Prevalence of anti-protein S antibodies in patients with systemic lupus erythematosus

OBJECTIVE: To determine the prevalence of circulating anti-protein S (anti-PS) antibodies in association with PS deficiency in patients with systemic lupus erythematosus (SLE). METHODS: Plasma was obtained from blood samples collected from 27 patients with SLE (5 men, 22 women; mean +/- SD age 32 +/- 10 years). Anti-PS antibodies were detected by immunoblotting according to a previously described method. Levels of free and total PS antigen were measured by enzyme-linked immunosorbent assay. PS activity was assayed by a clotting method. Levels of C4b binding protein (C4bBP) were measured by latex immunoassay. RESULTS: Among 27 patients with SLE, 19 (70.4%) had PS activity, and 12 (44.4%) had PS free antigen below the lower limit established for a normal population (mean -2SD). There was good correlation between PS activity and levels of PS free antigen (r = 0.851, P < 0.001), PS total antigen (r = 0.743, P < 0.001), and C4bBP (r = 0.597, P = 0.001). Circulating anti-PS antibodies and antiphospholipid antibodies (aPL) (IgG type) were detected in 7 (25.9%) and 14 (51.9%) of the 27 patients with SLE, respectively. Only 1 patient (3.7%) had both anti-PS antibodies and aPL. PS activities in patients who were positive for anti-PS antibodies (mean 38.7%) tended to be lower than those in patients who were negative for anti-PS antibodies (mean 54.9%), but the difference was not statistically significant. CONCLUSION: Anti-PS antibodies, independently of aPL, may play a role in the occurrence of PS deficiency in some patients with SLE, with possible effects on the function of PS that do not change the levels of PS antigens.     

Low levels of activated protein C in patients with systemic lupus erythematosus do not relate to lupus anticoagulants but to low levels of factor II

The presence of lupus anticoagulants (LAC) in plasma is a major risk factor for thrombosis. An attractive hypothesis to explain a LAC-mediated thrombotic tendency is that LAC interfere with activation of protein C, a natural antithrombotic in plasma. We investigated the relationship between LAC and protein C activation in vivo. We selected 20 patients with systemic lupus erythematosus (SLE) with LAC (and not using oral anticoagulants), 36 patients with SLE without LAC and 25 healthy volunteers. In these, we measured circulating levels of activated protein C (APC), prothrombin (FII), free protein S, C4BP, protein C, and antibodies to protein C, protein S, FII and beta2-glycoprotein I (beta2GPI). In SLE patients (n = 56), mean levels of APC, FII and free protein S were significantly (P < 0.001) lower than those in healthy volunteers (respectively 13%, 17% and 14%). Mean protein C levels and C4BP levels were similar for SLE patients and healthy volunteers. In contrast to the above hypothesis, the decreased levels of APC could not be attributed to the presence of LAC. Levels of APC were correlated with both FII levels and protein C levels. Decreased levels of APC, FII, protein C and free protein S were related to the presence of anti-FII antibodies. None of the patients had antibodies against protein C or protein S. In conclusion, although the mean levels of APC, FII and free protein S were significantly decreased in SLE patients, no correlation with LAC was found. However, anti-FII antibodies were related to decreased levels of APC, FII, protein C, free protein S and C4BP. As FII levels, and not protein C levels, were decreased in SLE patients and correlated with APC levels, we conclude that the decreased FII levels are responsible for the low levels of APC.     

Natural anticoagulants in systemic lupus erythematosus. Deficiency of protein S bound to C4bp associates with recent history of venous thromboses, antiphospholipid antibodies, and the antiphospholipid syndrome.

The association of thrombosis with antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE) could be due to their interference with natural phospholipid dependent anticoagulant mechanisms. We studied antigenic protein C (APC), functional protein C (FPC), free protein S (FPS), protein S bound to C4 binding protein (C4bp-S), antithrombin III (ATIII), as well as IgG and IgM anticardiolipin antibodies (aCL) in 38 patients with SLE with a history of thromboses and 70 patients with SLE without such history. We found a high frequency of deficiencies of natural anticoagulants in both groups of patients with SLE but, because of patient selection, we could not determine the actual prevalence of these defects. Patients having had a venous thrombosis in the previous year had low C4bp-S more frequently than patients with older or no thromboses. When we divided our patients with SLE into those who had a definite, probable, questionable or no antiphospholipid syndrome (aPS) we found the frequency of C4bp-S deficiency to be significantly higher in those with definite aPS than in those without aPS. Intermediate proportions were found in patients with probable and questionable aPS. The levels of C4bp-S decreased as the levels of aCL, particularly IgG, increased. Stepwise discriminant analysis of natural anticoagulants selected deficiencies of C4bp-S and FPC with increased ATIII as a set of variables with highest predictive power for classification of patients with and without aPS. Thus, deficiencies of natural anticoagulants may occur frequently in patients with SLE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thrombosis risk in systemic lupus erythematosus: the role of thrombophilic risk factors

