Thrombotic Antiphospholipid Syndrome Research Articles

Direct Oral Anticoagulants in Antiphospholipid Syndrome: Too Early or Too Late?

Ordi-Ros and colleagues reported the results of a randomized trial comparing rivaroxaban with dose-adjusted VKA therapy for patients with thrombotic APS. The editorial discusses the results in the ...

Prevalence of Antiphospholipid Antibodies Negativisation in Patients with Antiphospholipid Syndrome: A Long-Term Follow-Up Multicentre Study.

This article aims to analyse the rate of antiphospholipid antibodies (aPL) negativisation in patients with antiphospholipid syndrome (APS), and to evaluate potential new clinical manifestations after negativisation and/or aPL fluctuations in a long-term follow-up. Inclusion criteria are (1) any patients with an APS diagnosis according to the current Sydney criteria and (2) patients in whom aPL negativisation occurred. aPL negativisation was defined as repeated aPL measurements on at least two consecutive occasions at least 12 weeks apart, with a follow-up of at least 1 year since aPL first turned negative. Out of 259 APS patients, a total of 23 patients (8.9%) met the inclusion criteria for persistent aPL negativisation. Patients were followed-up for 14.4 ± 8.1 years, experienced aPL negativisation after a mean of 5.3 ± 3.5 years and were followed-up after experiencing the aPL negativisation for a mean of 7.6 ± 5.8 years. Seventeen patients (73.9%) presented with thrombotic APS, 2 with pregnancy morbidity (8.7%) and 4 (17.4%) with both. Most of the patients (18; 78.3%) had a single aPL positivity, 5 (21.7%) double, while no triple aPL positivity was observed. At the time of data collection, after aPL negativisation, anticoagulation was stopped in 8 patients with previous thrombotic venous event (8/21, 38%) according to the treating physicians' judgements. None of the patients experienced any recurrent thrombotic event during the follow-up period after their aPL negativisation. In our patient cohort consisting of 259 patients with definitive APS, we observed over a mean observation period of > 5 years, that aPL negativisation occurred in approximately 9% of patients. Negativisation occurred most often in patients who were previously found to be positive for only one aPL.

Antiphosphatidylserine/prothrombin complex antibodies as a determinant of prothrombotic plasma fibrin clot properties in patients with antiphospholipid syndrome

BackgroundAntiphosphatidylserine/prothrombin complex (aPS/PT) antibodies are recognized as a marker for antiphospholipid syndrome (APS). Dense and poorly lysable fibrin clots occur in thrombotic APS. Compact clots predict thromboembolism, but determinants of the unfavorable clot phenotype remain unknown in APS. We hypothesized that elevated aPS/PT antibodies determine unfavorable clot features. MethodsIn a cohort study involving 124 consecutive patients with thrombotic APS, we measured at baseline plasma fibrin clot permeability (Ks), efficiency of fibrinolysis (clot lysis time, CLT), and turbidity (off anticoagulation) along with immunoglobulin (Ig)G/IgM aPS/PT. During follow‐up, symptomatic thromboembolic events were recorded. ResultsElevated IgG and IgM aPS/PT antibodies >30 international enzyme units (UI) were detected in 54.8% and 42.7% of APS patients, including 76.2% and 54% of lupus anticoagulant‐ (LA, n = 63) positive patients, respectively. Elevated IgG and IgM aPS/PT antibodies predicted low Ks (lower quartile, <6 × 10−9 cm2; odds ratio [OR] = 5.93, 95% confidence interval [CI] 2.09‐16.82 and OR = 11.79, 95% CI 4.10‐33.92) and prolonged CLT (top quartile, ≥116 min; OR = 4.85, 95% CI 2.42‐25.07 and OR = 6.04, 95% CI 2.42‐15.07). No such associations were observed for anticardiolipin or β2‐glycoprotein I antibodies or LA presence. During follow‐up (median 72.5, range 66‐83 months), thromboembolic events observed in 32 (26.7%, 4.6%/year) patients were independently predicted by IgG aPS/PT antibodies >30 UI (hazard ratio [HR] = 3.04, 95% CI 1.20‐8.88) and low Ks (HR = 3.00, 95% CI 1.41‐6.50). ConclusionsWe identified aPS/PT antibodies as a determinant of denser and poorly lysable plasma fibrin clot formation in APS patients. The association of elevated aPS/PT antibodies with thromboembolism in APS could be at least in part mediated by prothrombotic clot properties.

