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The aim of this study was to evaluate the impact of methylene tetrahydrofolate reductase (MTHFR) rs1801133 (CâT667 transition) on age at first idiopathic portal vein thrombosis (PVT) and to identify clinical and/or laboratory variables influencing age at first PVT, including plasma homocysteine and the prothrombin rs1799963 PT (GâA transition at position 20210) (PT) mutation. A retrospective cross-sectional cohort, including 15 MTHFR TT, 32 MTHFR TC and 22 MTHFR CC idiopathic PVT participants contributing demographics, age at PVT, plasma concentrations of homocysteine and of natural anticoagulants. MTHFR TT carriers presented with a lower age at PVT than heterozygous or wild-type genotypes (31â±â8 vs. 48â±â15 vs. 52â±â13âyears, P â=â0.001) and were more likely to have a plasma HC concentration above the cut-off (73.3 vs. 32 vs. 50%, P â=â0.04). MTHFR TT and protein C predicted age at PVT ( P â<â0.0001 and P â=â0.06); MTHFR TT predicted plasma homocysteine ( P â=â0.05). In the MTHFR TT group, plasma homocysteine inversely related to protein C ( P â=â0.03). Plasma homocysteine predicted the extent of PVT ( P â=â0.03). Compound MTHFR TT + PT GA did not lower age at first PVT compared to MTHFR TT alone (35â±â9 vs. 30â±â8âyears). MTHFR TT is associated with a 20-year earlier PVT presentation than heterozygous and wild-type MTHFR genotypes. The inverse relation between plasma homocysteine and protein C contributes to the prematurity of PVT in the MTHFR TT group, whereas plasma homocysteine contributes to the extent of PVT. The recent exclusion of MTHFR genotyping from the thrombophilia screen needs revisiting in this setting.
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Metilenotetrahidrofolato Reductasa (NADPH2) , Vena Porta , Trombosis de la Vena , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Transversales , Genotipo , Homocisteína/sangre , Homocigoto , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Vena Porta/patología , Protrombina/genética , Estudios Retrospectivos , Trombosis de la Vena/genética , Trombosis de la Vena/sangre , Anciano de 80 o más AñosRESUMEN
PURPOSE: To assess age at 1st central retinal vein occlusion (CRVO) in carriers ≤ 45 years old of the methylenetetrahydrofolate reductase (MTHFR) C667T genotype compared to heterozygous and wild type, and to identify predictors of age at CRVO. METHODS: Retrospective cohort study consisting of 18 MTHFR TT, 23 MTHFR TC and 28 MTHFR CC participants; information regarding age, sex, age at CRVO, history of dyslipidaemia, hypertension, smoking and plasma HC measured by immunoassay were collected. RESULTS: Age at CRVO was lower in MTHFR TT than MTHFR TC and CC (32 ± 6 vs 38 ± 5 vs 37 ± 6 years, respectively, p = 0.005); plasma HC was higher in MTHFR TT than in the other genotypes [14.4 (10.8, 19.6) vs 10.4 ((8.6,12.5) vs 8.5 ((7.5,9.8) µmol/l, p = 0.0002). Smoking (cigarettes/day) independently predicted age at CRVO (p = 0.039) and plasma HC (p = 0.005); smoking status (yes/no) predicted ischemic CRVO (p = 0.01) that was more common in the MTHFR TT group (p = 0.006). CONCLUSIONS: Carriers of the MTHFR TT genotype ≤ 45 years old develop their 1st CRVO on average 5 years earlier than the MTHFR CC genotype; smoking contributes to the prematurity and severity of CRVO in MTHFR TT carriers.
