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1.  Antiphospholipid antibodies (aPL) in systemic lupus erythematosus. Are they specific tools for the diagnosis of aPL syndrome? 
Annals of the Rheumatic Diseases  1994;53(2):140-142.
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.
PMCID: PMC1005268  PMID: 8129460
2.  The persistence of anticardiolipin antibodies is associated with an increased risk of the presence of lupus anticoagulant and anti-β2-glycoprotein I antibodies 
Rheumatology (Oxford, England)  2006;45(9):1116-1120.
We studied antiphospholipid antibodies (aPL) in blood samples from a cohort of individuals followed for thrombosis to determine whether the persistent presence of anticardiolipin antibodies (aCL) is associated with a greater likelihood of having lupus anticoagulant and/or anti-β2-glycoprotein I antibodies (LA/aβ2GPI).
Blood samples from 353 individuals who had been tested for aCL on at least two occasions were tested for aβ2GPI and LA. Two groups were defined: aCL-persistent, who tested aCL-positive on at least two occasions, and aCL non-persistent, who tested aCL-positive on fewer than two occasions. Multivariate logistic regressions were performed using LA/aβ2GPI, LA and aβ2GPI as outcome variables and the percentage of aCL-positive tests as the predictor variable, adjusted for age, gender, family history of cardiovascular disease (CVD), systemic lupus erythematosus (SLE), smoking and number of venous (VT) and arterial thromboses (AT).
Sixty-eight (19%) individuals were aCL persistent and 285 (81%) were aCL non-persistent. LA/aβ2GPI was found in 36 (53%) of the aCL persistent group and 38 (13%) of the aCL non-persistent group. The two groups were similar for age, gender and smoking. Family history of CVD, SLE, VT and AT were more frequent in the aCL persistent group. Multivariate analyses revealed that odds ratios for LA/aβ2GPI, LA and aβ2GPI were 1.34 [95% confidence interval (CI)=1.22–1.47], 1.36 (95% CI=1.24–1.50) and 1.47 (95% CI=1.31–1.65) respectively for each 10% increase in aCL-positive tests vs 0% positive tests.
Persistence of aCL positivity is associated with an increased risk of LA/aβ2GPI.
PMCID: PMC3435425  PMID: 16510527 CAMSID: cams2311
Antiphospholipid antibodies; Anticardiolipin antibodies; Lupus anticoagulant; Anti-β2-glycoprotein I antibodies
3.  Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis 
Thrombosis and haemostasis  2004;92(6):1312-1319.
Although antiphospholipid antibodies (aPL) are associated with thrombosis, it is not known who with aPL is at higher risk for thrombosis. It was the aim of this cross-sectional study to investigate how thrombophilic factors contribute to venous or arterial thrombosis in aPL-positive individuals. In outpatient test centres at two tertiary care hospitals, two hundred and eight (208) persons requiring aPL testing were matched by age, gender and centre to 208 persons requiring a complete blood count. Persons were classified as aPL-positive (having anticardiolipin, lupus anticoagulant and/or anti-β2-glycoprotein I antibodies) or aPL-negative. Several thrombophilic factors were studied using logistic regression modelling. Results showed that the aPL-positive group had three-fold more events (37%) than the aPL-negative group (12%). In unadjusted analyses, clinically important associations were observed between factor V Leiden and venous thrombosis, hyperhomocysteinemia and arterial thrombosis, and activated protein C resistance (APCR) and venous thrombosis (OR, 95% CI = 4.00, 1.35–11.91; 4.79, 2.03–11.33; and 2.03, 1.03–3.97, respectively). After adjusting for recruitment group, persons with both APCR and aPL had a three-fold greater risk (OR, 95% CI = 3.31, 1.30–8.41) for venous thrombosis than those with neither APCR nor aPL. Similarly, after adjusting for hypertension, family history of cardiovascular disease, gender and recruitment group, persons with both hyperhomocysteinemia and aPL had a five-fold increased risk (OR, 95% CI = 4.90, 1.37–17.37) for arterial thrombosis compared to those with neither risk factor. In conclusion, APCR phenotype and hyperhomocysteinemia are associated with a higher risk of venous and arterial thrombosis, respectively, in the presence of aPL.
PMCID: PMC3482245  PMID: 15583739 CAMSID: cams2359
Antiphospholipid antibodies; antiphospholipid syndrome; thrombosis; activated protein C resistance; hyperhomocysteinemia
4.  Hydroxychloroquine Use is Associated with Lower Odds of Persistently Positive Antiphospholipid Antibodies and/or Lupus Anticoagulant in SLE 
The Journal of rheumatology  2012;40(1):30-33.
Antiphospholipid antibodies (aPL Abs) play an active role in the pathogenesis of the antiphospholipid syndrome (APLS). Primary prevention in APLS may be aimed at decreasing existing elevated aPL Ab levels, or preventing high aPL titers and/or lupus anticoagulant (LAC) from developing in the first place. Hydroxychloroquine (HCQ) has been shown to decrease aPL titers in laboratory studies, and to decrease thrombosis risk in systemic lupus erythematosus (SLE) patients in retrospective studies. We investigated an association between HCQ use and persistent aPL Abs and/or LAC in SLE.
We identified all patients over 21 years old with SLE, from an urban tertiary care center, who had aPL Abs and LAC measured on at least 2 occasions, at least 12 weeks apart. We defined the presence of persistent LAC+ and/or at least one aPL Ab ≥ 40 units (IgA, IgG or IgM) as the main outcome variable.
Among 90 patients included in the study, 17 (19%) had persistent LAC+ and/or at least one aPL Ab ≥ 40 units. HCQ use was associated with significantly lower odds of having persistent LAC+ and/or aPL Abs ≥ 40 U, OR 0.21 (95% CI 0.05, 0.79) p=0.02, adjusted for age, ethnicity, and gender.
