Intima media thickness of the carotid artery in primary antiphospholipid syndrome: A systematic review and meta-analysis.

BACKGROUND: Primary antiphospholipid syndrome (PAPS) has been associated with an increase in clinical events associated with atherosclerotic vascular disease. Intima media thickness (IMT) of carotid arteries is a surrogate marker of atherosclerotic vascular disease. OBJECTIVES: To conduct a systematic review and meta-analysis of studies evaluating IMT and their clinical correlates in PAPS. METHODS: Systematic search of EMBASE and PubMed databases from January 2000 to December 2023; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events. RESULTS: The meta-analysis included 21 studies (20 case control and 1 cohort) showing that PAPS patients (n = 1103) had thicker IM than controls (n = 832) (p < 0.0001) with wide heterogeneity (I2 = 86.9 %); PAPS patients (n = 782) also had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1 % vs 2.97 %, p < 0.0001). A sensitivity analysis by meta-regression indicated that mean age, gender, disease duration, lipid profile, blood pressures, smoking and statin use all explained the heterogeneity variance; a sensitivity analysis by subgroups confirmed smoking status and statin use as explanatory variables with the addition of ethnicity. CONCLUSION: Atherosclerosis of the carotid artery represents a clinical feature of PAPS in relation to the traditional risk factors and to statin use. Minimising the atherogenic risk with statins could reduce the late arterial atherothrombotic risks of PAPS.

Acquired factor V and factor X Deficiency coexisting with acquired dysfibrinogenaemia in a patient with light chain myeloma.

An elderly woman with light chain myeloma presented with prolonged epistaxis and extensive cutaneous haematomas: her kappa/lambda ratio was high at 395, her coagulation screen, thrombin and reptilase times were abnormal, her FV and FX were in the low range in the absence of specific inhibitors, her Clauss fibrinogen was low at 0.95 g/l but antigenic FNG was 1.58 g/l. The patient denied treatment and died of progressive renal failure. We wish to describe the unusual association of FX and FV deficiency co-existing with an acquired dysfibrinogenaemia.

Relevance of vein wall thickness in Behcet's disease: A systematic review and meta-analysis.

OBJECTIVES: To perform a meta-analysis on articles evaluating the common femoral vein wall thickness (VWT) in Behcet's disease and its possible clinical, laboratory and treatment correlates (BD). METHODS: Systematic search of EMBASE and PubMed databases from inception to October 2023; we employed random effect meta-analyses for continuous outcomes. RESULTS: The meta-analysis included 9 case-control and 1 cohort study: the VWT was greater in BD (n = 650) than in controls (n = 396) (p < 0.0001) with wide heterogeneity (I2 = 94.4%); a sensitivity analysis that included mean age of BD participants, gender, disease duration and activity, C-reactive protein, smoking status, immune-suppressive and anti-inflammatory medication, revealed that the heterogeneity variance was partly explained by age (p < 0.0001), male gender (p = 0.03), disease duration (p < 0.0001) and smoking (p = 0.06). The VWT was greater in BD with thrombotic/vascular (n = 189) than in non-thrombotic/vascular BD (n = 140) (p = 0.006) with no heterogeneity. CONCLUSION: VWT is greater in BD than controls: age, male gender, disease duration and smoking relate to VWT that was greater in BD patients with a history of thrombotic/vascular disease. Prospective studies are required to assess whether VWT may be considered a vascular marker of disease activity.

Subclinical atherosclerosis in Behcet's disease and its inverse relation to azathioprine use: an updated meta-analysis.

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.

Earlier onset of peripheral arterial thrombosis in homozygous MTHFR C677T carriers than in other MTHFR genotypes: a cohort study.

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.

Juvenile patients with the homozygous MTHFR C677T genotype develop ischemic stroke 5 years earlier than wild type.

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 → 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.

Homozygous methylentetrahydrofolate reductase C667T genotype anticipates age at venous thromboembolism by one decade.

