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.

Viewpoint: Lupus anticoagulant detection and interpretation in antiphospholipid syndrome.

Lupus anticoagulant (LA) is a well-established risk factor for the clinical manifestations of antiphospholipid syndrome (APS). Accurate LA detection is an essential prerequisite for optimal diagnosis and management of patients with APS or aPL carriers. Variability remains a challenge in LA testing, with reliable detection influenced by multiple factors, including pre-analytical conditions, anticoagulation treatment, choice of tests and procedures performed, as well as interpretation of results, that can lead to false-positives or negatives. A standardised approach to LA testing, following current guidance, based on published data and international consensus, and with attention to detail, is required to underpin accurate detection of LA. Future work should focus on better characterisation of the nature of LA, which may ultimately lead to improved diagnosis and management of patients with APS and aPL carriers. This article reviews current practice and challenges, providing an overview on detection of LA.

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-ß2-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.

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").

BACKGROUND: Long-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. OBJECTIVES: To 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/METHODS: Using 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. RESULTS: As 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). CONCLUSION: Fourteen 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.

Damage measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in antiphospholipid antibody-positive patients included in the APS ACTION registry.

OBJECTIVES: Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. METHODS: In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. RESULTS: Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aß2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). CONCLUSIONS: DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.

Associations Among Antiphospholipid Antibody Types, Isotypes, and Titers: An AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Study.

Several antiphospholipid antibody (aPL) profiles ("triple" and lupus anticoagulant [LA] positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-ß2 glycoprotein-I antibody (aß2GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aß2GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aß2GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aß2GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA.

Fluctuation of Anti-Domain 1 and Anti-ß2 -Glycoprotein I Antibody Titers Over Time in Patients With Persistently Positive Antiphospholipid Antibodies.

OBJECTIVE: The present study was undertaken to longitudinally evaluate titers of antibodies against ß2 -glycoprotein I (anti-ß2 GPI) and domain 1 (anti-D1), to identify predictors of variations in anti-ß2 GPI and anti-D1 titers, and to clarify whether antibody titer fluctuations predict thrombosis in a large international cohort of patients who were persistently positive for antiphospholipid antibodies (aPL) in the APS ACTION Registry. METHODS: Patients with available blood samples from at least 4 time points (at baseline [year 1] and at years 2-4 of follow-up) were included. Detection of anti-ß2 GPI and anti-D1 IgG antibodies was performed using chemiluminescence (BIO-FLASH; INOVA Diagnostics). RESULTS: Among 230 patients in the study cohort, anti-D1 and anti-ß2 GPI titers decreased significantly over time (P < 0.0001 and P = 0.010, respectively). After adjustment for age, sex, and number of positive aPL tests, we found that the fluctuations in anti-D1 and anti-ß2 GPI titer levels were associated with treatment with hydroxychloroquine (HCQ) at each time point. Treatment with HCQ, but not immunosuppressive agents, was associated with 1.3-fold and 1.4-fold decreases in anti-D1 and anti-ß2 GPI titers, respectively. Incident vascular events were associated with 1.9-fold and 2.1-fold increases in anti-D1 and anti-ß2 GPI titers, respectively. Anti-D1 and anti-ß2 GPI titers at the time of thrombosis were lower compared to titers at other time points. A 1.6-fold decrease in anti-D1 titers and a 2-fold decrease in anti-ß2 GPI titers conferred odds ratios for incident thrombosis of 6.0 (95% confidence interval [95% CI] 0.62-59.3) and 9.4 (95% CI 1.1-80.2), respectively. CONCLUSION: Treatment with HCQ and incident vascular events in aPL-positive patients predicted significant anti-D1 and anti-ß2 GPI titer fluctuations over time. Both anti-D1 and anti-ß2 GPI titers decreased around the time of thrombosis, with potential clinical relevance.

A one-point increase in the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality in thrombotic antiphospholipid syndrome.

