Thrombotic Antiphospholipid Syndrome Research Articles

Predictors of damage accrual and its impact on health-related quality of life of thrombotic antiphospholipid syndrome: Independent validation of the damage index for antiphospholipid syndrome (DIAPS).

We aim to independently assess the validity of the damage index for antiphospholipid syndrome (DIAPS) in thrombotic antiphospholipid syndrome (APS) patients by exploring the prevalence and risk factors of organ damage and evaluating its impact on health-related quality of life (HR-QoL). Cross-sectional study including all thrombotic APS patients (Sydney criteria) attending a Portuguese tertiary centre. Damage was assessed using the DIAPS, and HR-QoL using the 3- and 5-level EuroQol HR-QoL (EQ-D5-3L and 5L), and Visual Analogue Scale (VAS) applied via a phone questionnaire. Spearman's correlation between DIAPS and the HR-QoL scales was performed. Risk factors for damage accrual and HR-QoL impairment were explored using univariate and multivariate logistic regression. Among the 108 patients (female, 65.7%; white, 90.7%; primary APS, 75.9%; median disease duration, 6years), damage (DIAPS≥1) developed in 48.2% of patients (mean ± SD DIAPS, 3.08 ± 1.83). DIAPS's neuropsychiatric domain was the most affected (24.2%), followed by the peripheral vascular domain (20.3%). No clinical, demographic nor laboratory parameters were significantly associated with damage. Regarding HR-QoL, pain/discomfort, anxiety/depression and usual activities domains were the most frequently impaired in both scales. DIAPS's domains correlated similarly with the EQ-5D-3L and 5L scales' individual domains. Female sex, medical disorders, secondary APS and type of presenting thrombosis (arterial) increased the risk of HR-QoL impairment. Total DIAPS was associated with higher odds of mobility, self-care and pain/discomfort impairment in both EQ-5D-3L and 5L scales but lost its independent risk in multivariable analysis. This external validation of DIAPS reinforces the ability of the score to correlate with HR-QoL while also highlighting risk factors for HR-QoL impairment other than damage accrual.

Obstetric antiphospholipid syndrome carries an increased lifetime risk for obstetric and thrombotic complications—a population-based study

BackgroundAntiphospholipid syndrome (APS) can present with either a thromboembolic event (thrombotic APS, TAPS) or an obstetric complication (obstetric APS, OAPS). Data on long-term complications in the different APS phenotypes are limited. ObjectivesWe aimed to compare obstetric history, antiphospholipid antibody profiles, obstetric and thromboembolic complications, and pregnancy outcomes between TAPS and OAPS. MethodsThis retrospective cohort study included women who delivered singleton pregnancies between 1998 and 2020. One hundred sixteen thousand four hundred nine women were included, resulting in 320,455 deliveries. Among the included patients, 71 were diagnosed with APS, 49 were classified as OAPS, and 22 as TAPS. The demographics, obstetric, neonatal, and thrombotic outcomes were compared among TAPS, OAPS, and the general obstetric population. ResultsOAPS patients had an increased risk of thrombotic events compared with the general obstetric population (odds ratio [OR] 18.0; 95% CI, 8.7-37.2). In pregnancies following the diagnosis of APS, despite standard antithrombotic treatment, OAPS patients exhibited an elevated risk of placenta-related and neonatal complications compared with the general obstetric population (late fetal loss [adjusted OR {aOR}, 15.3; 95% CI, 0.5-27.5], stillbirth [aOR, 5.9; 95% CI, 2.2-15.4], placental abruption [aOR, 4.8; 95% CI, 1.5-15.3], preeclampsia [aOR, 4.4; 95% CI, 2.5-7.7], fetal growth restriction [aOR, 4.3; 95% CI, 8.5-27.5], small for gestational age neonate [aOR, 4.0; 95% CI, 2.4-6.6], and low Apgar scores [Apgar'1: aOR, 2.6; 95% CI, 1.3-10.4; Apgar'5: aOR, 3.7; 95% CI, 1.3-10.4]). TAPS patients exhibited increased risk of preeclampsia (aOR, 3.1; 95% CI, 1.2-8). ConclusionOAPS patients exhibit a heightened risk of thrombotic events compared with the general obstetric population. Despite treatment, OAPS and TAPS still presented obstetric complications. These findings, after confirmation in prospective studies, need to be taken into consideration when planning the treatment approach for these patients.

