Selection of patients with the antiphospholipid syndrome by serological measurement of lupus anticoagulant activity in conjunction with anticardiolipin antibodies

Summary The significance of anti-cardiolipin antibodies (ACLA) in patients with a range of autoimmune and infective disorders was investigated in this study. Although lower levels of IgG and IgM ACLA were present in 77 of 400 patients' sera (19%), high antibody levels were found in < 5% of patients. These latter patients belonged to three clinical categories: patients with connective tissue disease (CTD), infectious mononucleosis or biological false positive serology. An assay was developed to measure lupus anticoagulant (LA) activity in serum: significant LA activity was found in the CTD patients alone (in 6 of 15 tested) and all of these had high titre ACLA. Features of the antiphospholipid syndrome (APS) were present in these six patients but also in three additional CTD patients with normal LA results and high levels of ACLA. In two CTD patients with APS features, the high ACLA were of IgM isotype. These results stress the importance of measuring both ACLA and LA in an investigation of the APS: a high positive ACLA supports the diagnosis of APS, particularly in patients with autoimmune disease, whilst a high positive ACLA in association with LA activity is specific for this syndrome.     

Anti-platelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody syndrome: their relationship with the observed thrombocytopenia

The role of antiphospholipid antibodies in the pathogenesis of the thrombocytopenia observed during primary antiphospholipid antibody syndrome (APAS) and systemic lupus erythematosus (SLE) remains controversial. We have used the MAIPA test to examine the frequency and specificity of anti-platelet antibodies directed against the major platelet membrane glycoproteins (GP IIb–IIIa, GP Ib–IX, GP Ia–IIa and GP IV) in patients where SLE and APAS were associated or not with thrombocytopenia. Results were compared with a series of 26 ITP patients, 46% of whom were shown to possess anti-platelet antibodies directed against one or more of the platelet surface glycoproteins. When APAS was associated with thrombocytopenia, 7/10 patients possessed antibodies against GP IIb–IIIa and/or GP Ib–IX. For SLE patients with thrombocytopenia, 6/10 patients were shown to have antiplatelet antibodies against GP IIb–IIIa, GP Ib–IX or GP IV. In contrast, for APAS ( n =11) and SLE patients ( n =11) without thrombocytopenia, only one patient had an antibody directed against GP IIb–IIIa and one patient had an antibody to GP IV. Our results suggest that antibodies directed against major platelet membrane glycoproteins may play a role in the thrombocytopenia that is seen during SLE and APAS.     

Clinical associations of anti-endothelial cell antibodies in patients with systemic lupus erythematosus

The aim of this study was to define the clinical associations of anti-endothelial cell antibody (AECA) in systemic lupus erythematosus (SLE) patients by measuring serum AECA titers to correlate with the disease activity and clinical manifestations. Forty-one SLE patients and 27 controls were studied. Serum samples were collected at the time of patient presentation with disease exacerbation and 4 weeks after the start of treatment. The disease activity was evaluated by the SLE Disease Activity Index (SLEDAI). AECA was detected by enzyme-linked immunosorbent assay (ELISA) methods with the surface antigen of the immortalized human microvascular endothelial cell line (HMEC-1). The mean immunoglobulin (Ig)G-AECA and IgM-AECA optical densities (ODs) were significantly higher in patients with SLE compared with controls [mean ± standard deviation (SD), 0.32 ± 0.15 vs 0.18 ± 0.16 and 0.29 ± 0.14 vs 0.21 ± 0.09, respectively]. There was a positive correlation between IgG-AECA and the SLEDAI scores. The positivity rate of AECA in the groups with digital vasculitis, neuropsychiatric lupus, and anti-cardiolipin antibody was significant. In conclusion, AECA may be involved in the pathogenesis of SLE and was correlated with the disease activity. It was also associated with clinical manifestations such as digital vasculitis, neuropsychiatric lupus, and anti-cardiolipin antibody positivity. Received: 10 January 2000 / Accepted: 4 May 2000     

Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody

We investigated anti-annexin V antibody (aANX) in patients with systemic lupus erythe-matosus (SLE), and correlated to positivity with lupus anticoagulant (LA)/anticardiolipin antibody (aCL). aANX was positive in 12/47 SLE patients (26%), including 7 with β₂-glycoprotein 1 (GPl)-dependent aANX. The positivity of aANX was higher in patients with aCL (19%) and LA/aCL (50%) than in those without LA/aCL (10%). From these results, it is concluded that aANX is an autoantibody closely related to LA/aCL, and can be a possible new risk marker for thrombosis. © 1994 Wiley-Liss, Inc.     

