The clinical relevance of different antiphospholipid antibody profiles in pediatric rheumatology patients.

BACKGROUND: The clinical relevance of different antiphospholipid antibody (aPL) profiles, including low level anticardiolipin (aCL) and anti-ß2-glycoprotein-I (aß2GPI) antibodies, is ill-defined in the pediatric population. Our purpose is to describe the demographic, clinical, and laboratory characteristics of aPL positive pediatric patients based on different aPL profiles. FINDINGS: In this single center retrospective cohort study, based on the screening of our pediatric (age ≤ 18) rheumatology electronic medical records (2016-2022), we identified patients who had at least one "positive" aPL (lupus anticoagulant [LA], aCL IgG/M, or aß2GPI IgG/M) result. Patients were grouped into high- (LA positive and/or aCL/aß2GPI IgG/M > 40U [ELISA]) and low-risk (LA negative and aCL/aß2GPI IgG/M 20-39U) aPL profiles; those with persistently positive aPL were descriptively analyzed for demographic and clinical characteristics. Of 57 included patients, 34 (59%) had initial high- and 23 (40%) had initial low-risk profiles. Based on subsequent aPL results available in 42/57 (74%) patients, 25/27 (93%) in the high-, and 7/15 (47%) in the low-risk groups remained still positive. Of these 32 patients with persistently positive aPL, moderate-to-large vessel or microvascular thrombosis occurred in nine (28%) patients with high-risk and in none with low-risk aPL profiles; non-thrombotic aPL-related manifestations were reported in 15 (47%) patients with persistent aPL positivity. CONCLUSION: An initial high-risk aPL profile was persistent in approximately 90% of our cohort, a third of whom had thrombosis, and half had non-thrombotic aPL manifestations. Our results underscore the need for a large-scale effort to better characterize aPL-related manifestations in pediatric patients with persistent high-risk aPL-profiles.

In vitro differential inhibition of the factor XI activity assay in the setting of a lupus anticoagulant.

Acquired factor XI deficiencies due to factor-specific inhibitors are rare and may be associated with lupus anticoagulant. We report a 63-year-old male with suspected postsurgical bleeding, prior surgical site infection, an isolated prolonged activated partial thromboplastin time, and a positive lupus anticoagulant. Although the factor II assay was normal, factor VIII and IX assays initially demonstrated nonparallelism with factor activity that consistently increased to normal reference ranges with serial dilutions. A discrepancy in factor XI activity results was discovered when the in-house method demonstrated undetectable activity (<3%); send-out testing using different instrument/reagent combinations revealed the presence of factor XI activity between 70% and 76%. The patient received surgical follow-up and was subsequently discharged home. Given the differential in vitro inhibition of factor XI activity on our initial in-house testing, this case highlights the importance of recognizing factor assay interference in the presence of a known lupus anticoagulant inhibitor, with strategies to mitigate potentially erroneous results.

Lupus Anticoagulant-Hypoprothrombinemia Syndrome: Literature Review and Description of Local Case in a 3-Year-Old Chinese Girl.

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare, acquired coagulopathy syndrome. Here, we aim to summarize the clinical features of LAHPS to improve the understanding of the disease. The clinical data of 52 patients with LAHPS retrieved through PubMed from 2019 to 2023, supplemented with a local case of a child with LAHPS, were retrospectively analyzed, and the clinical characteristics were summarized. 56.6% of LAHPS patients were female, the median age at onset was 13.0 years (range, 1.2-85 years), and the median activity of factor II was 18.0% (range, 0.1-69%). 64.2% of LAHPS patients experienced hemorrhage, with 29.4% having multisite hemorrhage and 20.6% experiencing both nonsevere and severe hemorrhage. Most of the reported cases were secondary to autoimmune diseases (60.6%), followed by infections (33.3%). Corticosteroids were administered to 79.3% of patients with hemorrhage, and 90.6% of patients with LAHPS showed improvement. In conclusion, LAHPS is most commonly observed in female patients, particularly those under 18 years of age. LAHPS is characterized by hemorrhage, occurring at various sites and with varying degrees of severity, but the majority of patients improve with appropriate treatment and management.

Taipan snake venom time has high sensitivity for lupus anticoagulants in non-anticoagulated, triple positive antiphospholipid syndrome patients.