OBJECTIVES: Thromboembolic episodes are frequent manifestations of systemic lupus erythematosus (SLE). Although the presence of anti-phospholipid antibodies (aPL) is known to contribute to thromboembolism (TE), the relative contribution of other TE risk factors is unknown. The aim of this study was to determine the prevalence of TE in a Caucasian SLE population, to identify the risk factors of highest importance, and to assess the clinical value of thrombophilia screening among SLE patients. METHODS: Samples from 105 patients were analysed with a screen including aPL, activated protein C resistance, factor V Leiden (FVL) and prothrombin G20210A mutations; protein C, protein S and antithrombin activity; factor VIII (FVIII) and von Willebrand factor (vWF), and homocysteine (Hcy) levels. RESULTS: The annual incidence of arterial and venous TE events in our SLE population was 5.4 and 12.4 per 1000, respectively. The highest risk of thrombosis was carried by the simultaneous presence of lupus anticoagulant (LA) and anti-cardiolipin (aCL) [relative risk (RR) = 4.03, 95% confidence interval (CI) 2.06-7.86] or anti-beta2-glycoprotein I antibodies (abeta2-GPI) (RR = 5.10, 95% CI 2.58-10.1). Positivity for the individual aPL tests all carried an elevated TE risk. The presence of other risk factors seemed to be of less importance. CONCLUSIONS: In SLE patients, the presence of aPL is a more significant risk factor for the development of thrombosis than the known inherited deficiencies. Based on these data, routine screening for additional hereditary risk factors seems to be unwarranted.     

Clinical significance of acquired activated protein C resistance in patients with systemic lupus erythematosus

Antiphospholipid antibodies (aPL) may induce acquired activated protein C resistance (acquired APCR). The role of acquired APCR in patients with systemic lupus erythematosus (SLE) is not well known. To evaluate the prevalence of acquired APCR and its association with clinical manifestations we studied 103 consecutive SLE patients and 103 matched controls. APCR in the undiluted test and after dilution in factor V deficient plasma, factor V Leiden, protein C and S, lupus anticoagulant, and anti-cardiolipin, anti-beta2-glycoprotein I and anti-prothrombin antibodies were determined. Factor V Leiden was found in 4% in both patients and controls. The prevalence of acquired APCR was 22% for the undiluted assay and 17% in the diluted test. In SLE patients, acquired APCR was associated with aPL (39 vs 13% in undiluted assay, P = 0.007; and 33 vs 7% in the diluted test, P = 0.001). Arterial thromboses were found in 24% of patients with acquired APCR and in 6% of patients without (P = 0.04). However, no relationship was found with venous thrombosis. Acquired APCR was also associated with pregnancy losses: miscarriages in 70% of women with acquired APCR vs 32% in those without (P=0.03). Thus, in SLE patients acquired APCR seems to be associated with increased prevalence of arterial thrombosis and pregnancy losses.     

Determinants of enhanced thromboxane biosynthesis in patients with systemic lupus erythematosus

