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1.  Thromboembolic risk in patients with high titre anticardiolipin and multiple antiphospholipid antibodies 
Thrombosis and haemostasis  2003;90(1):108-115.
Summary
Asymptomatic antiphospholipid antibody (aPL) carriers with high risk for thrombosis may benefit from preventive anticoagulation.
It was our objective to test whether the risk of thrombosis increases with: 1) increasing titres of anticardiolipin antibodies (aCL) after adjustment for other cardiovascular risk factors and 2) the number of aPL detected.
In a cross-sectional study, blood was collected from clinics in two teaching hospitals. The study included 208 individuals suspected of having an aPL and 208 age- and sex-matched controls having blood drawn for a complete blood count.
Clinical variables included history of previous arterial (ATE) or venous (VTE) thrombotic events, traditional risk factors for cardiovascular disease, and systemic lupus erythematosus (SLE). Laboratory variables included IgG/IgM aCL, lupus anticoagulant, and IgG/IgM anti-β2-glycoprotein I.
Mean age was 46.5 years and 83% were female. Seventy-five of the 416 participants had ≥ 1 aPL, and 69 had confirmed ≥ 1 ATE or VTE. Family history was positive in 48% of participants, smoking in 28%, hypertension in 16%, diabetes in 6%, and SLE in 20%. A 10-unit increase in aCL IgG titre was associated with an odds ratio (OR) [95% CI] of 1.07 [1.01–1.13] for ATE and 1.06 [1.02 – 1.11] for VTE. The odds of a previous thrombosis increased with each additional aPL detected: 1.5 [0.93–2.3] for ATE and 1.7 [1.1–2.5] for VTE.
These results indicate that increased titres of aCL and multiple aPL were associated with an increased risk of a previous thrombotic event.
doi:10.1267/THRO03010108
PMCID: PMC3482244  PMID: 12876633 CAMSID: cams2357
Antiphospholipid syndrome; antiphospholipid antibodies; anti-cardiolipin antibody; thrombosis
2.  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.
Objective
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.
Design
Cross-sectional study
Setting
Montefiore Medical Center, a large urban tertiary care center
Patients
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.
Results
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.
Conclusion
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.
doi:10.1136/jclinpath-2011-200613
PMCID: PMC3760969  PMID: 22389514
Antiphospholipid antibodies; statins; endothelial damage; thrombosis
3.  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.
doi:10.1136/ard.2004.031856
PMCID: PMC1755632  PMID: 15731290
4.  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
5.  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.
doi:10.1186/1749-8090-5-101
PMCID: PMC2987921  PMID: 21047408
6.  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.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.3899/jrheum.120157
PMCID: PMC3768146  PMID: 22859353
Lupus Erythematosus, Systemic; Antiphospholipid Antibodies; Lupus Anticoagulant; Hydroxychloroquine
7.  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.
doi:10.1155/2014/314704
PMCID: PMC4055657  PMID: 24967354
8.  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.
Objective
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).
Methods
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).
Results
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.
Conclusion
Persistence of aCL positivity is associated with an increased risk of LA/aβ2GPI.
doi:10.1093/rheumatology/kel050
PMCID: PMC3435425  PMID: 16510527 CAMSID: cams2311
Antiphospholipid antibodies; Anticardiolipin antibodies; Lupus anticoagulant; Anti-β2-glycoprotein I antibodies
9.  APhL antibody ELISA as an alternative to anticardiolipin test for the diagnosis of antiphospholipid syndrome 
Background
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.
Methods
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]).
Results
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.
Conclusion
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
10.  Prevention of fetal loss in experimental antiphospholipid syndrome by in vivo administration of recombinant interleukin-3. 
Journal of Clinical Investigation  1993;91(4):1834-1837.