INTRODUCTION: Dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT) are the mainstay assays in lupus anticoagulant (LA) detection yet they have limitations, particularly in relation to interferences and specificity. The recently validated Taipan snake venom time (TSVT) screening with ecarin time (ET) confirmatory assays overcome many of those limitations due to the innate specificity engendered from direct prothrombin activation, and insensitivity to the effects of vitamin K antagonists (VKA). The present study aimed to further evidence diagnostic utility of TSVT/ET by performing them in samples from 116 nonanticoagulated patients with established triple-positive antiphospholipid syndrome (APS). METHODS: Samples were identified in three expert centres who performed dRVVT, APTT and solid phase antiphospholipid antibody assays with reagents from a variety of manufacturers. All samples additionally received TSVT/ET analysis using standardised reagents. RESULTS: Ninety seven of 116 (83.6%) were dRVVT- and APTT-positive, 85/97 (87.6%) of which were TSVT/ET-positive, 9/116 (7.8%) were dRVVT-positive only, 6 of which were TSVT/ET-positive, and 10/116 (8.6%) were APTT-positive only, 5 of which were TSVT/ET-positive. 96/116 TSVT/ET-positivity returned a high sensitivity for LA of 82.8%. Low coefficients of determination revealed weak relationships between LA potency and anticardiolipin and anti-ß2-glycoprotein I antibody titres for all three LA assays. CONCLUSIONS: TSVT/ET has high sensitivity for the clinically significant LA found in triple positive APS patients. TSVT/ET can establish multiple LA assay positivity in nonanticoagulated patients negative for one of dRVVT or APTT, and is the only assay pairing insensitive to VKAs, the recommended anticoagulation for APS.

Anti-Phosphatidylserine/Prothrombin Antibodies at Two Points: Correlation With Lupus Anticoagulant and Thrombotic Risk.

Antibodies to phospholipids (aPL) and associated proteins are a hallmark in the diagnosis of anti-phospholipid syndrome (APS). Those included in the classification criteria are the lupus anticoagulant (LA) and the IgG and IgM isotypes of anticardiolipin (aCL) and anti-beta-2 glycoprotein I (ß2GPI) antibodies. Non-classification criteria markers such as autoantibodies that recognize the phosphatidylserine/prothrombin (aPS/PT) complex have been proposed as biomarkers for APS. Studies of aPS/PT antibodies have shown a strong correlation to clinical manifestations and LA. We aimed to study the value and the persistence of aPS/PT IgG and IgM antibodies in a cohort of consecutive patients with clinical suspicion of APS and their utility as thrombotic risk markers. Our study, with 103 patients, demonstrates that persistently positive results for aPS/PT IgG antibodies were significantly associated with APS classification, thrombosis, triple aPL positivity, LA positive result, and the Global APS Score (GAPSS) > than 9 points (p < 0.01, for each condition). On the other hand, no association was seen with pregnancy morbidity (p = 0.56) and SLE (p = 0.07). Persistence of aPS/PT antibodies, defined according to the current laboratory classification criteria, likely improves the diagnosis and clinical assessment of patients with APS.

Clinical and laboratory characteristics of Brazilian versus non-Brazilian primary antiphospholipid syndrome patients in AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) clinical database and repository.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by episodes of thrombosis, obstetric morbidity or both, associated with persistently positive antiphospholipid antibodies (aPL). Studying the profile of a rare disease in an admixed population is important as it can provide new insights for understanding an autoimmune disease. In this sense of miscegenation, Brazil is characterized by one of the most heterogeneous populations in the world, which is the result of five centuries of interethnic crosses of people from three continents. The objective of this study was to compare the clinical and laboratory characteristics of Brazilian vs. non-Brazilian primary antiphospholipid syndrome (PAPS) patients. METHODS: We classified PAPS patients into 2 groups: Brazilian PAPS patients (BPAPS) and PAPS patients from other countries (non-BPAPS). They were compared regarding demographic characteristics, criteria and non-criteria APS manifestations, antiphospholipid antibody (aPL) profile, and the adjusted Global Antiphospholipid Syndrome Score (aGAPSS). RESULTS: We included 415 PAPS patients (88 [21%] BPAPS and 327 [79%] non-BPAPS). Brazilian patients were significantly younger, more frequently female, sedentary, obese, non-white, and had a higher frequency of livedo (25% vs. 10%, p < 0.001), cognitive dysfunction (21% vs. 8%, p = 0.001) and seizures (16% vs. 7%, p = 0.007), and a lower frequency of thrombocytopenia (9% vs. 18%, p = 0.037). Additionally, they were more frequently positive for lupus anticoagulant (87.5% vs. 74.6%, p = 0.01), and less frequently positive to anticardiolipin (46.6% vs. 73.7%, p < 0.001) and anti-ß2-glycoprotein-I (13.6% vs. 62.7%, p < 0.001) antibodies. Triple aPL positivity was also less frequent (8% vs. 41.6%, p < 0.001) in Brazilian patients. Median aGAPSS was lower in the Brazilian group (8 vs. 10, p < 0.0001). In the multivariate analysis, BPAPS patients still presented more frequently with livedo, cognitive dysfunction and sedentary lifestyle, and less frequently with thrombocytopenia and triple positivity to aPL. They were also less often white. CONCLUSIONS: Our study suggests a specific profile of PAPS in Brazil with higher frequency of selected non-criteria manifestations and lupus anticoagulant positivity. Lupus anticoagulant (not triple positivity) was the major aPL predictor of a classification criteria event.