OBJECTIVE: To evaluate the rate of thromboxane biosynthesis in patients with systemic lupus erythematosus (SLE), exploring the interplay between antiphospholipid antibodies (aPL) and 2 markers of endothelial perturbation: thrombin generation and platelet activation. METHODS: A comparison of 11-dehydrothromboxane B2 (TXB2) excretion, which is a marker of in vivo platelet activation, aPL, von Willebrand factor (vWF) and tissue plasminogen activator (tPA), which are 2 circulating markers of endothelial perturbation, and plasma levels of the prothrombin fragment F1+2, which is a marker of thrombin generation, was performed in 40 SLE patients and 40 healthy subjects. Thromboxane metabolite excretion was also measured in 8 SLE patients before and after treatment with low-dose aspirin. RESULTS: SLE patients had significantly higher 11-dehydro-TXB2 excretion, plasma F1+2, vWF, and tPA levels than controls. A statistically significant correlation was found between plasma levels of vWF and tPA and excretion of thromboxane metabolite. Moreover, significantly higher 11-dehydro-TXB2 was found in patients with aPL positivity and endothelial perturbation. Low-dose aspirin suppressed 11-dehydro-TXB2 by 80%, suggesting a predominant platelet source of enhanced thromboxane biosynthesis. After a median followup of 48 months, all SLE patients who experienced major cardiovascular events had thromboxane metabolite excretion, aPL positivity, and signs of endothelial perturbation. CONCLUSION: We have characterized a sensitive marker of platelet activation, which is abnormal in SLE patients who were positive for aPL and endothelial perturbation. This analytical approach may help identify those patients at increased risk of thrombosis as potential candidates for antiplatelet therapy.     

Homocysteine, antiphospholipid antibodies and risk of thrombosis in patients with systemic lupus erythematosus

Cardiovascular disease is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Antiphospholipid syndrome (APS) is one of the most important causes of thrombosis in SLE. In addition, an association between hyperhomocysteinemia and increased cardiovascular risk has also been reported. Our aim is to analyse the association of thrombosis with plasma total homocysteine (ptHcy), antiphospholipid antibodies (aPL) and other vascular risk factors in SLE patients. Fasting plasma levels of ptHcy, vitamin B12, folate, total cholesterol and creatinine were measured in 117 SLE patients. Clinical and immunological data were obtained from our prospective computerized database. aPL-positivity was defined according to Sapporo criteria. There was no association between aPL and ptHcy. ptHcy was higher in patients with arterial (median 13.02 versus 10.16 micromol/L, P = 0.010) but not venous thrombosis. In the subgroup analysis, this association was only seen in aPL-negative patients. In logistic regression, aPL (OR 6.60, 95% CI 1.86-23.34) and ptHcy (OR 1.10, 95% CI 1.01-1.19) were independently associated with arterial thrombosis. However, when hypertension, smoking and plasma total cholesterol were added to the model, only aPL (OR 7.38, 95% CI 2.02-26.91) and hypertension (OR 7.70, 95% CI 2.33-25.39), but not ptHcy, remained independently related to arterial events. aPL was the only variable independently related to venous thrombosis (OR 7.68, 95% CI 1.60-36.86). ptHcy concentrations are higher in SLE patients with arterial thrombosis. No interaction between homocysteine and aPL was found. Raised ptHcy may be a marker of increased vascular risk in aPL-negative SLE patients. The role of homocysteine as a marker of vascular risk may depend on the presence of traditional risk factors, although a modest intrinsic effect cannot be entirely excluded.     

Regulation of coagulo-fibrinolytic activity and lupus anticoagulants in systemic lupus erythematosus

We determined the following coagulo-fibrinolytic activities in 24 patients with systemic lupus erythematosus (SLE) and 20 healthy adults: prothrombin time (PT), activated partial thromboplastin time (A-PTT), factor VIII: coagulant activity), von Willebrand factor antigen (vWF: Ag), antithrombin-III (AT-III), plasminogen (PLG), alpha 2 plasmin inhibitor (alpha 2 PI), alpha 2-plasmin inhibitor-plasmin complex (PIC), protein C (PC: activity and antigen concentration), and protein S (PS: total PS and free PS). PLG, AT-III, PC antigen concentration and total PS were significantly decreased in ten female controls as compared with ten male controls. Therefore, we used the ten healthy females as controls and excluded two male SLE patients in the analysis of the correlations of coagulo-fibrinolytic activities with lupus anticoagulant (LA), clinical and laboratory features in 22 female patients with SLE. In the SLE patients, PT was significantly shortened, while A-PTT was prolonged. PLG, PC activity and antigen, and total PS were significantly increased, and free PS levels were decreased in SLE. The shortened PT and decreased free PS suggest hypercoagulable states in SLE patients. A significant prolongation of A-PTT and a decrease of F VIII activity were observed in the six LA-positive SLE patients, and the results were considered as known effects of LA. Furthermore, vWF: Ag, AT-III and PC antigen levels were significantly increased in the LA-positive patients as compared with LA-negative patients. These changes indicate both vascular endothelial cell damages and a compensatory increase in coagulation inhibitors in the LA-positive patients.     