The aim of the study was to compare age at first venous thromboembolism (VTE), plasma homocysteine and activated partial thromboplastin time ratio (aPTTr) amongst unprovoked VTE patients with the methylentetrahydrofolate reductase (MTHFR) C667T genotypes, and to identify predictors of age at first VTE, of plasma homocysteine and of the aPTTr; to evaluate whether heterozygous or homozygous prothrombin (PT) G20210A mutation lowered the age at first VTE when associated with MTHFR TT. Retrospective cohort study on 259 MTHFR TT, 76 MTHFR TC and 64 MTHFR CC participants with unprovoked VTE; each participant contributed age, sex, age at VTE, history of dyslipidaemia, hypertension, smoking, homocysteine (measured by enzyme immunoassay) and aPTTr (measured by standard coagulation assay). Age at first VTE was lower in MTHFR TT than MTHFR TC and CC (41 ±â€Š14 vs. 50 ±â€Š16 vs. 51 ±â€Š12 years, respectively, P < 0.0001); plasma homocysteine was higher in MTHFR TT than in the other groups (22 ±â€Š21 vs. 12 ±â€Š11.6 vs. 10 ±â€Š3.3 µmol/l, respectively, P = 0.0005) whilst aPTTr was not different. MTHFR TT independently predicted age at first VTE (P = 0.001), plasma homocysteine (P < 0.0001) alongside sex (P = 0.0007), age and smoking (P = 0.03 for both). Compound MTHFR TT with PT GA or AA had no lowering effect on age at first VTE compared with MTHFR TT alone (41 ±â€Š13 vs. 41 ±â€Š14 years). Plasma homocysteine inversely related to aPTTr in the MTHFR TT group (P = 0.003). MTHFR TT anticipates age at first VTE by an average of 10 years compared with MTHFR TC and CC genotypes.

Predictive Value of Oxidized Low-Density Lipoprotein/ß2-Glycoprotein-I Complexes (oxLDL/ß2GPI) in Nonautoimmune Atherothrombosis.

INTRODUCTION: Lipid oxidation is a definite feature of atherosclerosis, and oxidized low-density lipoprotein (oxLDL) is not only highly immunogenic but toxic to several cell types. Beta-2-glycoprotein-I (ß2GPI) dampens oxLDL toxicity by forming binary oxLDL/ß2GPI complexes. We evaluated whether circulating oxLDL/ß2GPI complexes are associated to atherosclerosis-related events (ARE) and to venous thromboembolism (VTE). METHODS: In a cross-sectional case-control study, cases were (a) 57 consecutive patients (male/female [M/F] 33/24, mean age 57 [10] years) attending a thrombosis unit for ARE (myocardial infarction [MI] n = 20, peripheral vascular disease n = 7, and ischemic strokes n = 30); (b) 52 consecutive patients (M/F 22/30, mean age 55 [17] years) attending the same unit for unprovoked (VTE); (c) normal controls comprised 90 participants (M/F 35/55, mean age 41 [15] years); and (d) oxLDL/ß2GPI complexes were measured by immunoassay and resulting levels divided into quartiles. RESULTS: The odds ratio (OR) of ARE was greater in the fourth and second quartiles than in the first quartile (8.5 and 6.0, respectively); the OR of developing MI was greatest in the fourth quartile (17.8). By multivariable analysis with age, sex, smoking, lipid status, statin, and ARE phenotypes as independent variables and oxLDL/ß2GPI as the dependent variable, only MI predicted oxLDL/ß2GPI ( P < .0001). CONCLUSIONS: OxLDL/ß2GPI may be regarded as a marker of ARE, in particular of MI.

DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity.

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity.

Autoimmune haemolytic anaemia emerging during Campath treatment in a patient with CD5 negative chronic lymphocytic leukaemia.

Campath is being employed for the treatment of autoimmune haemolytic anemia (AIHA) whether or not associated to B cell chronic lymphoid leukaemia (CLL). CD5 negative CLL is relatively uncommon and runs an indolent course. We report a CD5 negative CLL patient who developed AIHA associated with cytomegalovirus infection reactivation whilst on treatment with Campath for progressive disease.

Improvement of chronic osteomyelitis after granulocyte colony stimulating factor.

