Search Results (84)

Background: Raynaud’s phenomenon (RP) may occur in the pediatric age span, sometimes representing the forerunner of devious underlying conditions. Objective: To investigate the prevalence of vitamin D deficiency in a single-center cohort of children and adolescents with idiopathic RP and evaluate changes in RP severity following cholecalciferol supplementation. Patients and Methods: Sixty-one children and adolescents with RP regularly followed at the pediatric rheumatology unit of our University between 2010 and 2025 were retrospectively evaluated. Clinical, laboratory, and nailfold videocapillaroscopy (NVC) findings were collected at baseline; patients were periodically examined for a mean investigation period of 3 ± 1.6 years. RP severity was assessed using the 2-week Raynaud’s Condition Score (RCS). Patients found to have serum 25-hydroxyvitamin D levels < 20 ng/mL received cholecalciferol supplementation for at least 12 weeks. Results: Nineteen out of 61 patients with RP (31.1% of the cohort) had vitamin D deficiency, while other laboratory parameters including inflammatory markers, complement fractions, liver and renal function tests, lipid profile, and autoimmune panel were non-informative. Univariate analysis demonstrated significant differences between vitamin D-deficient and non-deficient patients in terms of mean RP duration (p = 0.0002), baseline 2-week RCS (p = 0.0001), lupus-like anticoagulant positivity (p < 0.001), NVC pattern (p < 0.001), pain visual analogue scale (VAS) (p = 0.0001), and global quality of life VAS (p = 0.0001). After adjustment for age and sex, baseline 2-week RCS remained significantly associated with vitamin D deficiency. In addition, RCS significantly decreased during follow-up among vitamin D-deficient patients who received supplementation of cholecalciferol. Conclusions: Vitamin D deficiency may be common in pediatric idiopathic RP and pinpoint its severity: our exploratory study supports the routine assessment of vitamin D in children and adolescents with severe forms of RP, warranting prospective randomized controlled trials to determine whether correction of vitamin D deficiency may potentially improve disease severity. Full article

Background: Hereditary thrombophilia testing is frequently performed outside guideline-supported indications, generating low-value results and diagnostic uncertainty. We evaluated the spectrum, laboratory validity, and appropriateness of thrombophilia testing in patients referred to hematology. Methods: This single-center retrospective cohort included 131 adults referred between September 2021 and November 2022 with a completed six-variant hereditary thrombophilia panel. Demographic, clinical, thrombotic, and laboratory data were reviewed, and testing appropriateness was assessed against the 2011 Turkish Society of Hematology guideline. Results: Ischemic stroke (25.2%), pulmonary embolism (21.4%), and recurrent pregnancy loss (16.0%) were the leading indications. Of 120 evaluable requests, only seven (5.8%) met guideline-supported criteria, and 42 (32.0%) were ordered during acute thrombosis. Factor V Leiden was associated with pulmonary embolism (48.6% vs. 22.1%, p = 0.003) and deep vein thrombosis (28.6% vs. 9.5%, p = 0.003), whereas ischemic stroke was less frequent among carriers (11.4% vs. 33.7%, p = 0.017). PAI-1, MTHFR c.1298A>C, and prothrombin G20210A showed no consistent associations. Of six low protein C results, only two were confirmed; none of eight low protein S results remained valid after timing and confirmation criteria were applied. Lupus anticoagulant was positive in 18 patients, yet only six underwent appropriately timed repeat testing, establishing four new antiphospholipid syndrome diagnoses. Conclusions: Most thrombophilia panels were ordered inappropriately, and test timing frequently compromised interpretability. Clinically meaningful information arose mainly from factor V Leiden and properly confirmed acquired thrombophilia testing. Targeted, indication-driven testing with strict attention to timing and confirmation should replace indiscriminate panel use. Full article

