment of
affinity-isolated Ab (Sigma) was used, and the color was developed by
means of tetramethylbenzidine solution (Moss, Inc). The absorbance was
measured at 450 nm. The absorbance of blank wells (i.e., coated only
with TBS) was subtracted from the absorbance in the antigen-coated
wells to account for nonspecific binding. We studied the concentrations
of these aPL Abs in 80 healthy control subjects. The mean + 3 SD of
each Ab in controls was chosen as the cutoff point. The cutoff values
for anti-ß2-GPI, anti-prothrombin, anti-protein
C, anti-protein S, and anti-annexin V Abs were 392.1, 500.8, 499.2,
500.0, and 299.8 milliabsorbance units, respectively. Monoclonal
anti-human ß2-GPI, anti-human prothrombin,
anti-human protein C, anti-human protein S (BML), or anti-human annexin
V (KBC) were used in each plate as a positive control, and selected
control plasma samples were used as a negative control.
statistical analysis
Pearson’s correlation coefficients (r) were calculated
for pairs of Abs. The nonparametric Mann–Whitney test was used to
compare the concentrations of Abs among groups. Fisher’s exact
probability test was used to evaluate the association between the
prevalence of each Ab and clinical complications. As an approximation
of the relative risk, the odds ratio (OR) was calculated for several
putative risk factors by multivariate logistic regression analysis with
the statistical program Stat Flex (Ver. 4.2; Artech Inc.). The variable
that achieved statistical significance in the first analysis was tested
in a second analysis by multivariate logistic regression analysis. An
OR was considered statistically significant when the lower limit of the
95% confidence interval (CI) was >1.0. In the multivariate logistic
regression analysis, a P value <0.05 was considered
statistically significant for risk factors.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-irradiated polystyrene plates were used, the prevalence
of Abs to each of the five plasma proteins in the 168 patients with SLE
was 21–56% (Table 1
). In contrast, none of these Abs was detected in 168 plasma
samples from the SLE patients when plain polystyrene plates were used.
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relationship of LA with Abs to ß2-GPI,
prothrombin, protein C, protein S, and annexin V in SLE patients
LA activity was detected in 83 of the 168 cases (49%) with the
use of both the tissue thromboplastin inhibition and STACLOT LA tests.
When we examined the prevalence of each IgG Ab in LA-positive (n =
83) and LA-negative (n = 85) patients, IgG Abs to prothrombin and
ß2-GPI were detected in LA-positive patients at
a higher rate than in LA-negative patients (71% vs 42% for
anti-prothrombin Abs, P <0.0002; 49% vs 13% for
anti-ß2-GPI Abs, P <0.0001). On the
other hand, the prevalences of IgG Abs to protein C, protein S, and
annexin V were not statistically different between patients with
and without LA (28% vs 15% for anti-protein C Abs; 31% vs 25%
for anti-protein S Abs; 30% vs 28% for anti-annexin V Abs; Fig. 1
).
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We also studied IgM Abs to prothrombin and ß2-GPI. The prevalence of IgM Abs to prothrombin was significantly higher in LA-positive patients than in LA-negative patients (19% vs 2.4%; P <0.0004), whereas there was no significant difference in the prevalence of IgM Abs to ß2-GPI between LA-positive and -negative groups (9.6% vs 5.9%; data not shown).
correlation between the concentrations of Abs
to ß2-GPI, prothrombin, protein C, protein S, and annexin
V in the patients with SLE
In the plasma of 168 SLE patients, a highly significant
correlation was found between the concentrations of aCL and IgG Abs to
ß2-GPI (r = 0.86; P
<0.001; Fig. 2A
). However, the concentrations of aCL showed no significant
correlation with those of IgG Abs to prothrombin (r =
0.23), protein C (r = 0.12), protein S
(r = 0.09), or annexin V (r = 0.10;
data not shown). In addition, there was no significant correlation
between anti-ß2-GPI Abs and anti-prothrombin
(r = 0.26) Abs, anti-protein C Abs (r =
0.21), anti-protein S Abs (r = 0.06), or anti-annexin V
Abs (r = 0.17; data not shown). The concentrations of
IgG Abs to prothrombin correlated significantly with the concentrations
of IgG Abs to protein C (r = 0.61; P
<0.001; Fig. 2B
), as well as to protein S (r = 0.48;
P <0.01; Fig. 2C
). IgG Abs to protein C were significantly
correlated with protein S (r = 0.66; P
<0.001; Fig. 2D
). There were no significant correlations between the
concentrations of IgG Abs to the following combinations: prothrombin
and annexin V (r = 0.18), protein C and annexin V
(r = 0.33), and protein S and annexin V
(r = 0.18; data not shown).
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concentrations of aCL and IgG Abs
to ß2-GPI, prothrombin, protein C, protein S, and annexin
V in SLE patients with or without complications
The 168 SLE patients were divided into five groups according to
their complications: arterial thrombosis (30 cases), venous thrombosis
(19 cases), thrombocytopenia without thrombosis (14 cases), fetal loss
(14 cases), and no thrombotic or thrombocytopenic complications (91
cases). The concentrations of each Ab were examined. As shown in Fig. 3
, the concentrations of aCL were significantly higher in the
patients with arterial thrombosis (1740 ± 196, mean ± SE;
P <0.0001), venous thrombosis (998 ± 229;
P <0.0005), and thrombocytopenia (774 ± 164;
P <0.002) than in those without complications (297 ± 37).
