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Introduction: It is recommended to use two chronometric assays of different principles for the diagnosis of lupus anticoagulant (LA), consisting in diluted Russell Viper Venom Time (dRVVT) and activated Partial Thromboplastin Time (aPTT). Yet, there are only a few integrated aPTT assays; this study aims to evaluate one of them: Cephen LS/Cephen (Hyphen Biomed). Method: 249 samples of patients were included in this study. Normal reference ranges were determined with platelet‐poor plasma (PPP) from healthy blood donors. Performances were then evaluated by comparing Cephen LS/Cephen test results to the results of the laboratory's reference assay for the diagnosis of LA and to clinical data, both on non‐anticoagulated and anticoagulated patients' samples (Unfractioned heparin (UFH), Low Molecular Weight Heparin (LMWH), Vitamin K Antagonists (VKA) and apixaban). Interference of UFH, LMWH and VKA were also evaluated thanks to spiking experiment of increasing heparin concentrations or factor deficiency. Results: Cephen LS/Cephen test had 48.6% sensitivity towards LA. Although UFH and VKA seemed to interfere with this assay and were likely to cause false negative, LMWH and apixaban did not. Finally, combination of Cephen LS/ Cephen with dRVVT had 89.0% sensitivity. Conclusion: Cephen LS/Cephen seems relevant for LA diagnosis, in combination with dRVVT, and might be used in patients undergoing LMWH or apixaban therapy. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by antiphospholipid antibodies associated with thrombosis and pregnancy complications. Catastrophic APS is a severe form involving multiple organ systems with a high mortality rate. The pathogenesis involves antiphospholipid antibodies which target phospholipid-binding proteins and damage endothelial cells thus activating coagulation, triggering a pro-thrombotic state. Laboratory tests for antiphospholipid antibody detection include lupus anticoagulant testing in the coagulation laboratory and serological detection of anticardiolipin and anti-beta 2 glycoprotein I antibodies. Despite recent updates in the diagnostic criteria for APS the recent decades and our improved knowledge of this disease, there remain several key issues pertaining to diagnosis and testing with potential implications to patient management. Here we briefly review APS pathophysiology, strengths and weaknesses of classification criteria, laboratory challenges leading to test interpretation, and clinical management of this complex condition.

Distinguishing lupus nephritis (LN) from other glomerulopathies, such as immunoglobulin A nephropathy (IgAN), poses a diagnostic challenge owing to overlapping clinical and histopathologic findings. Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare and potentially fatal disorder characterized by the presence of lupus anticoagulant and acquired factor II deficiency. We report a pediatric case of LN with LAHPS, which was initially diagnosed as IgAN. An 8-year-old girl presented with gross hematuria with nephrotic syndrome. Based on the kidney biopsy results, treatment for IgAN with membranoproliferative pattern was initiated. Two months later, she developed left upper extremity swelling with multiple vein thromboses requiring anticoagulation; treatment led to remission, allowing discontinuation of immunosuppressants within 8 months. Gross hematuria recurred 10 months later and was accompanied by hypocomplementemia; positive antinuclear, anti-double stranded DNA, and triple antiphospholipid antibodies; and factor II deficiency, prompting revision of the diagnosis to LN and LAHPS. Initial delay in LN diagnosis was attributed to the patient’s young age, nonspecific symptoms, and inconclusive laboratory and histopathological findings. Immunosuppressive therapy for IgAN partially improved LN, further complicating the diagnosis. This case emphasized the importance of clinical suspicion; integrating clinical, serological, and histopathological data; and considering LAHPS in differential diagnosis of glomerulonephritis with coagulopathy.

Distinguishing lupus nephritis (LN) from other glomerulopathies, such as immunoglobulin A nephropathy (IgAN), poses a diagnostic challenge owing to overlapping clinical and histopathologic findings. Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare and potentially fatal disorder characterized by the presence of lupus anticoagulant and acquired factor II deficiency. We report a pediatric case of LN with LAHPS, which was initially diagnosed as IgAN. An 8-year-old girl presented with gross hematuria with nephrotic syndrome. Based on the kidney biopsy results, treatment for IgAN with membranoproliferative pattern was initiated. Two months later, she developed left upper extremity swelling with multiple vein thromboses requiring anticoagulation; treatment led to remission, allowing discontinuation of immunosuppressants within 8 months. Gross hematuria recurred 10 months later and was accompanied by hypocomplementemia; positive antinuclear, anti-double stranded DNA, and triple antiphospholipid antibodies; and factor II deficiency, prompting revision of the diagnosis to LN and LAHPS. Initial delay in LN diagnosis was attributed to the patient's young age, nonspecific symptoms, and inconclusive laboratory and histopathological findings. Immunosuppressive therapy for IgAN partially improved LN, further complicating the diagnosis. This case emphasized the importance of clinical suspicion; integrating clinical, serological, and histopathological data; and considering LAHPS in differential diagnosis of glomerulonephritis with coagulopathy. [ABSTRACT FROM AUTHOR]

Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare entity characterized by the presence of lupus anticoagulant (LA) and prothrombin (factor II) deficiency. It may cause severe bleeding contrary to classical antiphospholipid syndrome. Here, we report a case of LAHPS presenting with a hemorrhagic ovarian cyst in a 17-year-old girl with systemic lupus erythematosus (SLE) nephritis. She had been followed up for 8 years. Her first manifestation of SLE was prolonged gingival bleeding after tooth extraction at 9 years of age. During the follow-up period, she had neither severe bleeding nor thrombotic complications despite a positive LA and a prolonged activated partial thromboplastin time (aPTT). At this visit, the patient presented with colicky abdominal pain, a hemorrhagic ovarian cyst, a prolonged prothrombin time, a prolonged aPTT, a low factor II level, and a positive LA, leading to the diagnosis of LAHPS. While a hemorrhagic ovarian cyst resolved completely in 3 months, she received oral pill, transfusions of red blood cells and plasma, and intravenous cyclophosphamide pulse therapy in combination with glucocorticoids due to persistent menorrhagia, anemia, prolonged aPTT, and lupus flaring. Thus, LAHPS needs to be considered in SLE patients with positive LA and prolonged aPTT.

Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare entity characterized by the presence of lupus anticoagulant (LA) and prothrombin (factor II) deficiency. It may cause severe bleeding contrary to classical antiphospholipid syndrome. Here, we report a case of LAHPS presenting with a hemorrhagic ovarian cyst in a 17-year-old girl with systemic lupus erythematosus (SLE) nephritis. She had been followed up for 8 years. Her first manifestation of SLE was prolonged gingival bleeding after tooth extraction at 9 years of age. During the follow-up period, she had neither severe bleeding nor thrombotic complications despite a positive LA and a prolonged activated partial thromboplastin time (aPTT). At this visit, the patient presented with colicky abdominal pain, a hemorrhagic ovarian cyst, a prolonged prothrombin time, a prolonged aPTT, a low factor II level, and a positive LA, leading to the diagnosis of LAHPS. While a hemorrhagic ovarian cyst resolved completely in 3 months, she received oral pill, transfusions of red blood cells and plasma, and intravenous cyclophosphamide pulse therapy in combination with glucocorticoids due to persistent menorrhagia, anemia, prolonged aPTT, and lupus flaring. Thus, LAHPS needs to be considered in SLE patients with positive LA and prolonged aPTT. [ABSTRACT FROM AUTHOR]

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. • Recurrent thrombosis rate in single-positive antiphospholipid syndrome (APS) is low and nears non-APS group with prior clot. • Recurrent thrombosis rate in single-positive APS was not higher on DOACs versus warfarin. • Systemic lupus erythematous (SLE) was associated with recurrent thrombosis in single-positive APS. [ABSTRACT FROM AUTHOR]

Background: Life-long vitamin K antagonist (VKA) therapy is recommended as a standard of care in antiphospholipid syndrome (APS) patients with thrombosis. Concerns have been raised about the validity of international normalized ratio (INR) measurements in lupus anticoagulant (LA)-positive APS patients because LA may interfere with phospholipid-dependent coagulation tests and could elevate INR measurements. Objectives: Here, we aimed to determine the interference of antigen-specific monoclonal and isolated patient antibodies with LA activity on INR measurements. Methods: Pooled normal plasma and control plasma from patients on VKA (without LA) were incubated with monoclonal and isolated patient immunoglobulin G antiprothrombin and anti–beta-2-glycoprotein I antibodies that express LA activity. INR was determined before and after addition using 3 laboratory assays (Owren STA-Hepato Prest, Quick STA-NeoPTimal, and Quick STA-Neoplastine R) and 1 point-of-care test device (CoaguChek Pro II). Results: Antiprothrombin and anti–beta-2-glycoprotein I antibodies with LA activity interfered with recombinant human thromboplastin reagents (Quick STA-Neoplastine R and CoaguChek Pro II), particularly when added to plasma of VKA-treated controls. This effect was most evident on point-of-care test INR measurements, while the recombinant Quick reagent exhibited a lesser degree of interference. In contrast, tissue-derived thromboplastin reagents (Owren STA-Hepato Prest and Quick STA-NeoPTimal) remained largely unaffected by these antibodies, both in pooled normal plasma and VKA anticoagulated control plasma. Among these reagents, the Owren INR reagent exhibited the lowest sensitivity to the influence of LA antibodies. This observed difference in sensitivity is independent of the plasma dilution factor or the presence of factor V or fibrinogen in Owren reagent. Conclusion: INR reagents that utilize recombinant human thromboplastin are more sensitive to the presence of monoclonal and patient-derived antibodies with LA activity. Consequently, APS patients positive for LA should be monitored using tissue-derived thromboplastin reagents, given its reduced susceptibility to interference by LA-causing antibodies.

BACKGROUND Coagulation abnormalities are frequently encountered in patients with coronavirus disease 2019 (COVID-19), especially in those with more severe disease. These hematologic abnormalities are suspected to occur in the context of underlying immune dysregulation and endothelial dysfunction. Elevated D-dimer levels, COVID-19-associated coagulopathy (CAC), disseminated intravascular coagulation (DIC), and positive lupus anticoagulants are the most common findings to date. Current guidelines suggest that all patients with COVID-19 should receive pharmacologic thromboprophylaxis. CASE REPORT An 89-year-old man with a medical history of hypertension, type 2 diabetes, and advanced prostate cancer in remission presented with generalized weakness. At our center, a reverse transcription-polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus 2, but the patient did not have symptoms of COVID-19. He was also found to have a prolonged activated partial thromboplastin time, secondary to both a high titer of factor VIII inhibitor and a lupus anticoagulant. He eventually developed respiratory compromise, during which his disease manifested as a bleeding rather than a prothrombotic state. CONCLUSIONS This report highlights the importance of a comprehensive evaluation of prolonged partial thromboplastin time, rather than making an assumption based on a positive lupus anticoagulant result. In the case presented, the concomitant factor VIII inhibitor caused the patient to have a greater bleeding tendency. It is imperative that physicians balance the risk of bleeding and clotting in patients with COVID-19 because patients seem to have varying presentations based on disease severity and level of immune dysregulation.