Background: Antiphospholipid antibodies (aPLs) are essential for antiphospholipid syndrome (APS) diagnosis, which is based on clinical and laboratory parameters, including the detection of lupus-anticoagulant (LAC), anti-cardiolipin (aCL) and anti-β2-glycoprotein-I (aβ2-GPI) antibodies. The enzyme-linked immunosorbent assay (ELISA) is the reference methodology for classification criteria, although chemiluminescence immunoassays (CLIA) are more common in clinical practice. Methods: Since LAC reflects the functional activity of a large subset of antiphospholipids, through coagulation assays that enhance a phospholipid-dependent inhibitory effect, it has been used as a reference for assessing ELISA and CLIA reliability. Samples, separated into positive and negative LAC, were selected by CLIA detection in negative and positive IgG/IgM aCL and aβ2-GPI (cut-off > 20 U/mL). Results: The ELISA/CLIA comparison showed a 100% concordance in triple negative groups, highlighting an optimal analytical specificity; a higher concordance in the aβ2-GPI IgM-positive groups compared to positive aCL IgM (100% vs. 76% in LAC-positive groups; 82% vs. 71% in LAC-negative groups), as well as in aβ2-GPI IgM-negative groups compared to negative aCL IgM in LAC-positive groups (100% vs. 87.5%); and a massive concordance reduction in positive IgG aβ2-GPI and aCL groups (44% vs. 50% in LAC-positive groups; 4.8% vs. 4.5% in LAC-negative groups). Concordance increased in all groups with a higher CLIA cut-off (>50 U/mL). Conclusions: Although CLIA performances partly differed from ELISA, this does not preclude their use in APS diagnosis, which aims for higher sensitivity in detecting cases of disease. ELISA is confirmed to be more reliable for classification criteria that aim for high specificity to reduce false positives. Full article

Background: Antiphospholipid syndrome (APS) is diagnosed by characteristic clinical manifestations supported by positivity for lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies. However, a proportion of patients, especially those with systemic lupus erythematosus, remain seronegative despite high clinical suspicion. Anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have emerged as potential biomarkers in this setting. We conducted an expert perception-based Health Technology Assessment (HTA) to evaluate the clinical, ethical, and organizational impact of implementing aPS/PT testing. Methods: A structured HTA was performed across five domains: safety, perceived efficacy, equity, ethics, and organizational implications. A survey was distributed to 110 APS specialists; 50 experts contributed responses (45.5% response rate; 66% clinicians, 18% laboratory personnel, 8% nurses, 8% administrative/other). For each domain, Z-scores were calculated to compare current diagnostic practice (AS IS) with a scenario integrating aPS/PT testing (TO BE). Correlation analyses explored relationships across domains. Results: Across all five domains, the TO BE scenario scored substantially higher than standard practice. The largest improvements were observed in perceived diagnostic efficacy (ΔZ = +2.65) and safety (ΔZ = +2.03), followed by equity (ΔZ = +2.25), ethical/social impact (ΔZ = +1.96), and organizational feasibility (ΔZ = +1.61). Perceived diagnostic effectiveness showed a strong positive correlation with both equity (r = 0.70, p < 0.001) and ethics (r = 0.67, p < 0.001). Participants consistently rated the assay as safe, clinically useful, equitable, and organizationally easy to introduce in routine laboratory workflows. Conclusions: Experts perceived the addition of aPS/PT testing as a meaningful enhancement to APS diagnostics, particularly for SLE patients who are seronegative on conventional assays. Its favorable profile across all HTA domains supports further evaluation in prospective cohorts and consideration for integration into future diagnostic algorithms. Full article

Pulmonary embolism (PE) is one of the most serious complications of antiphospholipid syndrome (APS), a systemic autoimmune disorder defined by thrombotic events and persistent antiphospholipid antibodies (aPLA). PE occurs in 11–20% of patients and may constitute the initial clinical manifestation. Young and middle-aged women are most frequently affected, and triple-positive aPLA profiles markedly increase the risk of recurrence and long-term morbidity, including chronic thromboembolic pulmonary hypertension (CTEPH). This review article summarizes current evidence on the epidemiology, pathophysiology, diagnostic approach, and management of PE in APS. Key mechanisms include anti-β2-glycoprotein I-mediated endothelial and platelet activation, complement engagement, and neutrophil extracellular trap formation, resulting in immunothrombosis. Diagnostic pathways follow standard PE algorithms; however, chronically elevated D-dimer levels and lupus anticoagulant-related aPTT prolongation require careful interpretation and consideration. Long-term vitamin K antagonist therapy remains the standard of care, whereas direct oral anticoagulants are not recommended in high-risk APS. Future directions include improved risk stratification through detailed aPLA profiling and the use of emerging biomarkers, early screening for CTEPH, and the development of targeted therapies such as complement inhibition and anti-NETosis strategies. Full article