This is the first study to show that HCQ use is associated with lower odds of having persistently positive LAC and/or aPL Abs. Data from this study provides a basis for the design of future prospective studies investigating the role of HCQ in primary and secondary prevention of APLS.
PMCID: PMC3768146  PMID: 22859353
Lupus Erythematosus, Systemic; Antiphospholipid Antibodies; Lupus Anticoagulant; Hydroxychloroquine
5.  Real world experience with antiphospholipid antibody tests: how stable are results over time? 
Annals of the Rheumatic Diseases  2005;64(9):1321-1325.
Objective: To determine the stability and the degree of variation of antiphospholipid antibody (aPL) results over time in a large cohort of well evaluated aPL positive patients; and to analyse factors contributing to aPL variation and the validity of aPL in a real world setting in which aPL tests are done in multiple laboratories.
Methods: The clinical characteristics, drug treatment, and 1652 data points for lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-ß2 glycoprotein I antibodies (anti-ß2GPI) were examined in 204 aPL positive patients; 81 of these met the Sapporo criteria for antiphospholipid syndrome (APS) and 123 were asymptomatic bearers of aPL.
Results: 87% of initially positive LA results, 88% of initially negative to low positive aCL results, 75% of initially moderate to high positive aCL results, 96% of initially negative to low positive anti-ß2GPI results, and 76% of initially moderate to high positive anti-ß2GPI results subsequently remained in the same range regardless of the laboratory performing the test. Aspirin, warfarin, and hydroxychloroquine use did not differ among patients whose aCL titres significantly decreased or increased or remained stable. On same day specimens, the consistency of aCL results among suppliers ranged from 64% to 88% and the correlation ranged from 0.5 to 0.8. Agreement was moderate for aCL IgG and aCL IgM; however, for aCL IgA agreement was marginal.
Conclusions: aPL results remained stable for at least three quarters of subsequent tests, regardless of the laboratory performing the test; the small amount of variation that occurred did not appear to be caused by aspirin, warfarin, or hydroxychloroquine use.
PMCID: PMC1755632  PMID: 15731290
6.  Influence of chronic inflammation and autoimmunity on coronary calcifications and myocardial perfusion defects in systemic lupus erythematosus patients 
Inflammation Research  2011;60(10):973-980.
Conventional risk factors for coronary artery disease fail to explain the increased frequency or cardiovascular morbidity in systemic lupus erythematosus (SLE) patients. This study was conducted to determine the possible influence of autoimmune and inflammatory phenomena markers on coronary artery calcifications and myocardial perfusion abnormalities in SLE patients.
Materials and methods
Multi-detector computed tomography (MDCT)-based coronary calcium scoring and single photon emission computerized tomography (SPECT) studies (Tc-99m sestamibi) were performed in 60 SLE patients in stable clinical condition, without a prior history of coronary artery disease. Laboratory evaluation included serum C-reactive protein (CRP), complement C3c and C4 components and antiphospholipid antibodies (aPL). The latter included anticardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies, of both IgG and IgM classes, and lupus anticoagulant (LA) in plasma.
SPECT revealed persistent perfusion defects in 22 (36.7%) patients and exercise-induced defects in eight (13.3%), while MDCT revealed coronary calcifications in 15 (25%). Calcium scores ranged from 1 to 843.2 (mean 113.5 ± 259.7). No association was found between conventional coronary artery disease risk factors (obesity, hypertension, tobacco use, hyperlipidaemia, diabetes) nor CRP, C3c or C4 levels and coronary calcifications or myocardial perfusion defects. On the contrary, in patients with these pathologies, augmented autoimmunization was found, reflected by increased aCL IgG and antiβ2GPI IgG levels. In patients with aCL IgG >20 RU/ml or antiβ2GPI IgG >3 RU/ml, the relative risk of coronary calcification formation was 4.1 compared to patients with normal values. Accordingly, in LA-positive patients the relative risk of coronary calcification formation was 4.4 compared to LA-negative patients.
Conventional risk factors for coronary artery disease as well as markers of an ongoing inflammation did not show any association with perfusion defects and/or coronary artery calcifications in SLE patients. On the contrary, calcified atherosclerotic plaques and myocardial perfusion defects were observed mainly in patients with elevated levels of anticardiolipin and aβ2GPI antibodies of the IgG class. It might be speculated that coronary artery calcifications and perfusion defects are a result of antiphospholipid antibodies-induced coronary artery microthrombosis.
PMCID: PMC3171653  PMID: 21744266
Systemic lupus erythematosus; Autoimmune diseases; Coronary calcification; Atherosclerosis; MDCT; SPECT; Perfusion scintigraphy
Arthritis and Rheumatism  2012;64(7):2311-2318.
Which serologic and clinical findings predict adverse pregnancy outcome (APO) in patients with antiphospholipid antibody (aPL) is controversial.
PROMISSE is a multicenter, prospective observational study of risk factors for APO in patients with aPL (lupus anticoagulant [LAC], anticardiolipin antibody [aCL] and/or antibody to β2 glycoprotein I [anti-β2-GP-I]). We tested the hypothesis that a pattern of clinical and serological variables can identify women at highest risk for APO.
Between 2003 and 2011 we enrolled 144 pregnant patients, of whom 28 had APO. Thirty-nine percent of patients with LAC had APO, compared to 3% who did not have LAC (p < 0.0001). Only 8% of women with IgG aCL ≥40 u/mL but not LAC suffered APO, compared to 43% of those with LAC (p = 0.002). IgM aCL or IgG or IgM anti-β2-GP-I did not predict APO. In bivariate analysis, APO occurred in 52% of patients with and 13% of patients without prior thrombosis (p = 0.00005), and in 23% with SLE compared to 17% without SLE (not significant); SLE was a predictor in multivariate analysis. Prior pregnancy loss did not predict APO, nor did maternal race. Simultaneous aCL, anti-β2-GP-I, and LAC did not predict APO better than did LAC alone.