Pregnancy in systemic lupus erythematosus and antiphospholipid syndrome

Systemic lupus erythematosus (SLE) is the autoimmune disease that most commonly compromises pregnancy. Moreover, the relationship between SLE and pregnancy is in both directions. However, the current experience indicates that pregnancy in patients with SLE should not be regarded as an unacceptable high risk condition for the mother or her baby provided that careful planning of conception and multidisciplinary monitoring and treatment are carried out.     

Idiopathic portal hypertension associated with systemic lupus erythematosus

A case of idiopathic portal hypertension (IPH) associated with systemic lupus erythematosus (SLE) is reported in a 38-year-old man who had been diagnosed with SLE and treated for 18 years. Esophageal varices, found in 1994 on endoscopic examination, had been followed up for 2 years. On July 16, 1996, he was admitted to Nagoya University Hospital because there was a high risk of bleeding from the esophageal varices due to severe thrombocytopenia. As partial splenic embolization had temporarily controlled the thrombocytopenia, splenectomy and devascularization of the stomach vessels were performed after endoscopic ligation of the esophageal varices. Histological specimens of wedge biopsied liver showed chronic inactive hepatitis without cirrhosis. The presence of anticardiolipin antibody, indicated by positivity for lupus anticoagulant, was suggestive of the presence of a common immunological mechanism in the etiology of SLE and IPH. Received: January 20, 1999 / Accepted: July 23, 1999     

Clinical audit of antiphospholipid antibody testing in tertiary practice: towards improved relevance in thrombophilia investigations

Background: The antiphospholipid syndrome (APS) is an autoimmune condition characterised by vascular thromboses and/or pregnancy morbidity. Diagnosis of APS typically requires laboratory evidence of antiphospholipid antibodies (aPL). Depending on their clinical presentation, affected individuals might be seen by a variety of clinical specialities. Aim: To evaluate clinical ordering patterns for aPL/APS at a tertiary level public facility. Methods: We performed an audit of internal clinical requests for aPL tests at our institution for a 6‐month period. Results: We identified a wide variety of clinical ordering background for aPL, of predominantly obstetric (72/268; 26.9%) or thrombophilic (78/268; 29.1%) patients. Only 11/268 samples (4.1%) were positive for lupus anticoagulant (LA) and 14/268 (5.2%) were positive for anticardiolipin antibody (aCL). The percentage of aCL positivity in the LA‐positive group was 46% (5/11). None of the 72 obstetric patients tested was identified to have aPL. Of the 11 LA‐positive patients, the reasons identified for testing comprised: prolonged Activated Partial Thromboplastin Time (assay) (n= 3), thrombosis (n= 3), APS (n= 2), systemic lupus erythematosus (n= 2), vasculitis (n= 1). Conclusion: We determined a wide variety of clinical ordering background for aPL at a tertiary level institution, with an overall low rate (<10%) of aPL positivity among a hospital population of predominantly obstetric or thrombophilic patients. That no positive obstetric aPL cases were identified suggests local clinical ordering guidelines may need review, as also potentially practised at other institutions. We also observed a moderate rate (46%) of coincidence of aCL and LA, in agreement with guidelines indicating that multiple tests are required to identify APS.     