Background and Objectives: Idiopathic inflammatory myopathies (IIMs) are rare autoimmune diseases with extra-muscular manifestations. A firm association with malignancy, mainly observed in dermatomyositis (DM) is well established and several predictors of malignancy were previously published. However, given the low prevalence of IIMs, large population-based studies are scarce, hindering a comprehensive understanding of site-specific cancer patterns and risk factors. This study aimed to evaluate malignancy patterns and predictors, in a large, diverse cohort of patients with DM and PM. Materials and Methods: This retrospective cohort study used the Clalit Health Services electronic database, including 1557 DM patients and 528 PM patients diagnosed between 2002 and 2018, along with age-, sex-, and residence-matched controls at a 1:5 ratio. The incidence and risk of malignancies were assessed using Cox proportional hazards models, and predictors of solid and hematologic malignancies within the PM/DM cohort were analyzed using adjusted logistic regression. Results: In our cohort, DM was associated with an increased risk of both solid and hematologic malignancies (HR 1.89, 95%CI 1.47–2.41), whereas in PM the association was less pronounced and limited to solid malignancies (HR 1.50, 95%CI 1.06–2.11). In DM, higher risks were observed for breast cancer (HR 1.86) and chronic leukemia (HR 5.02). Across both subtypes, older age at diagnosis, the presence of specific autoantibodies were associated with increased malignancy risk. Significant markers included antiphospholipid antibodies (OR 2.28), lupus anticoagulant (OR 2.29), anti-Mi2 (OR 2.09), any of the antinuclear antibodies (OR 2.37), and individually anti-RNP/Sm (OR 1.70), anti-Ro/La (OR 1.79), anti-Scl-70 (OR 1.60), and anti-DNA (OR 1.97). Conclusions: Our study demonstrates an increased risk of malignancy in both DM and PM, with the relationship being stronger and broader in DM, involving both solid and hematologic cancers. Older age at diagnosis, and a distinct serological profile, particularly antiphospholipid antibodies and various antinuclear antibodies, identify patients at highest risk, warranting heightened clinical vigilance. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease frequently complicated by hematologic abnormalities, which may reflect disease activity or treatment effects. To characterize the clinical, laboratory, and immunological features of adult SLE patients referred to hematology during routine rheumatology follow-up. Methods: We retrospectively analyzed 84 adult SLE patients who fulfilled the 2012 SLICC or 2019 EULAR/ACR criteria and were referred to hematology during follow-up. Clinical, laboratory, and immunological data were collected. Associations between hematologic manifestations, organ involvement, autoantibodies, and complement levels were evaluated. Results: The cohort included 92.6% females with a median age of 46 (IQR 36–62). Hematologic abnormalities commonly appeared within three years of disease onset. Lymphadenopathy was more frequent in patients with cutaneous vasculitis and lupus nephritis (p = 0.046 and p = 0.045). Splenomegaly was associated with serositis, anti-β2 glycoprotein I IgG, and lupus anticoagulant (LA) positivity; anti-β2GPI IgG independently predicted splenomegaly (OR 26.02, p = 0.006). Low C4 was associated with increased autoimmune hemolytic anemia risk (OR 5.88, p = 0.009), while low C3 was linked to lupus nephritis (p = 0.017). Antiphospholipid antibodies were significantly associated with venous thrombosis, with anti-cardiolipin IgG as an independent predictor (OR 7.43, p = 0.007). Stroke history, anti-histone antibodies, and higher steroid doses were associated with mortality. Remission was linked to fewer comorbidities (p = 0.008). Conclusions: Hematologic complications in SLE arise early and carry prognostic significance, with splenomegaly associated with lupus anticoagulant and anti-β2GPI IgG, and mortality linked to anti-histone antibodies. Full article