Insight into antiphospholipid syndrome: the role and clinical utility of neutrophils extracellular traps formation

Antiphospholipid syndrome (APLS) is a systemic immune dysregulation distinguished by repetitive complications and pregnancy loss in the absence of definite etiology. Most research focuses on the laboratory detection and clinical features of APLS, but its precise etiology remains to be deeply explored. NETosis is a newly developed theory in the pathophysiology of APLS which may serve as the missing bridge between coagulation and inflammation reaching the disease progression and severity. We aimed in this study to navigate the prognostic role of NETosis in thrombotic APLS. Our study included 49 newly diagnosed APLS patients (both 1ry and 2ry) who met clinical and laboratory criteria as per the international consensus statement on the update of the classification criteria for definite APLS and were sub-classified according to the occurrence of thrombotic events in thrombotic and non-thrombotic types. In addition, 20 sex and age-matched reactive subjects and 20 sex and age-matched healthy volunteer controls were enrolled. NETosis formation was assessed by measuring serum Myeloperoxidase (MPO) and Histones level using the enzyme-linked immunosorbent assay (ELISA) technique. Both MPO and Histones levels were able to discriminate among APLS cases from normal controls, showing significant cutoffs of > 2.09 ng/ml for MPO and > 1.45 ng/ml for Histones (AUC values were 0.987and 1.000, respectively). These values can be used as predictors for NETosis pathophysiology in APLS patients. Additionally, these markers demonstrated a significant association with several prognostic indicators, including thrombosis, higher PT and INR, and lower hemoglobin (Hb) levels which are supposed to be ameliorated by using NETs inhibitors. In conclusion, we suggest that measuring NETosis markers, MPO, and Histones, in the early course of APLS using proposed cutoff values will facilitate the timely initiation of anti-NETosis therapy and improve the overall prognosis, particularly for patients with thrombotic APLS.

Low recurrent thrombosis rates in single positive antiphospholipid syndrome regardless of type of anticoagulation

Thrombotic antiphospholipid syndrome (TAPS) is characterized by thrombosis and persistently positive tests for antiphospholipid antibodies or lupus anticoagulant (LAC). Triple-positive APS has the highest risk of recurrent thrombosis, but no studies have focused on recurrent thrombosis in patients with single-positive TAPS. We conducted a retrospective cohort study of patients with single-positive TAPS diagnosed at Lifespan Health System, Rhode Island, to determine the rates and risk factors for recurrent thrombosis. Between January 2001 and April 2022, 128 patients were assessed who had single-positive APS (LAC = 98, aCL = 21, aβ2GPI = 9) and who had been followed for a total of 1453.8 patient-years (median follow-up 3.04 years). The initial antithrombotic regimen was warfarin in 44 %, a direct oral anticoagulant (DOAC) in 34 %, enoxaparin in 2 %, and no antithrombotic therapy or antiplatelet therapy only in 20 %. Recurrent thrombosis occurred in 16 (12.5 %) with a recurrent thrombosis rate of 3.08 per 100 patient-years. Systemic lupus erythematosus was the only variable significantly associated with recurrent thrombosis in a model adjusted for age, sex, body mass index, and type of positive APS test. All 16 patients with recurrent thrombosis were initially treated with warfarin, and, at the time of recurrent thrombosis, 13 patients remained on warfarin and three were off anticoagulation. In conclusion, the recurrent thrombosis rate in single-positive APS is low, and not all patients with a single-positive test may need indefinite anticoagulation with warfarin. Larger prospective studies are required to confirm this finding and establish optimal anticoagulation regimens for low-risk TAPS.

Can complement activation be the missing link in antiphospholipid syndrome?