Antiphospholipid antibodies are strongly associated with arterial and venous thrombosis and with fetal loss. Recently an experimental model for antiphospholipid syndrome (APLS) was established in our laboratory. In this model, mice are immunized passively or actively with anticardiolipin antibodies and acquire the syndrome, which is characterized by prolonged activated partial thromboplastin time (APTT), thrombocytopenia, low fecundity rate, and fetal loss. In a normal process of pregnancy, lymphokines affect fetal implantation and development. Cytokines from the colony stimulating factor family, like GM-CSF and IL-3, were shown to be positive signals for implantation and to promote placental development and fetal growth. Given our preliminary findings of low IL-3 in mice with APLS and the efficacy of IL-3 in preventing fetal loss in a strain of mice prone to fetal resorption, our aim in the present study was to examine the effect of murine recombinant IL-3 (mrIL-3) on pregnant mice induced with experimental APLS. Mice were passively transfused to the tail vein, 24 h following mating, with anticardiolipin antibodies. The mice were divided into two groups: one group was injected intraperitoneally with mrIL-3 on days 6.5, 8.5, and 10.5 after mating, while the control group was injected with PBS. When the mice were killed on day 15 of pregnancy a 32% +/- 4.2 resorption rate was observed in the anti-cardiolipin-immunized group, which was reduced to 4% +/- 0.3 following treatment with mrIL-3. The thrombocytopenia associated with the experimental APLS was also corrected following lymphokine administration. IL-3 may be effective in prevention of recurrent fetal loss in APLS.
Images
PMCID: PMC288166  PMID: 8473523
11.  Patent foramen ovale, cardiac valve thickening and antiphospholipid antibodies as risk factors for subsequent vascular events: The PICSS-APASS Study 
Objectives
(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).
Background
PFO is associated with cryptogenic ischemic stroke. Also, the presence of aPL is associated with ischemic cerebrovascular disease.
Design/Methods
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
Results
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.
Conclusions
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.
doi:10.1161/STROKEAHA.108.539171
PMCID: PMC2761081  PMID: 19498198
patent foramen ovale; anti-phospholipid antibodies; cardiac valve thickening; stroke recurrence risk; stroke risk factors; Risk Factors
12.  Clinical Implications of Elevated Antiphospholipid Antibodies in Adult Patients with Primary Immune Thrombocytopenia 
Background/Aims
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3904/kjim.2011.26.4.449
PMCID: PMC3245394  PMID: 22205846
Antibodies, anticardiolipin; Antiphospholipid syndrome; Purpura, thrombocytopenic, idiopathic; Lupus coagulation inhibitor; Thrombosis
13.  Antiphospholipid antibodies predict imminent vascular events independently from other risk factors in a prospective cohort 
Thrombosis and haemostasis  2009;101(1):100-107.
Summary
Antiphospholipid antibodies (aPL) are associated with vascular events, but the magnitude of this risk, alone, or in combination with other atherogenic and thrombophilic risk factors, remains unclear. A prospective cohort of 415 persons was studied for arterial and venous events (AE and VE) over a median time of 7.4 years. aPL and coagulation abnormalities were measured upon beginning of the study and annually for the first four years. Within the cohort, a nested case-control study was conducted to investigate the role of endothelial and inflammatory markers in predicting new vascular events. Forty-five individuals had new vascular events: 18 occurred during the first year of follow-up. The proportion of event-free survivors at eight years was 90% (95%CI = 87%, 94%) for aPL-negative and 72% (60%, 85%) for aPL-positive individuals, respectively. Predictors for new AE were previous AE (HR=5.7 [2.7, 12.0]), diabetes (5.6 [2.4, 13.2]), aPL positivity (2.6 ([1.2, 5.9]), and age (1.04 [1.01, 1.07]). New VE were predicted by previous VE (6.1 [1.9, 19.9]), anti-β2-glyco-protein I (aβ2GPI) positivity (5.8 [1.4, 24.1]), activated protein C resistance (APCR) (4.1 [1.1, 15.1]), and gender (3.7 [1.1, 12.9]). In the nested case-control study, similar predictors were observed for AE, while abnormal APCR (OR=5.5 [1.1, 26.6]) and elevated von Willebrand factor (vWF) (OR=5.0 [1.2, 19.8]) best predicted VE. We demonstrate that aPL independently predict new vascular events and discriminate between individuals with and without events in the first two years of follow-up, indicating that aPL are associated with a short-term risk of developing new and recurrent vascular events.