OBJECTIVES: To determine whether early damage and its kinetics measured by the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality. METHODS: We carried out a single-centre retrospective analysis of thrombotic APS patients (2006 Sydney criteria), using the DIAPS for damage assessment. Early damage was considered to be at six months after disease onset; early damage increase (delta-DIAPS) was deemed to be at least a one-point rise in DIAPS within the first five years of illness. Groups were compared using appropriate statistical tests. Survival was analysed by the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of mortality. RESULTS: A total of 197 patients (71.1% female; 65.9% primary APS; 72.4% Caucasian) were followed for up to 43 years (median 10). Damage developed in 143 (73.6%) patients. Twenty-three patients (12%) died. Secondary APS (HR 3.07, 95%CI 1.32-7.12, p=0.009), male sex (HR 3.14, 95%CI 1.35-7.33, p=0.008) and age at APS onset ≥40 years (HR 5.34, 95%CI 1.96-14.53, p=0.001) were risk factors for death. Early damage (n=69, 35.0%) was not associated with death (p=0.231). Having a first arterial event was associated with early damage (p<0.001), but not with delta-DIAPS (p=0.539) nor with the risk of death (p=0.151). Delta-DIAPS (n=53/181, 29.3%) predicted mortality (HR 5.40, 95%CI 2.33-12.52, p<0.001), even after adjusting individually for APS category (secondary), sex (male), early damage and age at APS onset (≥40 years) (all p<0.005). CONCLUSIONS: Evolving damage in the first five years of illness, but not early damage, predicted mortality regardless of the nature of the first thrombotic event, sex, APS category and age.

Development of biodegradable films using sunflower protein isolates and bacterial nanocellulose as innovative food packaging materials for fresh fruit preservation.

This study presents the valorization of side streams from the sunflower-based biodiesel industry for the production of bio-based and biodegradable food packaging following circular economy principles. Bacterial cellulose (BC) was produced via fermentation in 6 L static tray bioreactors using nutrient-rich supplements derived from the enzymatic hydrolysis of sunflower meal (SFM) combined with crude glycerol as carbon source. Novel biofilms were produced using either matrices of protein isolates extracted from sunflower meal (SFMPI) alone or SFMPI matrices reinforced with nanocellulose biofillers of commercial or bacterial origin. Acid hydrolysis was employed for ex-situ modification of BC to nanostructures (56 nm). The biofilms reinforced with bacterial nanocellulose structures (SFMPI-BNC) showed 64.5% higher tensile strength, 75.5% higher Young's modulus, 131.5% higher elongation at break, 32.5% lower water solubility and 14.1% lower water vapor permeability than the biofilms produced only with SFMPI. The biofilms were evaluated on fresh strawberries packaging showing that the SFMPI-BNC-based films lead to effective preservation at 10 °C considering microbial growth and physicochemical profile (weight loss, chemical characterization, color, firmness and respiration activity). The SFMPI-BNC-based films could be applied in fresh fruit packaging applications.

Characteristics of Patients With Antiphospholipid Antibody Positivity in the APS ACTION International Clinical Database and Repository.

OBJECTIVE: To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes. METHODS: The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-ß2 -glycoprotein I [anti-ß2 GPI]) antibodies by aPL profiles (LAC only, single, double, and triple aPL positivity). RESULTS: The 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n = 660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-ß2 GPI only. CONCLUSION: Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.

COVID-19 and antiphospholipid antibodies: A position statement and management guidance from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION).

Coronavirus disease 2019 (COVID-19) is associated with a high rate of thrombosis. Prolonged activated partial thromboplastin times (aPTT) and antiphospholipid antibodies (aPL) are reported in COVID-19 patients. The majority of publications have not reported whether patients develop clinically relevant persistent aPL, and the clinical significance of new aPL-positivity in COVID-19 is currently unknown. However, the reports of aPL-positivity in COVID-19 raised the question whether common mechanisms exist in the pathogenesis of COVID-19 and antiphospholipid syndrome (APS). In both conditions, thrombotic microangiopathy resulting in microvascular injury and thrombosis is hypothesized to occur through multiple pathways, including endothelial damage, complement activation, and release of neutrophil extracellular traps (NETosis). APS-ACTION, an international APS research network, created a COVID-19 working group that reviewed common mechanisms, positive aPL tests in COVID-19 patients, and implications of COVID-19 infection for patients with known aPL positivity or APS, with the goals of proposing guidance for clinical management and monitoring of aPL-positive COVID-19 patients. This guidance also serves as a call and focus for clinical and basic scientific research.

Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.

BACKGROUND: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. METHODS: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aß2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I ß2GPI (aD1ß2GPI) IgG. FINDINGS: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2 R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2. INTERPRETATION: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management. FUNDING: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.

Coexistent antiphospholipid syndrome and myeloproliferative neoplasm.

Antiphospholipid syndrome (APS) and myeloproliferative neoplasms (MPN) are associated with an increased risk of thrombosis. The optimal management of patients with coexistent APS and MPN has not been defined. A single centre and systematic literature review of patients with coexistent APS and MPN was performed. Cases were divided into two groups based on whether they met international consensus criteria for APS. Of the 12 studies identified, eight were excluded (leaving five of a total 54 patients), as although antiphospholipid antibodies (aPL) were documented, the diagnosis of APS was not conclusively demonstrated. Another ten patients with definite APS were identified at our centre. Fifteen patients (ten females, five males) were therefore included in this analysis (eleven definite APS and four highly likely), median age 44 (range: 13-71) years. Nine had polycythaemia vera and six, essential thrombocythaemia. Thirteen of the 15 patients (86.7%) had thrombotic APS (seven with initial venous events and six arterial) and two (13.3%) had obstetric APS. Nine patients were single-positive, and six double-positive for aPL. None were triple aPL-positive. Four patients at our centre had recurrent thrombotic/obstetric events, including while on anticoagulation/antiplatelet treatment.

Comparison of Acquired Activated Protein C Resistance, Using the CAT and ST-Genesia® Analysers and Three Thrombin Generation Methods, in APS and SLE Patients.

BACKGROUND: Acquired activated protein C resistance (APCr) has been identified in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). OBJECTIVE: To assess agreement between the ST-Genesia® and CAT analysers in identifying APCr prevalence in APS/SLE patients, using three thrombin generation (TG) methods. METHODS: APCr was assessed with the ST-Genesia using STG-ThromboScreen and with the CAT using recombinant human activated protein C and Protac® in 105 APS, 53 SLE patients and 36 thrombotic controls. Agreement was expressed in % and by Cohen's kappa coefficient. RESULTS: APCr values were consistently lower with the ST-Genesia® compared to the CAT, using either method, in both APS and SLE patients. Agreement between the two analysers in identifying APS and SLE patients with APCr was poor (≤65.9%, ≤0.20) or fair (≤68.5%, ≥0.29), regardless of TG method, respectively; no agreement was observed in thrombotic controls. APCr with both the ST Genesia and the CAT using Protac®, but not the CAT using rhAPC, was significantly greater in triple antiphospholipid antibody (aPL) APS patients compared to double/single aPL patients (p < 0.04) and in thrombotic SLE patients compared to non-thrombotic SLE patients (p < 0.05). Notably, the ST-Genesia®, unlike the CAT, with either method, identified significantly greater APCr in pregnancy morbidity (median, confidence intervals; 36.9%, 21.9-49.0%) compared to thrombotic (45.7%, 39.6-55.5%) APS patients (p = 0.03). CONCLUSION: Despite the broadly similar methodology used by CAT and ST-Genesia®, agreement in APCr was poor/fair, with results not being interchangeable. This may reflect differences in the TG method, use of different reagents, and analyser data handling.

Anti-protein C antibodies and acquired protein C resistance in SLE: novel markers for thromboembolic events and disease activity?