Multiorgan failure due to rapid occlusive vascular disease in antiphospholipid syndrome: the ‘catastrophic’ antiphospholipid syndrome

The term ‘catastrophic’ antiphospholipid syndrome (CAPS) is defined as an accelerated form of antiphospholipid syndrome (APS) usually resulting in multiorgan failure. These patients have in common: (i) clinical evidence of multiple organ involvement developing in a very short time period; (ii) histopathological evidence of multiple small vessel occlusions (a minority also have large vessel thrombosis); and (iii) laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titres. Although less than 1% of patients with the APS develop this complication, its potentially lethal outcome emphasizes its importance in clinical medicine.     

Risk of arterial thrombosis in patients with anticardiolipin antibodies and lupus anticoagulant

The relationship between arterial or venous thrombosis and the levels of anticardiolipin antibodies (aCL) and/or existence of lupus anticoagulant (LA) was studied. The 141 patients with systemic lupus erythematosus (SLE) were divided into four groups: aCL single positive (25 cases), LA single positive (11 cases), aCL and LA double positive (25 cases), aCL and LA double negative (80 cases). The prevalence of thrombosis was higher in aCL and LA double positive patients (21/25 cases, 84.0%, P  < 0.01) than that in aCL single positive patients (4/25 cases, 16.0%), LA single positive patients (1/11 cases, 9.1%) and double negative patients (3/80 cases, 3.8%). Furthermore, in these double positive patients, all patients (10/10 cases) with a high positive level of aCL (>10 units/ml) had arterial thrombosis, whereas only 2/15 patients (13.3%) with a low positive level of aCL (3–10 units/ml) were affected. Venous thrombosis was frequently found in the low positive group (9/15 cases, 60.0%). On the contrary, none of 105 LA negative patients had arterial thrombosis and only seven (6.7%) had venous thrombosis. These findings indicate that a high aCL activity combined with a LA positive result might be a risk factor for arterial thrombosis.     

Strongyloides stercoralis hyperinfection in systemic lupus erythematosus and the antiphospholipid syndrome

OBJECTIVE: The Strongyloides stercoralis hyperinfection syndrome (SHS) may develop in individuals with asymptomatic infection receiving immunosuppressive treatment. This report summarizes current knowledge regarding SHS in patients with systemic lupus erythematosus (SLE) and associated antiphospholipid syndrome (APS). METHODS: Two patients with active SLE and associated APS presenting with SHS are reported. Additional cases of strongyloidiasis in SLE were identified and reviewed. RESULTS: Patient 1: A 34-year-old woman with SLE and APS characterized by active glomerulonephritis, stroke, and several hospital-acquired infections presented with vomiting and diffuse abdominal pain. Intestinal vasculitis was suspected, and treatment with methylprednisolone and cyclophosphamide was given. Response was partial. A gastric biopsy revealed S. stercoralis larvae. She received ivermectin and eventually recovered. Patient 2: A 37-year-old man with active glomerulonephritis and APS with recurrent thrombosis presented with digital necrosis. Necrotizing vasculitis was suspected and treated with immunosupressants. He suddenly developed respiratory failure secondary to alveolar hemorrhage and bronchoalveolar lavage was performed. The patient developed Gram-negative septic shock and died. The postmortem result of bronchoalveolar lavage yielded Strongyloides larvae. Nine cases of strongyloidiasis and the SHS in SLE patients reported in the literature were identified and reviewed. Five of these patients died; none had associated APS. CONCLUSIONS: These cases suggest that the SHS can exacerbate SLE and APS, predisposing to Gram-negative sepsis and death. Immunocompromised patients need an early diagnosis and specific treatment of parasitic diseases and their complications. The SHS should be considered in the differential diagnosis of lupus complications in patients from endemic areas.     

