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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.

Patients with primary antiphospholipid syndrome (PAPS) may suffer from venous and/or arterial thrombosis, but studies addressing eventual clinical and laboratory features that may discriminate between arterial thromboembolism (ATE) from venous thromboembolism (VTE) have been poorly addressed.Cross sectional comparison of baseline characteristics of 100 patients enrolled in the multi center ATHERO-APS cohort study; patients with previous ATE and VTE were compared with regards to clinical and biochemical variables as well as to echocardiographic features and ankle-brachial index (ABI) measured at enrolment.Mean age of patients was 51 years, 72 were women. 60 patients suffered VTE and 40 ATE. Compared to VTE, ATE patients displayed a higher prevalence of hypertension (43.3% vs. 65%, p = 0.034) and diabetes (3.3% vs. 17.5%, p = 0.015). Mean concentration of inflammation and complement activation markers were similar between the two groups as well as autoantibodies titres; mean D-dimer concentration was greater in VTE patients (184 ng/ml vs. 347 ng/ml; p = 0.024) whereas mean platelet count was greater in ATE patients (263 × 10Clinical, laboratory and cardiovascular variables distinguish arterial from venous APS patients, amongst which the ABI and left atrial enlargement. Implications for these two distinct clinical phenotypes of APS patients need further investigation.

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 ± 14 vs. 50 ± 16 vs. 51 ± 12 years, respectively, P

The dual positivity (DP) and triple positivity (TP) concepts bypass the poor comparability of immune/clotting assay for the laboratory classification of antiphospholipid syndrome (APS). To evaluate intensity of immune/clotting assays and DP/TP through different clinical severity groups (CSG) as follows: (1) non-thrombotic asymptomatic carriers of aPL (N-THR), thrombotic primary APS (THR), deceased (D) for recurrent and fatal thrombosis. Activated partial thromboplastin time ratio (aPTTr), dilute Russell viper venom time ratio (DRVVTr), IgG/IgM anticardiolipin (aCL) and anti β-2-glycoprotein-I (aβ2GPI). Participants: 33 N-THR, 64 THR and 11 D. The frequency of DP and TP (DRVVTr or aPTTr partnered with respective IgG aCL or aβ2GPI) increased across CSG (p = 0.006 and p = 0.003); mean DRVVTr and IgG aCL/aβ2GPI were always greater in TP versus non-TP within each CSG and progressively increased across the CSG. The intensity of individual lupus anticoagulants partnered with their corresponding IgG aPL related to the frequency of multiple positivity throughout CSG suggesting that of intensity of immune/clotting assays and multiple positivity are the different faces of the same diagnostic coin in our thrombotic PAPS cohort.

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

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 (β2GPI) dampens oxLDL toxicity by forming binary oxLDL/β2GPI complexes. We evaluated whether circulating oxLDL/β2GPI 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/β2GPI 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/β2GPI as the dependent variable, only MI predicted oxLDL/β2GPI ( P < .0001). Conclusions: OxLDL/β2GPI may be regarded as a marker of ARE, in particular of MI.

Objective The aim of this study was to examine the concurrent effects of vital exhaustion and depression on the development of cardiovascular disease (CVD) morbidity. Method The sample of this representative, 4-year longitudinal study comprised 2,725 participants (43.56% male, Mage = 58.39 years, SDage = 14.39 years). Individuals being treated for hypertension (n = 277) and cardio- and/or cerebrovascular incidents (n = 131) for the first time during the follow-up period were compared with participants never treated for CVD (n = 2,317). Joint principal component analysis was conducted on the items of the vital exhaustion (shortened Maastricht Questionnaire) and depression (shortened Beck Depression Inventory) measures simultaneously resulting in 3 components representing depression, vital exhaustion, and sleep difficulties. The role of these 3 components in predicting the incidence of CVD morbidity was examined using logistic regression-controlling for traditional risk factors such as sex, age, education, body mass index, smoking, alcohol use, and physical inactivity. Results In the multivariate analyses, vital exhaustion (OR = 1.20, CI = 1.03-1.39, p = .021) and sleep-related problem (OR = 1.16, CI = 1.00-1.33, p = .044) scores proved to be independent predictors of treatment initiation for hypertension, while sleep-related difficulties predicted CVD event incidence (OR = 1.27, CI = 1.06-1.52, p = .009). However, depressive symptomatology factor scores were not associated with either cardiovascular outcome in the regression analyses. Conclusions Vital exhaustion and depressive symptomatology showed a different pattern in their relationship with CVD incidence, with vital exhaustion being the more robust predictor. These results suggest that the 2 constructs are not identical and that vital exhaustion deserves consideration when planning and implementing interventions to reduce CVD risk. (PsycINFO Database Record

