Phosphatidylserine-Dependent Anti-prothrombin Antibodies as a Key Predictor for Systemic Lupus Erythematosus in Patients with Primary Antiphospholipid Syndrome: A retrospective longitudinal cohort study.

OBJECTIVES: Primary antiphospholipid syndrome (PAPS) is an autoimmune disorder characterized by thrombosis and pregnancy morbidity. Although PAPS is distinct from systemic lupus erythematosus (SLE), the two conditions share clinical features and susceptibility genes. Progression from PAPS to SLE is well-recognized. However, risk factors for this transition are poorly understood. We aimed to identify predictors of progression to SLE in patients with PAPS. METHODS: A longitudinal single-center study was conducted at Hokkaido University Hospital from 1990 to 2021. Baseline characteristics including clinical features, laboratory data, aPL profiles were compared between patients who progressed to SLE (SLE group) and those who did not (non-SLE group). RESULTS: Among 64 patients diagnosed with PAPS at baseline, nine (13.8%) progressed to SLE over a mean follow-up of 9 years (incidence rate, 1.61 per 100 person-years). At the diagnosis of PAPS, the SLE group had a higher prevalence of anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and anti-dsDNA antibodies compared to the non-SLE group. Other clinical findings, autoantibody profiles, and serum complement levels were similar between the two groups. Multivariate Cox analysis showed that IgG aPS/PT was significantly associated with SLE development (Hazard ratio: 10.3, 95% CI: 1.13-92.6, p=0.04). CONCLUSION: IgG aPS/PT may be a predictive factor for new-onset SLE in patients with PAPS, suggesting its utility in guiding risk stratification and monitoring strategies for these patients.

Interest of IgG and IgM antiprothrombin autoantibodies in the exploration of antiphospholipid syndrome: a 5-year retrospective study.

OBJECTIVES: Non-conventional aPL have been described in patients presenting clinical manifestations of antiphospholipid syndrome but negative for conventional markers. Among them, detection of autoantibodies against prothrombin has been proposed to improve diagnosis and management of these patients. However autoantibodies against prothrombin are heterogeneous and their use in clinical practice still remains unclear. The aim of this study was to evaluate the interest of IgG and IgM autoantibodies directed against the prothrombin only (aPT). METHODS: We retrospectively studied IgM and IgG aPT results, conventional antiphospholipid syndrome markers and clinical data of a large cohort of 441 patients referred for antiphospholipid syndrome exploration with aPT detection over a period of 5 years. RESULTS: We observed a total prevalence of 17% of aPT-positive patients (75/441). A significant association was found between aPT and thrombosis (P = 0.035), with 70% of patients having unexplained thrombosis, aPT representing the sole aPL detected. aPT positivity was significantly more frequent in venous thrombosis than in arterial thrombosis (P = 0.004). Interestingly, we demonstrated for the first time that aPT IgG levels were higher in recurrent thrombosis than in isolated thrombosis (P = 0.013), leading us to propose a predictive level of recurrence for thrombosis. CONCLUSION: Our results show that aPT are associated with thrombosis and demonstrate the interest of assessing both IgG and IgM aPT, in particular in venous thrombosis when conventional markers are negative. Quantification of aPT could predict recurrence of thrombosis and influence subsequent treatment strategy. Prospective clinical studies are now required to confirm these results.

Prevalence of autoantibodies directed against prothrombin in unprovoked venous thromboembolism.

The anti-phospholipid syndrome (APS) is defined by the laboratory detection of at least one of three anti-phospholipid autoantibodies (lupus anticoagulant, or anti-cardiolipin or anti-ß2-glycoprotein I antibodies) in the clinical setting of thrombosis or pregnancy morbidity in a patient. Recognising APS and administering appropriate secondary thromboprophylaxis is important to reduce risk of recurrent thrombosis and/or pregnancy morbidity. In some instances, patients having clinical manifestations highly suggestive of APS are persistently negative for these antibodies but instead have other autoantibodies. Autoantibodies directed against prothrombin (PT) have been associated with increased thrombotic risk and comprise anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies. Detection of aPT and aPS/PT may help stratify patients for more effective treatment, however, their prevalence among patients with unprovoked venous thromboembolism (VTE) is unknown and determination of their frequencies is the objective of this study. Sera from 148 patients with unprovoked VTE were analysed. Autoantibodies directed against PT collectively, aPT and aPS/PT were present in 24.3%, 14.9% and 13.5%, respectively. Prevalence of these autoantibodies in unprovoked VTE is much lower compared to cohorts comprising mainly patients with systemic autoimmune disorders. Detection of these autoantibodies in unprovoked VTE has potential therapeutic implications for patients including the duration of anticoagulation and administration, or otherwise, of direct oral anticoagulants. Data from this study will assist in the design of future clinical studies to estimate risk of recurrent VTE and to determine optimal management.