TO CLOT OR NOT TO CLOT

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Autoimmune disorders predispose to venous thromboembolism (VTE), which can be difficult to manage. We present a unique case of difficult to control acute on chronic VTEs in a patient with multiple, overlapping, autoimmune disorders. CASE PRESENTATION: A 48-year-old nulligravida African-American female with a history of recurrent VTEs requiring inferior vena cava filter presented with sudden onset shortness of breath. On presentation, the patient was tachycardic but otherwise stable. Physical exam revealed an obese female in distress with an exquisitely tender left calf. Heparin drip was started for presumed new VTE. EKG showed sinus tachycardia without S1Q3T3 or ST segment or T wave abnormalities. CT PE confirmed bilateral segmental mismatched defects concerning for pulmonary emboli in the bilateral lung bases. Echocardiogram revealed flattening of the interventricular septum consistent with right ventricular strain. Lower extremity ultrasound revealed occlusive DVTs in both common femoral veins. The patient was admitted to the intensive care unit for possible thrombolysis vs thrombectomy, however, she had an acute 3 point drop in Hb (to 6.1) secondary to severe menorrhagia. She was deemed ineligible due to her refusal of blood transfusions and was started on medroxyprogesterone. Given a history of acute on chronic VTEs, autoimmune work up was pursued, which revealed positive lupus anticoagulant and ANA, elevated SSA, anti-Smith, and anti-RNP, and decreased antithrombin-III. Given her highly prothrombotic status, chronic anticoagulation therapy was discussed. The patient specifically requested an easily manageable non-Warfarin regimen. She was started on rivaroxaban and discharged to home with close follow up. The patient re-presented 9 days later with similar symptoms. Her Hb was 3.5. She was transfused 6 units of pRBCs with her consent. An intrauterine device was emergently placed with plans for future hysterectomy. Heparin drip was started post-procedure, however, the patient developed worsening tachycardia and left calf pain. Repeat ultrasound revealed propagation of her known DVT to the left greater saphenous vein. However, vascular surgery noted that the patient would need definitive treatment of uterine bleeding prior to any intervention. Per hematology, the patient was bridged to warfarin given her underlying coagulopathy. The patient’s clinical status remained stable for the next few days, and she was discharged to home on warfarin, medroxyprogesterone, and follow ups within one week. DISCUSSION: Autoimmune diseases are more common in females of reproductive age and can predispose to recurrent VTEs. Anticoagulation with warfarin is preferred, especially in patients with antiphospholipid syndrome. CONCLUSIONS: Patient comorbidities, and preferences, must be taken into account for proper management of the potentially deadly pulmonary manifestations of systemic autoimmune disorders. Reference #1: Cohen H, Hunt BJ, Efthymiou M et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016 Sep;3(9):e426-36. https://doi.org/10.1016/S2352-3026(16)30079-5. DISCLOSURES: No relevant relationships by Temidayo Abe, source=Web Response No relevant relationships by Iheoma Alinnor, source=Web Response No relevant relationships by Eric Chang, source=Web Response No relevant relationships by Anyanwoke Chisom, source=Admin input No relevant relationships by Melvin Crawford, source=Web Response No relevant relationships by Chima Odinkemere, source=Web Response No relevant relationships by Parris Tanksley, source=Web Response No relevant relationships by Benjamin Wibonele, source=Web Response

IgG Anti-high-Density Lipoproteins Antibodies Discriminate Between Arterial and Venous Events in Thrombotic Antiphospholipid Syndrome Patients.