Lupus anticoagulant-hypoprothrombinaemia syndrome (LAHPS) is a rare disorder caused by the presence of lupus anticoagulant (LA) and acquired prothrombin deficiency, which may present with severe haemorrhagic manifestations. LAHPS is usually associated with systemic lupus erythematosus (SLE), or infections and it is more frequent in the paediatric population and female gender. We describe a 42-year-old man with thrombotic antiphospholipid syndrome (APS) on chronic anticoagulation treatment with acenocoumarol who presented with spontaneous intracranial bleeding, prolongation of prothrombin time (PT), activated partial thromboplastin time (APTT) and low factor II levels (after optimal anticoagulation reversal) as a debut of SLE. [ABSTRACT FROM AUTHOR]

The ISTH-SSC guidelines for lupus anticoagulant (LA) testing recommend using in-house determined cut-off values, pooled normal plasma (PNP) for ratio normalization, and a ratio for the mixing test interpretation. They strongly support the mixing step role in the diagnostic process. To investigate and compare the LA testing results and interpretations obtained following the ISTH-SSC guidelines or the available alternatives. Blood samples for LA testing from 462 consecutive patients were evaluated for screening, mixing and confirmatory tests. The analysis focused on the interpretation differences between using (1) the in-house cut-off values versus the manufacturer's cut-off values, (2) a normalized ratio calculated using PNP at each run versus the mean of the reference interval, (3) a normalized ratio versus the index of circulating anticoagulant to interpret the mixing step, and (4) a two-step versus three-step procedure. LA testing outcomes were comparable when using the in-house and manufacturer's cut-off values. More positive dilute Russell's viper venom (DRVV) time results were obtained with the normalized ratio based on PNP than with the mean of the reference interval. Overall, the mixing test results obtained with the normalized ratio and the index of circulating anticoagulant showed a good agreement. Among the 97 DRVV Screen test-positive samples, 33 and 89 were classified as LA-positive with the 3-step and the 2-step procedure, respectively. The cut-off value used and the way to normalize ratios had a limited impact. Conversely, it is important to understand the mixing test characteristics to maximize its diagnostic potential. [Display omitted] • The current ISTH-SSC guidelines for LA testing aim to harmonize practices. • However, methodologies are not always consistent and alternatives are possible. • The impact of the cut-off value used and the way to normalize ratios remained limited. • It is important to understand the mixing test characteristics. [ABSTRACT FROM AUTHOR]

IntroductionThe dilute Russell viper venom time (dRVVT) detects lupus anticoagulant (LA). International Society for Thrombosis and Haemostasis (ISTH) guidelines specify positivity criteria, which differ from the assay manufacturer's criteria.MethodsTwo years of dRVVT testing at our institution were reviewed. For patients with prolonged dRVVT screening times, we evaluated dRVVT results by ISTH and manufacturer's criteria and correlated with the results of other antiphospholipid syndrome (APS) testing (LA-sensitive activated partial thromboplastin time and antiphospholipid antibodies) and with history of thromboembolism and other APS manifestations.ResultsApproximately one-fifth of dRVVTs exhibited a prolonged screening time. Among first prolonged dRVVTs, 35% were positive by both ISTH and manufacturer criteria, 44% met neither criteria, and 20% were equivocal (positive by only ISTH or manufacturer). Positivity by ISTH guidelines alone correlated better with other positive APS tests than manufacturer criteria positivity. Positive dRVVTs by both criteria correlated even more strongly with other positive APS assays. We investigated the likelihood of eventual APS diagnosis depending on the testing indication. No patient tested for LA solely for prolonged screening aPTT was subsequently diagnosed with APS. In patients with thrombosis, prolonged dRVVT clotting time not meeting both ISTH and manufacturer criteria was rarely associated with eventual APS diagnosis.ConclusionWe examined the correlation of dRVVT results with other APS testing and clinical outcomes. Interpretation method impacted how dRVVT results related to other APS testing, and, in limited data, to clinical findings. Patients with prolonged dRVVTs meeting only one set of positivity criteria rarely received an APS diagnosis.