Anticardiolipin antibodies of the immunoglobulin G isotype (IgG aCL) have been suggested as risk factor for arterial and venous thrombosis. No conclusive data in patients with coronary artery disease (CAD) do exist. We investigate the risk of recurrent CAD according to the presence of IgG aCL.We performed a systematic review and meta-analysis to evaluate the risk of recurrent major adverse cardiac events (MACE) associated with the presence of IgG aCL in patients with CAD. MEDLINE and Cochrane databases were searched. We conducted a meta-analysis of the relative risk (RR) both at 12 and 24 months.We included 11 eligible studies with a total of 2425 patients, 283 IgG aCL+ and 2142 IgG aCL-. The prevalence of IgG aCL+ ranged from 6.1% to 43.3%. A total of 341 cardiac events were reported: 71 (25.1%) in IgG aCL+ and 270 (12.6%) in IgG aCL- patients. We found an increased risk of recurrent MACE in patients with high IgG aCL both at 12 (RR 2.17, 2.5-97.5%CI, 1.54-3.00) and 24 months (RR 2.11, 2.5-97.5%CI, 1.62-2.66). This association was even stronger in patients with juvenile CAD (i.e.50 years) at both 12 (RR 3.21, 2.5-97.5%CI, 1.74-5.41) and 24 months (RR 3.24, 2.5-97.5%CI, 1.84-5.21).Patients with CAD and elevated IgG aCL have a doubled risk of recurrent MACE at 12 and 24 months. The presence of aCL should be suspected in patients with recurrent CAD events or in patients with juvenile CAD.

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-β2-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

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.

SummaryThe vascular mortality of antiphospholipid syndrome (APS) ranges from 1.4 % to 5.5 %, but its predictors are poorly known. It was the study objective to evaluate the impact of baseline lupus anticoagulant assays, IgG anticardiolipin (aCL), plasma fibrinogen (FNG) and von Willebrand factor (VWF), platelets (PLT) and of genetic polymorphisms of methylenetetrahydrofolate reductase C677T, of prothrombin G20210A and of paraoxonase-1 Q192R on survival in primary APS (PAPS). Cohort study on 77 thrombotic PAPS and 33 asymptomatic carriers of aPL (PCaPL) seen from 1989 to 2015 and persistently positive for aPL as per annual review. At baseline all participants were tested twice for the ratios of kaolin clotting time (KCTr), activated partial thromboplastin time (aPTTr), dilute Russell viper venom time (DRVVTr), IgG aCL, FNG, VWF and once for PLT. All thrombotic PAPS were on warfarin with regular INR monitoring. During follow-up 11 PAPS deceased (D-PAPS) of recurrent thrombosis mostly arterial, despite adequate anticoagulation yielding an overall vascular mortality of 10 %. D-PAPS had the strongest baseline aPTTr and DRVVTr and the highest mean baseline IgG aCL, FNG, VWF and PLT. Cox proportional hazards model identified baseline DRVVTr and FNG as main predictors of mortality with adjusted hazard ratios of 5.75 (95 % confidence interval [CI]: 1.5, 22.4) and of 1.03 (95 %CI: 1.01, 1.04), respectively. In conclusion, plasma DRVVTr and FNG are strongly associated with the risk of vascular death in PAPS; while FNG lowering agents exist further research should be directed at therapeutic strategies able to dampen aPL production.