PMCID: PMC3435426  PMID: 19132195 CAMSID: cams2314
Antiphospholipid antibodies; thrombosis; anti-beta2-glycoprotein I; activated protein C resistance; von Willebrand factor
14.  Antibodies to Serine Proteases in the Antiphospholipid Syndrome 
Current Rheumatology Reports  2010;12(1):45-52.
It is generally accepted that the major autoantigen for antiphospholipid antibodies (aPL) in the antiphospholipid syndrome (APS) is β2-glycoprotein I (β2GPI). However, a recent study has revealed that some aPL bind to certain conformational epitope(s) on β2GPI shared by the homologous enzymatic domains of several serine proteases involved in hemostasis and fibrinolysis. Importantly, some serine protease–reactive aPL correspondingly hinder anticoagulant regulation and resolution of clots. These results extend several early findings of aPL binding to other coagulation factors and provide a new perspective about some aPL in terms of binding specificities and related functional properties in promoting thrombosis. Moreover, a recent immunological and pathological study of a panel of human IgG monoclonal aPL showed that aPL with strong binding to thrombin promote in vivo venous thrombosis and leukocyte adherence, suggesting that aPL reactivity with thrombin may be a good predictor for pathogenic potentials of aPL.
doi:10.1007/s11926-009-0072-7
PMCID: PMC2824841  PMID: 20425533
Thrombosis; Thrombin; Activated protein C; Plasmin; Hemostasis
15.  Factor V Leiden and Thrombosis in Patients with Systemic Lupus Erythematosus (SLE): A Meta-analysis 
Genes and immunity  2009;10(5):495-502.
To perform a meta-analysis of the association between the factor V Leiden polymorphism (FVL) and thrombosis among patients with SLE and/or antiphospholipid antibody (aPL) positivity. Included studies recruited patients based on SLE or aPL positive status, confirmed subjects' SLE diagnosis as defined by the American College of Rheumatology, and documented thrombotic events. Excluded studies were non-English or considered only arterial thrombosis. Individual patient data, available from five studies, together with unpublished data from 1210 European-American SLE patients from the UCSF Lupus Genetics Collection genotyped for FVL, were further analyzed. Seventeen studies (n=2090 subjects) were included in the initial meta-analysis. Unadjusted odds ratios (OR) were calculated to assess association of FVL with thrombosis. The OR for association of thrombosis with FVL was 2.88 (95% C.I. 1.98-4.20). In the secondary analysis with our individual patient dataset (n=1447 European-derived individuals), SLE subjects with the FVL polymorphism still had more than two times the odds of thrombosis compared to subjects without this polymorphism, even when adjusting for covariates such as gender, age, and aPL status. SLE and/or aPL positive patients with the FVL variant have more than two times the odds of thrombosis compared to those without this polymorphism.
doi:10.1038/gene.2009.32
PMCID: PMC2766554  PMID: 19421222
Systemic lupus erythematosus; factor V Leiden polymorphism; thrombosis; risk factors; antiphospholipid antibodies
16.  Antiphospholipid syndrome 
Antiphospholipid syndrome is diagnosed when arterial or venous thrombosis or recurrent miscarriages occur in a person in whom laboratory tests for antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant and/or anti-beta 2-glycoprotein I) are positive. Despite the strong association between antiphospho-lipid antibodies and thrombosis, their pathogenic role in the development of thrombosis has not been fully elucidated. Novel mechanisms involving both the complement pathway and micro-particles have been described. The knowledge of these new pathogenic approaches might identify novel therapeutic targets and therefore may improve the management of these patients.
doi:10.1186/ar2536
PMCID: PMC2656223  PMID: 19090981
17.  Platelet Activation and Anti-Phospholipid Antibodies Collaborate in the Activation of the Complement System on Platelets in Systemic Lupus Erythematosus 
PLoS ONE  2014;9(6):e99386.