ObjectiveTo determine, in a large, multiethnic/multiracial, prospective inception cohort of patients with systemic lupus erythematosus (SLE), the frequency, attribution, clinical, and autoantibody associations with lupus psychosis and the short- and long-term outcomes as assessed by physicians and patients.MethodsPatients were evaluated annually for 19 neuropsychiatric (NP) events including psychosis. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and the Short Form 36 (SF-36) were recorded. Time to event and linear regressions were used as appropriate.ResultsOf 1,826 SLE patients, 88.8% were female and 48.8% were Caucasian. The mean ± SD age was 35.1 ± 13.3 years, the mean ± SD disease duration was 5.6 ± 4.2 months, and the mean ± SD follow-up period was 7.4 ± 4.5 years. There were 31 psychotic events in 28 of 1,826 patients (1.53%), and most patients had a single event (26 of 28 [93%]). In the majority of patients (20 of 25 [80%]) and events (28 of 31 [90%]), psychosis was attributed to SLE, usually either in the year prior to or within 3 years of SLE diagnosis. Positive associations (hazard ratios [HRs] and 95% confidence intervals [95% CIs]) with lupus psychosis were previous SLE NP events (HR 3.59 [95% CI 1.16-11.14]), male sex (HR 3.0 [95% CI 1.20-7.50]), younger age at SLE diagnosis (per 10 years) (HR 1.45 [95% CI 1.01-2.07]), and African ancestry (HR 4.59 [95% CI 1.79-11.76]). By physician assessment, most psychotic events resolved by the second annual visit following onset, in parallel with an improvement in patient-reported SF-36 summary and subscale scores.ConclusionPsychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. As determined by patient and physician report, the short- and long-term outlooks are good for most patients, although careful follow-up is required.

Background: The presence of antiphospholipid antibodies (aPL) has been suggested as a potential cause of moyamoya angiopathy (MMA), but this remains uncertain. In this case-control study, we aimed to compare the prevalence of circulating aPL in patients with MMA and in non-MMA cerebrovascular controls., Methods: For comparison, we included 95 patients with MMA from the French National Referral Centre for this condition and 182 age- and sex-matched non-MMA controls with a different cerebrovascular disease, all younger than 55 years. Anticardiolipin antibodies, anti-β2-glycoprotein I antibodies, and lupus anticoagulant were assessed using the guidelines of the International Society on Thrombosis and Haemostasis., Results: aPL prevalence was 22% in patients with MMA and 25% in controls ( P =0.74) with no differences in aPL subtypes between the 2 groups. The prevalence of transient ischemic attacks, ischemic stroke, and hemorrhagic stroke did not differ between patients with aPL-positive and aPL-negative MMA., Conclusions: The prevalence of aPL in patients with MMA is comparable to that in non-MMA controls. The present results do not support any causal relationship between aPL and MMA., Competing Interests: None.

Objective To identify the variables associated with the development of non-criteria manifestations in the presence of antiphospholipid antibodies (aPLs) in a paediatric cohort. Methods Multicentric historical cohort study of children under the age of 18 years to determine thrombotic events (TEs) and non-criteria manifestations in the presence of aPL. Results Eighty-two children were included; 8.5% had at least one TE and 69.5% at least one non-criteria manifestation. Of them, 96.5% did not associate TEs. Haematological manifestations were the most frequent (43.65%), followed by cutaneous (22%), neurological (15.9%) and cardiac (4.9%) events. The most frequent aPLs were: 77.8% LA; 42.7% aCL and 41.5% aβ2GP. The positivity rate was: 64.6% simple, 18.3% double and 17.1% triple. ANA positivity was 68.1%. A bivariate analysis revealed that children with IgM aCL+, IgM aβ2GP+, ANA+, an SLE diagnosis or the absence of TEs had a significantly higher percentage of non-criteria manifestations (P  <0.05). The logistic regression showed family history of autoimmune diseases [odds ratio (OR) 4.26, 95% CI: 0.8, 22.2, P  =0.086] and the absence of TEs (OR 17.18, 95% CI: 1.2, 244.6, P  =0.03) as independent risk factors of developing non-criteria manifestations. An SLE diagnosis, aPL profile and ANA+ were not identified. Conclusion Non-criteria manifestations were more frequent than TEs. A positive family history of autoimmune diseases and the absence of TEs were associated with a higher risk of developing non-criteria manifestations. Therefore, their inclusion as APS classification criteria should be considered in order to get an improved prognosis in the paediatric population. [ABSTRACT FROM AUTHOR]

Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies are the major contributor to activated Protein C resistance (APC-R) in tetra-positive thrombotic high-risk patients with Antiphospholipid Syndrome (APS). To evaluate the role of phospholipids (PL) on aPS/PT mediated APC-R. Total IgG were purified from plasma of 6 tetra-positive patients and IgG aPS/PT were affinity-purified from 3 of these patients. Purified material was spiked into Normal Pooled Plasma (NPP) and tested for APC-R in thrombin generation assay and in Factor Va inactivation assay using increasing amounts of phospholipids. Total IgG showed APC-R at low PL concentration (1.5 μg/mL) that disappeared at increasing PL concentrations (5.8, 11.6 and 46.6 μg/mL). In the same way, affinity purified aPS/PT showed a robust (59 %, 52 %, 36 %) APC-R in patients #4, #5 and #6, respectively at low PL concentration (1.5 μg/mL) that was completely reversed at higher concentration (11.6 μg/mL). The inactivation of FVa by activated Protein C (aPC) was impaired in the presence of aPS/PT at low aPL concentration and reversed by increasing amounts of PL. These data point out the relevance of PL in reversing APC-R in this 'in vitro' system. The mechanism for reversal might be explained by loss of PL availability for aPC. These results may give some insight into the pathogenesis of thrombosis or suggestions for alternative treatments. • High-risk APS have antibodies to aβ2-Glycoprotein I (aβ2GPI) and to phosphatidyl-serine/prothrombin (aPS/PT). • APS/PT have a major role in Lupus Anticoagulant (LA) activity • APS/PT confer activated Protein C resistance (APC-R) due to impaired degradation of Factor Va. • APC-R is reversed by increasing amount of phospholipid [ABSTRACT FROM AUTHOR]