APS is an autoimmune disorder with life-threatening complications that, despite therapeutic advantages, remains associated with thrombotic recurrences and treatment failure. The role of complement activation in APS pathogenesis is increasingly recognised, specifically in obstetric APS. However, its exact role in thrombotic APS and on the severity of the disease is not yet fully elucidated. Further mechanistic studies are needed to delineate the role of complement activation in the various APS clinical manifestations with aim to identify novel markers of disease severity, together with clinical trials to evaluate the efficacy of complement inhibition in APS. This could ultimately improve risk stratification in APS, patient tailored targeted therapy with complement inhibition identified as an adjunctive treatment. This article reviews current findings and challenges about complement activation in APS, discusses the potential role of platelet mediated complement activation in this setting and provides an overview on clinical implications and current therapeutics.

7-year follow-up atherosclerotic plaque progression in patients with antiphospholipid syndrome versus diabetes mellitus and healthy controls.

Patients with antiphospholipid syndrome (APS) carry a substantial burden of cardiovascular disease and subclinical atherosclerosis. We aimed to assess a 7-year follow-up atherosclerotic plaque progression in APS patients vs diabetes mellitus (DM) and healthy controls (HC). Eighty-six patients with thrombotic APS, 86 with DM and 86 HC (all age- and sex-matched) who underwent a baseline ultrasound of carotid and femoral arteries were invited for a 7-year follow-up ultrasonography examination. We compared atherosclerosis progression among the three groups and examined determinants of plaque progression in APS patients. Sixty-four APS patients (75% females, 43.8% with primary APS), 58 patients with DM and 66 HC were included in the 7-year ultrasound re-evaluation. New plaque was detected in 51.6%, 36.2% and 25.8% of APS, DM and HC subjects, respectively. After adjusting for traditional cardiovascular risk factors (CVRFs) and baseline plaque presence, APS patients showed a 3-fold (OR = 3.07, p= 0.007) higher risk for atherosclerosis progression vs HC and 2-fold (OR = 2.25, p= 0.047) higher risk than DM patients. In multivariate analysis in the APS group, plaque progression was independently associated with systemic lupus erythematosus (SLE) co-existence (OR = 7.78, p= 0.005) and number of CVRFs (OR = 3.02, p= 0.002), after adjusting for disease-related parameters and CVRF-related medications. Sustained low-density lipoprotein target attainment reduced plaque progression risk (OR = 0.34, p= 0.021). Half of APS patients develop new atherosclerotic plaques over a 7-year follow-up, having a three-times higher risk vs HC. Concomitant SLE and number of traditional CVRFs are associated with plaque progression, supporting the need for thorough CVRF assessment and control.

Platelets and Thrombotic Antiphospholipid Syndrome

Antiphospholipid antibody syndrome (APS) is an autoimmune disorder characterised by thrombosis and the presence of antiphospholipid antibodies (aPL): lupus anticoagulant and/or IgG/IgM anti-β2-glycoprotein I and anticardiolipin antibodies. APS carries significant morbidity for a relatively young patient population from recurrent thrombosis in any vascular bed (arterial, venous, or microvascular), often despite current standard of care, which is anticoagulation with vitamin K antagonists (VKA). Platelets have established roles in thrombosis at any site, and platelet hyperreactivity is clearly demonstrated in the pathophysiology of APS. Together with excess thrombin generation, platelet activation and aggregation are the common end result of all the pathophysiological pathways leading to thrombosis in APS. However, antiplatelet therapies play little role in APS, reserved as a possible option of low dose aspirin in addition to VKA in arterial or refractory thrombosis. This review outlines the current evidence and mechanisms for excessive platelet activation in APS, how it plays a central role in APS-related thrombosis, what evidence for antiplatelets is available in clinical outcomes studies, and potential future avenues to define how to target platelet hyperreactivity better with minimal impact on haemostasis.