What you need to know A 55 year old woman with severe aortic stenosis underwent valve replacement with a mechanical valve. She has been started on warfarin and is maintaining an international normalised ratio (INR) within the target range of 2.0-3.0. She finds monitoring INR levels cumbersome. She has heard about newer direct oral anticoagulants and asks if she can switch to one of these. Valve replacement or repair is the definitive treatment in those with severe valvular heart disease. The choice of valve depends on valve durability, the need for antithrombotic therapy, and patient preferences.12 Mechanical heart valves are preferred in patients under 65.3 Bioprosthetic valves do not require lifelong anticoagulation but have a greater rate of primary failure and are associated with a higher reoperation rate. They last only 10 to 15 years compared with 20 to 30 years for mechanical heart valves.3 Warfarin is an anticoagulant prescribed to patients with mechanical heart valves. Patients with mechanical heart valves have a risk of thrombosis on the valve and subsequent embolism. Blood flows at high shear stress around the valve, which activates platelets and local coagulation. Latest European, US, and National Institute of Health and Care Excellence (NICE) guidelines recommend lifelong treatment with warfarin to prevent this.1245 Warfarin is a vitamin K antagonist. Other drugs in this group are acenocoumarol and dicoumarol. Warfarin inhibits the synthesis of the vitamin K dependent …

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

To evaluate the effect of antiphospholipid antibodies (aPL) on renal allograft outcome after kidney transplantation.A systematic search of EMBASE and PubMed databases from inception to July 2018 was run according to PRISMA guidelines; Peto's odds ratio (OR) for rare events was used for the meta-analysis.Our inclusion/exclusion criteria were met by 22 cohort studies having different outcomes: allograft thrombosis (n = 9) and thromboprophylaxis (n = 3), allograft loss from any cause (n = 9), allograft malfunction (n = 3), duration (n = 2), glomerular filtration rate at 1 year (n = 3) and allograft rejection (n = 5). The pooled prevalence of allograft thrombosis and of thrombotic microangiopathy was greater in aPL+ve than negative recipients (10.4% vs 1.7%, p 0.0001 and 10.2% vs 0%, p = 0.005, respectively). The pooled prevalence of allograft thrombosis was 75% in patients not taking anticoagulation whereas none of the anticoagulated recipients developed thrombosis (p 0.0001). The pooled prevalence of allograft loss was greater in aPL+ve recipients (28% vs 18% respectively, p 0.0001); the pooled prevalence of aPL was greater in allograft loss recipients compared to those who did not lose it (51% vs 33%, p 0.0001). The pooled prevalence of allograft malfunction and rejection was similar in aPL-ve and aPL+ve recipients (32.2% vs 40.3% and 14.9% vs 14.4%, respectively) but graft duration was shorter in aPL+ve than aPL-ve recipients (p = 0.001) and glomerular filtration rate at 1 year was lower in aPL + ve than aPL-ve recipients (p 0.0001).APL relate strongly to allograft thrombosis, loss and duration but not to allograft malfunction and rejection. Oral antivitamin K anticoagulants effectively prevent allograft thrombosis in aPL recipients. The debate on the role of aPL in renal transplant is limited by the expression of data as percentage of recipients positive for aPL rather than aPL titres in many studies.

Quantitative and qualitative defects of high-density lipoprotein (HDL) are important in atherogenesis. In this study, we investigated whether antibodies against HDL components had additional value to conventional cardiovascular risk factors for the diagnosis of ischaemic stroke (IS) and coronary artery disease (CAD). Cross-sectional study was conducted on 53 patients with IS, 51 with CAD and 55 healthy controls, and in vitro studies to validate findings of the clinical study. We determined serum immunoglobulin G (IgG) antibodies against HDL (aHDL), apolipoproteins (aApoA-I, aApoA-II and aApoC-I) and paraoxonase-1 (aPON1) as well as PON1 activity (PON1a), total antioxidant capacity and biomarkers of endothelial activation (serum nitric oxide metabolites, 3-nitrotyrosine, VCAM-1 and ICAM-1); in vitro assays tested the capacity of IgG aHDL purified from high titer patients to inhibit PON1a and to reverse protective effect of HDL on endothelial cells. IgG aHDL, aApoA-I and aPON1 were higher in IS and CAD than controls (p

To further the knowledge of oxidative stress in systemic sclerosis (SSc), we performed a systematic review and meta-analysis on studies measuring isoprostane, a vasoactive agent deriving from arachidonic acid and implicated in the vasculopathy of SSc.Systematic search following the PRISMA guidelines in PubMed and EMBASE between January-1990/December-2017 using the terms: oxidative stress, isoprostane, systemic sclerosis and scleroderma.After the screening process, 8 studies including 240 SSc patients and 192 controls were included in the systematic review and meta-analysis, 6 investigating urinary and 2 serum isoprostane: random effect meta-analysis revealed isoprostane overgeneration in SSc (p .001) with wide heterogeneity (IThere is some evidence for isoprostane overgeneration in SSc that confirms the occurrence of oxidative stress in this setting: further prospective studies with specified outcomes are needed to evaluate the prognostic value of this functional biomarker.