Abstract Background The use of direct oral anticoagulants (DOACs) is a convenient therapeutic option for patients at risk of thrombosis. DOACs interfere with clot‐based testing for the identification of lupus anticoagulant antibodies (LACs) in patients with antiphospholipid syndrome (APS), a common cause of acquired thrombotic disease. Objectives To evaluate a commercially available reagent DOAC‐Stop for the removal of DOAC interference encountered in LAC testing. Patients/Methods We collected a cohort of 73 test samples from patients on DOAC therapy identified at a large institutional coagulation laboratory from March to December 2019, along with samples from 40 LAC positive and negative control patients not on therapy. Samples were treated with DOAC‐Stop and tested for anti‐Xa activity and thrombin time for the removal of apixaban, rivaroxaban, argatroban, and dabigatran activity from patient samples. Treated and untreated samples were tested using the activated partial thromboplastin time, silica clotting time, and dilute Russell’s viper venom time to evaluate the reliability and utility of DOAC‐Stop. Results DOAC‐Stop markedly reduced DOAC interference from test samples (P

Acquired hemophilia A, caused by autoantibodies that bind to and neutralize the activity of coagulation factor VIII (FVIII), almost universally presents as a severe bleeding diathesis. Lupus anticoagulants (LAs), autoantibodies directed against phospholipids or protein-phospholipid complexes, manifest clinically with an increased risk of thrombosis. While these autoantibodies are uncommon, the distinctive clinical presentation in conjunction with the typical laboratory findings often enable straightforward identification of the underlying autoantibody. However, the presence of a concomitant acquired FVIII inhibitor and LA is exceedingly rare with fewer than 20 documented cases. All prior patients presented with life-threatening hemorrhage, thrombosis, or both, prompting comprehensive hematologic evaluation and subsequent identification of the pathologic antibodies. We describe a novel case of a patient with no signs of hemorrhage or thrombosis who was incidentally found to have both a FVIII inhibitor and LA during evaluation of a prolonged partial thromboplastin time (PTT). This finding resulted in FVIII inhibitor-directed management, including immunosuppressive therapy. The unique presentation of an incidental FVIII inhibitor and LA in an asymptomatic patient without thrombotic or bleeding complications highlights the potential challenge in elucidating the etiology of a prolonged PTT, as LAs and FVIII inhibitors both prolong the PTT, and each entity can interfere with assays designed to detect the presence of the other autoantibody. This case underscores the importance of recognizing that patients with major underlying disturbances in their hematologic physiology, but in whom clinical symptoms have yet to manifest, may potentially be overlooked until such symptoms are evident. [ABSTRACT FROM AUTHOR]

The emergence of severe acute respiratory syndrome coronavirus 2 has made it crucial to develop safe vaccines. Three main types of vaccines are currently available. Although they have proven to be very secure, they have caused various adverse effects. We here report a rare case of livedo reticularis following the administration of COVID-19 vaccine in a 54-year-old woman. It occurred 24 hours after vaccination, accompanied by respiratory, digestive, and neurological disorders and deterioration in general condition. Examinations revealed skin lesions compatible with livedo reticularis, mild inflammatory syndrome and hypercholesterolemia. Imaging showed no abnormalities. Immunological tests were positive for lupus anticoagulant. The patient received symptomatic treatment, with improvement in neurological and joint symptoms and a slight regression of skin rashes. After three months, the lupus anticoagulant test remained positive, confirming post-vaccination antiphospholipid syndrome (APS). The association of livedo reticularis with COVID-19 vaccine should not be underestimated and its degree of severity remains to be determined. More data and cases need to be collected for a more in-depth and detailed analysis., Competing Interests: Les auteurs ne déclarent aucun conflit d´intérêts., (Copyright: Meryem Ouhaddach et al.)

Abstract Background Heparins and heparinoids interfere with functional clotting assays used for lupus anticoagulant (LAC) detection. However, current guidelines for LAC testing do not provide clear guidance on this matter. Objectives We aimed to assess to effect of unfractionated heparin (UFH), enoxaparin, and danaparoid on LAC assays over broad anti‐Xa activity ranges and to evaluate whether activated carbon (AC) is able to neutralize these effects. Methods UFH (0.1‐3.0 IU/mL), enoxaparin (0.2‐2.9 IU/mL), and danaparoid (0.6‐2.2 IU/mL) were spiked to normal pooled plasma. AC was added at multiple activity levels. Anti‐Xa assays and LAC tests were performed on all samples using Stago analyzers and reagents. Results Abnormal activated partial thromboplastin time (APTT) screening and mixing tests were obtained at the lowest levels for all compounds. Abnormal APTT confirmation tests were seen from 2.5 and 1.9 anti‐Xa IU/mL for enoxaparin and danaparoid, respectively. Abnormal dilute Russell’s viper venom test (dRVVT) screening tests were obtained from 1.6, 1.4, and 1.1 anti‐Xa IU/mL for UFH, enoxaparin, and danaparoid, respectively. Mixing tests were abnormal from 2.5 and 1.3 anti‐Xa IU/mL for enoxaparin and danaparoid, respectively. Abnormal dRVVT confirmation results were seen for danaparoid only from 1.9 anti‐Xa IU/mL. AC was unable to neutralize anti‐Xa activity in plasma and overcome the effect of the tested anticoagulants on LAC assays but may cause prolongation of APTT clotting times. Conclusions UFH, enoxaparin, and danaparoid clearly affected LA tests; however, false‐positive LAC conclusions were obtained at supratherapeutic enoxaparin and danaparoid levels only. AC may prolong APTT screen clotting times, requiring 3‐step testing to avoid potential misdiagnosis of LAC.