Introduction: Recurrent thrombotic events are a hallmark of Antiphospholipid Syndrome (APS). However, biomarkers to identify if a patient with antiphospholipid antibodies (aPL) is at higher risk to develop an arterial or a venous event are lacking. Recently, the pathogenic role of anti-high-density lipoproteins antibodies (anti-HDL) in the occurrence of cardiovascular disease (CVD) in autoimmunity has emerged. The aim of the present study was to evaluate the presence of IgG anti-HDL antibodies in a cohort of thrombotic APS patients and to investigate their association with clinical outcomes.Methods: Serum levels of IgG anti-HDL antibodies, total IgG, and complete aPL profile were assessed in 60 APS patients and 80 healthy donors (HDs) by immunoassays.Results: Higher levels of IgG anti-HDL were found in APS patients compared to HDs (p < 0.001), even after correcting for total IgG levels (p < 0.001). No associations with treatments or traditional cardiovascular risk factors, except for smoking habit (p < 0.0001), were found. Patients who experienced at least one arterial event (n = 30) had significantly higher levels of anti-HDL antibodies when compared to patients with venous thrombosis (n = 30, p = 0.046), this difference being stronger when adjusting for total IgG (p = 0.007). Additionally, patients tested positive for antiphosphatidylserine/prothrombin (IgG/IgM) antibodies had significantly higher levels of anti-HDL antibodies (p = 0.045).Conclusions: Increased levels of IgG anti-HDL antibodies can be found in APS, mainly in patients with arterial thrombosis, independently of aPL antibodies and traditional risk factors. These findings point to a role of anti-HDL antibodies in APS and support their use as a potential biomarker for arterial thrombotic events.

Guideline: EULAR provided recommendations for thrombotic and obstetric antiphospholipid syndrome.

Source Citation Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019. [Epub ahead of print]. 31092409

Treatment in thrombotic antiphospholipid syndrome: a review.

Antiphospholipid syndrome an autoimmune disease characterized by thrombosis and/or pregnancy morbidity alongside the presence of antiphospholipid antibodies (aPL). This review evaluates primary and secondary thromboprophylaxis in patients with aPL and thrombotic events. In primary thromboprophylaxis a risk-stratified approach is needed based on aPL, comorbidity with other autoimmune conditions and cardiovascular vascular risk factors. In primary thromboprophylaxis, the efficacy of low-dose aspirin is debatable and requires better-designed controlled studies. So far warfarin has not been shown to improve venous and/or arterial thrombosis incidence in aPL carriers and instead increased safety concerns. The benefit of hydroxychloroquine is inconclusive despite promising data, requiring large, controlled trials. For secondary thromboprophylaxis warfarin seems to be the best option with potential in renal transplant recipients and better efficacy at high intensity, although maintenance of target international normalized ratio needs careful monitoring. Aspirin has not shown to be beneficial, and data on rivaroxaban are limited and contradictory. Despite all data being informative, there are limitations that need to be addressed with robust clinical trials.

Influence of anticardiolipin and anti‐β2 glycoprotein I antibody cutoff values on antiphospholipid syndrome classification

BackgroundAnticardiolipin (aCL) and anti‐β2 glycoprotein I (aβ2GPI) immunoglobulin (Ig) G/IgM antibodies are 2 of the 3 laboratory criteria for classification of antiphospholipid syndrome (APS). The threshold for clinically relevant levels of antiphospholipid antibodies (aPL) for the diagnosis of APS remains a matter of debate. The aim of this study was to evaluate the variation in cutoffs as determined in different clinical laboratories based on the results of a questionnaire as well as to determine the optimal method for cutoff establishment based on a clinical approach. MethodsThe study included samples from 114 patients with thrombotic APS, 138 patients with non‐APS thrombosis, 138 patients with autoimmune disease, and 183 healthy controls. aCL and aβ2GPI IgG/IgM antibodies were measured at 1 laboratory using 4 commercial assays. Assay‐specific cutoff values for aPL were obtained by determining 95th and 99th percentiles of 120 compared to 200 normal controls by different statistical methods. ResultsNormal reference value data showed a nonparametric distribution. Higher cutoff values were found when calculated as 99th rather than 95th percentiles. These values also showed a stronger association with thrombosis. The use of 99th percentile cutoffs reduced the chance of false positivity but at the same time reduced sensitivity. The decrease in sensitivity was higher than the gain in specificity when 99th percentiles were calculated by methods wherein no outliers were eliminated. ConclusionsWe present cutoff values for aPL determined by different statistical methods. The 99th percentile cutoff value seemed more specific. However, our findings indicate the need for standardized statistical criteria to calculate 99th percentile cutoff reference values.