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To evaluate the intima media thickness of carotid arteries (IMT) and its clinical, laboratory and treatment correlates in Behcet's disease (BD). Systematic search of EMBASE and PubMed databases from January 2016 to October 2022; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events. The meta-analysis included 36 case control studies: the IMT was greater in BD (n = 1103) than in controls (n = 832) (p < 0.0001) with wide heterogeneity (I2 = 86.9%); a sensitivity analysis that included mean age of BD participants, gender, disease duration and activity, atherogenic index of plasma, blood pressure, C-reactive protein, ethnicity, smoking status, anti-inflammatory and immune suppressive agents, revealed that male gender, mean age of participants and azathioprine use (the latter two in inverse fashion) partly explained the heterogeneity variance (p = 0.02, p = 0.005, and p = 0.01). The IMT was greater in vascular (n = 114) than in non-vascular BD (n = 214) (p = 0.006). BD patients (n = 782) had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1% vs. 2.97%, p < 0.0001). Subclinical carotid artery atherosclerosis represents a vascular feature of BD, independently of the traditional cardiovascular risk factors. The inverse correlations between IMT, age and azathioprine use suggest that thicker carotid arteries at disease onset eventually regress with immune suppressive treatment: this assumption needs verification on adequately designed clinical trials.
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Aterosclerosis , Síndrome de Behçet , Placa Aterosclerótica , Humanos , Masculino , Síndrome de Behçet/complicaciones , Síndrome de Behçet/tratamiento farmacológico , Grosor Intima-Media Carotídeo , Azatioprina/uso terapéutico , Factores de RiesgoRESUMEN
To investigate whether age at first presentation of pure peripheral arterial thrombosis (PAT) in lower and upper limbs and in the splanchnic circulation occurs earlier in carriers of the methylenetetrahydrofolate reductase (MTHFR) T677T genotype compared to the heterozygous and wild type and to identify predictors of a possible earlier onset. Retrospective cohort study on 27 MTHFR TT, 29 MTHFR TC and 29 MTHFR CC participants; data regarding age, sex, age at PAT, clinical history (dyslipidaemia, hypertension, smoking, obesity) and homocysteine (HC) measured by immunoassay were collected. Age at PAT was lower in MTHFR TT than MTHFR TC and CC (43 ± 9 vs 47 ± 9 vs 51 ± 4 years, respectively, p = 0.02); plasma HC was higher in MTHFR TT than in the other groups (25 ± 19 vs 12.7 ± 6.7 vs 11.3 ± 3.3 µmol/l, respectively, p < 0.001) while the activated partial thromboplastin ratio (aPTTr) was lower in MTHFR TT than in other genotypes (0.90 ± 0.10 vs 0.97 ± 0.12 vs 0.97 ± 0.08 µmol/L p < 0.001). Among categorical variables, MTHFR TT and dyslipidaemia independently predicted age at AT (p = 0.01 & p = 0.03, respectively) whereas among the continuous variables HC independently predicted age at PAT (p = 0.02) as well as the aPTTr (p = 0.001); smoking predicted lower limb PAT (p = 0.005). MTHFR TT carriers develop their first PAT an average of 4 and 8 years earlier than MTHF CT and CC genotypes; MTHFR TT, dyslipidaemia and plasma HC contribute to the prematurity of the PAT while the interplay between elevated HC and smoking may affect type of arterial district occlusion.
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Metilenotetrahidrofolato Reductasa (NADPH2) , Trombosis , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Estudios de Cohortes , Estudios Retrospectivos , Genotipo , Trombosis/genéticaRESUMEN
BACKGROUND AND AIM: Age at portal vein thrombosis (PVT) in liver cirrhosis (LC) carriers of the methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C â T667 transition) polymorphism has never been addressed; we compared age at PVT in LC patients genotyped for the MTHFR and explored the interrelated clinical and laboratory factors predicting age at PVT. APPROACH AND RESULTS: Retrospective cross-sectional cohort study. PVT participants: MTHFR CC n = 36, MTHFR CT n = 53, MTHFR TT n = 19; age, sex, age at PVT, Child-Pugh score, rs1799963 PT polymorphisms (G â A 20,210 transition), plasma HC and natural anticoagulants available for all participants. Age at PVT was lower in MTHFR TT than CT and CC (56 ± 13 vs. 57 ± 13 vs. 64 ± 9 years, p = 0.001); median (IQR) plasma HC was higher in MTHFR TT than in the other groups [(17 (9.4, 23.3) vs 13 (8,14.7) vs 11 (8.9, 12.7) µmol/l, p = 0.03)]. MTHFR TT, male gender and protein C predicted age at PVT (p = 0.02, p = 0.04 and p = 0.08); MTHFR TT and Child-Pugh score predicted plasma HC (p = 0.005 and p = 0.01) as well as low plasma protein C (p < 0.0001 and p = 0.0002). Plasma HC inversely related to protein C in the MTHFR TT group (p < 0.0001). Compound MTHFR TT with PT GA had lower age at PVT compared to MTHFR TT alone (49 ± 18 vs 58 ± 12 years). CONCLUSIONS: MTHFR TT anticipates PVT associated with LC by an average of 8 years; MTHFR TT associates with severity of liver disease and to high plasma HC; the latter may contribute to the prematurity of PVT by interfering with the anticoagulant activity of protein C.