Anti-phospholipid (aPL) antibodies are important contributors to development of thrombosis in patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE). The underlying mechanism of aPL antibody-mediated thrombosis is not fully understood but existing data suggest that platelets and the complement system are key components. Complement activation on platelets is seen in SLE patients, especially in patients with aPL antibodies, and has been related to venous thrombosis and stroke. The aim of this study was to investigate if aPL antibodies could support classical pathway activation on platelets in vitro as well as in SLE patients. Furthermore, we investigated if complement deposition on platelets was associated with vascular events, either arterial or venous, when the data had been adjusted for traditional cardiovascular risk factors. Finally, we analyzed if platelet complement deposition, both C1q and C4d, was specific for SLE. We found that aPL antibodies supported C4d deposition on platelets in vitro as well as in SLE patients (p = 0.001 and p<0.05, respectively). Complement deposition on platelets was increased in SLE patients when compared with healthy individuals (p<0.0001). However, high levels of C4d deposition and a pronounced C1q deposition were also seen in patients with rheumatoid arthritis and systemic sclerosis. In SLE, C4d deposition on platelets was associated with platelet activation, complement consumption, disease activity and venous (OR = 5.3, p = 0.02), but not arterial, thrombosis, observations which were independent of traditional cardiovascular risk factors. In conclusion, several mechanisms operate in SLE to amplify platelet complement deposition, of which aPL antibodies and platelet activation were identified as important contributors in this investigation. Complement deposition on platelets was identified as a marker of venous, but not arterial thrombosis, in SLE patients independently of traditional risk factors and aPL antibodies. Further studies are needed to elucidate the role of complement deposition on platelets in development of venous thrombosis.
doi:10.1371/journal.pone.0099386
PMCID: PMC4055750  PMID: 24922069
18.  Clinical and laboratory characteristics of children positive for antiphospholipid antibodies 
Blood Transfusion  2011;10(3):296-301.
Background.
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.
Results.
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).
Discussion.
Our study shows that aPL-positive children have different features that should be taken into account in the classification of criteria for paediatric APS.
doi:10.2450/2011.0069-11
PMCID: PMC3417728  PMID: 22244004
activated partial thromboplastin time; antiphospholipid antibodies; children; thrombosis
19.  Assessment of the 2006 revised antiphospholipid syndrome classification criteria 
Annals of the Rheumatic Diseases  2007;66(7):927-930.
Objective
To analyse antiphospholipid (aPL) antibody‐positive patients using the 2006 revised antiphospholipid syndrome (APS) classification criteria.
Methods
A descriptive study of 200 aPL‐positive patients identified in a local, hospital‐based registry, analysing demographic, clinical and aPL characteristics. Patients were analysed for (1) fulfilment of the 1999 original (Sapporo) and 2006 revised APS classification criteria; (2) non‐criteria aPL features (for all aPL‐positive patients, based on the 2006 revised criteria definitions); and (3) non‐aPL thrombosis risk factors at the time of the clinical events (for patients with APS, based on the 2006 revised criteria stratifications).
Results
Of the 200 patients, 183 patients had sufficient data for analysis. Of these, 39 (21%) patients did not meet the laboratory requirement of the original 1999 criteria. Of 81 patients with APS who met the 1999 classification criteria, 47 (58%) also met the 2006 revised criteria. Of 63 asymptomatic (no vascular or pregnancy events) aPL‐positive patients who met the laboratory requirement of the 1999 classification criteria, 38 (60%) also met the laboratory requirement of the 2006 revised criteria. More than 50% of the patients with APS with vascular events had identifiable non‐aPL thrombosis risk factors at the time of clinical events.
Conclusions
Only 59% of the patients meeting the 1999 APS Sapporo classification criteria met the 2006 APS classification criteria. The revised criteria will have positive implications in APS research by way of limiting the inclusion of a heterogeneous group of patients and also by way of providing a risk‐stratified approach.
doi:10.1136/ard.2006.067314
PMCID: PMC2497429  PMID: 17337473
20.  IgA Anti-β2-Glycoprotein I Autoantibodies Are Associated with an Increased Risk of Thromboembolic Events in Patients with Systemic Lupus Erythematosus 
PLoS ONE  2010;5(8):e12280.
Background
The clinical utility of testing for antiphospholipid antibodies (aPL) of IgA isotype remains controversial.