LAC is the primary predictor of APO after 12 weeks gestation in aPL-associated pregnancies. ACL and anti-β2-GP-I, if LAC is not also present, do not predict APO.
PMCID: PMC3357451  PMID: 22275304
8.  Diagnosis of antiphospholipid syndrome in routine clinical practice 
Lupus  2013;22(1):18-25.
The updated international consensus criteria for definite antiphospholipid syndrome (APS) are useful for scientific clinical studies. However, there remains a need for diagnostic criteria for routine clinical use. We audited the results of routine antiphospholipid antibodies (aPLs) in a cohort of 193 consecutive patients with aPL positivity-based testing for lupus anticoagulant (LA), IgG and IgM anticardiolipin (aCL) and anti-ß2glycoprotein-1 antibodies (aß2GPI). Medium/high-titre aCL/aβ2GPI was defined as >99th percentile. Low-titre aCL/aβ2GPI positivity (>95th < 99th percentile) was considered positive for obstetric but not for thrombotic APS. One hundred of the 145 patients fulfilled both clinical and laboratory criteria for definite APS. Twenty-six women with purely obstetric APS had persistent low-titre aCL and/or aβ2GPI. With the inclusion of these patients, 126 of the 145 patients were considered to have APS. Sixty-seven out of 126 patients were LA-negative, of whom 12 had aCL only, 37 had aβ2GPI only and 18 positive were for both. The omission of aCL or aβ2GPI testing from investigation of APS would have led to a failure to diagnose APS in 9.5% and 29.4% of patients, respectively. Our data suggest that LA, aCL and aβ2GPI testing are all required for the accurate diagnosis of APS and that low-titre antibodies should be included in the diagnosis of obstetric APS.
PMCID: PMC4108293  PMID: 22988029
9.  Antiphospholipid syndrome; its implication in cardiovascular diseases: a review 
Antiphospholipid syndrome (APLS) is a rare syndrome mainly characterized by several hyper-coagulable complications and therefore, implicated in the operated cardiac surgery patient. APLS comprises clinical features such as arterial or venous thromboses, valve disease, coronary artery disease, intracardiac thrombus formation, pulmonary hypertension and dilated cardiomyopathy. The most commonly affected valve is the mitral, followed by the aortic and tricuspid valve. For APLS diagnosis essential is the detection of so-called antiphospholipid antibodies (aPL) as anticardiolipin antibodies (aCL) or lupus anticoagulant (LA). Minor alterations in the anticoagulation, infection, and surgical stress may trigger widespread thrombosis. The incidence of thrombosis is highest during the following perioperative periods: preoperatively during the withdrawal of warfarin, postoperatively during the period of hypercoagulability despite warfarin or heparin therapy, or postoperatively before adequate anticoagulation achievement. Cardiac valvular pathology includes irregular thickening of the valve leaflets due to deposition of immune complexes that may lead to vegetations and valve dysfunction; a significant risk factor for stroke. Patients with APLS are at increased risk for thrombosis and adequate anticoagulation is of vital importance during cardiopulmonary bypass (CPB). A successful outcome requires multidisciplinary management in order to prevent thrombotic or bleeding complications and to manage perioperative anticoagulation. More work and reporting on anticoagulation management and adjuvant therapy in patients with APLS during extracorporeal circulation are necessary.
PMCID: PMC2987921  PMID: 21047408
10.  APhL antibody ELISA as an alternative to anticardiolipin test for the diagnosis of antiphospholipid syndrome 
Persistent levels of antiphospholipid (aPL) antibodies [lupus anticoagulant (LA), anticardiolipin (aCL), anti-beta 2 glycoprotein I (aβ2GPI) IgG and/or IgM] in association with clinical features of thrombosis and/or pregnancy associated morbidity are indicative of antiphospholipid syndrome (APS). Of the aPL antibodies, aCL is the most sensitive for APS, however, their lack of specificity constitute a laboratory and clinical challenge. IgG/IgM antibodies directed against APhL (a mixture of phospholipids) has been reported to predict APS more reliably than aCL tests. The main objective of this study was to evaluate the performance characteristics of the APhL IgG/IgM ELISA, relative to the aCL and aβ2GPI tests.
Sixteen (16) clinically confirmed APS and 85 previously tested serum (PTS) samples for aCL and aβ2GPI IgG/IgM antibodies were evaluated with the APhL IgG/IgM ELISA. Clinical specificity was determined in 100 serum samples (50 healthy and 50 infectious disease controls [parvo- and syphilis-IgG/IgM positive]).
The IgG antibody prevalence for aCL and APhL in the APS and PST groups was comparable with marginal differences in clinical specificities. In contrast to the aCL IgM ELISA, the APhL test showed improved clinical specificities (72% aCL vs 94% APhL in the healthy controls; 38% aCL vs 78% APhL in the infectious disease controls) with implications for increased reliability in the diagnosis of APS. The overall agreement of the APhL with the aCL or aβ2GPI for the IgG tests was 89% and 85% respectively, and that of the APhL IgM to the aCL or aβ2GPI IgM tests was 72% and 86% respectively.
Routine use of the APhL IgG/IgM ELISA may substantially reduce the high number of false positives associated with the aCL test without loss in sensitivity for APS.
PMCID: PMC3341677  PMID: 22558475
Anticardiolipin; APhL; antiphospholipid antibodies; method comparison
11.  Clinical and laboratory characteristics of children positive for antiphospholipid antibodies 
Blood Transfusion  2011;10(3):296-301.
It is difficult to estimate the actual prevalence of antiphospholipid syndrome (APS) in the paediatric population since there are no standardised criteria. We aimed to assess clinical and laboratory characteristics of a cohort of children positive for antiphospholipid antibodies (aPL) to contribute to the understanding of the heterogeneous aPL-related features in childhood.
Materials and methods.