Characterization of IgG monoclonal anti-cardiolipin/anti-beta2GP1 antibodies from two patients with antiphospholipid syndrome reveals three species of antibodies

Antiphospholipid antibodies (aPL), including antibodies detected in anti-cardiolipin (aCL) enzyme-linked immunosorbent assays and in lupus anticoagulant (LA) tests, are strongly associated with recurrent thrombosis and recurrent fetal loss, i.e. the antiphospholipid syndrome (APS). Although recent studies suggest that most APS-associated aCL are directed against the phospholipid (PL)-binding plasma protein beta2-glycoprotein 1 (beta2GP1), the precise nature of aCL binding specificities remains controversial. To address the issue of aCL specificity we generated five new monoclonal IgG aCL from two patients with APS. Characterization of these five aCL, as well as two previously published IgG aCL, revealed three patterns of reactivity: (1) four antibodies reacted strongly with human beta2GP1-cardiolipin (CL) complexes and weakly with human beta2GP1 alone; (2) two antibodies recognized bovine beta2GP1, but not human beta2GP1; (3) one antibody reacted with complexes of human beta2GP1 and CL, but not with human beta2GP1 alone. Only one monoclonal displayed weak LA activity. These patient-derived IgG monoclonal antibodies, and additional ones to be generated, may help define varying species of antibodies detected in aCL assays and identify the specific antibodies that may be pathogenic.     

Clinical significance of anti-annexin V antibodies in patients with systemic lupus erythematosus

Annexin V has a calcium-dependent binding affinity for anionic phospholipids and activated platelets, and prevents prothrombinase activity. We investigated the clinical significance of IgG anti-annexin V antibodies in patients with SLE. The study population consisted of 140 patients with SLE. Sera were examined for IgG anti-annexin V antibodies by ELISA. IgG anti-annexin V antibodies were detected in 27 of 140 patients (19%). Significantly higher incidences of arterial or venous thrombosis, intrauterine fetal loss, and prolonged activated partial thromboplastin time were found in patients with anti-annexin V antibodies than in those without anti-annexin V antibodies. Three patients with thrombosis were found not to have anticardiolipin antibodies, but to show sustained serological reactions for anti-annexin V antibodies, irrespective of prednisolone administration. These results indicated the clinical characteristics of SLE patients with anti-annexin V antibodies, and that these antibodies may be associated with the pathogenesis of thrombotic events. Am. J. Hematol. 54:209–213, 1997 © Wiley-Liss, Inc.     

Antiendothelial cell antibodies in systemic lupus erythematosus

Objective: Anti‐endothelial cell antibodies (AECAs) are a heterogeneous group of antibodies against a variety of antigenic determinants on endothelial cells (EC). AECAs are known to play an immunopathogenic role in triggering EC activation, leading to vascular damage. The purpose of this study was to assess: (i) the incidence of AECAs in systemic lupus erythematosus (SLE) patients with nephritis (LN) and to compare this with SLE patients without clinical evidence of nephritis; and (ii) to understand the association of AECAs with disease severity based on renal histopathological findings. Method: Fifty‐three clinically and histopathologically proven cases of LN were studied along with 20 patients without evidence of nephritis. AECAs were detected by immunofluorescence using cultured human umbilical vein endothelial cells (HUVECs). The titres and immunoglobulin subclass of AECAs were also identified. Other autoantibodies were also detected. Results: In the LN group, 21 (39.6%) were AECA positive and 19 (35.8%) were antineutrophil cytoplasmic antibody (ANCA) positive. Autoantibodies to double‐stranded DNA (anti‐dsDNA) were present in 49 (92.4%) cases. In patients without nephritis, seven (35%) tested positive for AECA, five for ANCA and all were antinuclear antibody (ANA) positive. Anti‐dsDNA was detected in 16 patients (80%), higher incidence of AECAs was noted in diffuse proliferative glomerulonephritis (41.2%) as compared to focal proliferative glomerulonephritis (37.5%) and membranoproliferative glomerulonephritis (33.3%). IgG‐AECA subclass was noted in 85.7% patients, IgM‐AECA and IgG + M AECA subclasses of AECA were detected in 7.1% cases. AECAs were also found to be associated with other autoantibodies such as ANA, anti‐dsDNA and ANCA. Conclusion: No significant differences in AECA positivity was found between SLE with and without nephritis.     