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. info:eu-repo/semantics/publishedVersion

To investigate possible abnormalities of vasoactive compounds, nitrative stress, and antioxidant activity of paraoxonase (PONa) in human hepatopulmonary syndrome (HPS), we determined endothelin-1 (ET), nitric oxide (NOx) metabolites, PONa alongside crude plasma nitrotyrosine (NT) as surrogate marker of nitrative stress.Liver cirrhosis (LC) patients with HPS (n = 12) were matched by age, sex, and Child-Pugh score to LC patients without HPS (n = 15) and to healthy controls (CTR) (n = 15); plasma NO2(-) (nitrite) (vascular metabolite), NO3(-) (nitrate) (inflammatory metabolite), and PONa were determined by a colorimetric assay, ET, and NT by immunoassays.HPS patients showed higher level of ET (p = 0.0002), NO2(-) (p = 0.002), NO3(-) (p = 0.0001), NT (p0.0001), and lower PONa (p = 0.0004) than CTR; post-hoc analysis revealed greater ET (p0.05) and NO3(-) (p0.005) in LC patients with HPS than in LC patients without HPS. NT correlated to Child-Pugh score within HPS (p = 0.04) and LC (p = 0.02).Our HPS patients are characterized by elevated plasma levels of ET and NOx metabolites and lower PONa. Reduced PONa alongside elevated NO3(-) and NT suggests that defective antioxidation may favor nitrative stress and both may be implicated in the pathogenesis of HPS.

The objective of the study is to perform a cost comparison of 1 year of oral anticoagulation management with warfarin vs. hypothetical rivaroxaban (RRX) in thrombotic primary antiphospholipid syndrome. Longitudinal study on 20 primary antiphospholipid syndrome patients followed-up for 1 year after anticoagulation stabilisation with warfarin: a dedicated software calculated number of clinic visits, time in therapeutic range and warfarin consumption for each patient; for RRX, we considered a visit every 3 months (baseline done in hospital before attending anticoagulant clinic); knowing the cost of both anticoagulants, the laboratory cost and the human cost we calculated and compared the yearly expenditure. Average time in therapeutic international normalized ratio range was 69 ± 11%: warfarin management required a total of 375 of visits compared with the 60 for RRX; the yearly cost of RRX was superior to that of warfarin (12 012 vs. 446.4 euros, P < 0.0001), and in spite of lower laboratory (738 vs. 1853 euros, P < 0.0001) and human costs (774.6 vs. 4841 euros), RRX thromboprophylaxis still yielded a hefty bill (13 525 vs. 7140 euros, P < 0.0001). Switching from warfarin to RRX will be 48% more expensive to our Healthcare Authority; unless ongoing clinical trials demonstrate improved long-term outcomes for RRX over warfarin, we feel that a 69% time in therapeutic range does not warrant a change to RRX at a 48% increased cost.

Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS: Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS: The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 μg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS: The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk. info:eu-repo/semantics/publishedVersion