Forty-four patients with prolonged activated partial thromboplastin time were enrolled and assigned to group I (“transiently positive”) or group II (“persistently positive”), based on the detection of elevated aPL plasma levels [lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I (anti-β2GPI) antibodies] on, respectively, one or more occasions, at least 12 weeks apart, by standard procedures. The clinical history and symptoms of all patients were recorded.
Thirty-three (75%) patients were assigned to group I, while the other 11 (25%) formed group II. Major associated diseases in group I were urticarial vasculitis (21%), acute infections (18%) and thalassaemia (12%). Five subjects (15%) were asymptomatic. Four out of the 11 subjects (36%) in group II had thrombotic events; they were all persistently aPL-positive and two of them had concomitant systemic lupus erythematosus. The rate of detection of LA-positivity was not significantly different between the two groups (76% vs 91%, p>0.05), whereas the percentage of patients positive for overall aCL was higher in group II than in group I (54% vs 42%, respectively; p<0.05). Specifically, aCL IgG and anti-β2GPI IgM subtypes were significantly more represented in group II than in group I (100% vs 62% and 75% vs 33%, respectively; p<0.05).
Our study shows that aPL-positive children have different features that should be taken into account in the classification of criteria for paediatric APS.
PMCID: PMC3417728  PMID: 22244004
activated partial thromboplastin time; antiphospholipid antibodies; children; thrombosis
12.  Utility of Antiphosphatidylserine/Prothrombin and IgA Antiphospholipid Assays in Systemic Lupus Erythematosus 
The Journal of rheumatology  2013;40(3):282-286.
Currently, 3 antiphospholipid assays are widely used clinically [lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (anti-β2-GPI)]. LAC is the most specific assay, conferring the highest risk of thrombosis and pregnancy loss, but it cannot be validly performed in an anticoagulated patient. We investigated the usefulness of antiphosphatidyl-serine/prothrombin (anti-PS/PT) and its association with thrombosis. Anti-PS/PT is strongly associated with the presence of LAC. We also studied the association of IgA antiphospholipid isotypes and specific domains of β2-GPI with thrombosis in systemic lupus erythematosus (SLE).
Stored samples from patients with SLE, with and without past thrombosis, were assayed for antibodies to the whole β2-GPI protein (IgG/IgM/IgA), to β2-GPI domain 1 (IgG), to β2-GPI domain 4/5 (IgA), aCL (IgG/IgM/IgA), and anti-PS/PT (IgG, IgM, and IgG/M). LAC was detected using the dilute Russell’s viper venom time (dRVVT) with confirmatory testing.
Anti-PS/PT IgG and IgG/M and anti-β2-GPI IgG, IgM, and IgA were highly associated with a history of LAC by dRVVT (p < 0.0001). For all thrombosis, of the traditional ELISA assays, anti-β2-GPI IgA, IgG, and aCL IgA were most associated. Anti-PS/PT IgG and IgG/M had a similar magnitude of association to the traditional ELISA. For venous thrombosis, of the traditional ELISA, anti-β2-GPI (IgG and IgA), anti-PS/PT (IgG and IgG/M), and aCL IgA were associated. Again, anti-PS/PT (IgG and IgG/M) had the same magnitude of association as the traditional ELISA. For stroke, significant association was seen with anti-β2-GPI IgA D4/5.
In anticoagulated patients, where LAC testing is not valid, anti-PS/PT, either IgG or IgG/IgM, might serve as useful alternative tests to predict a higher risk of thrombosis. Anti-PS/PT antibodies were associated with all thrombosis and with venous thrombosis. IgA isotypes in secondary antiphospholipid syndrome are associated with thrombosis. Anti-β2-glycoprotein domain 1 was not shown to be associated with thrombosis in SLE.
PMCID: PMC3605900  PMID: 23378459
13.  Clinical Implications of Elevated Antiphospholipid Antibodies in Adult Patients with Primary Immune Thrombocytopenia 
Antiphospholipid antibodies (aPL) have been detected in various proportions of patients with primary immune thrombocytopenia (ITP), but the clinical significance of this is debatable. The present study aimed to determine the frequency and clinical implications of elevated aPL in adult patients with ITP.
We prospectively studied newly diagnosed adult patients with ITP who were enrolled between January 2003 and December 2008 at Chungnam National University Hospital. They were evaluated for the presence of lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) at diagnosis and were followed for the development of thrombosis.
Seventy consecutive patients with ITP (median age, 48 years; range, 18 to 79) were enrolled. Twenty patients (28.5%) were positive for aPL at the time of diagnosis: aCL alone in 15 (75%), aCL and LA in two (10%), and LA alone in three (15%). Patients who had platelet counts < 50,000/µL were administered oral prednisolone with or without intravenous immune globulin. No difference was found between the aPL-positive and -negative groups regarding gender, initial platelet count, and response to the therapy. After a median follow-up of 20 months (range, 2 to 68), two of 20 patients who were aPL-positive (10%) developed thrombosis, whereas no thrombotic event was found among those who were aPL-negative.
Our data suggest that aPL levels should be determined at the initial presentation of ITP and that patients found to be aPL-positive should receive closer follow-up for thrombotic events.
PMCID: PMC3245394  PMID: 22205846
Antibodies, anticardiolipin; Antiphospholipid syndrome; Purpura, thrombocytopenic, idiopathic; Lupus coagulation inhibitor; Thrombosis
14.  Patent foramen ovale, cardiac valve thickening and antiphospholipid antibodies as risk factors for subsequent vascular events: The PICSS-APASS Study 
(1) Estimate risk of recurrent stroke/TIA/death in the subgroup of the Patent foramen ovale in the Cryptogenic Stroke Study (PICSS) cohort with patent foramen ovale (PFO) and antiphospholipid antibodies (aPL) and (2) Estimate risk of recurrent stroke/TIA/death in aPL positive patients who have thickened left-sided heart valves (VaT).
PFO is associated with cryptogenic ischemic stroke. Also, the presence of aPL is associated with ischemic cerebrovascular disease.