Clinical performance of antibodies to prothrombin and thrombin in Chinese patients with antiphospholipid syndrome: potential interest in discriminating patients with thrombotic events and non-thrombotic events.

A hallmark feature of antiphospholipid syndrome (APS) is the presence of a wide spectrum of antiphospholipid antibodies. In this study, we evaluated the clinical relevance of antibodies to prothrombin (PT) (aPT) and thrombin (aThr) in Chinese patients with APS. A total of 229 subjects were tested, including 86 patients with APS [35 patients with primary APS (PAPS), 51 patients with APS associated with other diseases (APSAOD)], 104 patients with non-APS diseases (disease controls), and 39 healthy controls. Serum IgG/IgM/IgA aPT and aThr were determined by ELISA. The levels of both IgG/IgM/IgA aPT and IgG/IgM/IgA aThr were significantly increased in patients with PAPS and APSAOD compared with patients with non-APS thrombosis and non-APS PRM, and HC. Both IgG aPT and IgG aThr exhibited promising diagnostic potentials for APS with sensitivities and specificities of 16.3 and 95.8% (IgG aPT), and 19.8 and 99.3% (IgG aThr), respectively. Importantly, both IgG aPT (OR 4.06; 95% CI 1.49-11.05) and IgG aThr (OR 4.49; 95% CI 1.62-12.45) were significantly correlated with arterial, but not venous, thrombotic events. Our findings highlighted that IgG aPT and IgG aThr could serve as promising biomarkers to identify patients at risk of arterial thrombosis in China.

Thrombotic risk assessment in antiphospholipid syndrome: the role of new antibody specificities and thrombin generation assay.

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by the presence of antiphospholipid antibodies (aPL) in subjects presenting with thrombosis and/or pregnancy loss. The currently used classification criteria were updated in the international consensus held in Sidney in 2005. Vascular events seem to result of local procoagulative alterations upon triggers influence (the so called "second-hit theory"), while placental thrombosis and complement activation seem to lead to pregnancy morbidity. The laboratory tests suggested by the current classification criteria include lupus anticoagulant, a functional coagulation assay, and anticardiolipin and anti-ß2-glycoprotein-I antibodies, generally detected by solid phase enzyme-linked immunosorbent assay. The real challenge for treating physicians is understanding what is the actual weight of aPL in provoking clinical manifestations in each case. As thrombosis has a multi-factorial cause, each patient needs a risk-stratified approach. In this review we discuss the role of thrombotic risk assessment in primary and secondary prevention of venous and arterial thromboembolic disease in patients with APS, focusing on new antibody specificities, available risk scoring models and new coagulation assays.

Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications.

Abstract Objective. To clarify the clinical significance of antiphospholipid antibody (aPL) profile in patients with obstetric antiphospholipid syndrome (APS). Methods. Clinical records of 13 pregnant patients (15 pregnancies) with obstetrical APS were reviewed over 10 years. Patients who met the Sapporo Criteria fully were studied, whereas those with only early pregnancy loss were excluded. In addition to classical aPL: lupus anticoagulant (LA), anticardiolipin antibody (aCL), and anti-ß2-glycoprotein I (aß2GPI); phosphatidylserine-dependent anti-prothrombin antibody (aPS/PT) and kininogen-dependent anti-phosphatidylethanolamine antibody (aPE) were also examined in each case. Results. Cases were divided into two groups according to patient response to standard treatment: good and poor outcome groups. All cases with poor outcome presented LA, with IgG aß2GPI and IgG aPS/PT were also frequently observed. IgG aPE did not correlate with pregnancy outcome. Conclusion. aPL profile may predict pregnancy outcome in patients with this subset of obstetric APS.

[Geriatric patient with neurological symptoms and prolonged aPTT]. / Geriatrischer Patient mit neurologischer Symptomatik und verlängerter aPTT.

A 73-year-old man with dementia was referred to our clinic with hypernatremia and volume depletion. New-onset neurogenic dysphagia was likely the reason for both. The patient had chronic embolic strokes on the computed tomography (CT) images. Documentation from previous hospitalizations in different hospitals revealed a repeatedly prolonged activated partial thromboplastin time (aPTT); 5 years prior, antiphospholipid antibody syndrome had already been suspected, but the necessary workup was never completed. We diagnosed the patient with primary antiphospholipid antibody syndrome and initiated therapy with vitamin K antagonists (phenprocoumon) and aspirin.