Antiphospholipid antibodies and cerebrovascular thrombosis in the pediatric population: Few answers to many questions.

Most of the knowledge in pediatric antiphospholipid syndrome (APS) is derived from studies performed on the adult population. As in adults, antiphospholipid antibodies (aPL) can contribute to thrombosis, especially cerebrovascular thrombosis, in neonates and children. Since aPL have the potential to cross the placental barrier, and since the pediatric population is prone to infections, re-testing for their positivity is essential to specify their role in cerebrovascular thrombosis.In this review, we aimed at assessing the prevalence of aPL, criteria or non-criteria, in neonatal and childhood ischemic stroke and sinovenous thrombosis trying to find an association between aPL and cerebrovascular thrombosis in the neonatal and pediatric population. Also, we looked into the effect of aPL and anticoagulants/antiplatelets on the long term neurological outcomes of affected neonates or children. The questions regarding the prevalence of aPL among pediatric patients with cerebrovascular thrombosis, the relationship between the titers of aPL and incidence and recurrence of cerebrovascular events, the predictability of the long term neurological outcomes, and the most optimal anticoagulation plan are still to be answered. However, it is crucial for clinicians to screen neonates and children with cerebrovascular thrombosis for aPL and confirm their presence if positive.

Applying index of circulating anticoagulant to mixing tests with lupus anticoagulant screen and confirm reagents can distinguish with high specificity between lupus anticoagulants and direct factor Xa inhibitors.

BACKGROUND: Lupus anticoagulants (LA) are detected by prolongation of clotting times for dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT) screening tests. Direct oral anticoagulants (DOACs) can interfere with both screening and confirmatory tests. The present study aimed to investigate the influence of direct factor Xa inhibitors (DiXaIs) on screen, confirm and mixing tests and establish a method for differentiation from other sample types. MATERIALS AND METHODS: A total of 257 samples including nonanticoagulated LA positive, LA positive with DiXaIs, factor deficiency, FVIII inhibitors, warfarin and non-APS DiXaIs were tested. APTT reagents Cephen LS/Cephen and dRVVT reagents LA1/LA2 were used, respectively, to screen/confirm the study group. Index of circulating anticoagulant (ICA) was calculated from clotting times based on the following formula as ICA screening and ICA confirmation. ICA= (1:1 Mix sample - Normal pooled plasma) / Screen patient x 100. An ICA matrix was established which suggested the presence of a DiXaI when both ICA screening and confirmation were above the cut-off. When only ICA screening is elevated, LA is suspected. RESULTS: Sensitivity and specificity of the ICA matrix were 52.2% and 92.8% for DiXaIs and 38.1% and 96.7% for LA in APTT, and 61.2% and 92.9% for DiXaIs and 22.2% and 88.4% for LA in dRVVT, respectively. CONCLUSION: The ICA matrix achieved high specificity with a lower apparent sensitivity for DiXaI samples comparatively to other devices but due only to less interferences: the matrix could contribute to differentiating DiXaIs from LA in samples where anticoagulation status is unknown.

Failure of Anticoagulation to Prevent Stroke in Context of Lupus-Associated Anti-Phospholipid Syndrome and Mild COVID-19.

Hypercoagulability and virally-mediated vascular inflammation have become well-recognized features of the SARS-CoV-2 virus infection, COVID-19. Of growing concern is the apparent ineffectiveness of therapeutic anticoagulation in preventing thromboembolic events among some at-risk patient subtypes with COVID-19. We present a 43-year-old female with a history of seropositive-antiphospholipid syndrome and systemic lupus erythematosus who developed an acute ischemic stroke in the setting of mild COVID-19 infection despite adherence to chronic systemic anticoagulation. The clinical significance of SARS-CoV-2-mediated endothelial cell dysfunction and its potential to cause macrovascular events in spite of full anticoagulation warrants further investigation and likely represents another disease-defining pathology of COVID-19.