Methodology/Principal Findings
To address this issue, we reasoned that if IgA aPL contribute to the clinical manifestations of the antiphospholipid syndrome, then an association with thromboembolic events should manifest in patients whose only aPL is of IgA isotype. We performed a retrospective chart review of 56 patients (31 with systemic lupus erythematosus [SLE] and 25 without SLE) whose only positive aPL was IgA anti-β2-glycoprotein I (isolated IgA anti-β2GPI) and compared their clinical features with 56 individually matched control patients without any aPL. Patients with isolated IgA anti-β2GPI had a significantly increased number of thromboembolic events, as compared to controls. When patients were stratified into those with and without SLE, the association between isolated IgA anti-β2GPI and thromboembolic events persisted for patients with SLE, but was lost for those without SLE. Titers of IgA anti-β2GPI were significantly higher in SLE patients who suffered a thromboembolic event. Among patients with isolated IgA anti-β2GPI, there was an increased prevalence of diseases or morbidities involving organs of mucosal immunity (i.e., gastrointestinal system, pulmonary system, and skin).
Conclusions/Significance
The presence of isolated IgA anti-β2GPI is associated with an increased risk of thromboembolic events, especially among patients with SLE. IgA anti-β2GPI is associated with an increased prevalence of morbidities involving organs of mucosal immunity.
doi:10.1371/journal.pone.0012280
PMCID: PMC2924386  PMID: 20808864
21.  The dual role of innate immunity in the antiphospholipid syndrome 
Lupus  2010;19(4):347-353.
The antiphospholipid syndrome (APS), as both a primary syndrome and a syndrome in association with systemic lupus erythematosus (SLE), can be a devastating disease. It is unclear what factors (genetic and/or environmental) lead to the generation of antiphospholipid antibodies (aPL). It is equally unclear why only certain individuals with aPL develop clinical events. We hypothesize that innate immune activation plays a critical role at two distinct stages of APS, namely, the initiation phase, in which aPL first appear, and the effector phase, in which aPL precipitate a thrombotic event. According to the model we propose, aPL alone are insufficient to cause thrombosis and a concomitant trigger of innate immunity, e.g. a toll-like receptor (TLR) ligand, must be present for thrombosis to occur. Here, we discuss our findings that mice immunized with β2-glycoprotein I (β2GPI) and lipopolysaccharide (LPS), a TLR ligand, produce high levels of aPL and other SLE-associated autoantibodies, and develop lupus-like glomerulonephritis. We also discuss our data showing that autoantibodies to heat shock protein 60 (HSP60), an ‘endogenous TLR ligand’, promote thrombus generation in a murine model of arterial injury. Thus, both pathogen-derived TLR ligands (e.g. LPS) and endogenous TLR ligands (e.g. HSP60) may contribute to the pathogenesis of APS. This putative dual role of innate immunity provides new insight into the generation of aPL as well as the enigma of why some individuals with aPL develop APS, while others do not.
doi:10.1177/0961203310361492
PMCID: PMC3440308  PMID: 20353968 CAMSID: cams2352
antiphospholipid syndrome; β2-glycoprotein I; heat shock protein 60; innate immunity; lipopolysaccharide; toll-like receptor ligands
22.  LUPUS ANTICOAGULANT, BUT NOT ANTICARDIOLIPIN ANTIBODY, PREDICTS ADVERSE PREGNANCY OUTCOME IN PATIENTS WITH ANTIPHOSPHOLIPID ANTIBODIES 
Arthritis and Rheumatism  2012;64(7):2311-2318.
BACKGROUND
Which serologic and clinical findings predict adverse pregnancy outcome (APO) in patients with antiphospholipid antibody (aPL) is controversial.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1002/art.34402
PMCID: PMC3357451  PMID: 22275304
23.  Cerebrovascular disease associated with antiphospholipid antibodies: more questions than answers 
Neurological syndromes occur in a significant number of patients with antiphospholipid antibodies. The optimal management for these patients however remains uncertain.
Our study is a descriptive analysis looking retrospectively at 45 patients who presented to the principal tertiary referral centre in the Australian Capital Territory, with either cerebral arterial or venous thrombosis for which there was no obvious cause for their presentation when initially reviewed. The diagnosis was based on the clinical findings made by one of three neurologists attached to our centre. Radiological findings and the presence of either IgM or IgG anticardiolipin antibodies, IgG anti-beta-2 glycoprotein 1 antibodies or a lupus anticoagulant were then documented.