Background The relationship between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) is unclear. Objectives To evaluate a link between aPL and MS. Methods EMBASE and PubMed search to August 2016; Peto's odds ratio (OR) meta-analysis. Results The pooled prevalence of participants positive for IgG and IgM anticardiolipin (aCL) from 12 case–control studies was superior in MS than controls (6.8% vs 1.8%, p = 0.01 and 8.58% vs 2.18%, p = 0.001) with medium and high heterogeneities respectively ( I 2 = 48.55% and 68.13%). The pooled prevalence of participants positive for IgG anti-beta 2 glycoprotein-I (aβ 2 GPI) from seven case–control studies was lower in MS than controls (0.93% vs 4.02%) with high heterogeneity ( I 2 = 53.92%) though the pooled prevalence of participants positive for IgM aβ 2 GPI was similar (7.24% vs 6.13%) with high heterogeneity ( I 2 = 52.85%). Five cohorts compared IgG/IgM aCL and IgM aβ 2 GPI in stable/remission vs active/relapsing MS: the pooled prevalence of IgG aCL was similar in active/relapsing and stable/remission MS (19% vs 18.9%) but the pooled prevalence of IgM aCL was higher in active than in stable MS (36.9% vs 21%, p 2 GPI (40.5% vs 3.2%, p Conclusion Data from case–control studies do not support a link between IgG/IgM aPL and MS. Data from cohort studies comparing active vs stable MS indicate a strong link between aPL of IgM isotype and active/relapsing MS but in the absence of aPL titres to comment upon this may either represent an epiphenomenon of active neuro-inflammation or natural autoantibodies devoid of pathogenic potential. Data expressed as frequency of aPL positive participants rather than average titres preclude further assumptions.

Objective To evaluate the clinical relevance of antiphospholipid antibodies (aPL) in systemic sclerosis (SSc). Methods A systematic search of EMBASE and PubMed databases from January 1983 to July 2016 was carried out according to PRISMA guidelines whereas Peto׳s odds ratio (OR) for rare events was used for the meta-analysis. Results The pooled prevalence of participants positive for IgG and IgM anticardiolipin (aCL) antibodies was higher in SSc than controls (12.8% vs 1.6% and 7.8% vs 0.6%; p 2 GPI) (6.1% vs 0.58%, p p = 0.001). The pooled prevalence of pulmonary arterial hypertension (PAH) was more common in SSc positive than negative patients for aCL (IgG/IgM combined) (26.5% vs 10.9%, p p = 0.02). The pooled prevalence of thrombosis was higher in IgG aCL, IgM aCL, and IgM aβ 2 GPI positive than negative SSc patients (12.6% vs 1.4%, p p = 0.002) and (15% vs 0.78%, p = 0.009), respectively. The pooled prevalence of digital infarction/ischemia (DI) was higher in IgG aCL and IgM positive than negative SSc (52.8% vs 39.8%, p = 0.002) and (68.1% vs 29%, p = 0.07). Conclusions A strong relationship exists between aCL and aβ 2 GPI of IgG/IgM isotype and SSc; patients positive for these antibodies are more likely to suffer from PAH, RD, thrombosis, and DI. However, data expressed as frequency of aPL positive patients rather than average antibody titers preclude further insight into the relevance of these assumptions.

Introduction Anedoctal reports suggest that some thrombotic primary antiphospholipid antibody syndrome (PAPS) patients on oral anticoagulation require higher than average doses to achieve given targets international normalized ratios (INR). Materials and methods To test the hypothesis of relative warfarin resistance in thrombotic PAPS and the effect of baseline IgG anticardiolipin antibodies, the cytochrome CYP2C9 and the vitamin K epoxide reductase (VKORC1) haplotypes we compared weekly warfarin consumption of 40 TPAPS (mean age 44 ± 16 years) with that of 65 thrombotic patients with inherited thrombophilia (IT) (mean age 52 ± 18) at similar target INR 2.0-3.0 followed up between January-1994 and January 2003. To investigate an involvement of the epoxidation pathway in this difference and to assess enhanced residual fibrin turnover decarboxylated prothrombin (PIVKA-II) and D-dimers (DD) were cross-sectionally investigated in the same patients between March and May 2008. Results CEX7 and VKORC1 polymorphisms explained 45.1% of the variability in warfarin consumption, whose age-adjusted mean weekly consumption was greater in PAPS than IT (27.62 vs 21.24 mg, p = 0.03). In PAPS baseline IgG aCL and VKORC1 predicted weekly warfarin consumption (p = 0.028 and p = 0.024). IgG β2GPI and warfarin dose independently predicted plasma PIVKA-II (p = 0.01 and p = 0.02). Age and sex adjusted DD was greater in PAPS than IT (132 ± 34 vs 83 ± 37 mg/dl, p = 0.03). Conclusions Thrombotic PAPS exhibit a degree of warfarin resistance partly accounted by antiphospholipid antibodies and are in a state of enhanced fibrin turnover despite oral anticoagulation that might have implications for re-thrombosis and atherosclerosis.