Antiphospholipid Antibodies in Young Adults with Stroke

Background. Antiphospholipid antibodies have been associated with a clinical syndrome consisting thrombosis and recurrent, unexplained fetal loss. Methods. The literature pertaining to stroke associated with antiphospholipid antibodies, with emphasis on stroke in young adults, was reviewed. Results. Antiphospholipid antibodies are an independent risk factor for stroke in young adults in five of six studies. Multiple antiphospholipid specificities or the Lupus Anticoagulant were tested in addition to anticardiolipin antibody in these studies. In the single study that found no increased risk for stroke, only anticardiolipin antibody was tested. Only one of these studies evaluated for risk of recurrent stroke in young adults with antiphospholipid antibodies and found it to be increased. No treatment trials have been conducted in young adults with antiphospholipid antibodies and stroke. In the single treatment trial comparing aspirin and low-INR producing doses of warfarin to prevent recurrent stroke, both were found to be equally effective. Conclusions. Antiphospholipid antibodies, particularly Lupus Anticoagulant, is an independent risk factor for first and possibly recurrent ischemic stroke in young adults. The best therapeutic strategy for preventing antiphospholipid antibody-associated recurrent stroke is not clear.     

Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients

OBJECTIVE: To describe the different types of malignancies associated with antiphospholipid antibodies (aPL). METHODS: We performed a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature from 1966 to 2003 to identify all cases of malignancies having aPL. RESULTS: One hundred twenty patients were found. The mean age was 56+/-17 years (range 5 to 88). Sixty-two (52%) patients were men and 58 (48%) were women. A heterogeneous group of malignancies were found. Regarding hematological malignancies, 10 (8%) patients suffered from B-cell lymphoma, 8 (7%) from spleen lymphoma, 7 (6%) from chronic myeloid leukemia, and 6 (5%) from non-Hodgkin's lymphoma (NHL). Regarding solid tumors, renal cell carcinoma was diagnosed in 7 (6%) patients, primary tumor with unknown origin in 7 (6%), lung adenocarcinoma in 6 (5%), breast carcinoma in 6 (5%), and melanoma in 6 (5%). The main aPL-related manifestations were thrombocytopenia (25%), cerebrovascular accidents (24%), deep vein thrombosis (19%), pulmonary embolism (15%), and heart valve lesions (9%). In 17 cases, catastrophic antiphospholipid syndrome was considered to be triggered by the malignancy. Seventy-one (63%) of 113 patients recovered or are still alive after cancer treatment. Twenty-three (35%) of 65 patients achieved aPL remission after proper treatment of the malignancy. CONCLUSIONS: It is important to bear in mind, especially in elderly patients, that thrombotic events associated with aPL can be the first manifestation of malignancy. At the same time, the presence of aPL in patients with malignancies has important implications in their treatment and prognosis.     

Real-world practice of obstetricians in respect of assays for antiphospholipid antibodies

Objective. The international classification criteria (CC) for definite antiphospholipid syndrome (APS) recommend confirmation of the sustained presence, for at least 12 weeks, of both lupus anticoagulant (LA), as determined by aPTT and RVVT, and anti β2glycoprotein I (β2GPI) or anticardiolipin (aCL) IgG and/or IgM. However, it remains unclear whether obstetricians comply with the aforementioned CC for the diagnosis of APS in daily clinical practice. We performed a nationwide survey to examine the attitudes of Japanese obstetricians toward the use of assays for antiphospholipid antibodies (aPLs).

Methods. A questionnaire was sent to 2,700 obstetric facilities where maternity checkups are carried out. The types of assays conducted for aPLs, ascertainment of persistence of the antibodies for at least 12 weeks, and the cutoff points used for the assays were examined.

Results. Of the facilities surveyed, 61.5% carried out the assay(s) only once. In regard to the type of assay performed, 97.1% carried out the assay for aCL IgG and/or β2GPI-dependent aCL, while 67.9% performed the LA-aPTT and/or LA-RVVT assay. Only 8.8% carried out assays for both LA. As for the cutoff points used, 98% of the facilities used lower cutoff points described in the manufacturers’ manuals rather than the cutoff values recommended in the CC.

Conclusion. Thus, only a limited number of facilities adhered precisely to the CC for the diagnosis of APS. Inappropriate treatment and unnecessary expense are potentially major concerns when facilities overdiagnose APS using lower cutoff points or without ascertaining the persistence of the antibodies for at least 12 weeks. On the other hand, some patients miss the opportunity to be treated for APS because of the absence of testing for LA.     