Background and Objectives: Thrombocytopenia and hemolytic anemia are common but non-criteria manifestations of antiphospholipid syndrome (APS). However, their relationship with specific immunological profiles remains poorly characterized. This study aimed to evaluate these hematologic manifestations and identify their serological associations in patients with APS. Materials and Methods: We retrospectively reviewed 346 patients diagnosed with APS. Demographic, clinical, and laboratory characteristics were analyzed. Logistic regression was used to identify risk factors associated with hemolytic anemia. Results: The mean age was 47.1 ± 13.1 years, and 71.7% were female. Thrombocytopenia was present in 34.5%, and hemolytic anemia in 16.5% of patients. Lupus anticoagulant (LAC) was the most common antibody (66.8%). In univariate analysis, hemolytic anemia was significantly associated with LAC positivity (OR 4.216, 95% CI: 2.326–7.640, p < 0.001), anticardiolipin IgG (OR 7.170, p = 0.007), triple positivity (OR 3.638, p = 0.002), and diabetes mellitus (OR 2.084, p = 0.007). DIAPS showed a protective trend (OR 0.547, p = 0.002). In multivariate analysis, only LAC remained an independent risk factor for hemolytic anemia (adjusted OR 3.557, 95% CI: 1.355–9.335, p = 0.003). Conclusions: LAC positivity is an independent predictor of hemolytic anemia in APS. These findings suggest a distinct immunologic profile among patients with hematologic involvement and highlight the need for further investigation into non-criteria manifestations. Full article

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis and obstetric complications, driven by antiphospholipid antibodies (APLAs). This review synthesizes the latest advancements and current understanding, diagnosis, and treatment of APS. APLAs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2-GPI), interfere with coagulation and endothelial function, as well as with placental health. APS can be primary or secondary; it is often associated with systemic autoimmune diseases like lupus. The pathogenesis of APS remains only partially understood. APLAs promote thrombosis through endothelial damage, platelet activation, and inflammatory signaling pathways. Laboratory diagnosis relies on persistent positivity for APLAs and LAC through tests like ELISA and clotting assays, following a three-step confirmation process. New integrated test systems have been introduced to improve standardization. Classification criteria have evolved, with the 2023 EULAR-ACR criteria providing a weighted, domain-based scoring system, enhancing diagnostic precision. Catastrophic APS (CAPS) is a severe, rare manifestation of APS, characterized by multi-organ failure due to rapid, widespread microthrombosis and systemic inflammation, which requires urgent anticoagulation. Seronegative APS is proposed for patients with clinical features of APS but negative standard antibody tests, possibly due to non-criteria antibodies or transient immunosuppression. Treatment primarily involves long-term anticoagulation with vitamin K antagonists; direct oral anticoagulants are generally not recommended. APS diagnosis and management remain complex due to clinical heterogeneity and laboratory challenges. Continued refinement of diagnostic tools and criteria is essential for improving outcomes in this life-threatening condition. Full article

Assessment for the presence or absence of lupus anticoagulant (LA) represents a common investigation in hemostasis laboratories. In particular, LA represents one of the laboratory criteria for the diagnosis of definite antiphospholipid syndrome (APS). The other laboratory criteria are the solid phase assays (anticardiolipin (aCL) and anti-β2Glycoprotein I (aβ2GPI) antibodies of IgG and IgM isotypes). Current International Society on Thrombosis and Haemostasis (ISTH) guidance recommends testing LA by at least two tests based on different principles, with the activated partial thromboplastin time (aPTT) and dilute Russell viper venom time (dRVVT) being preferred. Additional assays may be used in addition, or instead of these assays in particular situations. For example, aPTT and dRVVT assays are very sensitive to the presence of various anticoagulants, and this may lead to false-positive identification of LA. This is particularly problematic in the age of the DOACs (direct oral anticoagulants), which are now the leading anticoagulants in use worldwide. We review recent literature on LA testing as well as our local practice to provide an update on this common test procedure. Our experience should be useful for laboratories struggling with LA interpretation for diagnosis or exclusion of APS. Full article