Migraine is a common, debilitating, chronic neurovascular disorder. Triptans are considered the drugs of choice to treat migraine attacks; however, their use is limited owing to concerns about cardiovascular safety.The aim of this review is to describe: the mechanisms of action of triptans; the case-reports of acute myocardial infarction (AMI) associated with sumatriptan use; and the results of studies evaluating its tolerability and safety.Sumatriptan administration can be followed, in close temporal relationship, by AMI in young or adult migraine patients. Some of these cases have developed in subjects taking their first dose. Based on the results of prospective studies, the risk of severe cardiovascular adverse events after the use of a triptan is estimated at 1:100,000 treated attacks. These adverse events, albeit very infrequent, highlight the importance of careful adherence to the sumatriptan prescribing information.Inherent in its mechanism of action, sumatriptan could produce (coronary) vasospasm sometimes followed by AMI. The drug should not be prescribed to patients with history, symptoms or signs of ischemic vascular disease; an in-depth evaluation should be carried out in subjects at intermediate cardiovascular risk.

Objective.To assess the role of nitrite (NO2−), nitrate (NO3−), 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-beta2-glycoprotein I (anti-ß2-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 (NO2−), nitrate (NO3−), and total antioxidant capacity (TAC) were measured by colorimetric spectroscopic assays.Results.Average plasma NO2−was lower in PAPS, PCaPL, and IT (p < 0.0001); average NO3−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 NO2−(p = 0.03 and p = 0.001, respectively), whereas arterial occlusions and smoking positively predicted NO3−(p = 0.05 and p = 0.005), and CRP positively predicted NT (p = 0.004). In the PCaPL group IgG aCL negatively predicted NO3−(p = 0.03). In the SLE group IgG aCL negatively predicted NO2−(p = 0.03) and NO3−(p = 0.02).Conclusion.PAPS is characterized by decreased NO2−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.

The antiphospholipid syndrome (APS) has been associated with portal vein thrombosis (PVT). This study explored the contribution of antiphospholipid antibodies (aPL) to PVT in cirrhotic and noncirrhotic patients. Patients and methods: A total of 50 patients with liver cirrhosis and PVT, 50 patients with liver cirrhosis without PVT, 50 consecutive PVT without liver cirrhosis, and 50 controls. aPL tests: lupus anticoagulants (LAs), immunoglobulin G (IgG) anti-cardiolipin antibodies (aCL), IgG anti-beta-2-glycoprotein-I (β2GPI), and IgG β 2GPI-complexed with oxidized low-density lipoprotein antibodies (ox-LDL). Results: Lupus anticoagulants were negative in all patients. A titre of IgG aCL >40 IgG phospholipid units (GPL) was present in 2% of patients with liver cirrhosis and in none of the other groups. In all, 4% of patients with PVT without cirrhosis were positive for IgG β2GPI in the absence of any other positive aPL and labelled as primary APS. Conclusions: aPL play no role in PVT associated with liver cirrhosis but can be tested in idiopathic PVT.

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.

A series of case-control studies in the last decade have shown the role of inherited thrombophilia in the occurrence of adverse obstetric outcomes. In small series of cases, it has been proven that rare inherited causes of thrombophilia such as natural anticoagulant deficiencies can be associated with fetal losses. The confirmed presence of antiphospholipid antibodies in plasma, representing an acquired thrombophilic condition, is also an established cause of fetal losses, although other studies with a smaller sample size have found an association with other obstetric complications, namely preeclampsia, fetal growth restriction, and abruption placentae. Case-control studies have been performed regarding the potential association between unexplained fetal losses and mild hyperhomocysteinemia. Although case-control and prospective studies are also available regarding hyperhomocysteinemia and other gestational vascular complications, published data are conflicting. Intervention studies have been performed to prevent adverse obstetric outcomes in women with inherited or acquired thrombophilia and previous adverse outcomes. There is much debate in the literature regarding the need for treatment of women with thrombophilia during pregnancy. Although in most cases these are not randomized controlled trials, all studies found significantly better outcomes in treated pregnancies compared with those of untreated pregnancies.

The diagnosis of adult onset Still's disease is difficult in the absence of definite clinical and laboratory criteria. A delayed diagnosis of adult onset Still's disease was made in a 23-year-old female who developed multi-organ failure and disseminated intravascular coagulation with fingertip auto-amputation during a febrile illness considered septic due to the persistence of elevated serum procalcitonin concentration.