PF708 THE IMPACT OF ANTIPHOSPHOLIPID ANTIBODIES (APL) ON OUTCOMES OF PATIENTS WITH IMMUNE THROMBOCYTOPENIA AND AUTOIMMUNE HEMOLYTIC ANEMIA TREATED WITH SPLENECTOMY

Background:Antiphospholipid antibodies (aPL) are present in up to 40% of patients with autoimmune cytopenias. There is limited information about their clinical significance. Splenectomy is a second line therapy in both Immune Thrombocytopenia (ITP) and Autoimmune Hemolytic Anemia (AIHA) with high response rates and durable remissions. There is no information about the impact of aPL in patients treated with splenectomy and there are concerns about lower response rates and a higher incidence of thrombosis.Aims:Define the impact of aPL on the safety and efficacy of splenectomy for the treatment of ITP or AIHA.Methods:We performed a case‐control study, including patients with either ITP or AHAI treated with splenectomy between 2000 and 2018. The cases were patients with moderate to high aPL titers in two measurements with 12 weeks apart. They could have a clinical criterion of antiphospholipid syndrome (APS) but patients with another autoimmune disease were excluded. The control group included patients with IT or AIHA with a negative determination of aPL. Cases and controls were paired by age, diagnosis (IT or AIHA), and date of splenectomy.Results:We included 68 patients (34 in each group): ITP 53% and AIHA 47%. Most patients were female (78%) with a median age of 37 years (19 to 63). Among the cases (aPL patients), 41% had triple antibody positivity and 62% a lupus anticoagulant phenomenon (LA).Before splenectomy, aPL patients have received more steroid cycles (p = 0.05) and more lines of therapy other than steroids (p = 0.02) in comparison with controls. The time between diagnosis and splenectomy was longer in aPL patients (54 vs. 18 months, p = 0.02).At 30 days, complete response (CR) rates for aPL patients and controls were 65% and 79% respectively (p = 0.27). We identify as factors associated with lower CR rate: AIHA diagnosis, thrombotic APS, positive anti‐beta2‐glycoprotein, aPL with triple antibody positivity and a more than one line of treatment. On multivariate analysis, only AIHA remained significant (OR 0.07, IC 95% 0.0–0.4, p &lt; 0.001).Regarding splenectomy, most were laparoscopic (88%). There were no differences in medical complications (35% vs. 23% p = 0.42) however, patients with aPL had a higher incidence of early infections (21 vs. 3%, p = 0.05). On multivariate analysis, patients with thrombotic APS (OR 6.9, IC 95% 1.3–34.8, p = 0.01) and an open splenectomy (OR 6.1, IC 95% 1.1–32.7 p = 0.03) had a higher risk of medical complications, whereas women had a lower risk (OR 0.2, IC 95% 0.0–0.9 p = 0.04).Median follow‐up was 52 months vs. 41 months (p = 0.14) for aPL patients and controls. At last follow‐up 44% vs. 38% required a new treatment for ITP/AIHA (p = 0.8). There was no difference in treatment‐free survival among both groups (log rank, p = 0.83). The incidence of long term infections and thrombosis during follow‐up was similar between groups (21% vs 6% p = 0.07 and 15% vs 9% p = 0.7, respectively). Long term Infections were associated with a shorter treatment‐free survival period (HR = 5.3, IC 95% 1.9–14.1 p &lt; 0.00).Summary/Conclusion:Although patients with aPL (with or without APS) are taken to splenectomy later and with more previous treatment lines, the response rate and treatment‐free survival are similar to those of patients without aPL. The incidence of thrombosis is the same between groups, but there was a higher incidence of infections in aPL patients. The latter can be related to the more intensive immunosuppressive treatment before splenectomy. Patients with thrombotic APS had more medical complications and a trend of lower response rates that must be further explored.image

Obstetric outcomes in patients with primary thrombotic and obstetric antiphospholipid syndrome and its relation to the antiphospholipid antibody profile.

Introduction: Previous studies suggested different obstetric outcomes between patients with thrombotic or obstetric antiphospholipid syndrome, but the data are inconclusive. Aims: To investigate obstetric outcomes and their relation to the antiphospholipid antibody profile in primary thrombotic or obstetric antiphospholipid syndrome patients and compare those to a control population. Materials and methods: A retrospective single-centre study on a cohort of 30 pregnant women with primary antiphospholipid syndrome treated at Karolinska University Hospital Solna, Sweden between 2000 and 2016. The pregnancy outcomes were compared to the outcomes of all pregnancies in Stockholm County during the same period. Results: Preeclampsia (p < 0.001), low birth weight at delivery (p = 0.001), Apgar < 7 at 5 minutes (p < 0.001) and small infants (p < 0.001) were more common in antiphospholipid syndrome patients compared to controls. Obstetric antiphospholipid syndrome patients had a higher incidence of small infants (p = 0.023), lower birth weight (p = 0.013) and infants born with complications (p=0.004) compared to thrombotic antiphospholipid syndrome. Mothers with triple antibody positivity had a higher incidence of preeclampsia (p = 0.03), preterm delivery (p = 0.011), small infants (p=0.002) and infants born with complications (p = 0.012). Conclusions: Patients with primary antiphospholipid syndrome, especially those with obstetric antiphospholipid syndrome and triple antibody positivity, are at higher risk for adverse pregnancy outcomes, even under antithrombotic treatment. More frequent antenatal controls in high-risk patients can further improve outcomes.