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Metilenotetrahidrofolato Reductasa (NADPH2) , Trombosis de la Vena , Humanos , Masculino , Persona de Mediana Edad , Anciano , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Estudios Retrospectivos , Proteína C , Vena Porta/patología , Estudios Transversales , Cirrosis Hepática/complicaciones , Genotipo , Trombosis de la Vena/genética , Trombosis de la Vena/complicaciones , HomocisteínaRESUMEN
Thrombosis associated with thrombocytopaenia is an apparent paradox that is present across a wide spectrum of disorders. While thrombocytopaenia has been a controversial clinical classification criterion for APS, as initial reports failed to demonstrate a relation between low platelet count with other clinical or laboratory manifestations of the syndrome, recent data highlight the association between mild-moderate thrombocytopaenia and the risk of thrombosis. Although aPL antibodies may induce platelet activation in vitro, additional stimuli may contribute to their activation in vivo, among which are reactive oxygen and nitrogen species and lipid peroxidation products, which are elevated in patients with APS; an excess of the same stimuli may induce megakaryocyte and platelet apoptosis that leads to decreased platelet production and increased destruction, resulting ultimately in thrombocytopaenia. Herein we provide a novel plausible framework involving free radicals that could add to the understanding of the thrombocytopaenia-thrombosis paradox in APS.
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Síndrome Antifosfolípido , Leucopenia , Trombocitopenia , Trombosis , Humanos , Síndrome Antifosfolípido/complicaciones , Anticuerpos Antifosfolípidos , Radicales Libres , Trombocitopenia/complicacionesRESUMEN
We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle cell disease (SCD) and associated vaso-occlusive crisis (VOC) and ischemic stroke (IS). We identified in Embase and Medline 22 studies on plasma HC and 22 on MTHFR genotypes. Due to age-related HC differences, adult and paediatric SCD were separated: 879 adult SCD and 834 controls (CTR) yielded a neutral effect size; 427 paediatric SCD and 625 CTR favoured SCD (p = 0.001) with wide heterogeneity (I2 = 95.5%) and were sub-grouped by country: six studies (Dutch Antilles n = 1, USA n = 5) yielded a neutral effect size, four (India n = 1, Arab countries n = 3) favoured SCD (p < 0.0001). Moreover, 249 SCD in VOC and 419 out of VOC yielded a neutral effect size. The pooled prevalence of the MTHFR TT genotype in 267 SCD equalled that of 1199 CTR (4.26% vs. 2.86%, p = 0.45), and in 84 SCD with IS equalled that of 86 without IS (5.9% vs. 3.7%, p = 0.47); removal of one paediatric study yielded a significant effect size (p = 0.006). Plasma HC in paediatric SCD from Middle East and India was higher, possibly due to vitamin deficiencies. Despite its low prevalence in SCD, the MTHFR TT genotype relates to adult IS.