Combined data from 2 major sub studies of the Warfarin Aspirin Recurrent Stroke Trial (WARSS) were evaluated. PICSS subjects were included if they were enrolled in the Antiphospholipid Antibodies and Stroke Study (APASS) and had a baseline aPL test (lupus anticoagulant, anticardiolipin antibodies, or both) within one month of the stroke. All patients in PICSS underwent transesophageal echocardiography for PFO as well as VaT, which was performed blinded to aPL status and treatment arm (325mg/d aspirin or adjusted dose warfarin, target INR 1.4–2.8). The primary outcome event was the 2-year risk of recurrent stroke/TIA/death and was evaluated using Cox proportional hazards model. As there was no treatment effect, warfarin and aspirin groups were combined to increase power. For the combined endpoint, power to detect a HR of 2 was 47.8% for the PFO and aPL positive group, and 75.3% for the valve thickening and aPL positive group, assuming two-sided type I error of 0.05
525 subjects were tested for the combined presence of PFO and aPL and were available for evaluation. The primary outcome event rate was 23.9% (HR 1.39, 95% CI 0.75–2.59) in the PFO positive/aPL positive group, compared to 13.9% (HR 0.83, 95% CI 0.44–1.56) in the PFO positive/aPL negative group and 19.9% (HR 1.16 95% CI 0.68–1.90) in the PFO negative/aPL positive group.
545 subjects tested for combined presence of aPL and left sided cardiac VaT were available for evaluation. The primary event rate was 22.6% (HR1.65, 95% CI 0.88–3.09) in the VaT positive/aPL positive group, compared to 19.4% (HR 1.50, 95% CI 0.82–2.75) in the VaT positive/aPL negative group and 20.2% (HR 1.63, 95% CI 0.81–3.25) in the VaT negative /aPL positive group.
The combined presence of aPL with either a PFO or with left sided cardiac VaT did not significantly increase risk of subsequent cerebrovascular events in this PICCS/APASS cohort of patients.
PMCID: PMC2761081  PMID: 19498198
patent foramen ovale; anti-phospholipid antibodies; cardiac valve thickening; stroke recurrence risk; stroke risk factors; Risk Factors
15.  Possible Association of Etanercept, Venous Thrombosis, and Induction of Antiphospholipid Syndrome 
Case Reports in Rheumatology  2014;2014:801072.
Tumor necrosis factor α (TNF α) inhibitors are commonly used for treatment of aggressive rheumatoid arthritis and other rheumatic diseases. Etanercept is one of the medications approved for treatment of rheumatoid arthritis. Though many studies have documented the safety and efficacy of these medications, evidence for adverse effects is emerging including cancer, infections, and cardiovascular disease. There have been studies showing that these medications induce autoantibody production, including antinuclear antibodies and anti-dsDNA antibodies. Limited data exists, however, regarding induction of antiphospholipid antibodies (APLs) by TNF α inhibitors, including anticardiolipin antibodies (ACLs), lupus anticoagulant (LAC), and anti-β2-glycoprotein I (anti-β2 GPI), or an association between antibody development and clinical manifestations. In this case series, we describe five patients who developed venous thromboembolism (VTE) and APLs while receiving etanercept therapy. All five of our patients met the criteria for diagnosis of APS after receiving etanercept. Our case series supports the association between etanercept, APLs, and VTE. We believe that testing for APLs prior to initiation of anti-TNF therapy is reasonable, given this relationship and the risks associated with VTE.
PMCID: PMC4052498  PMID: 24949211
16.  Characterization of antiphospholipid antibodies in chronic hepatitis B infection 
Many infections are associated with antiphospholipid antibodies (aPLs). The purpose of this study was to investigate the prevalence, persistence, clinical significance, and characteristics of aPLs in hepatitis B virus (HBV)-infected patients.
This study included 143 patients with HBV infection and 32 healthy individuals as controls. The presence of anticardiolipin antibodies (aCL Ab), anti-β2-glycoprotein I antibodies (β2GPI Ab), and lupus anticoagulant (LA) was assessed.
The total prevalence of aPLs in HBV-infected patients was 12.6% (18 of 143). Of these 18 patients, 15 had low to medium titers of aCL Ab (10 with IgM, 4 with IgG, and 1 with both isotypes). β2GPI Ab and LA were detected in 3 (2.1%) and 2 (1.4%) patients with HBV infection, respectively. In follow-up specimens from 14 patients with elevated levels of aCL Ab or β2GPI Ab, 10 (71.4%) showed the persistent presence of aPLs. No clinical manifestations related to aPLs were identified.
In HBV-infected patients, the most frequently detected antiphospholipid antibodies were IgM aCL Ab, which have a weak association with the clinical manifestations of APS. Unlike the transient presence reported for other infection-associated aPLs, most aPLs were persistently detected over a 12-week period in patients with HBV infection.
PMCID: PMC3065625  PMID: 21461302
Anticardiolipin antibodies; Anti-β2-glycoprotein I antibodies; Lupus coagulation inhibitor; Hepatitis B virus
17.  The Presence of Multiple Prothrombotic Risk Factors Is Associated with a Higher Risk of Thrombosis in Individuals with Anticardiolipin Antibodies 
The Journal of rheumatology  2003;30(11):2385-2391.
To explore the effect of multiple prothrombotic risk factors in individuals with anticardiolipin antibodies (aCL), we evaluated immunologic, coagulation, and genetic prothrombotic abnormalities in a cohort of individuals with different aCL titers.
We recruited 87 individuals into 4 categories (normal, low, intermediate, or high) based on their baseline IgG aCL (aCL-IgG) titers. We measured at followup: repeat aCL-IgG, IgM aCL (aCL-IgM), antibodies to β2-glycoprotein I (anti-β2-GPI), lupus anticoagulant (LAC) antibodies, protein C, protein S, activated protein C resistance, factor V506 Leiden mutation, methyl tetrahydrofolate reductase (MTHFR) C677T genotype, and prothrombin 20210A gene mutation. Thrombotic events were confirmed.