BACKGROUND: chronic osteomyelitis represents a persistent bone and bone marrow infection easy to diagnose in the presence of pain, erythema, swelling, and a draining sinus but more difficult to detect in the absence of the preceding features and with a painful orthopaedic prosthesis. CASE DESCRIPTION: we report upon an elderly gentleman with myelodysplasia requiring revision surgery for a fractured prosthetic left knee. He had clinical, laboratory, and radiological features of chronic osteomyelitis that improved only with administration of granulocyte colony stimulating factor (G-CSF). LITERATURE REVIEW: G-CSF has been successfully employed to treat resistant osteomyelitis in three young patients with primary defects of monocyte and neutrophil killing. A randomized trial confirmed the efficacy of G-CSF in the treatment of chronic osteomyelitis in twenty patients with diabetic foot ulcers and a rat model confirmed the efficacy of G-CSF in acute osteomyelitis. CLINICAL RELEVANCE: our case highlights the usefulness of G-CSF treatment for immune suppressed patients with resistant chronic osteomyelitis.

ß2-glycoprotein I and oxidative inflammation in early atherogenesis: a progression from innate to adaptive immunity?

The innate immune system represents the first line of host defense against a wide variety of pathogens and endogenous danger signals. It relies on trans-membrane signaling and cytoplasmic receptors (danger sensors) to trigger early inflammatory responses. As with the adaptive immunity, an innate immune response can cause tissue injury, chronic inflammation and disease. Nucleotide-binding leucine-rich proteins (NLRs) are a family of cytoplasmic receptors for endogenous danger signals. Inflammasomes are multi-molecular complexes of pyrin-containing NLRs (NLRPs) that regulate pro-inflammatory caspases and interleukin 1 cytokines in response to various stimuli. Cholesterol crystals and oxidation-specific epitopes (oxLDL, ROS) are some of the endogenous signals capable of activating NLRP inflammasomes. Thus, an inflammasome-induced IL-1ß dysregulation may represent an early atherogenic mechanism that initiates atherosclerosis. The plasma protein, ß2-glycoprotein I (ß2GPI), complexed to anionic phospholipids is the main antigenic target for antiphospholipid antibodies. In addition to anticoagulant properties, circulating ß2GPI has more pleiotropic functions affecting fibrinolysis, angiogenesis, apoptosis and atherogenesis. OxLDL interacts with ß2GPI to form oxLDL/ß2GPI pro-atherogenic complexes in both autoimmune-mediated and non-autoimmune atherothrombotic diseases. Due to its interaction with oxLDL, the contribution and implication of ß2GPI in early atherogenesis via the innate (inflammasome/IL-1) system are hypothesized.

Eosinophilia and thrombosis in parasitic diseases: an overview.

It is known that peripheral blood eosinophilia (PBE) is a normal hematopoietic response to several parasitic diseases, but it is less known that PBE promotes a hypercoagulable state that may favor thrombosis. Scope of this article is to explore which parasitic infestations are most likely to be complicated by thrombosis and to highlight the pathogenetic contribution of PBE to vascular occlusions in this setting. A review of the world literature revealed 18 cases in which PBE was associated with vascular occlusion though no specific surveys were dedicated to this topic. The eosinophil exerts its thrombogenic potential by inhibition of the natural anticoagulant pathways and release of tissue factor with enhanced coagulation activation leading to vascular occlusion. It is hoped that this review contributes to the awareness of the link between PBE and thrombosis in parasitic disorders to foster research in this area.

Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome.