The prevalence and incidence of thrombotic primary antiphospholipid syndrome in adults aged 18–49 years: A population-based study in a mountain community in northern Italy

ObjectiveTo estimate prevalence and incidence of thrombotic Primary Antiphospholipid Syndrome (PAPS) in the general population aged 18–49 years. MethodsThe study was carried out in Valtrompia, a valley in northern Italy, in 2011–2015. The identification of PAPS cases leveraged three integrated sources: 1) Rheumatology Unit at the University Hospital; 2) General Practitioners; 3) hospital discharge codes of patients admitted for thrombotic events. ResultsPrevalence and incidence were estimated as 22.9 (95% C.I. 11.4–41.0) and 5.0 (2.6–8.7) cases per 100,000 individuals, respectively. The estimates were 28.3 and 4.8, and 17.2 and 5.1 in males and females, respectively. The type of disease onset was mainly of arterial type in men and venous in women. ConclusionsThrombotic PAPS was found to be a rare disease in this population-based study. Prevalence and incidence were not significantly different between males and females aged 18–49 years, but a different type of onset was observed.

Thrombosis recurrence and major bleeding in non-anticoagulated thrombotic antiphospholipid syndrome patients: Prospective study from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) clinical database and repository (“Registry”)

BackgroundLong-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. ObjectivesTo prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups. Patients/MethodsUsing an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model. ResultsAs of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01). ConclusionFourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation.

Cytokine Profiling in Antiphospholipid Syndrome Demonstrates Persistent Immune Dysregulation and a Procoagulant Phenotype

Background: The antiphospholipid syndrome (APS) is an autoimmune thromboinflammatory disease characterized by thrombosis and the persistent detection of antiphospholipid antibodies (aPL). The rate of recurrent thrombosis in APS is between 3 and 24% despite standard of care anticoagulation with a vitamin K antagonist, suggesting a persistent prothrombotic milieu in APS which may be driven by altered cytokine signaling. Objective: To test the hypothesis that cytokine signaling is dysregulated in APS and contributes to thrombotic risk, we profiled cytokine levels in patients with thrombotic APS and healthy individuals. Methods: We measured a panel of 46 serum cytokines using the Meso Scale Discovery electrochemiluminescent platform, a validated measurement system that provides linear readouts of analytes over several logs of concentration, in 21 APS patients and 12 healthy individuals. All APS patients met the Revised Sapporo Criteria for thrombotic APS. Measurements were performed in triplicate and the log2 transformed averages were analyzed, setting significance at a FDP-adjusted p value of &amp;lt;0.05, while controlling for age and sex. Cytokine values were correlated with clinical history and antibody isotype profile. Results: Our cohort was 67% female and 85% identified as white. All APS patients had thrombotic disease: 57% with history of VTE, 19% with ATE, and 24% with both VTE and ATE. 14% had catastrophic APS. 67% were triple-positive for anti-cardiolipin (aCL), anti-β2 glycoprotein 1 (aβ2GP1), and lupus anticoagulant (LAC). 10% had isolated IgM isotypes of aCL or aβ2GP1. We found significantly elevated levels of TNF-α, IL-6, IL-7, IL-8, IL-10, IL-16, IL-12/IL-23p40, soluble VCAM-1, soluble ICAM-1, PIGF, SAA and CRP and significantly decreased levels of IL-17genB, IL-22 and IL-31 in APS compared with healthy controls (Figure 1). Cytokine levels were measured a median of 5 months (1-240) from the last thrombotic event, demonstrating persistence of the inflammatory response. To determine if cytokine levels were predictive of thrombotic risk, we correlated the number and pattern of positive aPL isotypes and LAC with cytokine levels. We found that TNF-α, IL-8, IL-10, sVCAM-1, sICAM-1, VEGF, IL-7, IL-12/IL-23p40, IL-4, IL-6, IL-16, PIGF, IL-23 and IL-17A each correlated with aPL positivity, with higher levels in triple-positive APS, and the highest levels observed in patients positive for all five measured antibody isotypes (aCL IgG, IgM, IgA; aβ2GP1 IgG, IgM) plus the functional LAC (Figure 2). IL-31 level inversely correlated to the number of positive aPL tests. A sub-analysis of cytokines in patients with isolated IgM aCL or aβ2GP1 antibodies with or without LAC showed significantly increased levels of TNF-α compared to healthy controls, and did not differ from APS patients with other patterns of aPL positivity. This suggests that a similar proinflammatory or procoagulant background is present in patients with isolated antiphospholipid IgM antibodies as those with IgG. Discussion: The sustained differences in cytokine levels measured in APS patients suggests a picture of ongoing immune dysregulation and compensation capable of driving vascular cell activation, and tipping the hemostasis balance into thrombosis. We find upregulation of proinflammatory cytokines, such as TNF-α and IL-6, capable of activating endothelial cells and triggering amplification loops leading to chemokine and acute phase reactant release, cell adhesion molecule expression, recruitment of leukocytes, and accumulation of complement and coagulation proteins, with the net effect of driving inflammation and thrombosis. Decreased levels of IL-17, IL-22 and IL-31 are indicative of dysregulation of the Th17 CD4+ T cell response, which has been implicated in autoimmune pathogenesis. The correlation of cytokine levels with triple or greater aPL positivity suggests a model for advancing risk stratification and has utility as a biomarker of thrombosis. Our study, although limited by size, represents one of the most extensive profiling of cytokines in thrombotic APS.