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Anemia de Células Falciformes , Homocisteína , Metilenotetrahidrofolato Reductasa (NADPH2) , Adulto , Niño , Humanos , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/genética , Genotipo , Homocisteína/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo GenéticoRESUMEN
To compare age at 1st ischaemic stroke (IS) in a cohort of juvenile (< 46 years of age) IS patients evaluated for the rs1801133 polymorphism (C â T677) of the methylene tetrahydrofolate reductase (MTHFR) gene; to identify predictors of age at IS and of type of cerebral vessel involvement, small vessel disease (SVD) vs large vessel disease (LVD) responsible for the IS; to evaluate possible associations between other clinical and laboratory variables. Retrospective cohort study on 82 MTHFR TT, 54 MTHFR TC and 34 MTHFR CC participants; data regarding age, sex, age at IS, history of dyslipidaemia, hypertension, smoking, migraine and homocysteine (HC) as well as neuroimaging were collected. Age at IS was lower in MTHFR TT than MTHFR TC and CC (35 ± 4 vs 38 ± 0 vs 40 ± 3 years, respectively, p = 0.002); plasma HC (median, interquartile range) was higher in MTHFR TT than in the other groups [16.7 (11.8, 28.6) vs 11.4 (8.2, 16.1) vs 9.8 (7.9, 1.3) respectively, p < 0.0001)] and was higher in SVD than LVD [17.4 (12.4, 32.5) vs 11.4 (8.8, 16.4) p < 0.0001]. MTHFR TT independently predicted age at IS (p = 0.0008) alongside smoking both as a categorical (p = 0.003) or continuous variable (p = 0.02), whereas HC independently predicted SVD as categorical (p = 0.01) and continuous variable (p < 0.0001). Smoking positively predicted plasma HC (p = 0.005) and negatively the activated partial thromboplastin ratio (aPTTr) (p = 0.02). Juvenile IS carriers of the MTHFR TT genotype develop their 1st occlusion on average 5 years earlier compared to the CC genotype; smoking contributes to this prematurity adversely affecting plasma HC and coagulation whereas plasma HC predicts IS secondary to SVD. Public health campaigns against smoking should highlight the prematurity of IS in the juvenile population.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Accidente Cerebrovascular , Isquemia Encefálica/complicaciones , Isquemia Encefálica/genética , Genotipo , Homocisteína/genética , Humanos , Accidente Cerebrovascular Isquémico/genética , Persona de Mediana Edad , Estudios Retrospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/genéticaRESUMEN
AIM: To evaluate the relevance of plasma homocysteine (HC) in Behcet's disease (BD) and its clinical manifestations. METHODS: Systematic review of EMBASE and PubMed databases according to PRISMA guidelines from inception to July 2021; random-effects meta-analyses for continuous outcomes. RESULTS: The search strategy retrieved 48 case-control (2,669 BD and 2,245 control participants) and 5 cohort studies (708 BD participants). Plasma HC was higher in BD than in controls (p < 0.0001) with wide heterogeneity (I2 = 89.7%) that remained unchanged after sensitivity analysis according to year of article publication, age of BD participants, study size, study quality, method of HC determination, and male/female ratio >1.5; some pooled ethnicities explained a small part of the heterogeneity (I2 = 16.3%). Active BD participants had higher HC than inactive ones (p < 0.0001), with moderate heterogeneity (I2 = 49.2%) that disappeared after removal of an outlier study with very high disease activity. BD participants with any vascular involvement had higher HC than those without (p < 0.0001) with wide heterogeneity (I2 = 89.7%); subgroup analysis on venous thrombosis only changed neither effect size (p < 0.0001) nor heterogeneity (I2 = 72.7%). BD participants with ocular involvement had higher HC than those without (p < 0.0001) with moderate heterogeneity (I2 = 40.3%). CONCLUSION: Although causality cannot be inferred, the consistency of the elevation of plasma HC in BD, particularly in patients with active disease, with vascular and ocular involvement suggests an intrinsic involvement of HC in these clinical manifestations.
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Síndrome de Behçet , Trombosis de la Vena , Síndrome de Behçet/diagnóstico , Estudios de Casos y Controles , Femenino , Homocisteína , Humanos , MasculinoRESUMEN
Alzheimer's disease is a neurodegenerative disorder whose pathological mechanisms, despite recent advances, are not fully understood. However, the deposition of beta amyloid -peptide and neuroinflammation, which is probably aggravated by dysbiotic microbiota, seem to play a key role. Anti-Gal are the most abundant xenoreactive natural antibodies. They are supposed to stem from immunization against the gut microbiota and have been implicated in the pathogenesis of several diseases, including multiple sclerosis. These antibodies target the alpha-Gal epitope, expressed on the terminal sugar units of glycoprotein or glycolipid of all mammals except apes, Old World monkeys and humans. The alpha-Gal is constitutively expressed in several bacteria constituting the brain microbiota, and alpha-Gal-like epitopes have been detected in gray matter, amyloid plaque, neurofibrillary tangles and corpora amylacea of the human brain, suggesting a potential link between anti-Gal and Alzheimer's disease etiopathogenesis. For the first time, our study searched for possible alterations of anti-Gal immunoglobulin levels in Alzheimer's disease patients. IgG and IgM blood levels were significantly lower, and IgA significantly higher in patients than in healthy subjects. These results suggest that such immunoglobulins might be implicated in Alzheimer's disease pathogenesis and open new scenarios in the research for new biomarkers and therapeutic strategies.