At recruitment, 20 individuals were negative for aCL-IgG and 67 were positive (22 low, 20 intermediate, and 25 high titer). Twenty of the 87 participants had experienced a previous thrombotic event: 4 in the aCL-IgG negative group and 16 in the aCL-IgG positive group. Among the 87 individuals, the number of those with concomitant prothrombotic risk factors was as follows: 5 had no other prothrombotic risk factors, 32 had 1 risk factor, 24 had 2 risk factors, 10 had 3 risk factors, 10 had 4 risk factors, and 6 had 5 risk factors. Thrombotic events were observed in 20%, 13%, 33%, 10%, 30%, and 50% of these groups, respectively, and the odds ratio associated with a previous thrombotic event was 1.46 per each additional prothrombotic risk factor (95% confidence interval: 1.003–2.134).
In individuals with positive aCL-IgG, we observed an association between the number of prothrombotic risk factors and history of thrombotic events. (J Rheumatol 2003;30:2385–91)
PMCID: PMC3440310  PMID: 14677182 CAMSID: cams2358
18.  Antiphospholipid Antibodies in Women Undergoing In Vitro Fertilization Treatment: Clinical Value of IgA Anti-β2glycoprotein I Antibodies Determination 
BioMed Research International  2014;2014:314704.
Implantation failure could be related to antiphospholipid antibodies (aPL). We retrospectively analyzed the usefulness of aPL determination in women undergoing IVF. Conventional aPL of the antiphospholipid syndrome, lupus anticoagulant (LA), anticardiolipin antibodies (aCL), anti-β2glycoprotein I (aβ2GPI) antibodies, and IgG and IgM isotypes as well as IgA isotype were analyzed in women presenting with at least two implantation failures after in vitro fertilization (IVF). In a population of 40 IVF patients, a total prevalence of 20% (8/40) of aPL was found, significantly different from that of the control population (100 healthy blood donors, P < 0.0005). Among the panels of aPL tested, aβ2GPI IgA antibodies were the most prevalent (62.5% 5/8), significantly higher in IVF patients (12.5%, 5/40) than in controls (1%, 1/100) (P = 0.01). No difference according to the numbers of IVF attempts and success of embryo implantation was found between aPL positive and negative IVF patients. In contrast, no accomplished pregnancy with full-term live birth was observed in aPL positive IVF patients. Altogether our data led us to propose aPL assessment, in particular aβ2GPI IgA antibodies, in support of IVF treated women. In a perspective way, an early aPL detection could be the basis for defining novel therapeutic strategy.
PMCID: PMC4055657  PMID: 24967354
19.  High Antiphospholipid Antibody Levels are Associated with Statin Use and May Reflect Chronic Endothelial Damage in Non-Autoimmune Thrombosis: cross-sectional study 
Journal of clinical pathology  2012;65(6):551-556.
Persistently elevated antiphospholipid antibodies (aPL Ab) and positive lupus anticoagulant (LAC) are associated with an increased risk of thrombosis. Our objective was to explore whether aPL Ab and/or LAC positivity were associated with the traditional risk factors for thrombosis or with medication use in patients without autoimmune diseases hospitalized with arterial or venous thrombosis.
Cross-sectional study
Montefiore Medical Center, a large urban tertiary care center
Two hundred and seventy patients (93 with deep vein thrombosis (DVT) or pulmonary embolism (PE), and 177 with non-hemorrhagic stroke (CVA)) admitted between January 2006 and December 2010 with a discharge diagnosis of either DVT, PE or CVA, who had LAC and aPL Abs measured within six months from their index admission. We excluded patients with lupus or antiphospholipid syndrome.
Main Outcome Measures
The main dependant variable was aPL Ab ≥ 40 units (aPL Ab+) and/or LAC+. Independent variables: traditional thrombosis risk factors, statin use, aspirin use, and warfarin use.
Thirty one (11%) patients were LAC+ and/or aPL Ab+ (aPL/LAC+). None of the traditional risk factors at the time of DVT/PE/CVA was associated with aPL/LAC+. Current statin use was associated with an OR of 3.2 (95% CI 1.3, 7.9, p = 0.01) of aPL/LAC+, adjusted for age, ethnicity and gender. Aspirin or warfarin use was not associated with aPL Ab levels.
If statin therapy reflects the history of prior hyperlipidemia, high levels of aPL Abs may be a marker for prior endothelial damage caused by hyperlipidemia.
PMCID: PMC3760969  PMID: 22389514
Antiphospholipid antibodies; statins; endothelial damage; thrombosis
20.  Testing for Antiphospholipid Antibody (aPL) Specificities in Retrospective “Normal” Cerebral Spinal Fluid (CSF) 
Antiphospholipid antibodies (aPL) have been found in the blood of patients with systemic and neurological disease. The rare reports of aPL in cerebral spinal fluid (CSF) have been limited mostly to IgG and IgM anticardiolipin (aCL). Our published finding of IgA aPE in the CSF of a young stroke victim prompted us to establish “normal” CSF aPL values for a panel of aPL, which included aCL, antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE) and antiphosphatidylcholine (aPC). CSF samples were tested by ELISA for IgG, IgM and IgA aPL. In addition, the CSF samples were tested for activity in the presence and absence of phospholipid (PL) binding plasma-proteins. A total of 24 data points were obtained for each CSF sample.We tested 59 CSF samples obtained from 59 patients who were undergoing evaluation for systemic or neurologic diseases. All CSF samples had normal protein, glucose and cell counts. Ten of the 59 CSF samples (17%) had elevated aPL optical density (OD) values an order of magnitude higher than the other 49 CSF samples for one or more aPL specificity and/or isotype. One CSF sample had both PL-binding protein dependent and independent IgG aPE activity. Another CSF sample showed both IgG aPE and aPC reactivity. The remaining eight CSF samples showed single aPL findings; IgG aPE (5), IgG aPC (1), IgG aCL (1) and IgM aPC (1). Seven of 10 patients with elevated CSF values were females. As expected, most “normal” aPL OD values were substantially lower in CSF than those we have reported in blood samples from volunteer blood donors.