Oral contraceptives and gender affect protein S status

Protein S is a plasma protein that serves as a cofactor for the anticoagulant effects of activated protein C. Congenital protein S deficiency is often associated with thromboembolic disease. During pregnancy a decrease in the functional and antigenic levels of protein S occurs; this change in protein S status may contribute to the thromboembolic complications that sometimes occur during pregnancy. In certain patients, oral contraceptive use has also been associated with thrombotic complications. In this study, protein S status was determined in 21 women taking oral contraceptives and compared with that of 21 women not taking oral contraceptives and that of 21 men. The results show that women taking oral contraceptives have significantly lower total protein S (24.3 +/- 3.6 micrograms/mL; mean +/- SD) than women not taking oral contraceptives (28.6 +/- 3.9 micrograms/mL) (P less than .005). Men had significantly higher protein S levels (30.9 +/- 3.9 micrograms/mL, P less than .01) than age-matched women not taking oral contraceptives. In plasma, an equilibrium exists between free (functionally active) protein S and protein S complexed to C4b-binding protein, which is functionally inactive. The mean levels of C4b-binding protein were essentially the same among the three groups, but the levels of free protein S were significantly different and reflected different total protein S antigen levels. Additionally, we found that inflammation significantly elevated C4b-binding protein levels and could result in a further significant decrease in free protein S levels. These data indicate that plasma protein S levels are significantly affected by hormonal status and inflammation.     

Increase in plasma thrombin-activatable fibrinolysis inhibitor may not contribute to thrombotic tendency in antiphospholipid syndrome because of inhibitory potential of antiphospholipid antibodies toward TAFI activation

The causes of thrombosis in antiphospholipid syndrome (APS) remain unknown, though several hypotheses in regard to hypofibrinolysis have been proposed. To clarify the mechanism, we measured plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) in APS patients. Both the TAFI antigen (TAFI:Ag) level measured with an ELISA, and thrombin-thrombomodulin-dependent TAFI activity (TAFI:Ac) were elevated in 68 APS patients as compared with those in 66 healthy controls, though they were lower than those in 46 patients with autoimmune diseases. As for the influence of antiphospholipid antibodies (aPL) on TAFI levels, the mean TAFI:Ac level in 39 SLE patients positive for APS was significantly lower than that in 27 SLE patients without APS, whereas there was no difference in TAFI:Ag between those groups. Furthermore, purified IgG from patients positive for aPL, and monoclonal aPL (EY2C9 and 23-1D) inhibited the activation of TAFI in a concentration dependent manner. These results suggest that aPL inhibits TAFI activation by affecting the function of thrombomodulin-thrombin complex through phospholipids. Although TAFI in plasma is elevated in autoimmune diseases including APS, we concluded that an elevated level is not likely a risk factor for thrombosis in APS patients, because of the inhibition of TAFI activation by aPL.     

Acquired activated protein C resistance is associated with the co-existence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus

Venous thromboembolism (VTE) is one of the common manifestations in the anti-phospholipid (aPL) syndrome. We examined the levels of IgG antibodies (Abs) to beta2-glycoprotein I (beta2-GP I) and prothrombin, lupus anticoagulant (LA) activity, activated protein C resistance (APC-R), and factor V Leiden in 96 patients with systemic lupus erythematosus (SLE); 19 with VTE and 77 without VTE. Acquired APC-R, which was not found in any patient with the factor V Leiden mutation, was present in 33 (34.4%) out of the 96 patients with SLE. The presence of acquired APC-R was a strong risk factor for VTE. The SLE patients were divided into four groups according to the results of enzyme-linked immunosorbent assay (ELISA) and LA activity for each aPL Abs: ELISA+, LA+; ELISA+, LA-; ELISA-, LA+; and ELISA-, LA-. A significant association was observed between APC-R and the co-existence of anti-beta2-GP I Abs and LA activity or of anti-prothrombin Abs and LA activity. There was no association between APC-R and the presence of anti-beta2-GP I Abs, anti-prothrombin Abs, or LA activity alone. However, when multivariate logistical regression analysis was performed, it was clear that only the co-existence of anti-prothrombin and LA activity was a significant risk factor for APC-R. These findings indicate that the co-existence of anti-prothrombin Abs and LA activity may be an important factor in the pathogenesis of acquired APC-R in patients with SLE.     