Lupus Anticoagulant Single Positivity During the Acute Phase of COVID-19 Is Not Associated With Venous Thromboembolism or In-Hospital Mortality.

OBJECTIVE: The clinical relevance of antiphospholipid antibodies (aPLs) in COVID-19 is controversial. This study was undertaken to investigate the prevalence and prognostic value of conventional and nonconventional aPLs in patients with COVID-19. METHODS: This was a multicenter, prospective observational study in a French cohort of patients hospitalized with suspected COVID-19. RESULTS: Two hundred forty-nine patients were hospitalized with suspected COVID-19, in whom COVID-19 was confirmed in 154 and not confirmed in 95. We found a significant increase in lupus anticoagulant (LAC) positivity among patients with COVID-19 compared to patients without COVID-19 (60.9% versus 23.7%; P < 0.001), while prevalence of conventional aPLs (IgG and IgM anti-ß2 -glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti-ß2 -glycoprotein I, IgG and IgM isotypes of anti-phosphatidylserine/prothrombin, and IgG and IgM isotypes of antiprothrombin) was low in both groups. Patients with COVID-19 who were positive for LAC, as compared to patients with COVID-19 who were negative for LAC, had higher levels of fibrinogen (median 6.0 gm/liter [interquartile range 5.0-7.0] versus 5.3 gm/liter [interquartile range 4.3-6.4]; P = 0.028) and C-reactive protein (CRP) (median 115.5 mg/liter [interquartile range 66.0-204.8] versus 91.8 mg/liter [interquartile range 27.0-155.1]; P = 0.019). Univariate analysis did not show any association between LAC positivity and higher risks of venous thromboembolism (VTE) (odds ratio 1.02 [95% confidence interval 0.44-2.43], P = 0.95) or in-hospital mortality (odds ratio 1.80 [95% confidence interval 0.70-5.05], P = 0.24). With and without adjustment for CRP level, age, and sex, Kaplan-Meier survival curves according to LAC positivity confirmed the absence of an association with VTE or in-hospital mortality (unadjusted P = 0.64 and P = 0.26, respectively; adjusted hazard ratio 1.13 [95% confidence interval 0.48-2.60] and 1.80 [95% confidence interval 0.67-5.01], respectively). CONCLUSION: Patients with COVID-19 have an increased prevalence of LAC positivity associated with biologic markers of inflammation. However, LAC positivity at the time of hospital admission is not associated with VTE risk and/or in-hospital mortality.

Abnormal immunothrombosis and lupus anticoagulant in a catastrophic COVID-19 recalling Asherson's syndrome.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a complex disease with many clinicopathological aspects, including abnormal immunothrombosis, and the full comprehension of its pathogenetic mechanisms is urgently required. METHODS/RESULTS: By means of a multidisciplinary approach, we here report a catastrophic COVID-19 in a 44-year-old Philippine male patient, discovered lupus anticoagulant (LAC)-positive shortly before death, occurred 8 days after hospitalization in a clinical scenario refractory to standard high acuity care recalling Asherson's syndrome (catastrophic antiphospholipid syndrome). CONCLUSION: A parallelism between this severe form of COVID-19 and Asherson's syndrome can be so drawn. Both the diseases in fact exhibit hypercytokinemia, thrombotic microangiopathy, disseminated intravascular coagulation and multiple organ failure, they show a relationship with viral infections, and they are burdened by a high mortality rate. A genetic predisposition to develop these two overlapping conditions may be supposed.

Association of antiphospholipid antibodies with clinical activity and renal pathological activity in patients with lupus nephritis.

OBJECTIVES: This study aimed to investigate the association of antiphospholipid antibodies (aPL) with clinical activity and renal pathological activity in patients with lupus nephritis (LN). METHODS: Levels of anticardiolipin () antibodies, anti-ß2-glycoprotein I (anti-ß2-GPI) antibodies and lupus anticoagulant (LAC) were measured, and other clinical and pathological data were also obtained during the same period before renal biopsy. RESULTS: A total of 83 patients with LN were included in this study, 40 patients (48.2%) in the s positive group and 43 patients in the aPL negative group. LN patients with positive aPL had significantly higher SLEDAI (p = 0.012), more hematuria (p = 0.043), lower serum C3 (p = 0.003) and C4 (p = 0.014), and a higher pathological activity index (p = 0.012), more micro-thrombosis (p = 0.046) and more C3 deposits (p = 0.038) in the glomerulus than patients with negative aPL The level of IgG- was significantly correlated with SLEDAI and serum level of C3 (r = 0.44, p < 0.001; r = -0.39, p = 0.003, respectively). The level of IgM- was significantly correlated with SLEDAI, and serum levels of C3 and C4 (r = 0.27, p = 0.014; r = -0.22, p = 0.041; r = -0.23, p = 0.035, respectively). CONCLUSIONS: Our work suggests that aPL, especially, are correlated with both clinical activity and renal pathological activity in patients with LN.