PMCID: PMC2275414  PMID: 15154606
21.  Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort 
PLoS Medicine  2011;8(3):e1001013.
Jane Salmon and colleagues studied 250 pregnant patients with SLE and/or antiphospholipid antibodies and found an association of risk variants in complement regulatory proteins in patients who developed preeclampsia, as well as in preeclampsia patients lacking autoimmune disease.
Pregnancy in women with systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APL Ab)—autoimmune conditions characterized by complement-mediated injury—is associated with increased risk of preeclampsia and miscarriage. Our previous studies in mice indicate that complement activation targeted to the placenta drives angiogenic imbalance and placental insufficiency.
Methods and Findings
We use PROMISSE, a prospective study of 250 pregnant patients with SLE and/or APL Ab, to test the hypothesis in humans that impaired capacity to limit complement activation predisposes to preeclampsia. We sequenced genes encoding three complement regulatory proteins—membrane cofactor protein (MCP), complement factor I (CFI), and complement factor H (CFH)—in 40 patients who had preeclampsia and found heterozygous mutations in seven (18%). Five of these patients had risk variants in MCP or CFI that were previously identified in atypical hemolytic uremic syndrome, a disease characterized by endothelial damage. One had a novel mutation in MCP that impairs regulation of C4b. These findings constitute, to our knowledge, the first genetic defects associated with preeclampsia in SLE and/or APL Ab. We confirmed the association of hypomorphic variants of MCP and CFI in a cohort of non-autoimmune preeclampsia patients in which five of 59 were heterozygous for mutations.
The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL Ab who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease, links complement activation to disease pathogenesis and suggests new targets for treatment of this important public health problem.
Study Registration NCT00198068
Please see later in the article for the Editors' Summary
Editors' Summary
Most pregnancies culminate in the birth of a healthy baby but, sadly, about a quarter of women lose their babies during pregnancy. A common pregnancy-related medical problem that threatens the life of both baby and mother is preeclampsia. Mild and severe preeclampsia affects up to 10% and 1%–2% of pregnancies, respectively. Preeclampsia occurs because of a problem with the function of the placenta, the organ that transfers nutrients and oxygen from mother to baby and removes waste products from the baby. Although preeclampsia begins early in pregnancy, it is diagnosed by the onset of high blood pressure (hypertension) and the appearance of protein in the urine (proteinuria) after 20 weeks of pregnancy. Other warning signs include headaches and swelling of the hands and face. The only cure for preeclampsia is delivery, and labor is usually induced early to prevent eclampsia (seizures), stroke, liver and kidney failure, and breathing and blood vessel problems developing in the mother. Although delivery before 37 weeks of pregnancy is not generally recommended, in cases of preeclampsia it may be too dangerous for both the baby and the mother to allow the pregnancy to continue. Unfortunately when severe preeclampsia occurs in the second trimester, babies weighing only 500 grams may be delivered and they may not survive.
Why Was This Study Done?
Because the exact cause of preeclampsia is unknown, it is difficult to develop treatments for the condition or to find ways to prevent it. Many experts think that immune system problems—in particular, perturbations in complement activation—may be involved in preeclampsia. The complement system is a set of blood proteins that attacks invading bacteria and viruses. The activation of complement proteins is usually tightly regulated (overactivation of the complement system causes tissue damage) and, because preeclampsia may run in families, one hypothesis is that mutations (genetic changes) in complement regulatory proteins might predispose women to preeclampsia. In this study, the researchers test this hypothesis by sequencing genes encoding complement regulatory proteins in pregnant women with the autoimmune diseases systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL Ab) who developed preeclampsia. In autoimmune diseases, the immune system attacks healthy human cells instead of harmful invaders. Both SLE and APL Ab are characterized by complement-mediated tissue injury and are associated with an increased risk of preeclampsia and miscarriage.
What Did the Researchers Do and Find?
Two hundred fifty women with SLE and/or APL Ab were enrolled into the PROMISSE study (a multi-center observational study to identify predictors of pregnancy outcome in women with SLE and/or APL Ab) when they were 12 weeks pregnant and followed through pregnancy. Thirty patients developed preeclampsia during the study and ten more had had preeclampsia during a previous pregnancy. The researchers sequenced the genes for complement regulatory proteins: membrane cofactor protein (MCP), factor I, and factor H in these 40 patients. Seven women (18%) had mutations in one copy of one of these genes (there are two copies of most genes in human cells). Five mutations were alterations in MCP or factor I that are gene variants that increase the risk of hemolytic uremic syndrome, a disease characterized by blood vessel damage. The sixth mutation was a new MCP mutation that impaired MCP's ability to regulate complement component C4b. The final mutation was a factor H mutation that did not have any obvious functional effect. No mutations in complement regulatory proteins were found in 34 matched participants in PROMISSE without preeclampsia but, among a group of non-autoimmune women who developed preeclampsia during pregnancy, 10% had mutations in MCP or factor I.
What Do These Findings Mean?
These findings identify MCP and factor I mutations as genetic defects associated with preeclampsia in pregnant women with SLE and/or APL Ab. Importantly, they also reveal an association between similar mutations and preeclampsia in women without any underlying autoimmune disease. Taken together with evidence from previous animal experiments, these findings suggest that dysregulation of complement activation is involved in the development of preeclampsia. Although further studies are needed to confirm and extend these findings, these results suggest that proteins involved in the regulation of complement activation could be new targets for the treatment of preeclampsia and raise the possibility that tests could be developed to identify women at risk of developing preeclampsia.