Protein C (PC) is the main anticoagulant protein of the hemostasis system. It can inhibit the blood clotting cascade before the formation of a thrombus, while its concentration can decrease significantly during strong activation of blood clotting. The PC concentration was found to decrease during systemic lupus erythematosus (SLE) (with a median of 75%) and depended heavily on the inflammation index. It was also associated with the accumulation of soluble fibrin monomeric (SFMCs) (with a median of 7 µg/mL). A low PC level was detected during severe ischemic heart disease (IHD) (with medians of 60 and 63%, respectively). These pathologies also were associated with clotting activation. During abdominal aortic aneurysm (AAA), the PC level in blood plasma before surgery was found to range from 40% to 119%. A decrease in the PC level in the blood plasma of patients with AAA before surgery, lower than 78%, was associated with high blood loss (more than 1.5 L). A decrease in the PC level can lead to an imbalance between coagulation and anticoagulation. Thus, during the treatment of complex pathologies associated with the activation of coagulation, specific attention should be paid not only to classic markers of thrombus formation but also to the state of the anticoagulant link. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease associated with an increased prevalence of cardiac and cerebrovascular events. Despite advancements in management, no validated tools exist that can predict the risk of ischemic stroke in SLE patients. However, several studies have demonstrated an association between a higher CHA₂DS₂-VASc score and an enhanced risk of ischemic stroke in autoimmune diseases without atrial fibrillation (AF) or atrial flutter (AFL). Recently, the European Society of Cardiology suggested the use of a revised score of CHA₂DS₂-VASc without taking sex into account (CHA₂DS₂-VA). Therefore, we sought to check if the new CHA₂DS₂-VA score might predict stroke or other cardiovascular events in SLE patients without AF/AFL. Patients and Methods: We retrospectively analyzed the records of patients with SLE treated at the University Hospital in Kraków, Poland, from 2012 to 2022. Patients with a history of AF/AFL were excluded. Results: This study enrolled 787 SLE patients without AF/AFL (aged 49 (38–60) years) with a predominance of women (n = 705, 89.58%). Common comorbidities included arterial hypertension (n = 376, 47.78%) and hypercholesterolemia (n = 345, 43.84%). Most non-AF/AFL SLE patients had 0–1 points in the CHA₂DS₂-VA score (n = 514, 65.31%). Overall, ischemic stroke occurred in 47 cases during a median follow-up of 8 (4–17) years regarding time from the SLE diagnosis to the stroke, with the incidence rising from 0% (n = 0/297) to 28% (n = 14/50) as the CHA₂DS₂-VA score increased from 0 to ≥5 points. No ischemic strokes or other thromboembolic events occurred among the 575 (73.06%) patients with a CHA₂DS₂-VA score of 0–2 points. In the whole cohort, patients with ≥3 points in the CHA₂DS₂-VA score (n = 212, 26.94%) were older at the last visit, had longer disease duration, were more commonly of the male sex, and were diagnosed more frequently with ischemic stroke or other thromboembolic events in their medical history (p < 0.05, for all) compared to those with 0–2 points (n = 575, 73.06%). However, in multivariable logistic regression, among the CHA₂DS₂-VA components, only older age (≥50 years) was related to the increased risk of thromboembolic complications (OR = 2.09, 95% CI: 1.36–3.22). Other determining factors included the presence of lupus anticoagulant (OR = 3.39, 95% CI: 2.20–5.27) and neurological SLE symptoms (OR = 2.19, 95% CI: 1.19–4.02). Interestingly, male sex (OR = 0.34, 95% CI: 0.22–0.52) and general SLE symptoms (OR = 0.43, 95% CI: 0.28–0.67) were associated with a decreased risk of thromboembolic events in this model (p = 0.034, for the model). Conclusions: SLE-related factors seem important for the onset of thromboembolic episodes. However, a higher CHA₂DS₂-VA score may also help to identify SLE patients with an increased risk of cardiovascular events, including stroke. Prospective studies with a long-term analysis need to be validated using the CHA₂DS₂-VA score to predict stroke risk in SLE patients. Full article