ABSTRACT Introduction: Thrombophilia is a thrombosis susceptibility of genetic, acquired or mixed nature. Among acquired causes, the antiphospholipid syndrome (APS) stands out as an autoimmune disease characterized by antiphospholipid antibodies, thrombotic events or recurrent gestational loss. Laboratory diagnosis is based on the detection of lupus anticoagulant (LAC), anti-β2-glycoprotein 1 and anticardiolipin; however the determination of LAC still demands uniformity. The last guideline published by the Clinical and Laboratory Standards Institute (CLSI) prioritizes the screening and confirmatory steps, to the detriment of the mixing phase. Objectives: To compare the forms of releasing the LAC and to adopt an investigation protocol in agreement with the international guidelines. Methods: Thirty-six samples with prolonged results in the screening step by the dilute Russell viper venom time (dRVVT) or activated partial thromboplastin time (APTT) were subjected to the mixing steps (1:1) and to the confirmatory steps with high concentrations of phospholipids. Results: For APTT, values whose indexes of circulating anticoagulant (ICA) were greater than 15% were considered positive. For dRVVT, the ratio between screening and confirmation was also used. Of the 36 tested samples, 14 showed correction in the mixing step, but only one resulted negative. Conclusion: ICA aided in identifying the weak antibodies that were probably diluted in the mixing step. There is no gold standard test for the diagnosis of APS, and LAC detection still requires standardization of technique and interpretation.

Objective: Unknown ethiology • Unusual clinical course Background: COVID-19 was declared a pandemic in March 2020 in the United States. It has been associated with high mortality and morbidity all over the world. COVID-19 can cause a significant inflammatory response leading to coagulopathy and this hypercoagulable state has been associated with worse clinical outcomes in these patients. The published data regarding the presence of lupus anticoagulant in critically ill COVID-19-positive patients is limited and indicates varying conclusions so far. Case Report: Here, we present a case of a 31-year-old man who was admitted to the hospital with COVID-19 pneumonia, complicated with superadded bacterial empyema and required video-assisted thoracoscopic surgery with decortication. This patient also had prolonged prothrombin time on preoperative labs, which was not corrected with mixing study. Further workup detected positive lupus anticoagulant and anti-cardiolipin IgM along with alteration in other coagulation factor levels. The patient was treated with fresh frozen plasma and vitamin K before surgical intervention. He had an uneventful surgical course. He received prophylactic-dose low molecular weight heparin for venous thromboembolism prophylaxis and did not experience any thrombotic events while hospitalized. Conclusions: COVID-19 infection creates a prothrombotic state in affected patients. The formation of micro-thrombotic emboli results in significantly increased mortality and morbidity. Routine anticoagulation with low molecular weight heparin can prevent thrombotic events and thus can improve patient outcomes. In patients with elevated prothrombin time, lupus anticoagulant/anti-cardiolipin antibody-positivity should be suspected, and anticoagulation prophylaxis should be continued perioperatively for better outcomes. [ABSTRACT FROM AUTHOR]

Lupus anticoagulant is a misnomer as it is commonly associated with thromboembolic events. In few cases, the name retains its literal meaning when it characterizes patients with a bleeding disorder. We describe a patient with lupus anticoagulant, hypoprothrombinemia, and major bleeding (lupus anticoagulant/hypoprothrombinemia syndrome). Immunological studies revealed a huge amount of circulating monoclonal immunoglobulin M lambda (IgMλ) antiphosphatidylserine/prothrombin antibodies (14,400 U/mL). Affinity purified monoclonal antibodies (440 U/mL) prolonged the coagulation time of normal plasma by 12.2 seconds (diluted Russell viper venom time) and 25.5 seconds (silica clotting time). The original patient's plasma mixed 1:1 with normal plasma showed a marked prolongation of coagulation times (lupus cofactor) from a ratio of 2.94 to 5.23 in diluted Russel viper venom time and from 2.30 to 3.00 using the silica clotting time. Human prothrombin added to original patient's plasma caused a marked prolongation of coagulation times in diluted Russell viper venom test thus unequivocally explaining the lupus cofactor phenomenon. In conclusion, we have shown that lupus anticoagulant/hypoprothrombinemia syndrome is attributable to monoclonal IgMλ antibodies directed to phosphatidylserine/prothrombin and that prothrombin is the protein responsible for the observed lupus cofactor phenomenon.