Additional Information
Please access these Web sites via the online version of this summary at
Tommy's, a UK charity that funds scientific research into the causes and prevention of miscarriage, premature birth, and stillbirth, has information on preeclampsia
The March of Dimes Foundation, a nonprofit organization for pregnancy and baby health, has information on preeclampsia
The UK National Health Services Choices website also has information about preeclampsia
Wikipedia has pages on the complement system, on autoimmune disease, and on preeclampsia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information on the PROMISSE study is available
PMCID: PMC3062534  PMID: 21445332
22.  European registry of babies born to mothers with antiphospholipid syndrome 
Annals of the Rheumatic Diseases  2012;72(2):217-222.
This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the child's immunological profile with their mothers.
A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening. Children were examined at 3, 9, 24 months and 5 years.
134 children were analysed (female sex in 65 cases, birth weight 3000±500 g, height 48±3 cm). Sixteen per cent had a preterm birth (<37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Four children displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotony with psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-β2 glycoprotein-I (anti-β2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-β2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-β2GPI IgG were correlated with the same mother's antibodies before 6 months of age (p<0.05).
Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.
PMCID: PMC3551221  PMID: 22589374
23.  Value of IgA anticardiolipin and anti-ß2-glycoprotein I antibody testing in patients with pregnancy morbidity 
Annals of the Rheumatic Diseases  2003;62(6):540-543.
Objective: To study the prevalence of IgA antiphospholipid antibodies, particularly anticardiolipin antibodies (aCL) and anti-ß2-glycoprotein I (aß2GPI), in a cohort of patients with pregnancy morbidity.
Patients and methods: Serum samples from four groups of patients were studied by an in house enzyme linked immunosorbent assay (ELISA). Group I: 28 patients with primary antiphospholipid syndrome (PAPS) (median age 32.5 years, range 25–34). Twelve patients had a history of thrombosis. All were positive for IgG/M aCL or lupus anticoagulant (LA), or both. Group II: 28 patients with unexplained pregnancy morbidity (median age 35 years, range 23–48). Seven had history of thrombosis. Nine patients were positive for IgG/M aCL. None from this group fulfilled Sapporo criteria for APS. Group III: 28 patients with systemic lupus erythematosus (SLE) (median age 34 years, range 25–52). Eleven had a history of thrombosis. Twenty one patients had IgG/M aCL and/or LA, but only 19 fulfilled Sapporo criteria for APS.
Results: IgA aCL were found in 12, 6, and 14 patients from the groups with PAPS, unexplained pregnancy morbidity, and SLE, respectively. Most patients had these antibodies together with IgG/IgM aCL. Three patients from the group with unexplained pregnancy morbidity and two with SLE had IgA aCL alone. IgA aß2GPI was present in one patient from each group. All IgA aß2GPI were present together with IgG and/or IgM aß2GPI.
Conclusions: The prevalence of IgA aCL is high in patients with pregnancy morbidity, although IgA aCL are usually present together with IgG and/or IgM aCL. IgA aß2GPI are not useful in identifying additional women with APS and pregnancy morbidity.
PMCID: PMC1754554  PMID: 12759291
24.  Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies 
Lupus  2009;18(6):530-538.
Complement plays a major role in inflammation and thrombosis associated with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). A cross-sectional retrospective analysis was performed to evaluate serum complement fixation on platelets and thrombotic incidence using banked sera and clinical data from patients with SLE (n = 91), SLE with antiphospholipid antibodies (aPL) or APS (n = 78) and primary aPL (n = 57) or APS (n = 96). In-situ complement fixation was measured as C1q and C4d deposition on heterologous platelets using an enzyme-linked immunosorbent assay approach. Platelet activation by patient serum in the fluid phase was assessed via serotonin release assay. Enhanced in-situ complement fixation was associated with the presence of IgG aPL and IgG anti-β2 glycoprotein 1 antibodies (P < 0.05) and increased platelet activation (P < 0.005). Moreover, enhanced complement fixation, especially C4d deposition on heterologous platelets, was positively associated with arterial thrombotic events in patients with SLE and aPL (P = 0.039). Sera from patients with aPL possess an enhanced capacity for in-situ complement fixation on platelets. This capacity may influence arterial thrombosis risk in patients with SLE.
PMCID: PMC2707931  PMID: 19395455
antiphospholipid syndrome; systemic lupus erythematosus; thrombosis
25.  Antiphospholipid antibodies in black south africans with hiv and acute coronary syndromes: prevalence and clinical correlates 
BMC Research Notes  2011;4:379.
HIV infection is associated with a high prevalence of antiphospholipid antibodies (aPL) and increased thrombotic events but the aetiopathogenic link between the two is unclear.
Prospective single centre study from Soweto, South Africa, comparing the prevalence of aPL in highly active anti-retroviral therapy (HAART) naïve HIV positive and negative patients presenting with Acute Coronary Syndromes (ACS). Between March 2004 and February 2008, 30 consecutive black South African HIV patients with ACS were compared to 30 black HIV negative patients with ACS. The HIV patients were younger (43 ± 7 vs. 54 ± 13, p = 0.004) and besides smoking (73% vs. 33%, p = 0.002) and lower HDL levels (0.8 ± 0.3 vs. 1.1 ± 0.4, p = 0.001) had fewer risk factors than the control group. HIV patients had a higher prevalence of anticardiolipin (aCL) IgG (47% vs. 10%, p = 0.003) and anti-prothrombin (aPT) IgG antibodies (87% vs. 21%, p < 0.001) but there was no difference in the prevalence of the antiphospholipid syndrome (44% vs. 24%, p = N/S) and aPL were not predictive of clinical or angiographic outcomes.
Treatment naïve black South African HIV patients with ACS are younger with fewer traditional coronary risk factors than HIV negative patients but have a higher prevalence and different expression of aPL which is likely to be an epiphenomenon of the HIV infection rather than causally linked to thrombosis and the pathogenesis of ACS.
PMCID: PMC3199261  PMID: 21970576

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