Circulating Platelets in Thrombotic Antiphospholipid Syndrome Display High Procoagulant Activity and Surface Complement Deposition: Correlation with Thrombotic Risk

Background Antiphospholipid syndrome (APS) is characterized by circulating antiphospholipid antibodies (aPL) accompanied by arterial and/or venous thrombosis, and/or recurrent pregnancy loss. It commonly affects young women in whom it dramatically increases their risk of myocardial infarction, ischemic stroke, deep vein thrombosis and pulmonary embolism. Although the thrombotic risk associated with aPL is established, the underlying mechanisms are still incompletely defined and there are no definitive predictive biomarkers. As a result the management of APS involves indefinite anticoagulation. Increased activation of vascular cells, including platelets is considered to underlie the pathogenesis of APS, and may be mediated in some cases by complement. There is a considerable crosstalk between platelets and complement at various levels during thrombosis. First, activated complement proteins stimulate platelets through their cognate receptors on the platelet surface, and genetic deficiency of complement proteins in mice leads to decreased platelet responsiveness. Second, platelets secrete complement proteins into the medium upon activation. Third, agonist-stimulated platelets contribute to activation of both the classical and alternative pathways of the complement cascade. Hence, we sought to investigate the association between the complement-platelet axis and the prothrombotic pathology observed in APS. Methods Venous blood was drawn from patients with APS and healthy controls, and washed human platelets were prepared by differential centrifugation. Platelets either remained unstimulated or were treated with thrombin (0.1, 0.25, 0.5 U/ml) for 5 min and then labelled with FITC-PAC1, PE-anti-CD62P antibody, Alexa Fluor 488-anti-C4d conjugate, PE-Annexin V, Mitotracker Red, MitoSOX Red, Fluo4-AM, Rhod2-AM, Cell Event Green Caspase 3/7 detection reagent and FITC-IETD-FMK for 30 min in the dark, and then analyzed by flow cytometry to measure integrin activation, P-selectin expression (α-granule secretion), complement C4d binding, phosphatidylserine (PS) exposure, mitochondrial membrane potential, mitochondrial ROS, cytosolic calcium, mitochondrial calcium, caspase 3/7 activity (apoptosis) and caspase 8 activity (extrinsic apoptosis pathway), respectively. Platelet markers were correlated with complement binding and clinical characteristics of APS patients including number of thrombotic events and circulating levels of aPL. Results Thrombin-induced platelet integrin activation and P-selectin expression were identical in APS patients and healthy controls. However, platelets isolated from APS patients had significantly higher procoagulant activity (PS exposure) as well as complement C4d binding in both unstimulated and thrombin-stimulated states compared to healthy controls. There was a strong positive correlation between platelet PS exposure and C4d binding in APS patients, but not healthy individuals, suggesting a role for complement activation in formation of procoagulant platelets in APS. A subset of APS patients with high platelet procoagulant activity (PS exposure &amp;gt; mean + 2SD observed in healthy individuals) had lower mitochondrial membrane potential and increased mitochondrial calcium transients compared to healthy individuals, suggesting mitochondrial permeability transition pore (mPTP)-driven PS exposure. Another subset of APS patients with PS exposing platelets showed caspase activation indicating apoptosis. Platelet PS exposure and C4d binding correlated strongly with the number of thrombotic events as well as levels of circulating aPL, which identifies complement-induced procoagulant platelets as predictors and possible underlying mechanisms for thrombosis in APS. Conclusion Our preliminary studies suggest that PS-exposing platelets are generated in APS by multiple mechanisms including agonist-induced mPTP formation and apoptosis-associated caspase activation. Platelet PS exposure in APS is positively correlated with C4d binding, suggesting a role for complement activation in driving platelet procoagulant activity. Complement activation and PS exposure on platelets are strong predictors of thrombotic risk in APS and could serve as promising targets for novel antithrombotic agents in APS management.