Antiphospholipid antibodies (APLA) are present in one-third of systemic lupus erythematosus (SLE) patients, and they are associated with both criteria and non-criteria manifestations. We studied the prevalence, clinical associations, and impact on mortality of APLA in SLE patients from India. Among the Indian SLE inception cohort (INSPIRE), patients who had data on all five routinely performed APLAs [lupus anticoagulant (LA), IgG and IgM anticardiolipin antibody (aCL) and anti-β2-glycoprotein I(β2GPI)] at enrolment were selected. Patients were divided into four categories based on the presence/absence of APLA associated manifestations and presence/absence of the APLA viz SLE-APS, SLE-APLA, SLE: events but no APLA, and SLE: no events, no APLA (reference group). 1035 SLE patients at least 1 APLA antibody was detected in 372 (35.9%). LA was present in 206 (19.9%), aCL in 126 (12.2%) and β2-GPI in 178 (17.2%). There were 88 thrombotic events in 83 patients (8.0%); 73 (82.9%) being arterial; APLA positivity was present in 37 (44.6%) [AOR 1.70 (1.054, 2.76)]. SLE-APS patients were younger and had higher mortality [AOR 4.11 (1.51, 11.3)], neuropsychiatric and hematologic disease. SLE-APLA also had a higher mortality rate [AOR 2.94 (1.06, 8.22)] than the reference group. The mortality was highest in the subset of patients with thrombotic events in the presence of APLA [AOR 7.67 (1.25, 46.9)]. The mere presence of APLA also conferred higher mortality even in the absence of thrombotic events [AOR 3.51 (1.43, 8.63)]. Hematologic manifestations (36.1%) were the most common non-criteria-manifestation. One-third of SLE patients have APLA and its presence is associated with non-criteria hematologic manifestations, arterial thrombosis and higher mortality rate., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although clear and detailed recommendation regarding the lupus anticoagulant mixing test exist, various sources of NPP are used. We decided to inspect the possible differences in mixing studies depending on the mixing media. Four types of mixing media were prepared for 45 random remnant plasma samples: standard human plasma, control plasma N, previously analyzed patient with normal coagulation values, and home-made normal pool plasma (NPP). Samples were analyzed by using Siemens Dade Actin FSL Activated PTT Reagent on BCS XP analyzer. The median aPTT values of mixing studies with commercial lyophilized NPP, with commercial IQC, as well as with a patient did not differ (26.6, 26.3, and 26.8 s, respectively). Median value of a mixing study with home-made NPP was significantly higher from the rest of the group (27.9 s) ( P  < 0.05). According to the obtained results, we decided to employ the commercial lyophilized NPP for future lupus anticoagulant mixing studies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti β2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: To determine the impact of residual platelets on dilute Russell's viper venom time (DRVVT) assay in frozen-thawed plasma submitted for lupus anticoagulant (LAC) testing., Methods: We measured platelet counts in frozen-thawed samples submitted for LAC testing and evaluated the association between platelet count and the DRVVT screening time and ratios. We also spiked platelets into a LAC-positive sample to observe the effect on the DRVVT., Results: Progressive increase in platelet count resulted in a statistically significant shortening of the DRVVT assay results on plasma after 1 freeze-thaw cycle. A similar effect was noted on the LAC-positive sample., Conclusions: Residual platelets in plasma samples result in shortening of DRVVT assay after 1 freeze-thaw cycle. This may result in a false-negative LAC test result., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Lupus anticoagulant (LAC) is typically associated with thrombosis but also rarely with hemorrhage. Some patients exhibit a prozone effect on LAC testing. Antiphosphatidylserine/prothrombin (aPS/PT) antibodies may provide a mechanism for both hemorrhage and prozone effect. Our goal was to evaluate whether antibody specificities, isotypes, and titers were associated with LAC prozone effect, factor II levels, hemorrhage, and thrombosis.Methods: Patients with prozone effect noted on LAC testing were entered into a database over 3 years. Factor II activity and aPS/PT antibody testing were performed when a sufficient residual sample was available.Results: All patients with LAC prozone effect and antibody testing were positive for at least 1 class of aPS/PT antibodies. In addition, aPS/PT IgG titers were significantly associated with thrombosis and significantly inversely associated with factor II levels.Conclusions: In prozone effect patients, aPS/PT antibodies are associated with LAC prozone effect as well as thrombosis and decreased factor II levels. [ABSTRACT FROM AUTHOR]