In this group of patients three subgroups were identified:
1. Individuals that fulfilled the Sapporo Classification Criteria
2. Individuals with transiently positive antiphospholipid antibodies and
3. Individuals with persistently low positive antiphospholipid antibodies.
The most interesting of these three groups are those individuals with transiently positive antiphospholipid antibodies. A potential cause for presentation was identified in only one patient of this group with documented infective endocarditis and bacteraemia. Comparison with the other two groups suggested that there was little in terms of clinical presentation, radiological findings or intercurrent risk factors for thrombotic disease to distinguish between them. With disappearance of antiphospholipid antibodies, the individuals within this group have not had further thrombotic events.
Our observations emphasise the problems that continue to exist in relation to the occurrence of cerebrovascular disease in the context of antiphospholipid antibodies and the optimal management of these stratified groups. Our findings also raise an as yet unanswered question as to the signficance of these transiently positive antiphospholipid antibodies. In the absence of significant intercurrent risk factors our findings would suggest that in the group we describe that they are likely to be of clinical significance.
doi:10.1186/1740-2557-3-3
PMCID: PMC1448177  PMID: 16573816
24.  Role of tissue factor in thrombosis in antiphospholipid antibody syndrome 
Lupus  2010;19(4):370-378.
Antiphospholipid syndrome (APS) is an acquired autoimmune disorder defined by the presence of an antiphospholipid antibody (aPL) and the occurrence of at least one associated clinical condition that includes venous thrombosis, arterial thrombosis or pregnancy morbidity. The aPL detected in APS have long been thought to have a direct prothrombotic effect in vivo. However, the pathophysiology underlying their coagulopathic effect has not been defined. Emerging data suggest a role for the procoagulant protein tissue factor (TF). In this review we provide an overview of TF, describe mouse models used in the evaluation of the role of TF in thrombosis, as well as summarize recent work on TF and APS.
doi:10.1177/0961203309360810
PMCID: PMC3057926  PMID: 20353972
antiphospholipid syndrome; thrombosis; coagulation; tissue factor; DIC
25.  Anti-Phosphatidylserine-Prothrombin Antibodies are Associated with Outcome in a TIA Cohort 
Background: Antiphospholipid antibodies (aPLs) have been associated with thrombosis in the antiphospholipid antibody syndrome (APS) and with atherosclerotic vascular events in patients without APS. We examined the significance of aPLs in transient ischemic attack (TIA). Patients/methods: Patients with TIA <48 h from symptom onset were prospectively enrolled. Traditional aPLs, including anticardiolipin and β2-glycoprotein-I (β2GPI), and newer aPLs, including anti-phosphatidylserine/prothrombin (aPS/PT), β2GPI Domain 4/5 and β2GPI Domain 1 were measured. Primary outcome was a composite of stroke or death within 90 days or identification of a high risk stroke mechanism. Secondary outcomes were stroke or death and the presence of clinical/sub-clinical atherosclerosis. Results: Over 4.5 years, 167 patients were enrolled. Forty one patients (25%) had the composite endpoint. Antibodies were measured in 158 subjects. aPS/PT IgG antibodies were significantly associated with stroke/death (OR 16.3, 95% CI 2.3–116.7, p = 0.005) and were non-significantly associated with the composite endpoint (OR 4.7, 95% CI 0.8–29.2, p = 0.10). In multivariate analysis adjusting for ABCD2 risk score, aPS/PT IgG remained associated with stroke/death (OR 15.7, 95% CI 2.0–125.6, p = 0.009). Other aPLs were not associated with clinical outcome and no association between APLs and atherosclerosis was identified. Conclusion: In contrast to other aPLs, aPS/PT IgG antibodies are independently associated with stroke or death in patients with TIA.
doi:10.3389/fneur.2012.00137
PMCID: PMC3460224  PMID: 23060855
anticardiolipin; antiphospholipid; biomarker; infarction; thrombosis; transient ischemic attack; aPS/PT antibodies

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