OBJECTIVES: Risk factors for thromboembolism in SLE are poorly understood. We hypothesized a possible role for protein C, based on its dual activity in inflammation and haemostasis and on the evidence of an association between acquired activated protein C (APC) resistance (APCR) and high-avidity anti-protein C antibodies (anti-PC) with a severe thrombotic phenotype in venous thrombosis APS patients. METHODS: In a cross-sectional study of 156 SLE patients, the presence and avidity of IgG anti-PC was established by in house-ELISA, and APCR to exogenous recombinant human APC (rhAPC) and Protac (which activates endogenous protein C) was assessed by thrombin generation-based assays. Associations with aPL profile, thrombotic history and disease activity (BILAG and SLEDAI-2K) were also established. RESULTS: Anti-PC were detected in 54.5% of patients and APCR in 59%. Anti-PC positivity was associated with APCR to both rhAPC (P <0.0001) and Protac (P =0.0001). High-avidity anti-PC, detected in 26.3% of SLE patients, were associated with APCR in patients with thrombosis only (P <0.05), and with the development of thrombosis over time (range: 0-52 years; P =0.014). High-avidity anti-PC levels correlated with SLEDAI-2K (P =0.033) and total BILAG (P =0.019); SLEDAI-2K correlated inversely with APCR to Protac (P =0.004). CONCLUSION: Anti-PC occur in patients with SLE, independently of aPL profile, and are associated with APCR. High-avidity anti-PC are associated with thrombosis and with active disease and might prove a novel marker to monitor the risk of thrombosis and disease progression in SLE.

Antiphospholipid Antibody Profile Stability Over Time: Prospective Results From the APS ACTION Clinical Database and Repository.

OBJECTIVE: The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time. METHODS: A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-ß2 glycoprotein-I (anti-ß2-GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis. RESULTS: Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate (P = 0.906) and multivariable analysis (P = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10-0.64, P = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53-7.13, P = 0.002) the odds of an unstable aPL profile over time. CONCLUSION: Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories.

Monitoring of anticoagulation in thrombotic antiphospholipid syndrome.

Anticoagulation is central to the management of thrombotic antiphospholipid syndrome (APS). The standard anticoagulant treatment for thrombotic APS is life-long warfarin or an alternative vitamin K antagonist. The role of direct oral anticoagulants for thrombotic APS is not established due to the lack of definitive evidence and has recently been addressed in international guidance. Other anticoagulant options include low molecular weight heparin, unfractionated heparin, and fondaparinux. In APS patients, lupus anticoagulant can affect phospholipid-dependent coagulation monitoring tests, so that they may not reflect true anticoagulation intensity. Accurate assessment of anticoagulation intensity is essential, to optimize anticoagulant dosing and facilitate thrombus resolution; minimize the risk of recurrent thrombosis or bleeding; inform assessment of whether recurrent thrombosis is related to breakthrough thrombosis while on therapeutic anticoagulation, subtherapeutic anticoagulation, non-adherence, or spurious results; and guide the management of bleeding. Knowledge of anticoagulant intensity also informs assessment and comparison of anticoagulation regimens in clinical studies. Considerations regarding anticoagulation dosing and/or monitoring of thrombotic APS patients underpin appropriate management in special situations, notably APS-related severe renal impairment, which can occur in APS or APS/systemic lupus erythematosus-related nephropathy or catastrophic APS; and APS-related thrombocytopenia. Anticoagulant dosing and monitoring in thrombotic APS patients also require consideration in anticoagulant-refractory APS and during pregnancy. In this review, we summarize the tests generally used in monitoring anticoagulant therapy, use of the main anticoagulants considered for thrombotic APS, lupus anticoagulant effects on anticoagulation monitoring tests, and strategies for appropriate anticoagulant monitoring in thrombotic APS.

Management of anticoagulant-refractory thrombotic antiphospholipid syndrome.

Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.

Cluster analysis for the identification of clinical phenotypes among antiphospholipid antibody-positive patients from the APS ACTION Registry.

OBJECTIVE: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients. METHODS: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients. RESULTS: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors. CONCLUSIONS: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.