Abstract: Thrombosis is an important manifestation of the antiphospholipid syndrome (APS). The thrombin generation (TG) test is a global hemostasis assay, and increased TG is associated with thrombosis. APS is currently diagnosed based on clinical and laboratory criteria, the latter defined as anti-cardiolipin, anti-β2-glycoprotein I antibodies, or lupus anticoagulant (LA). APS testing is often performed after a thrombotic episode and subsequent administration of anticoagulation, which might hamper the interpretation of clotting assays used for LA testing. We set out to develop an artificial neural network (NN) that can diagnose APS in patients who underwent vitamin K antagonist (VKA) treatment, based on TG test results. Five NNs were trained to diagnose APS in 48 VKA-treated patients with APS and 64 VKA-treated controls, using TG and thrombin dynamics parameters as inputs. The 2 best-performing NNs were selected (accuracy, 96%; sensitivity, 96%-98%; and specificity, 95%-97%) and further validated in an independent cohort of VKA-anticoagulated patients with APS (n = 33) and controls (n = 62). Independent clinical validation favored 1 of the 2 selected NNs, with a sensitivity of 88% and a specificity of 94% for the diagnosis of APS. In conclusion, the combined use of TG and NN methodology allowed for us to develop an NN that diagnoses APS with an accuracy of 92% in individuals with VKA anticoagulation (n = 95). After further clinical validation, the NN could serve as a screening and diagnostic tool for patients with thrombosis, especially because there is no need to interrupt anticoagulant therapy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: This study aimed to assess the risk factors for symptomatic osteonecrosis (ON) in systemic lupus erythematosus (SLE) and identify clinical characteristics and laboratory markers for predicting symptomatic ON occurrence in SLE patients., Methods: Seventy (6.0%) of 1175 SLE patients diagnosed with symptomatic ON were included in this study. An equal number of SLE patients without symptomatic ON, matched in terms of age and gender, were enrolled in the control group. Clinical symptoms, routine laboratory examinations, lymphocyte subsets, and treatments of these patients were retrospectively reviewed and compared between the two groups. Logistic regression analysis was employed to identify risk factors associated with symptomatic ON in SLE., Results: Among the 70 cases in the symptomatic ON group, 62 (88.6%) patients experienced femoral head necrosis, with bilateral involvement observed in 58 patients. Bone pain was reported in 32 cases (51.6%), and 19 cases (30.6%) presented with multiple symptoms. Univariate analysis revealed significant differences between the two groups in various factors, including disease duration (months), cumulative steroid exposure time, history of thrombosis, neurological involvement, the number of affected organs, myalgia/myasthenia, and the use of medications such as glucocorticoids, immunosuppressants, aspirin, and statins (P<0.05). Moreover, lupus anticoagulant (LA) levels were significantly higher in the symptomatic ON group than in the control group (P<0.05). Furthermore, notable distinctions were observed in peripheral blood immune cells, including an elevated white blood cell count (WBC), a decreased percentage of Ts cells (CD3+CD8+), and an elevated Th/Ts ratio. Logistic regression analysis revealed that a history of thrombosis, LA positivity, and an elevated Th/Ts ratio remained positive factors associated with symptomatic ON (P<0.05)., Conclusion: Decreased Ts cells and changes in the T lymphocyte subset play an important regulatory role in the development of symptomatic ON. A history of thrombosis and LA are associated with an increased probability of symptomatic ON in SLE and may serve as potential predictors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hou, Lei, Xue, Jing, Mi, Guo, Xu and Zhang.)

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic and non-thrombotic macro- and microvascular manifestations and pregnancy complications in the setting of persistent antiphospholipid antibodies (aPL), namely anticardiolipin antibodies, anti-β2 glycoprotein-I antibodies and lupus anticoagulant. Four decades after its first description, APS prevalence and incidence are still not completely understood due to the limited number of well-designed, population-based multi-ethnic studies. Furthermore, despite decades of efforts to standardise aPL immunoassays, considerable intraassay and interlaboratory variances in aPL measures still exist. Large multicentre APS cohorts have shown a 10-year survival of ∼91% and the presence of catastrophic APS occurs in about 1% of the entire population, associated with a 50% mortality rate. Clinically, any organ can be affected in the context of large, medium or small vessel (artery and/or vein) thrombosis. Macrovascular thrombosis is the hallmark of the disease and veins are more frequently affected than arteries. Deep vein thrombosis/pulmonary embolism thromboembolic disease is the most common APS manifestation, while stroke and transient ischaemic attack are the most frequent arterial thrombosis events. Myocardial infarction can also occur and contributes to increased mortality in APS. A minority of patients present with thrombosis affecting the intraabdominal organs, including the liver, spleen, small and large bowel, and the kidneys. Microvascular thrombosis, including APS nephropathy, chronic skin ulcers and livedoid vasculopathy represent a diagnostic challenge requiring histologic confirmation. In this narrative review we summarize the available evidence on APS epidemiology, focusing on the description of the prevalence of macro- and microvascular manifestations of the disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Several non-criteria (NC) anti-phospholipid antibodies (APLA) have been proposed as candidates for antiphospholipid antibody syndrome (APS) diagnosis. The objectives of this study were 1) to determine the association of five different NC-APLA with positivity for Lupus anti-coagulant (LAC) and the criteria antibodies anti-cardiolipin (aCL) and anti-beta glycoprotein (aB2GPI), and 2) to assess the ability of NC-APLA to predict LAC presence and clinical APS diagnoses., Material and Methods: Results from 486 patients tested for LAC and APLA were retrieved. Patients were grouped according to LAC and serology positivity into three groups: Single-positives (SP) for LAC, aCL or aB2GPI; Double-positives for aCL and aB2GPI; Triple-positives (TP) for LAC, aCL and aB2GPI. NC-ALPA titers were compared between LAC-positive and negative and APS and non-APS patients., Results: Forty-two of 486 patients were LAC-positive and 28 were diagnosed with APS. All criteria and NC-APLA titers were significantly higher in TP than SP patients. ROC analyses based on LAC status showed highest area under the curve (AUC, 95% CI) for aPS/PT IgG (0.75, 0.65-0.85) and aPS/PT IgM (0.73, 0.63-0.82). Based on APS diagnosis, aPS/PT IgM achieved highest AUC (0.87; 0.79-0.95)., Conclusion: Anti-phosphatidyl-serine/prothrombin (aPS/PT) antibodies are superior predictors of LAC presence and APS diagnoses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)