PB0436 Long-Term Use of Fondaparinux in Patients with Thrombotic Antiphospholipid Syndrome - A Retrospective Audit of Clinical Outcomes

PB0436 Long-Term Use of Fondaparinux in Patients with Thrombotic Antiphospholipid Syndrome - A Retrospective Audit of Clinical Outcomes

PB0757 Comparison of Clinical and Serological Features in Thrombotic Antiphospholipid Syndrome Patients, with and without Associated SLE, Followed for up to 42 Years: A Single Centre Retrospective Study

PB0757 Comparison of Clinical and Serological Features in Thrombotic Antiphospholipid Syndrome Patients, with and without Associated SLE, Followed for up to 42 Years: A Single Centre Retrospective Study

PB0432 Identification of a Subset of Thrombotic Antiphospholipid Syndrome Patients with Significant Discordance in Paired Capillary- and Venous- Monitoring with an International Normalized Ratio

PB0432 Identification of a Subset of Thrombotic Antiphospholipid Syndrome Patients with Significant Discordance in Paired Capillary- and Venous- Monitoring with an International Normalized Ratio

Comorbid association of obstructive sleep apnea (OSA) and thrombotic primary antiphospholipid syndrome (tPAPS): A more severe phenotype?

ObjectiveWe aimed to evaluate the frequency of obstructive sleep apnea (OSA) in patients with thrombotic primary antiphospholipid syndrome (tPAPS), to investigate the performance of screening tools for OSA in this scenario and to compare clinical/laboratorial differences in tPAPS patients with and without OSA. MethodsWe consecutively enrolled patients with tPAPS to undergo sleep studies using a portable monitor. OSA was defined as apnea-hypopnea index ≥15 events/h. Frequency of OSA in tPAPS was evaluated and compared with age-, gender-, and BMI-matched controls (1:3 ratio) from the Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Next, we tested the performance of three different screening tools for assessing OSA in patients with tPAPS. Finally, patients with tPAPS were stratified according to OSA status comparing their clinical and laboratory characteristics (including damage burden measured by Damage Index for Antiphospholipid Syndrome [DIAPS] and biomarkers associated with thrombosis) using standard statistical procedures. ResultsFifty-two patients were included for analysis (females: 82.7%; mean age: 48 ± 14 years; body-mass index: 31.1 ± 6.5 Kg/m2; 25% with moderate-severe OSA). When compared to matched controls from ELSA-Brasil (n = 115), there was no significant differences in the frequencies of OSA (tPAPS: 12/42 [28.6%] vs. controls: 35/115 [30.4%], p = 0.821). Among screening tools, NoSAS had the highest area under ROC curve (AUC 0.806, CI 95% 0.672–0.939, p = 0.001), followed by STOP-Bang (AUC 0.772, CI 95% 0.607–0.938, p = 0.004). Patients with comorbid tPAPS and OSA presented higher levels of von Willebrand factor (vWF) (median 38.9 vs. 32.6, p = 0.038) and DIAPS (median 5 vs. 2, p = 0.020), when compared to those without OSA. OSA remained statistically associated with higher DIAPS, even after controlling for age, disease duration and BMI. ConclusionOSA is common in patients with tPAPS, with rates comparable to a non-referred population. Both NoSAS and STOP-Bang scores seems to be useful for screening OSA in these patients. Patients with tPAPS+OSA had higher damage burden and higher levels of vWF, which might suggest a more severe phenotype of tPAPS in this scenario.