The concentrations of ß2-GPI IgG Abs were
increased significantly in the patients with arterial thrombosis
(1076 ± 140; P <0.0001) and venous thrombosis
(591 ± 132; P <0.0005), but not in the patients with
thrombocytopenia (276 ± 47), when compared with those in the
patients without complications (234 ± 26).
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The mean anti-prothrombin IgG Ab concentration was higher in the patients with arterial thrombosis (809 ± 43; P <0.0001), venous thrombosis (935 ± 98; P <0.0001), and thrombocytopenia (630 ± 61; P <0.04) than in those without complications (419 ± 49), as in the case of aCL. The concentrations of IgG Abs to protein C and protein S were significantly higher in the patients with venous thrombosis (600 ± 68 for anti-protein C, P <0.0001; 901 ± 98 for anti-protein S, P <0.0001) than in the patients without complications (anti-protein C, 315 ± 146; anti-protein S, 372 ± 306), but no statistical difference was observed in the patients with arterial thrombosis (anti-protein C, 375 ± 31; anti-protein S, 409 ± 37), or thrombocytopenia (anti-protein C, 288 ± 30; anti-protein S, 350 ± 51).
Anti-annexin V IgG Abs were higher in the patients with venous thrombosis (380 ± 61; P <0.001) and fetal loss (280 ± 31; P <0.02) as compared with the Abs in the patients without complications (189 ± 11). Thus, among aCL, anti-ß2-GPI, anti-prothrombin, anti-protein C, anti-protein S, and anti-annexin V Abs, only anti-annexin V Abs were significantly higher in the patients with fetal loss.
prevalence of LA, aCL, and IgG Abs to
ß2-GPI, prothrombin, protein C, protein S, and annexin V
in SLE patients with or without complications
LA, aCL, and anti-prothrombin Abs (Fig. 4
) were detected more in the patients with arterial thrombosis
(LA, 93%; aCL, 83%; anti-prothrombin, 97%), venous thrombosis (LA,
79%; aCL, 63%; anti-prothrombin, 95%), and thrombocytopenia (LA,
64%; aCL, 57%; anti-prothrombin, 71%) than in patients without
complications (LA, 29%; aCL, 19%; anti-prothrombin, 37%). There were
no statistical differences in the prevalence of LA, aCL, and
anti-prothrombin Abs among the patients with arterial thrombosis,
venous thrombosis, and thrombocytopenia. On the contrary, the
prevalence of anti-ß2-GPI Abs was significantly
higher in patients with arterial thrombosis (80%; P <0.01)
than in those with venous thrombosis (42%) or thrombocytopenia (21%).
Furthermore, we noted that the prevalences of anti-protein C and
anti-protein S Abs were significantly higher in patients with venous
thrombosis (68% for anti-protein C, P <0.002; 95% for
anti-protein S, P <0.0001) than in those with arterial
thrombosis (23% and 27%, respectively) or thrombocytopenia (0% and
21%, respectively). Interestingly, the prevalence of anti-annexin V
Abs was higher in patients with fetal loss (64%) than in the
patients without complications (18%; P <0.0001; Fig. 4
).
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multivariate logistic regression analysis
The results of the multivariate logistic regression analysis of
risk factors for arterial thrombosis, venous thrombosis, or fetal loss
are shown in Table 2
. In this analysis, all of the values are analyzed as positive
or negative, irrespective of the concentrations of Abs. Both
anti-ß2-GPI Abs and anti-prothrombin Abs were
significant risk factors for arterial thrombosis (ORs, 8.8 and 14.5;
95% CIs, 3.2–25 and 1.8–116 for anti-ß2-GPI
and anti-prothrombin, respectively), but not for venous thrombosis
(ORs, 0.80 and 2.9; 95% CIs, 0.22–3.0 and 0.24–34 for
anti-ß2-GPI and anti-prothrombin,
respectively). On the contrary, the presence of anti-protein S Abs was
a significant risk factor for venous thrombosis (OR, 30.4; 95% CI,
3.3–281), but not for arterial thrombosis (OR, 0.30; 95% CI,
0.09–0.98). The presence of anti-protein C Abs failed to be a
significant risk factor for either arterial (OR, 0.86; 95% CI,
0.25–2.9) or venous (OR, 3.1; 95% CI, 0.88–11) thrombosis in the
patients with SLE. The only significant risk factor for fetal
loss was the presence of anti-annexin V Abs (OR, 5.9; 95% CI,
1.4–14.8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-irradiated polystyrene plates
were used in place of plain polystyrene plates. Because there was no
significant difference in the amount of immobilized antigens in
the plain and -irradiated ELISA plates, we suggest that all of the
aPL Abs found in patients with SLE are specific for a conformationally
changed epitope(s) of each plasma protein.