Reliability of Lupus Anticoagulant and Anti-phosphatidylserine/prothrombin Autoantibodies in Antiphospholipid Syndrome: A Multicenter Study

Background: Is it well-known that one of the major drawbacks of Lupus Anticoagulant (LA) test is their sensitivity to anticoagulant therapy, due to the coagulation based principle. In this study we aimed to assess the reproducibility of LA testing and to evaluate the performance of solid assay phosphatidylserine/prothrombin (aPS/PT) antibodies.Methods: We included 60 patients that fulfilled the following inclusion criteria: (I) diagnosis of thrombotic antiphospholipid syndrome (APS); (II) patients with thrombosis and (a) inconstant previous LA positivity and/or (b) positivity for antiphospholipid antibodies (aPL) at low-medium titers [defined as levels of anti-β2Glycoprotein-I or anticardiolipin (IgG/IgM) 10–30 GPL/MPL] with no previous evidence of LA positivity. aPL testing was performed blindly in 4 centers undertaking periodic external quality assessment.Results: The 60 patients enrolled were distributed as follows: 43 (71.7%) with thrombotic APS, 7 (11.7%) with thrombosis and inconstant LA positivity and 10 (16.7%) with low-medium aPL titers. Categorical agreement for LA among the centers ranged from 0.41 to 0.60 (Cohen's kappa coefficient; moderate agreement). The correlation determined at the 4 sites for aPS/PT was strong, both quantitatively (Spearman rho 0.84) and when dichotomized (Cohen's kappa coefficients = 0.81 to 1.0). Discordant (as defined by lack of agreement in ≥3 laboratories) or inconclusive LA results were observed in 27/60 (45%) cases; when limiting the analysis to those receiving vitamin K antagonist (VKA), the level of discordant LA results was as high as 75%(15/20). Conversely, aPS/PT testing showed an overall agreement of 83% (up to 90% in patients receiving VKA), providing an overall increase in test reproducibility of +28% when compared to LA, becoming even more evident (+65%) when analyzing patients on VKA. In patients treated with VKA, we observed a good correlation for aPS/PT IgG testing (Cohen's kappa coefficients = 0.81–1; Spearman rho 0.86).Conclusion: Despite the progress in the standardization of aPL testing, we observed up to 45% of overall discrepant results for LA, even higher in patients on VKA. The introduction of aPS/PT testing might represent a further diagnostic tool, especially when LA testing is not available or the results are uncertain.

HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome.

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

HELLP Syndrome: Pathophysiology and Current Therapies.

HELLP syndrome is a disorder associated with serious maternal morbidity and mortality. Distinguishing HELLP from other pregnancy-related disorders is often challenging and may result in delay of treatment. Differential diagnoses include acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, and hemolytic uremic syndrome, and are reviewed in this chapter. While there is not any current treatment for HELLP, the mainstay of treatment involves maternal stabilization and timely delivery. Various treatment strategies have been attempted to help decrease the morbidity and mortality of HELLP, including the maternal use of corticosteroids. The authors review the studies and controversies surrounding the maternal use of corticosteroids, plasma exchange, and low molecular weight heparin for the treatment of HELLP, as well as the role of the complement system in HELLP. Further large, well-designed, randomized controlled trials are needed to address the role corticosteroids may play in the treatment of women with HELLP and to help improve maternal and fetal outcomes.