OBJECTIVE: To assess the role of nitrite (NO(2)(-)), nitrate (NO(3)(-)), and nitrative stress in thrombotic primary antiphospholipid syndrome (PAPS). METHODS: We investigated 46 patients with PAPS: 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE), and 29 healthy controls (CTR). IgG anticardiolipin (aCL), IgG anti-beta(2)-glycoprotein I (anti-ß(2)-GPI), IgG anti-high density lipoprotein (aHDL), IgG anti-apolipoprotein A-I (aApoA-I), crude nitrotyrosine (NT) (an indicator of nitrative stress), and high sensitivity C-reactive protein (CRP) were measured by immunoassays. Plasma nitrite (NO(2)(-)), nitrate (NO(3)(-)), and total antioxidant capacity (TAC) were measured by colorimetric spectroscopic assays. RESULTS: Average plasma NO(2)(-) was lower in PAPS, PCaPL, and IT (p < 0.0001); average NO(3)(-) was highest in SLE (p < 0.0001), whereas average NT was higher in PAPS and SLE (p = 0.01). In thrombotic PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO(2)(-) (p = 0.03 and p = 0.001, respectively), whereas arterial occlusions and smoking positively predicted NO(3)(-) (p = 0.05 and p = 0.005), and CRP positively predicted NT (p = 0.004). In the PCaPL group IgG aCL negatively predicted NO(3)(-) (p = 0.03). In the SLE group IgG aCL negatively predicted NO(2)(-) (p = 0.03) and NO(3)(-) (p = 0.02). CONCLUSION: PAPS is characterized by decreased NO(2)(-) in relation to type and number of vascular occlusions and to aPL titers. Nitrative stress and low grade inflammation are linked phenomena in PAPS and may have implications for thrombosis and atherosclerosis.

Eosinophilia and thrombophilia in churg strauss syndrome: a clinical and pathogenetic overview.

During the past decade, there has been an increased description of Churg Strauss syndrome (CSS) characterized by vascular occlusions possibly linked to the thrombogenic potential of the eosinophil that is poorly appreciated. The purpose of this overview is 3-fold: the first to evaluate the available prevalence of thrombosis in Churg Strauss series, the second to demonstrate that any vascular district may be affected, and the third to describe the pathogenesis of thrombosis in CSS. A Pubmed, EMBASE, and Google search of CSS series from 1951 to date revealed a prevalence of arterial occlusion ranging between 3.1% and 18.7% and a prevalence of venous occlusion between 5.8% and 30%, whereas a specific survey for venous thromboembolism in CSS yielded a prevalence of 8.1%. Eosinophils store and release tissue factor as well as other cationic proteins: the former initiates coagulation while the latter inhibits natural anticoagulant activity and activate platelets eventually culminating in excessive thrombin generation and clot formation. In addition, antineutrophil cytoplasmic antibodies may shift the endothelial lining to proadhesive and prothrombotic surface. It is hoped that the review will represent a basis to foster novel research on this topic.

Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.

OBJECTIVES AND METHODS: Splanchnic vein thrombosis (SVT), not associated with cancer or liver cirrhosis, is a rare event and scanty data are available on its natural history, long-term prognosis, and treatment. In this study 121 SVT patients consecutively seen from January 1998 to December 2005 were included and 95 of them were followed up for a median time of 41 months. Screening for thrombophilic factors was performed in 104 patients. New thrombotic or bleeding episodes were registered and anticoagulant therapy was performed according to preestablished criteria. RESULTS: SVT was an incidental finding in 34 (28.1%) patients; 34 (28.1%) presented with abdominal infarction; 39 (32.2%) had bowel ischemia or acute portal vein thrombosis; 14 (11.6%) had bleeding from portal hypertensive sources. Survival rates at 1, 3, and 7 yr were 95%, 93.3%, and 89.6%, respectively; 87.5% of deaths occurred at onset of SVT as complications of intestinal infarction. Patients with isolated portal vein thromboses had symptoms and intestinal infarction in 16/41 (39%) and 0/41 (0%) of the cases, respectively, whereas superior mesenteric vein thromboses, isolated or not, were associated with symptoms and intestinal infarction in 69/75 (92%) and 34/75 (45%), respectively. During the follow-up 14 (14.7%) suffered from 39 episodes of gastrointestinal bleeding with no deaths. A previous gastrointestinal bleed was associated with new hemorrhagic events during follow-up. New venous thrombotic episodes occurred in 10 of 95 patients (10.5%), of which 73% were in the splanchnic area. Seven out of these 10 patients had a chronic myeloproliferative disease (MPD) and none was on anticoagulation. CONCLUSIONS: Anticoagulant therapy was effective to obtain recanalization of acute SVT in 45.4% of patients and preserved patients from recurrent thrombosis when given lifelong.