High prevalence of thrombocytopenia in SLE patients with a high level of anticardiolipin antibodies combined with lupus anticoagulant

The relationship between thrombocytopenia and the level of anticardiolipin antibodies (aCL) and/or the existence of lupus anticoagulant (LA) ware studied in 146 patients with systemic lupus erythematosus (SLE). These patients were divided into six groups: A, those LA positive with a high level of aCL (>10 U/ml) (10 cases); B, those LA positive with a low level of aCL (3–10 U/ml) (15 cases); C, those LA positive but aCL negative (<3 U/ml) (12 cases); D, LA negatives with a high level of aCL (12 cases); E, LA negatives with a low level of aCL (16 cases); and F, aCL and LA double negatives (81 cases). The prevalence of thrombocytopenia (platelet count ≦ 100 × 10⁹/L) was by far the highest in group A (9/10 cases, 90.0%, P < 0.005, Fisher's exact probability test) as compared with group B (4/15 cases, 26.7%), group C (4/12 cases, 33.3%), group D (1/12 cases, 8.3%), group E (4/16 cases, 25.5%), and group F (9/81 cases, 11.1%). When the relationship between moderate thrombocytopenia and arterial or venous thrombosis was studied in these patients with SLE, thrombocytopenia was detected in 10 (83.3%, P < 0.005, Fisher's exact probability test) of 12 patients with arterial thrombosis; however, it was present in only 4 (23.5%) of 17 patients with venous thrombosis and in 14 (12.3%) of 114 patients without thrombosis. These findings suggest that a high aCL activity combined with LA positively reflects a high risk for both thrombocytopenia and arterial thrombosis. Am. J. Hematol 58:55–60, 1998. © 1998 Wiley-Liss, Inc.     

Anticardiolipin antibodies and lupus anticoagulant in patients treated with different methods of renal replacement therapy in comparison to patients with systemic lupus erythematosus

Summary Antiphospholipid antibodies were found to be associated with certain clinical manifestations such as recurrent venous thrombosis or arterial occlusions in a wide spectrum of immune disorders [6]. We analyzed the plasma concentration of two isotypes (IgG, IgM) of anticardiolipin antibodies (ACA) and lupus anticoagulant (LAC) activity in 84 patients with end-stage renal disease. They were receiving different types of renal replacement therapy and had a high frequency of thrombotic vascular complications. The prevalence of positive tests and the mean ACA concentration obtained in the plasma of renal patients were compared with those in patients with systemic lupus erythematosus (SLE) and in healthy controls. When analyzed as a whole group, renal patients maintained on dialysis (n=45: hemodialysis,n=20; peritoneal dialysis) or with a functioning kidney transplant (n=19) did not differ in mean ACA concentration and LAC activity (n=84, ACA: IgG 10±7 U/ml, IgM 2±1 U/ml, LAC ratio: 1.0±0.2) from healthy subjects (n=50, ACA: IgG 10±3, IgM 2±1 U/ml, LAC ratio: 1.0±0.1) but they had a higher incidence of raised IgG-ACA titers (renal replacement 14% vs. normal controls 4%,p<0.05). No significant correlation was found between thrombotic events and raised ACA or LAC activity in dialysis patients. In contrast, the proportion of SLE patients (n=51) with a raised concentration of ACA was significantly higher (IgG: 69%, IgM: 29%) than that among patients with renal replacement therapy (IgG: 14%, IgM: 4%) or normal controls (IgG: 4%, IgM: 2%,p<0.002). Moreover, recurrent manifestations of thrombosis in SLE were associated with very high IgG-ACA (n=11, IgG 117±91 U/ml) and LAC activity (LAC ratio: 2.4±0.7) in comparison to SLE patients without thrombotic events (n=40, ACA: IgG 23±13). The results of our investigations demonstrate that the pathogenetic role of these phospholipid antibodies in end-stage renal disease is far from established.