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The relationship between antiphospholipid antibodies (aPL) and sickle cell disease (SCD) has never been systematically addressed. Our aim was to evaluate potential links between SCD and aPL in all age groups. EMBASE/PubMed was screened from inception to May 2020 and Peto odds ratios for rare events were calculated. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) was higher in individuals with SCD than in controls (27.9% vs 8.7%, P < 0.0001), that of IgM aCL was similar in the two groups (2.9% vs 2.7%); only individuals with SCD were positive for lupus anticoagulant (LA) (7.7% vs 0%, P < 0.0001). The PP of leg ulcers was similar between aPL positive and negative individuals (44% vs 53%) and between patients in acute crisis and stable patients (5.6% vs 7.3%). Reporting of aPL as a binary outcome and not as a titer precluded further interpretation. The results indicate that a prospective case-control study with serial measurements of a panel of aPL in SCD patients might be warranted, in order to understand further the possible pathogenic role of aPL in SCD.
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Anemia de Células Falciformes/sangre , Anticuerpos Antifosfolípidos/metabolismo , Femenino , Humanos , MasculinoRESUMEN
INTRODUCTION/OBJECTIVE: The relationship between autoimmune haemolytic anaemia (AIHA) and antiphospholipid antibodies (aPL) has never been addressed via a meta-analysis in the paediatric age group. We evaluated the link between AIHA and aPL in childhood systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). METHODS: EMBASE and PubMed were screened from inception to May 2020 and Peto's odds ratio for rare events was employed for the between group comparisons. RESULTS: The meta-analysis included 11 articles for a total of 575 children: the pooled prevalence of AIHA was greater in (1) IgG aCL-positive than IgG aCL-negative children (39.7% vs 20.9%, p = 0.005); (2) in APS-positive than APS-negative SLE children (36.8% vs 13.2%, p = 0.01); and (3) in SLE-related APS than in primary APS children (53% vs 16.2%, p = 0.008). CONCLUSIONS: The pooled prevalence of AIHA is greatest in SLE with aPL/APS, low-moderate in SLE without aPL/APS, and lowest in primary APS. Key Points ⢠Antiphospholipid antibodies strongly relate to autoimmune haemolytic anaemia. ⢠Autoimmune haemolytic anaemia is more common in systemic lupus erythematosus with antiphospholipid antibodies.
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Anemia Hemolítica Autoinmune , Síndrome Antifosfolípido , Lupus Eritematoso Sistémico , Pediatría , Anemia Hemolítica Autoinmune/complicaciones , Anticuerpos Antifosfolípidos , Síndrome Antifosfolípido/complicaciones , Niño , Humanos , Lupus Eritematoso Sistémico/complicacionesRESUMEN
AIM: To evaluate the clinical relevance of antiphospholipid antibodies (aPL) in patients with lower extremity peripheral artery disease (PAD). DATA SOURCES: EMBASE and MEDLINE databases were searched from inception to March 2020 for clinical studies reporting on the association between of aPL [IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA)] and PAD. METHODS: We determined the pooled prevalence (PP) of patients positive for aPL in PAD or the PP of PAD in patients positive for aPL; we employed Peto's odds ratio with random effect for the meta-analysis. RESULTS: Twenty-one studies comprising 6,057 patients were evaluated: in patients with PAD, the PP of IgG aCL was 12% vs 4.1% in those without, IgM aCL was 13.2% vs 2.1%, and LA 13.3% vs 3.3%, respectively. The PP of patients with LA was greater in critical limb ischemia than in the control group (19.3% vs 4.2%). Also, the PP of patients with LA was greater in the failed than in the successful revascularisation group (35.8% vs 15.8%). The PP of post-procedural revascularisation failures was similar in the groups given or not given oral anticoagulation (59.2% vs 61.9%). CONCLUSION: All the aPL related to PAD regardless of diagnostic definition used, whereas LA related also to critical limb ischaemia and failed revascularisation. Data expressed as percentage of participants positive for aPL limit the interpretation of these relationships.