Identifying additional risk factors for arterial and venous thrombosis among pediatric antiphospholipid antibodies carriers.

BACKGROUND: Antiphospholipid antibodies (aPL) have been extensively reported in children, but investigations into thrombotic risks associated with aPL positivity in pediatric patients is scarce. Positive aPL are not uncommon in pediatric connective tissue diseases (CTD), but identification and management of these patients is challenging due to lack of validated criteria and a paucity of data. In this study, we identify potential additional risk factors for thrombosis in a unique cohort of pediatric aPL positive carriers. METHODS: Retrospective chart review was performed on 491 pediatric patients with CTD seen in our institution from 2001 to 2019. Patients without persistently moderate to high titer aPL at least 12 weeks apart were excluded. Univariate analysis was performed to evaluate correlation between different risk factors and thrombotic events. RESULTS: Seventy-one aPL positive children with underlying CTD are included in this cohort. The majority (87%) are female and of Hispanic ethnicity (56%). Mean age of the cohort at the diagnosis of connective tissue disease is 12.7 (SD 2.6) years, and mean age of first positive aPL is 13.3 (SD 2.5) years. Average length of follow-up is 4.3 (SD 2.5) years. Four (5.6%) patients experienced arterial thrombosis, and 11 (15.5%) had venous thrombosis. Fifty-seven (80.3%) patients did not have any thromboembolic events. Among traditional risk factors and signs of endothelial injury, only Raynaud's phenomena demonstrated significant association with arterial thrombosis (OR = 8.4, 95%CI 1.13-111, P = 0.039), and hypertension or anti-hypertensive use demonstrated significant association with venous thrombosis (OR = 8.387, 95%CI 1.2 - 94, P = 0.02). CONCLUSION: Data from our cohort suggest that Raynaud's phenomenon is a potential predictor of arterial thrombosis while the presence of hypertension or anti-hypertensive medication use is a potential predictor of venous thrombosis in aPL positive pediatric carriers. Further studies investigating pediatric aPL profiles and risk factors for development of thrombosis are needed to help guide clinicians in caring for these challenging patients.

Accidentally discovered high INR in pregnancy unmasks an inherited factor VII (FVII) deficiency that is paradoxically associated with thrombotic tendency.

A 32-year-old multiparous obese woman was referred to our center at 37 weeks of twin gestation. She was referred for birth planning following an accidentally discovered high international normalised ratio (INR) in routine preoperative labs. Her history was significant for recurrent pregnancy-associated deep venous thrombosis as well as two early pregnancy losses. Further work-up revealed transaminitis, mild splenomegaly and high lupus anticoagulant titre. A multidisciplinary team of physicians from the high-risk pregnancy, anaesthesiology, haematology, gastroenterology and hepatology departments put a management plan; it culminated into uncomplicated delivery of the patient by repeated caesarian section. The team was also able to figure out the cause of the patient's high INR that is associated with thrombophilia rather than haemophilia.

Acquired factor V inhibitor in the setting of coronavirus disease 2019 infection.

Factor V inhibitors are a rare cause of life-threatening bleeding. We present a case of an acquired factor V inhibitor likely caused by coronavirus disease 2019 infection. Bleeding was manifested by severe anemia requiring frequent red-cell transfusion, left psoas muscle hematoma, and left retroperitoneal cavity hematoma. Factor V activity was less than 1% and the factor V inhibitor titer was 31.6 Bethesda units. Severe acute respiratory syndrome coronavirus 2 RNA testing of the nasopharynx was positive 2 weeks before presentation and continued to be positive for 30 days. The patient failed treatment with intravenous immunoglobulin and dexamethasone. Three cycles of plasmapheresis with fresh frozen plasma replacement resulted in correction of the bleeding and laboratory coagulopathy. This is the first reported case of a factor V inhibitor in a coronavirus disease 2019 patient and suggests that plasmapheresis may be a successful treatment strategy.