In accordance with previous findings, the concentration and prevalence
of LA and aCL were significantly higher in the patients with arterial
thrombosis, venous thrombosis, or thrombocytopenia than in those
without complications (21)(22)(23). The prevalence and
concentrations of anti-ß2-GPI Abs were
increased in the patients with arterial thrombosis and venous
thrombosis but not significantly increased in the patients with
thrombocytopenia. The findings that aCL was significantly increased in
the thrombocytopenic patients suggests that thrombocytopenia may be
associated with aPL Abs. However, aPL Abs detected by the aCL ELISA
assay may be different from anti-ß2-GPI Abs. In
fact, although a significant correlation was observed between the
concentrations of aCL detected by the standard ELISA and
anti-ß2-GPI Abs by use of a specific ELISA
system (Fig. 2A
), 22 (34%) of the 65 aCL-positive patients had no
anti-ß2-GPI Abs. These findings raise the
possibility that the aCL ELISA may also detect Abs that are reactive
with some components of human plasma or bovine serum proteins bound to
the cardiolipin-coated wells. Indeed, of these 22 aCL-positive patients
without anti-ß2-GPI Abs, 5 had anti-prothrombin
Abs; 2 had both anti-prothrombin and anti-protein S Abs; 5 had Abs to
each of prothrombin, protein C, and protein S; and 10 had no Abs.
Anti-prothrombin Abs were detected at high concentrations in the SLE patients with arterial thrombosis, as well as in those with venous thrombosis or thrombocytopenia, suggesting that anti-prothrombin Abs may not be specific for each of these complications. On the contrary, both the concentrations and the prevalences of anti-protein C and anti-protein S Abs were significantly higher in the patients with venous thrombosis than in those with arterial thrombosis, thrombocytopenia, or in subjects without complications, whereas the prevalence of anti-ß2-GPI Abs was significantly higher in patients with arterial thrombosis than in those with venous thrombosis. Thus, anti-protein C and/or anti-protein S Abs and anti-ß2-GPI Abs may play a differential role in the occurrence of thrombotic complications, anti-protein C and/or anti-protein S Abs may be associated primarily with venous thrombosis, and anti-ß2-GPI Abs may be associated primarily with arterial thrombosis.
The concentration and prevalence of anti-annexin V Abs were significantly increased in SLE patients with venous thrombosis or fetal loss. In the case of venous thrombosis, 11 of the 19 SLE patients had anti-annexin V Abs, and 9 of these 11 anti-annexin V-positive patients had both anti-protein C and anti-protein S Abs. On the other hand, 9 of the 14 SLE patients with fetal loss had anti-annexin V Abs, but none of these patients showed both anti-protein C and anti-protein S Abs. These results suggest that anti-annexin V Abs might be closely related to fetal loss and that the combined effects of anti-annexin V, anti-protein C, and anti-protein S Abs might play a role in the pathogenesis of venous thrombosis.
The multivariate logistic regression analysis confirmed that the presence of anti-ß2-GPI and anti-prothrombin Abs is an important risk factor for arterial thrombosis. Furthermore, it confirmed that the presence of anti-protein S Abs is a strong risk factor for venous thrombosis. As mentioned above, the prevalence of anti-protein C Abs was also higher in patients with venous thrombosis than in patients with other complications, but it is not an important risk factor for venous thrombosis as indicated by the multivariate logistic regression analysis. This analysis also indicates that only the presence of anti-annexin V Abs is an important risk factor for fetal loss.
Anti-ß2-GPI Abs were reported to be associated with arterial and venous thrombosis and fetal loss in patients with SLE (41)(42)(43), and anti-prothrombin Abs were reported to be associated with venous thrombosis (42)(44)(45). In our study, both the concentrations and prevalences of anti-ß2-GPI and anti-prothrombin Abs were significantly higher in the patients with arterial thrombosis and venous thrombosis than in those without complications. Judging from these results, anti-ß2-GPI and anti-prothrombin Abs seemed associated with both arterial and venous thrombosis. However, multivariate logistic regression analysis of anti-protein C, anti-protein S, and anti-annexin V Abs in addition to anti-ß2-GPI and anti-prothrombin Abs indicated that the presence of anti-ß2-GPI and anti-prothrombin Abs was not a significant risk factor for venous thrombosis because the vast majority of the patients who had anti-ß2-GPI and anti-prothrombin Abs without anti-protein S Abs did not have venous thrombosis. Recently, it was also reported that LA is the strongest risk factor for both arterial and venous thrombosis in patients with SLE (41). As mentioned, LA activity can be produced by anti-ß2-GPI and/or anti-prothrombin Abs. We agree with Horbach et al. (41) that LA is a strong risk factor for arterial thrombosis because our results confirmed that both anti-ß2-GPI and anti-prothrombin Abs were significant risk factors for arterial thrombosis. However, our multivariate logistic regression analysis raises questions about the relationship between LA and venous thrombosis.
In summary, aPL Abs against phospholipid-bound proteins were present in the patients with SLE, and some aPL Abs, alone or in combination, may be associated with the pathogenesis of arterial and venous thrombosis and fetal loss.
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Footnotes |
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References |
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