Effect of smoking on thrombotic antiphospholipid syndrome: a 10-year prospective cohort study.

Cigarette smoking is an established risk factor for autoimmune diseases. However, whether smoking plays a clear role in thrombotic antiphospholipid syndrome (TAPS) has not been determined. We aimed to investigate the effects of smoking on clinical characteristics and prognosis of TAPS. This was a prospective cohort study from 2013 to 2022. During the study period, 297 patients were diagnosed with TAPS, including 82 smokers and 215 non-smokers. After propensity score matching, 57 smokers and 57 non-smokers matched by age and sex were analysed. Overall, smokers with TAPS had more cardiovascular risk factors (CVRFs) than non-smokers, including hypertension (36.59% vs. 14.42%, P<0.001), obesity (15.85% vs. 7.44%, P=0.029), dyslipidaemia (64.63% vs. 48.37%, P=0.012), and hyperhomocysteinaemia (62.20% vs. 36.28%, P<0.001). Arterial thrombotic events were more common in smokers at diagnosis (62.20% vs. 46.05%, P=0.013), especially myocardial infarction, visceral thrombosis, and peripheral vascular thrombosis. After matching, smokers showed balanced CVRFs with non-smokers at baseline, but retained a higher prevalence of arterial thrombosis (59.65% vs. 33.33%, P=0.005), mainly distributed in cerebral vascular, cardiovascular, and retinal vascular territories. During follow-up, smokers presented a tendency for more recurrent arterial thrombosis and less recurrent venous thrombosis. Smokers had significantly poorer outcomes for organ damage with higher DIAPS (median, 2.00 vs. 1.00, P=0.008), especially in the cardiovascular (26.32% vs. 3.51%, P=0.001), gastrointestinal (15.79% vs. 1.75%, P=0.016), and ophthalmologic (10.53% vs. 00.00%, P=0.027) systems. Smoking is related to increased arterial events and poor prognosis in TAPS patients. Patients with TAPS should be fully encouraged to avoid smoking.

A review on management of antiphospholipid syndrome in clinical practice

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic or obstetric events occurring in patients with persistent antiphospholipid antibodies. Thrombotic APS is characterized by venous, arterial, or microvascular thrombosis. The diagnosis is accepted when both one clinical and one laboratory criteria according to the updated Sapporo classification are established. APS may occur in combination with other autoimmune diseases, mainly systemic lupus erythematosus, or in its primary form. Long-term anticoagulation with a vitamin K antagonist is the standard of care for patients who develop thrombosis, considering the high rate of recurrent thrombosis. The current international guidelines are not in favor of recommending direct oral anticoagulants for secondary prevention of thrombotic antiphospholipid syndrome, especially in the context of arterial thrombosis and triple-positive antiphospholipid patients. The most common approach, endorsed by the American College of Chest Physicians guidelines is the combination of heparin and low-dose aspirin (75-100 mg) daily for women who fulfill the clinical and serologic criteria for obstetric APS. New potential therapeutic approaches are under evaluation but actually the anticoagulation remains the cornerstone of treatment.

Augmented oxidative stress, accumulation of DNA damage and impaired DNA repair mechanisms in thrombotic primary antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a rare autoimmune disorder with complex pathogenesis. Studies have shown that oxidative stress may contribute to APS pathophysiology. In peripheral blood mononuclear cells (PBMCs) from thrombotic Primary APS (thrPAPS) patients and age/sex-matched healthy controls (HC), as well as a control group of asymptomatic antiphospholipid antibody (aPL) positive individuals without APS (aPL+/non-APS), we examined oxidative stress, abasic (apurinic/apyrimidinic) sites, and DNA damage response (DDR)-associated parameters, including endogenous DNA damage (single- and double-strand breaks) and DNA repair mechanisms, namely nucleotide excision repair (NER) and double-strand breaks repair (DSB/R). We found that thrPAPS patients exhibited significantly higher levels of endogenous DNA damage, increased oxidative stress and abasic sites, as well as lower NER and DSB/R capacities versus HC (all P < 0.001) and versus aPL+/non-APS subjects (all P < 0.05). Our findings demonstrate that oxidative stress and decreased DNA repair mechanisms contribute to the accumulation of endogenous DNA damage in PBMCs from thrPAPS patients and, if further validated, may be exploited as therapeutic targets and potential biomarkers.