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Síndrome Antifosfolípido , Enfermedad Arterial Periférica , Anticuerpos Anticardiolipina , Anticuerpos Antifosfolípidos , Humanos , Extremidad Inferior , Inhibidor de Coagulación del LupusRESUMEN
INTRODUCTION: The relationship between autoimmune hemolytic anemia and antiphospholipid antibodies (aPL) and/or antiphospholipid syndrome has never been systematically addressed. METHODS: Systematic review of EMBASE and PubMed databases performed according to PRISMA guidelines from inception to March 2020; meta-analysis performed by Peto's odds ratio for rare events. FINDINGS: Forty-five studies with different outcomes met the inclusion/exclusion criteria. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) positivity was greater in end-stage renal disease (ESRD) than controls (20.2% vs. 2.6%, P = 0.001, I2 >80%; I2 = heterogeneity), particularly in hemodialysis patients (18.3% vs. 8%, I2 = 0%). The PP of lupus anticoagulant was greater in ESRD than controls (8.7% vs. 0.2%, P < 0.0001, I2 = 0%). The standardized mean difference of IgG aCL favored ESRD rather than controls (P < 0.0001, I2 =97%). The PP of fistula occlusion was greater in IgG aCL-positive patients than negative patients (39% vs. 27%, I2 =97%); the PP of IgG aCL positivity was greater in patients with fistula occlusion than without fistula occlusion (26.9% vs. 23.2%, P = 0.01, I2 =72%); the same applied to the PP of lupus anticoagulant positivity (23% vs. 0.3%, P < 0.0001, I2 = 0%). The standardized mean difference of IgG aCL favored fistula occlusion (P = 0.004, I2 = 91%). DISCUSSION: Lupus anticoagulant relates to ESRD regardless of management whereas IgG aCL relates specifically to ESRD on hemodialysis, but only lupus anticoagulant associates with fistula occlusion. The expression of aPL as patients positive for aPL rather than as titers precludes further assumptions on the relationship.
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Anticuerpos Antifosfolípidos/metabolismo , Fallo Renal Crónico/complicaciones , Diálisis Renal/métodos , HumanosRESUMEN
The relationship between antiphospholipid antibodies (aPL) and autoimmune haemolytic anaemia (AIHA) has never been systematically addressed. The aim of this study is to assess the link between aPL and AIHA in adult systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This study performed an EMBASE/PubMed search from inception to June 2019 and meta-analysis using Peto's odds ratios. The pooled prevalence (PP) of IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA) was greater in AIHA +ve than AIHA -ve patients (34.7% vs. 27.6%, p = 0.03; 33.3% vs. 21.8%, p < 0.0001; 20.9% vs. 8.3%, p = 0.01). The PP of AIHA was greater in: (1) IgG and IgM aCL +ve than -ve patients (21.8% vs. 11.1%, p = 0.001 and 18.7% vs. 6.3%, p < 0.0001), (2) in SLE related APS than in primary APS patients (22.8% vs. 3.9% p < 0.0001), (3) in APS +ve than APS -ve SLE patients (23.2% vs. 8.4%, p = 0.01), and (4) in thrombotic APS than non-thrombotic APS/SLE patients (26.8% vs. 10%, p = 0.03). The PP of IgG/IgM aCL and LA was greater in DAT +ve than DAT -ve patients (42.4% vs. 12.8%, p < 0.0001; 26.2% vs. 12.8%, p = 0.03 and 29.2% vs. 15.7%, p = 0.004 respectively). It was found that AIHA prevalence is maximal in SLE with aPL/APS, low-moderate in SLE without aPL and minimal in PAPS. Moreover, AIHA is rightly included among the classification criteria for SLE but not for APS/aPL. The significance of an isolated DAT positivity remains unclear in this setting.