Differential regulation of alpha and beta chains of C4b-binding protein during acute-phase response resulting in stable plasma levels of free anticoagulant protein S

Regulation of C4b-binding protein (C4BP) isoforms during acute phase and its relationship to the plasma concentration of free protein S was elucidated. An assay for beta chain containing C4BP (C4BP beta+) was developed and the concentrations of total C4BP, C4BP beta+, total, free, and bound protein S were measured in patients with acute-phase response. Even though total C4BP was increased to 162% (mean value) of controls, the corresponding value of C4BP beta+ was only 122%. In the acute-phase group, total protein S was increased to the same extent as C4BP beta+ (mean value of 124%), whereas free protein S was not decreased. In controls, total and bound protein S correlated with total C4BP and C4BP beta+. However, in the acute-phase group, the correlation between bound protein S and total C4BP was lost, although the correlation between C4BP beta+ and protein S remained. The present results suggest stable levels of free protein S during acute phase to be the result of differential regulation of C4BP alpha- and beta-chain expression, and the concentration of free protein S to be the resulting molar excess of protein S over C4BP beta+. This mechanism ensures functional levels of free anticoagulant protein S despite high levels of C4BP.     

Effects of danazol on plasma levels of protein S C4b-binding protein

In order to elucidate the response of protein S (PS) and C4b-binding protein (C4bp) to danazol, we investigated the serial changes in plasma levels of PS and C4bp during danazol administration in 4 patients with endometriosis. Both total and free PS levels were significantly increased at the time of 2 to 3 weeks after danazol administration as compared to the pretreatment values, while C4bp levels were not changed at all. These results imply that danazol administration to PS deficiency would produce a significant increase in the basal level of free PS, suggesting a potential adjunct to anticoagulant treatment in PS deficiency.     

Antiphospholipid antibodies (aPL) in systemic lupus erythematosus. Are they specific tools for the diagnosis of aPL syndrome?

OBJECTIVE--Antiphospholipid antibody (aPL) specificity for aPL-related events was evaluated in systemic lupus erythematosus (SLE). METHODS--A study was carried out on 105 patients affected with SLE comparing the prevalence of lupus anticoagulant (LA) and IgG and IgM anticardiolipin antibodies (aCL) between patients with and without features of antiphospholipid syndrome (APS). Antiphospholipid antibody profile was subsequently evaluated in the aPL positive patients with and without aPL-related events, thus excluding the patients with complications of APS possibly due to factors other than aPL. RESULTS--LA showed a strong association with thrombosis and livedo reticularis, and IgG aCL with thrombosis and neurological disorders, while no clinical features were associated with IgM aCL. A considerable number of aPL positive patients with no aPL-related manifestations was also observed, suggesting the low specificity of aPL assays (54.4%). When studying the 60 aPL positive patients, LA was specific (91.3%) for the diagnosis of aPL-related thrombosis, whereas aCL were not specific, although IgG aCL mean levels were higher in patients with arterial thrombosis than in those without APS features. CONCLUSIONS--LA but not aCL positivity is a specific tool for the diagnosis of thrombotic complications due to aPL in SLE.     

Decrease in serum antiphospholipid antibody levels upon development of nephrotic syndrome in patients with systemic lupus erythematosus: relationship to urinary loss of IgG and other factors.

PURPOSE: Having observed a decrease in antiphospholipid antibodies (aPL) upon the development of nephrotic syndrome, as well as a negative association between nephrotic syndrome and secondary antiphospholipid syndrome, in patients with systemic lupus erythematosus (SLE), we sought to determine if this could be due to urinary loss of aPL and/or other factors. SUBJECTS AND METHODS: IgG and IgM aPL as well as other autoantibodies were studied by enzyme-linked immunosorbent assay with cardiolipin as antigen in serum and urine from six patients with SLE who had elevated serum aPL levels and developed nephrotic syndrome (cases). For controls, we studied: (1) three SLE patients with nephrotic syndrome but low aPL levels; (2) three patients with non-SLE nephrotic syndrome; (3) three SLE patients with high-titer aPL but no proteinuria; and (4) 10 healthy volunteers. RESULTS: We found urinary IgG, but no IgM, aPL in all cases and in one control from Group 2. Serum IgG aPL had gradually decreased after the development of nephrotic syndrome and had become normal. IgM aPL had also decreased in the four patients who had elevated levels, having reached normal levels at the time of the study in two. There was an apparent correlation between serum and urine IgG aPL levels but not between urinary IgG aPL and total proteinuria. By Farr's method, we found no urinary anti-DNA despite high serum titers in three cases. The two cases and one of the controls in Group 1 who had serum antibodies to extractable antigens also had these antibodies in the urine. CONCLUSION: Urinary loss of IgG aPL during nephrotic syndrome does not completely explain the reduction in serum aPL, since IgM also decreases. There could also be decreased synthesis and/or increased catabolism of immunoglobulins.     