Correlation between neuropsychiatric systemic lupus erythematosus and immunological markers: a real-world retrospective study.

OBJECTIVES: This study aimed to investigate disparities in clinical profiles and autoantibody patterns between patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) in a cohort and to identify risk factors associated with NPSLE in the Chinese population. METHODS: SLE patients were retrospectively reviewed from two tertiary hospitals. The relationships between NPSLE and immunological biomarkers were explored. RESULTS: Among the 945 SLE patients, 75 (7.94%) were diagnosed with NPSLE. The most prevalent NP manifestations involved cognitive disorder (30.67%), headache (26.67%), seizure disorder (26.67%), and psychosis (26.67%).We observed significant associations between psychosis and anti-ß2GPI antibodies (F = 6.092, p = 0.015), polyneuropathy and anti-Scl70 antibodies (F = 20.161, p < 0.001), demyelinating syndrome and anti-cardiolipin antibodies (F = 6.637, p = 0.011), myasthenia gravis and anti-RNP (F = 5.864, p = 0.017), and anti-Smith antibodies (F = 5.096, p = 0.026). Multivariate logistics analysis showed that anti-prothrombin (aPT) IgM antibodies (OR = 10.985, CI 1.279-94.343, p = 0.029), age (OR = 1.169, CI 1.032-1.325, p = 0.014), and serum creatinine (SCr) (OR = 1.014, CI 1.003-1.025, p = 0.009) were independent risk factors of NPSLE, while anti-Sjogren syndrome antigen B (SSB) antibodies (OR 0.023, CI 0.002-0.622, p = 0.023) and high complement C3 (OR = 0.001, CI 0-0.045, p < 0.001) indicated reduced risk of NPSLE. CONCLUSION: Various neuropsychiatric manifestations in SLE were found to be correlated with specific autoantibodies. Independent risk factors for NPSLE included aPT IgM antibodies, age, and elevated serum creatinine, while the absence of anti-SSB antibodies and low complement C3 levels were associated with increased risk. KEY POINTS: •Significant associations were found between specific autoantibodies and neuropsychiatric symptoms, shedding light on potential biomarkers for predicting and understanding NPSLE. •The study identifies independent risk factors for NPSLE in the Chinese population, including the presence of anti-prothrombin IgM antibodies, older age, elevated serum creatinine, and lower complement C3 levels.

Correlation of Anti-Phosphatidylserine/Prothrombin and Anti-Phosphatidylserine Antibodies with Pregnancy Outcomes.

BACKGROUND: The objective of this study was to investigate the clinical relevance of anti-prothrombin antibodies (aPT) and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) in relation to pregnancy outcomes and coagulation parameters, as well as immune markers. METHODS: We retrospectively analyzed 477 pregnant women with experienced at least one spontaneous miscarriage who were tested for aPT and aPS/PT antibodies, and compared their clinical characteristics, coagulation indicators, immune biomarkers, and pregnancy outcomes to assess the diagnostic accuracy of these antibodies. RESULTS: We found that the aPT IgG and the aPS/PT IgM were independently associated with increased risk of pregnancy loss, with odds ratios (ORs) of 1.055 (95% confidence interval [CI]: 1.009-1.103, p = 0.017) and 1.041 (95% CI: 1.015-1.067, p = 0.002), respectively. Moreover, we found that the aPS/PT IgM had a higher diagnostic performance than the aPT IgG, as indicated by the AUC of 0.663 and 0.593, respectively. The pregnancy loss rate was positively correlated with the level of aPS/PT IgM, while the aPT IgG is not. We also found that in the pregnancy loss group, aPT IgG showed negative correlations with prothrombin time (PT); aPS/PT IgM showed positive correlations with aPS/PT IgG. However, none of aPT IgG, aPT IgM, aPS/PT IgM, or aPS/PT IgG was related to other adverse pregnancy outcomes, such as preterm delivery, fetal growth restriction (FGR), or preeclampsia (PE). CONCLUSION: Our findings suggest that aPT IgG and aPS/PT IgM are independent risk factors for pregnancy loss, especially aPS/PT IgM, which has a positive linear correlation with pregnancy loss.

[Contribution of antiphosphatidylserine/prothrombin (anti-PS/PT) antibody detection in the diagnosis and management of antiphospholipid syndrome (APS)]. / Apport de la détection des anticorps antiphosphatidylsérine/prothrombine (aPS/PT) dans le diagnostic et la prise en charge du syndrome des antiphospholipides (SAPL).