Prevalence and adverse consequences of delayed diagnosis and misdiagnosis in thrombotic antiphospholipid syndrome. An observational cohort study and a review of the literature

ObiectivesThis study aims to prospectively evaluate the frequency and adverse consequences of diagnostic delay and misdiagnosis in a cohort of patients with thrombotic antiphospholipid syndrome (TAPS). In addition, a systematic review of the literature concerning the diagnostic delay and misdiagnosis of TAPS was carried out.MethodsPatient enrollment occurred between 1999 and 2022. The study group was formed by TAPS patients whose diagnosis was delayed and those who were misdiagnosed. The control group was made up of patients who were timely and correctly diagnosed with TAPS.ResultsThe literature review showed 42 misdiagnosed patients, 27 of them were in one retrospective cohort study and 15 in 13 case reports. One hundred sixty-one out of 189 patients (85.2%) received a timely, correct diagnosis of TAPS; 28 (14.8%) did not. The number of patients with diagnostic issues was significantly higher for the first period (1999–2010), and the number of patients with a correct diagnosis was significantly higher for the second one (2011–2022). When the clinical and laboratory characteristics of the patients with delayed diagnosis were compared with those with misdiagnosis, there was a significantly higher number of severe adverse consequences characterized by permanent disability or death in the latter group. The two most common types of misdiagnoses were systemic lupus erythematosus (6 cases, 46.1%) and cardiovascular diseases (4 cases, 30.8%).ConclusionsThe study demonstrates that although knowledge about TAPS has improved over time, diagnostic delays and errors remains to be addressed as they are strongly associated to adverse consequences.Key Points•Although knowledge of thrombotic antiphospholipid syndrome has improved over time, it is still limited.•Diagnostic delay and misdiagnosis are still an important issue that remains to be addressed as they are strongly associated to adverse consequences.•The three more frequent misdiagnoses are multiple sclerosis, systemic lupus erythematosus and cardiovascular diseases.

Added value of antiphosphatidylserine/prothrombin antibodies in the workup of obstetric antiphospholipid syndrome: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies

BackgroundThe added value of antiphosphatidylserine/prothrombin antibodies (aPS/PT) in the diagnostic workup of antiphospholipid syndrome (APS) is unclear. Currently, diagnosis of thrombotic APS (TAPS) and obstetric APS (OAPS) requires persistent presence of lupus anticoagulant (LAC), anticardiolipin (aCL) immunoglobulin (Ig) G/IgM, or anti-β2-glycoprotein I (aβ2GPI) IgG/IgM antibodies. ObjectivesTo evaluate the role of aPS/PT IgG and IgM in OAPS. MethodsaPS/PT IgG/IgM, aCL IgG/IgM, aβ2GPI IgG/IgM, and LAC were determined in 653 patients (OAPS, TAPS, and controls). In-house aPS/PT cut-off values were calculated, titers and prevalence were compared between OAPS, TAPS, and controls and type of pregnancy morbidity. Sensitivity, specificity, likelihood ratios, and odds ratios (OR) with 95% CI were calculated. ResultsIn OAPS, aPS/PT IgG and IgM showed an OR of 4.32 (95% CI, 2.54-7.36) and 3.37 (95% CI, 1.93-5.89), respectively, but the association was not independent of LAC. Prevalence and titers of aPS/PT IgG and IgM were lower in OAPS than in patients with TAPS. aPS/PT were more prevalent and showed higher titers in patients with late pregnancy loss than in patients with early pregnancy loss with a positivity of 86.4% and 39.3%, respectively. Higher aPS/PT titers did not increase the likelihood of having OAPS. ConclusionThe added value of aPS/PT testing in the current diagnostic workup of OAPS seems limited compared with LAC, aCL, and aβ2GPI. aPS/PT might be useful in specific subsets of patients with OAPS. However, future multicentric studies are needed to elucidate the risk of less frequent and most severe obstetrical manifestations.