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Anemia Hemolítica Autoinmune/inmunología , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/inmunología , Lupus Eritematoso Sistémico/inmunología , Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido/complicaciones , Prueba de Coombs , Humanos , Lupus Eritematoso Sistémico/complicaciones , Trombosis/inmunologíaRESUMEN
Prothrombin fragment F1 + 2 (F1 + 2) and thrombin-antithrombin (TAT) have been assessed in antiphospholipid syndrome (APS) but without evaluating a direct relationship with antiphospholipid (aPL) antibody titers. This article aims to investigate a direct relationship between aPL and F1 + 2 and perform a systematic review and meta-analysis of F1 + 2 and TAT in APS. Systematic search was performed using EMBASE and PubMed databases from January 1982 to December 2018 and random effects meta-analyses for continuous outcomes. This is a cross-sectional case-control study; immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin (aCL) anti-ß2-glycoprotein-I, antiprothrombin (aPT) antibodies, F1 + 2, and lupus anticoagulants (LA) were measured in 25 thrombotic primary APS (PAPS), 9 nonthrombotic carriers of aPL, and 18 controls. The significant effect size (ES) for F1 + 2 between aPL +ve and aPL -ve systemic lupus erythematosus (SLE) and between aPL +ve SLE and control displayed high heterogeneity. The significant ES for F1 + 2 between aPL -ve SLE and controls displayed no heterogeneity. The ES for TAT between aPL +ve and aPL -ve SLE patients and between aPL -ve SLE and controls was low, without heterogeneity. Mean F1 + 2 was greater in PAPS (p < 0.0001), inversely correlated with IgG aCL, IgM aPT, and LA (p = 0.001, 0.03, and 0.01, respectively), though only IgG aCL negatively predicted F1 + 2 (p = 0.01). IgG aCL inversely predicts F1 + 2. IgG aCL positivity introduces heterogeneity in the F1 + 2 ES, whereas the lack of heterogeneity in the ES for TAT may indicate poor TAT formation in aPL +ve group. Thus, F1 + 2 measurements may be unfounded as already demonstrated for TAT in the 1990s.
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Síndrome Antifosfolípido/inmunología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterised from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that through an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress through different agents with antioxidant properties have not translated into a sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far used to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future.
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Antioxidantes/farmacología , Estrés Nitrosativo , Estrés Oxidativo , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/metabolismo , Animales , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Humanos , NADPH Oxidasa 4/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/inmunologíaRESUMEN
Among the various mechanisms involved in aging, it was proposed long ago that a prominent role is played by oxidative stress. A major way by which the latter can provoke structural damage to biological macromolecules, such as DNA, lipids, and proteins, is by fueling the peroxidation of membrane lipids, leading to the production of several reactive aldehydes. Lipid peroxidation-derived aldehydes can not only modify biological macromolecules, by forming covalent electrophilic addition products with them, but also act as second messengers of oxidative stress, having relatively extended lifespans. Their effects might be further enhanced with aging, as their concentrations in cells and biological fluids increase with age. Since the involvement and the role of lipid peroxidation-derived aldehydes, particularly of 4-hydroxynonenal (HNE), in neurodegenerations, inflammation, and cancer, has been discussed in several excellent recent reviews, in the present one we focus on the involvement of reactive aldehydes in other age-related disorders: osteopenia, sarcopenia, immunosenescence and myelodysplastic syndromes. In these aging-related disorders, characterized by increases of oxidative stress, both HNE and malondialdehyde (MDA) play important pathogenic roles. These aldehydes, and HNE in particular, can form adducts with circulating or cellular proteins of critical functional importance, such as the proteins involved in apoptosis in muscle cells, thus leading to their functional decay and acceleration of their molecular turnover and functionality. We suggest that a major fraction of the toxic effects observed in age-related disorders could depend on the formation of aldehyde-protein adducts. New redox proteomic approaches, pinpointing the modifications of distinct cell proteins by the aldehydes generated in the course of oxidative stress, should be extended to these age-associated disorders, to pave the way to targeted therapeutic strategies, aiming to alleviate the burden of morbidity and mortality associated with these disturbances.