Differences in plasma fibrin clot composition in patients with thrombotic antiphospholipid syndrome compared with venous thromboembolism

The prothrombotic fibrin clot phenotype has been reported in patients with thrombotic antiphospholipid syndrome (APS) and venous thromboembolism (VTE). Protein composition of plasma fibrin clots in APS has not been studied. We evaluated 23 patients with thrombotic APS, 19 with VTE alone, and 20 well-matched controls. A proteomic analysis of fibrin clots generated from citrated plasma was based on liquid chromatography-mass spectrometry. Plasma levels of thrombospondin-1 (TSP1), apolipoprotein(a), A-I, and B-100, complement components (C)3a, C5b-C9, histidine-rich glycoprotein (HRG), and prothrombin were evaluated using immunoenzymatic tests. In plasma fibrin clots of APS patients, compared with VTE subjects and controls, we identified decreased amounts of (pro)thrombin, antithrombin-III, apolipoprotein A-I, and HRG with no differences in plasma levels of antithrombin, prothrombin, along with lower plasma HRG and apolipoprotein A-I. In APS patients, plasma HRG positively correlated with amounts of clot-bound HRG, while apolipoprotein A-I was inversely associated with clot-bound levels of this protein. The most predominant proteins within the clots of APS patients were bone marrow proteoglycan, C5-C9, immunoglobulins, apolipoprotein B-100, platelet-derived proteins, and TSP1. Our study is the first to demonstrate differences in the protein composition of fibrin clots generated from plasma of thrombotic APS patients versus those with VTE alone.

Antiphospholipid Syndrome With Isolated Isotype M Anticardiolipin and/or Anti-B2GPI Antibody Is Associated With Stroke.

Background and Purpose- International classification criteria for antiphospholipid syndrome (APS) include IgM (immunoglobulin M), aCL (anticardiolipin), and aB2GPI (anti-β2-glycoprotein-I) antibodies, but their relevance is still debated. We aimed to assess whether patients with isolated IgM aCL and/or aB2GPI at diagnosis have specific characteristics and outcomes. Methods- We retrospectively included APS patients with isolated IgM antiphospholipid antibodies (isolated-IgM-APS) and compared them to APS patients with IgG and IgM, or IgG alone and/or lupus anticoagulant (nonisolated-IgM-APS). Results- Among the 168 APS patients included, 24 (14.3%) had isolated IgM. Median follow-up was 92.5 months (36-151.5). Isolated-IgM-APS patients were 9.5 years older. At diagnosis, stroke was more frequent in isolated-IgM-APS after adjustment for cardiovascular risk factors (odds ratio, 3.8; 95% CI, 1.3-11.5). IgM isotype remained isolated in 17 of 24 (70.8%) patients over time. Global relapse-free survival did not differ between the two groups. In thrombotic APS, monotherapy with antiplatelet agents was more frequently used in isolated-IgM-APS group with 14 of 20 versus 28 of 134 patients ( P<0.0001), with a higher relapse rate with antiplatelet agent alone compared to vitamin K antagonists, especially for patients presenting with a stroke (hazard ratio, 7.37; 95% CI, 1.19-19.0). Conclusions- Isolated IgM APS patients should not be disregarded because they represent 14.3% of an APS population. They have some characteristics: older age at diagnosis and a strong association with stroke. Clinicians must be aware of this situation because antiplatelet agent do not seem to well prevent relapses compared to vitamin K antagonist.

Thrombotic antiphospholipid syndrome.

Thrombotic antiphospholipid syndrome.

Antiphospholipid Antibodies to Domain I of Beta-2-Glycoprotein I Show Different Subclass Predominance in Comparison to Antibodies to Whole Beta-2-glycoprotein I.