Serum thrombomodulin and anticardiolipin antibodies in patients with systemic lupus erythematosus.

Since thrombomodulin (TM) is a specific cell surface glycoprotein for vascular endothelial cells, serum TM (s-TM) might be a useful marker of endothelial cell damage. Antiphospholipid antibodies (aPL) frequently detected in systemic lupus erythematosus (SLE) have been associated with vascular occlusive diseases. Therefore we measured the s-TM in 60 patients with SLE, in 23 patients with other diseases including aPL (disease control group) and in 26 healthy subjects, by means of an enzyme immunoassay using monoclonal antibodies to human TM. A significant positive correlation was found between s-TM and serum creatinine levels in SLE patients (r = 0.813, p less than 0.001). When the s-TM level was divided by the serum creatinine level (TM/Cr) to exclude the effect of renal clearance, the TM/Cr ratios were significantly increased in SLE patients with active lupus nephritis (LN) compared to those without LN (p less than 0.05). The ratios did not correlate with the presence of aPL or antiphospholipid antibody syndrome (APLS) in SLE patients or in the disease control group, although a weak correlation between the TM/Cr ratios and IgG-anticardiolipin antibody titers was found in the SLE patients without LN (r = 0.449, p less than 0.01). The present results suggest that elevated TM/Cr ratios reflect renal and possibly extra-renal endothelial cell damage in SLE patients with active LN, but that s-TM levels do not associate with the presence of aPL or a history of APLS.     

Autoantibodies against C-reactive protein: clinical associations in systemic lupus erythematosus and primary antiphospholipid syndrome

OBJECTIVE: To investigate the prevalence of anti-C-reactive protein (CRP) autoantibodies in patients with systemic lupus erythematosus (SLE) and non-SLE patients with persistent antiphospholipid antibodies (aPL) and their association with clinical manifestations. METHODS: Sera of 137 patients with SLE, 127 with persistent aPL and 30 with idiopathic venous thromboembolic disease, were assayed for the presence of anti-CRP reactivity by ELISA. Associations of anti-CRP reactivity with clinical features, with other autoantibodies, and with serum concentrations of C3 and CRP were assessed. RESULTS: Antibodies against CRP were seen in 51% (n = 137) of patients with SLE and in 54% (n = 127) of patients with aPL. SLE patients with anti-CRP antibodies showed increased frequencies of anti-dsDNA and aPL antibodies compared to those without anti-CRP (52% vs 26% and 68% vs 31%, respectively). Mean serum C3 levels were lower in the subgroup of patients with SLE positive for anti-CRP antibodies (79 +/- 25 vs 92 +/- 25 mg/dl; p = 0.004 ) and mean serum CRP levels were significantly higher (13 +/- 17 vs 5 +/- 8 mg/l; p = 0.01 ). The frequency of nephritis was higher in SLE patients with anti-CRP antibodies, than in those without (27% vs 13%; p = 0.058). In patients with clinical and serological evidence of antiphospholipid syndrome (APS) the frequency of anti-CRP antibodies was significantly higher than in asymptomatic aPL carriers, in both SLE patients [85% (23 of 27) vs 59% (19 of 32); p = 0.021] and non-SLE patients [76% (38 of 50) vs 19% (9 of 47); p < 0.001]. Among patients with APS with or without SLE, 26 had arterial events, 31 had venous events, 6 had combined arterial and venous events, and 14 had fetal loss. Mean titers of IgG anti-CRP (29 +/- 21, 30 +/- 19, 60 +/- 37, and 26 +/- 12 AU/ml) and frequencies of anti-CRP antibodies (88%, 71%, 50%, and 71%) in these subgroups of patients were comparable. CONCLUSION: We confirmed the high prevalence of anti-CRP autoantibodies both in patients with SLE and in non-SLE and aPL-positive patients. We observed that the presence of these antibodies was associated with lupus nephritis and with clinical features of the APS in patients with lupus and non-lupus patients.     

Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus

OBJECTIVE: Different prevalences of antiphospholipid antibodies (aPL) have been reported in different populations of patients with systemic lupus erythematosus (SLE). Chinese are generally believed to have lower risk of vascular thrombosis. We examined the prevalence of aPL including lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies, the level of thrombotic risk, and the association of aPL with thrombotic and pregnancy outcomes in a Chinese cohort with SLE at the university lupus clinic during the period 1986-2003. METHODS: aPL were measured in 272 SLE patients, and medical records were reviewed for vascular thrombosis and pregnancy outcomes. RESULTS: The prevalence of LAC, IgG aCL, and IgG anti-beta2-GPI antibodies was 22.4%, 29.0%, and 7.7%, respectively. There were 38 episodes of thrombosis after a mean duration of followup of 11.0 +/- 6.8 SD years, giving a thrombotic rate of 1.26/100 patient-years. All aPL were shown to be associated with vascular thrombosis. IgG anti-beta2-GPI antibodies were found to be associated with recurrent thrombosis [8.0/100 patient-years or 25.0% (7/28)]. Patients taking hydroxychloroquine were found to have fewer thrombotic complications than those who were not (OR 0.17, 95% CI 0.07-0.44; p < 0.0001). LAC was the strongest factor associated with recurrent miscarriages [relative risk 12.3, 95% CI 1.22-123.31; p = 0.03). The diagnosis of secondary antiphospholipid syndrome was satisfied in 8.9% of patients. CONCLUSION: The lifetime and recurrent thrombotic rates in our patients with aPL were not particularly different from those in the literature. However, the lower prevalence of aPL in our cohort may suggest a role of other prothrombotic factors in predisposition to thrombosis.     

Protein S deficiency occurs in the nephrotic syndrome

Protein S activity may be compromised in patients with the nephrotic syndrome and contribute to a thrombotic diathesis. Protein S is found in two forms in plasma as free and functionally active protein S, and complexed to C4b-binding protein. When compared with controls, patients with nephrotic syndrome had reduced functional levels of protein S (69% +/- 27% [SD], p less than 0.001) despite having elevated levels of total protein S antigen (139% +/- 42%, p less than 0.001). Decreased protein S activity was caused by significant reductions in free (active) protein S levels (90% +/- 38%, p less than 0.05) due to the selective urinary loss of free protein S and elevation of C4b-binding protein levels (170% +/- 52%, p less than 0.001) that favors complex formation; and in the specific activity of the circulating free protein S (0.76; p less than 0.001). Along with this reduction in specific activity, we noted the abnormal electrophoretic mobility of the protein S in the presence of calcium ions. We conclude that acquired protein S deficiency occurs in the nephrotic syndrome and may be a risk factor for the development of the thromboembolic complications.     

Potential for glomerular C4d as an indicator of thrombotic microangiopathy in lupus nephritis

OBJECTIVE: In patients with systemic lupus erythematosus (SLE) and lupus nephritis, the presence of antiphospholipid antibodies (aPL) is considered to be an indication of increased risk of thrombotic microangiopathy, a serious complication of SLE. Previous studies have demonstrated a critical role for activation of the classical pathway of complement that leads to thrombotic injury in the presence of aPL. This study was undertaken to investigate whether C4d deposition in lupus nephritis is related to circulating aPL and the presence of renal microthrombi. METHODS: Deposition patterns of C4d in 44 renal biopsy samples obtained from 38 patients with biopsy-proven lupus nephritis were determined by staining with a polyclonal anti-C4d antibody. A phosphotungstic acid-hematoxylin stain was used to identify fibrin microthrombi. Clinical data (serum creatinine levels and presence or absence of aPL) were obtained and correlated with findings in the renal biopsy specimens. Patients were categorized as having aPL (n = 20) or not having aPL (n = 18). RESULTS: A strong relationship between the intensity of glomerular C4d staining and the presence of microthrombi was found (P < 0.002). Intense glomerular C4d deposition was present in 7 of 8 biopsy samples showing renal microthrombi. Neither C4d deposition nor the presence of microthrombi was correlated with aPL status. CONCLUSION: Our findings suggest that activation of the classical pathway of complement plays a pathogenic role in the development of renal tissue injury leading to thrombosis, irrespective of the type of circulating antibodies present. Immunodetection of glomerular C4d deposition in renal biopsy samples could be a convenient method of identifying patients at risk of thrombotic microangiopathy.