Antiphospholipid syndrome (APS) is an autoimmune disease and one of the most common causes of acquired thrombophilia. It is characterised by the occurrence of thrombotic or obstetric events associated with the presence of persistent antiphospholipid antibodies. The diagnosis can be challenging, particularly because some biological tests can be disturbed by anticoagulant treatment or inflammation. In the recent years, new antiphospholipid antibodies, including anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT), have emerged but their clinical significance and causality remain uncertain. Biologically, several studies have found a strong correlation between the presence of lupus anticoagulant (LA) and anti-PS/PT antibodies. Clinically, the presence of anti-PS/PT antibodies is associated with an increased risk of thrombosis and obstetric complications. There is also an association with thrombocytopenia, suggesting that the presence of anti-PS/PT antibodies may be associated with more severe clinical APS. Among seronegative APS patients, 6-17% of patients are positive for anti-PS/PT antibodies. This might influence the therapeutic management of patients. This article aims to provide an update on contribution of anti-PS/PT antibodies detection for the diagnosis and management of APS.

Lupus anticoagulant-hypoprothrombinaemia syndrome: subdural haematoma as an unusual and initial manifestation.

We describe the case of a 50-year-old woman with a history of SLE and APS that presented with a spontaneous subdural haematoma, prolonged aPTT, PT and INR and positive LA. The activity of the coagulation factors II, VIII, IX and XI was extremely low, and anti-prothrombin antibody IgG was positive. LAHS was established, with inhibition of the intrinsic pathway, as an acquired haemophilia. The patient received corticosteroids and cyclophosphamide as treatment. To the best of our knowledge, this is one of the few reports of spontaneous intracranial bleeding, an unusual and initial manifestation of LAHS in an adult patient.HighlightsLAHS is characterised by the presence of LA and hypoprothrombinaemia caused by anti-prothrombin antibodies.Prolonged aPTT and INR, and positive LA are important laboratory findings that help the suspicion of LAHS.Intracranial bleeding is an unusual manifestation of LAHS associated with low factor II activity.Corticosteroids are the first-line treatment of LAHS.The prognosis of LAHS is good with adequate treatment, with a reported mortality of 5%.

Profiles of criteria and non-criteria anti-phospholipid autoantibodies are associated with clinical phenotypes of the antiphospholipid syndrome.

BACKGROUND: Specific anti-phospholipids antibodies (aPLs) are used as classification criteria of the antiphospholipid syndrome (APS). These aPLs, although essential for diagnosis, do not predict disease phenotypes, which may require specific therapies. Non-criteria aPLs are rarely evaluated and their role is yet to be defined. In the current study, we aimed to examine the association between criteria and non-criteria aPLs and APS phenotypes. METHODS: Serum samples from 188 subjects, 130 APS patients and 58 controls were analyzed for the presence of 20 aPLs (IgG and IgM isotypes to cardiolipin (CL), beta2-glycoprotein1 (ß2GP1), phosphatidic acid (P-acid), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), annexin-5 (AN) and prothrombin (PT) using a line immunoassay (GA Generic Assays, Germany). Sero-positivity to the different aPLs/aPLs profiles was correlated to APS phenotypes (i.e. arterial thrombosis, CNS manifestations, venous thrombosis, relapsing disease, obstetric morbidity). RESULTS: In this cohort, arterial thrombosis was associated with accumulative number of ≥ 7/20 aPLs evaluated (OR 4.1; CI 95% 1.9-96, p = 0.001) as well as the sole presence of aPT (IgG) (OR 2.3;CI 95% 1.1-5.1, p = 0.03). CNS manifestations were linked with a profile of 4 aPLs (IgG): aPT, aPG, aPI and aAN (OR 2.6;CI 95% 1.1-6.3, p = 0.03). Symptom-free period of ≥ 3 years was linked with lower number of aPLs and the presence of aPI (IgG) (OR 3.0;CI 95% 1.08-8.1, p < 0.05) or aAN (IgG) (OR 3.4;CI 95% 1.08-10.9, p < 0.05). APS related pregnancy morbidity correlated with a profile of 2 aPLs (IgG): aCL and aPS (OR 2.9; CI 95% 1.3-6.5, p < 0.05) or the sole presence of aAN (IgG) (OR 2.8; CI 95% 1.02-8, p = 0.05). CONCLUSION: In this study, we observed an association between specific criteria/non-criteria aPLs or aPLs profiles and clinical phenotypes of APS. Our data suggest that examination of a wider variety of aPLs may allow better characterization of APS.