Antiphospholipid antibodies (aPL), the serological hallmark of antiphospholipid syndrome (APS), are a heterogeneous group of autoantibodies raised against circulating blood proteins. Of these proteins, the phospholipid-binding b2-glycoprotein I (β2GPI) is considered to be the main autoantigen in APS. Indeed, IgG antibodies targeting b2GPI (ab2GPI) directly cause both thrombosis and pregnancy morbidity in several mouse models. While antibodies raised against all five domains of b2GPI have been reported, a subgroup of IgG ab2GPI raised against the first domain (DI) of b2GPI (aDI), strongly correlate with thrombotic APS, and drive thrombosis and pregnancy loss in vivo. Few studies have focused on determining the type of IgG subclass(es) for aPL. The subclass of an antibody is important as this dictates the potential activity of an antibody; for example, IgG1 and IgG3 can fix complement better and are able to cross the placenta compared to IgG2 and IgG4. It is unknown what subclass IgG aDI are, and whether they are the same as ab2GPI. To determine IgG subclass distribution for ab2GPI and aDI, we purified total IgG from the serum of 19 APS patients with known ab2GPI and aDI activity. Using subclass-specific conjugated antibodies, we modified our established in-house ab2GPI and aDI ELISAs to individually measure IgG1, IgG2, IgG3, and IgG4. We found that while IgG1, IgG2, and IgG3 ab2GPI levels were similar, a marked difference was seen in IgG subclass aDI levels. Specifically, significantly higher levels of IgG3 aDI were detected compared to IgG1, IgG2, or IgG4 (p < 0.05 for all comparisons). Correlation analysis of subclass-specific ab2GPI vs. aDI demonstrated that IgG3 showed the weakest correlation (r = 0.45, p = 0.0023) compared to IgG1 (r = 0.61, p = 0.0001) and IgG2 (r = 0.81, p = 0.0001). Importantly, total subclass levels in IgG purified from APS and healthy serum (n = 10 HC n = 12 APS) did not differ, suggesting that the increased IgG3 aDI signal seen in APS-derived IgG is antigen-specific. To conclude, our data suggests that aDI show a different IgG subclass distribution to ab2GPI. Our results highlight the importance of aDI testing for patient stratification and may point toward differential underlying aPL-driven pathogenic processes that may be subclass restricted.

Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

Circulating levels of tissue factor and the risk of thrombosis associated with antiphospholipid syndrome

The mechanisms behind the severe hypercoagulable state in antiphospholipid syndrome (APS) have not yet been fully elucidated. Knowledge on the etiology of thrombosis in APS is needed to improve treatment. We performed a case control study to evaluate the association of the levels of circulating tissue factor (TF) with thrombotic APS and unprovoked venous thromboembolism (VTE), as compared with controls without a history of thrombosis. Study participants were selected in the same geographic area. Linear regression was used to evaluate possible determinants of TF levels among controls and logistic regression was used to evaluate the association between TF, unprovoked VTE and t-APS. TF levels were grouped into three categories based on: below 50th percentile [reference], between 50-75th percentiles [second category] and 75th percentile [third category]. Two hundred and eighty participants were included in the study; 51 patients with unprovoked VTE, 111 patients with t-APS and 118 control individuals. The levels of TF were not associated with an increased risk of unprovoked VTE, as compared with controls. The adjusted odds ratio for t-APS was 2.62 (95%CI 1.03 to 6.62) with TF levels between 50-75th percentiles and 8.62 (95%CI 3.76 to 19.80) with TF levels above the 75th percentile, as compared with the reference category (below the 50th percentile). In the subgroup analysis, higher levels of TF were associated with both arterial and venous thrombosis in APS and with both primary and secondary APS. Circulating TF is associated with thrombotic complications related to APS, but not with the risk of unprovoked VTE.

Antiphospholipid syndrome – an update

Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia. It is characterized by the presence of antiphospholipid antibodies (APL) that are directed against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI). Its main manifestations are recurrent vascular thromboses (so-called "thrombotic APS") and pregnancy complications ("obstetric APS"). According to the current consensus criteria, a persistently positive functional lupus anticoagulant (LA) assay and/or the presence of anti-b2GPI and/or anti-cardiolipin antibodies, together with clinical symptoms, is mandatory for the diagnosis of APS. Other clinical features, such as thrombocytopenia, Coombs-positive haemolytic anaemia, heart valve disease, renal microangiopathy and neurologic disorders are also common in APL-positive patients. APS can be associated with other autoimmune disorders, such as systemic lupus erythematosus. In rare cases, catastrophic APS (CAPS) occurs, with the development of excessive thrombosis at multiple sites, usually affecting small vessels and leading to multi-organ dysfunction and organ failure. Treatment usually comprises antithrombotic therapy using antiplatelet and anticoagulant agents. However, there is no consensus concerning the intensity or duration of therapy. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high. For patients with CAPS, a combined therapeutic approach that includes anticoagulation, glucocorticoids, plasma exchange and/or intravenous immunoglobulin seems to be the best treatment option. Keywords: Antiphospholipid syndrome, lupus anticoagulants, anti-cardiolipin, anti-beta-2-glycoprotein I, vascular thrombosis, pregnancy complication.