(1) Background: Antiphospholipid syndrome (APS) is associated with thrombotic events and the laboratory identification of antiphospholipid antibodies (aPL), in which lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2 glycoprotein I antibodies are included. The aim of the current retrospective study is to examine clinical characteristics and risk factors of ischemic stroke as a clinical manifestation of APS. (2) Methods: Adult patients diagnosed with APS between 1 January 2009 and 1 June 2024 were retrospectively enrolled in this study. Sydney-revised Sapporo criteria were used for the diagnosis of APS, while ischemic stroke was diagnosed based on the acute onset of focal neurologic deficits and confirmed with radiological findings. (3) Results: We studied 115 patients with APS. Specifically, 28 (24.35%) patients, with a mean age (standard deviation) of 54 (±12.5), had ischemic stroke as a clinical manifestation of APS. In univariate analysis, stroke development was associated with the following factors: age (p < 0.001), livedo reticularis (p = 0.046), avascular necrosis (AVN) (p = 0.046), hypertension (p < 0.001), dyslipidemia (p = 0.013), aCL IgG (U/L) antibodies title (p = 0.035), and adjusted global APS score (aGAPSS) (p = 0.047), while in multivariate analysis, it was associated with age (p = 0.006), hypertension (p < 0.001), AVN (p = 0.006), livedo reticularis (p = 0.035), aCL IgG title (p = 0.004), and aGAPSS (p = 0.002). (4) Conclusions: Stroke is a common initial manifestation of APS, with cardiovascular risk factors, particularly hypertension, being highly prevalent. Full article

Antiphospholipid syndrome (APS) can affect the kidneys, leading to renal artery and vein thrombosis, allograft loss following transplantation, and microvascular damage referred to as aPL-nephropathy (aPL-N). APL-N is a complex and frequently underdiagnosed condition characterized by an incomplete understanding of its etiopathogenesis and associated with unfavorable renal outcomes. The 2023 ACR/EULAR classification criteria for APS included aPL-N within the microvascular domain. The gold standard for aPL-N is the biopsy, revealing lesions associated with acute thrombotic microangiopathy and chronic vascular changes. Nevertheless, reluctance for biopsies due to anticoagulation and thrombocytopenia underscores the need for noninvasive diagnostics. Common clinical features include hypertension, microscopic hematuria, proteinuria, and renal insufficiency. Antiphospholipid antibodies seem crucial to kidney damage through thrombotic and inflammatory processes. Studies and experimental models of thrombotic microangiopathy lesions suggest the involvement of the complement cascade, tissue factor, and mammalian target of the rapamycin complex activation pathway. Currently, the management of aPL-N is based mainly on expert opinion, with limited evidence supporting the use of anticoagulants, leading to controversy in their application. Treatment may include heparin, intravenous immunoglobulin, plasma exchange, and targeted therapies tailored to aPL-N mechanisms. Future multicenter studies are essential to clarify their roles. The goal of this review is to inform clinicians and create a research agenda to address the unmet needs in diagnosing and managing APL-N. Full article

Lupus anticoagulant (LAC) is a heterogeneous mix of autoimmune antibodies that prolongs phospholipid-dependent clotting assays. Its diagnosis can be a real challenge in the hemostasis laboratory. In this review, the author describes the main pitfalls affecting the preanalytical phase and how to proceed to reduce interferences. Because of the heterogeneity of these autoantibodies, two assays with different mechanism of action should be performed to detect the majority of LACs. The dilute Russell’s viper venom test and the use of a reagent very sensitive to LAC derived from the activated partial thromboplastin time, using silica as the activator, are the most frequent techniques. The algorithms for LAC detection are reported here, and every laboratory is encouraged to introduce its own diagnostic procedure. Results should be expressed in ratio to reduce inter- and intravariability. In addition, the effect of anticoagulation in LAC assays and possible strategies for a correct diagnosis are provided. Full article