Splenic infarction associated with transient anti-prothrombin antibodies is a rare manifestation of acute Mycoplasma pneumoniae infection.

We report the first paediatric case of splenic infarction following acute Mycoplasma pneumoniae infection with induction of anti-prothrombin (aPT) antibodies. A 12-year-old boy was admitted to the paediatric emergency department for a left pleuropneumonia and a splenic infarction. aPT antibodies were transitorily detected. The patient recovered fully after antibiotic therapy and a 3-month course of anticoagulation treatment. Antiphospholipid (aPL) antibodies induced by acute infections have already been reported but cases of clinically relevant thrombosis remain rare. The pathogenicity of aPT antibodies is discussed here. We hypothesize that these antibodies were involved in this symptomatic hypercoagulable state.

Lupus anticoagulant-hypoprothrombinemia syndrome and similar diseases: experiences at a single center in Japan.

Patients with lupus anticoagulant (LA), a thrombotic risk factor, along with decreased prothrombin (FII) activity are classified as lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) and occasionally show bleeding symptoms, although this is not essential for diagnosis. We treated 20 cases of LAHPS over a 3-year period. Median FII activity was 20.9% and the anti-prothrombin antibody (anti-II Ab), shown by ELISA findings, was detected in 55%. Bleeding symptoms were observed in 20%, although that finding was not correlated with FII activity or anti-FII Ab quantity. We also observed 21 LA cases with decreased activity of coagulation factors other than FII, which we have designated LAHPS-like syndrome (LLS). Among LLS patients, anti-FII Ab and bleeding symptoms were seen in 47.6% and 14.3%, respectively. Our findings suggest that bleeding in LAHPS and LLS cannot be explained only by FII activity decreased by anti-FII Ab. Low FVIII activity and the anti-FVIII antibody (anti-FVIII Ab) were detected in some LAHPS and LLS patients, making it difficult to distinguish those from acquired hemophilia A cases. Detection of anti-FVIII Ab quantity by ELISA may be useful for accurate determination, as that was not performed in our LAHPS or LLS patients.

Exploring the plasmatic platelet-activating factor acetylhydrolase activity in patients with anti-phospholipid antibodies.

PURPOSE: To explore the role of plasmatic platelet-activating factor acetylhydrolase (PAF-AH), a marker of cardiovascular risk, in patients with anti-phospholipid antibodies (aPL). METHODS: PAF-AH activity was assessed in a series of 167 unselected patients screened for aPL in a context of thrombotic events, risk of thrombosis or obstetric complications and in 77 blood donors. RESULTS: 116/167 patients showed positive results for at least one aPL among IgG/IgM anti-prothrombin/phosphatidylserine (aPS/PT), anti-cardiolipin (aCL), anti-beta2-glycoprotein I (aß2GPI) or lupus anticoagulant (LAC), while 51/167 patients resulted aPL-negative. LAC+ patients disclosed higher PAF-AH than LAC-negative (22.1 ± 6.4 nmol/min/ml vs. 19.5 ± 4.1 nmol/min/ml; p = 0.0032), and aPL-negative patients (p = 0.03). Patients presenting positive IgG aß2GPI disclosed higher PAF-AH than patients with only IgM aß2GPI-positive antibodies (23.1 ± 7.2 nmol/min/ml vs. 20.1 ± 5.3 nmol/min/ml; p = 0.035), as well as than patients showing only isolated LAC, aCL or aPS/PT (16.9 ± 3.8 nmol/min/ml; p = 0.003). CONCLUSIONS: PAF-AH plasmatic activity is particularly up-regulated in LAC+ and in aß2GPI IgG+ patients, possibly representing an alternative prognostic biomarker for the therapeutic management of APS patients.

The challenges of lupus anticoagulants.

The term "lupus anticoagulant" (LA) refers to a heterogeneous group of immunoglobulins behaving as acquired in vitro inhibitors of coagulation. These antibodies, namely anti-ß2GPI and anti-prothrombin antibodies, induce the in vitro elongation of clotting time interfering with phospholipid-dependent coagulation cofactors. Positive LA is associated with thrombosis and pregnancy complications, providing one of the three laboratory criteria for the classification of the anti-phospholipid syndrome. LA is the strongest predictor of clinical events, especially when associated with other anti-phospholipid antibodies. Much more controversial is the risk conveyed by isolated and weak LA. LA detection is technically laborious, envisaging screening, mixing and confirming tests. Hopefully critical issues in LA detection, such as the interference of anticoagulants, will be overcome, in the next future.