To test the atherosclerosis hypothesis in primary antiphospholipid syndrome (PAPS) we measured intima media thickness (IMT) of carotid arteries and other cardiovascular risk factors in 44 patients with PAPS (mean age 35 +/- 12 years), in 25 patients with inherited thrombophilia (mean age 40 +/- 10 years), and in 34 normal controls (mean age 38 +/- 11 years). The frequency of smoking, hypertension, and dyslipidemia was similar across groups. IMT was almost similar across groups at age groups below 40 years but IMT was greater in PAPS than controls at the common carotid (P = 0.01), at the bifurcation (P = 0.003), and at the internal carotid (P = 0.005) in the age group over 40 years. Atherosclerosis is a possibility in PAPS patients in their fourth decade of life or older.

Follow-up after curative treatment for breast cancer consists of frequent outpatient clinic visits, scheduled at regular intervals. Its aim is primarily to detect local disease recurrence, or a second primary breast cancer, but also to provide information and psychosocial support. The cost-effectiveness of these frequent visits is being questioned however, leading to a search for less intensive follow-up strategies, such as follow-up by the general practitioner, patient-initiated or nurse-led follow-up or contact by telephone. These strategies are generally considered to be safe, but they are not yet widely accepted in clinical practice. Since brief interventions based on self-education and information have been shown to be able to improve quality of life, we hypothesise that these interventions may lead to a better acceptance of reduced follow-up by both patients and professionals.

To explore whether antibodies against β2-glycoprotein I (β2GPI) complexed to 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and to oxidised low-density lipoproteins (oxLDL) relate to paraoxonase activity (PONa) and/or intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). As many as 29 thrombotic patients with PAPS, 10 subjects with idiopathic antiphospholipid antibodies (aPL) without thrombosis, 17 thrombotic patients with inherited thrombophilia and 23 healthy controls were investigated. The following were measured in all participants: β2GPI-oxLDL complexes, IgG anti-β2GPI-oxLig-1, IgG anti-β2GPI-oxLDL antibodies (ELISA), PONa, (para-nitrophenol method), IMT of common carotid (CC) artery, carotid bifurcation (B), internal carotid (IC) by high resolution sonography. β2GPI-oxLDL complex was highest in the control group (p < 0.01), whereas, IgG anti-β2GPI-oxLig1 and IgG anti-β2GPI-oxLDL were highest in PAPS (p < 0.0001). In healthy controls, β2GPI- oxLDL complexes positively correlated to IMT of the IC (p = 0.007) and negatively to PONa after correction for age (p < 0.03). PONa inversely correlated with age (p = 0.008). In PAPS, IgG anti-β2GPI-oxLig-1 independently predicted PONa (p = 0.02) and IMT of B (p = 0.003), CC, (p = 0.03) and of IC (p = 0.04). In PAPS, PONa inversely correlated to the IMTof B, CC and IC (p = 0.01, 0.02 and 0.003, respectively). IgG anti- β2GPI-oxLig-1 may be involved in PAPS related atherogenesis via decreased PON activity. publishersversion published

The aim of this study was to evaluate a possible association between lymphocyte subsets and intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). We used a cross-sectional study on PAPS patients ( n = 18) and healthy controls ( n = 16). IgG anti-cardiolipin antibody (aCL), IgG anti-β2glycoprotein-I (anti-β2GPI), IgG anti-β2glycoprotein-I complexed to oxidized low-density lipoprotein (oxLDL) and to a specific oxidized moiety of LDL (oxLig1), and β2GPI-oxLDL were measured by ELISA. Lymphocyte immunophenotyping was performed using pairs of monoclonal antibodies directly labelled with fluorescein isothiocyanate, or phycoerythrin or phycoerythrin-Texas-red-X. Intima media thickness (IMT) of carotid arteries was determined by high-resolution sonography. Total peripheral blood lymphocytes did not differ between PAPS and controls. Memory CD4+/CD45RO + T cells were lower in PAPS than controls ( P = 0.0007) as well as CD16+56+ natural killer cells ( P = 0.02). In PAPS memory T CD45RO + cells positively correlated with IgG anti-β2GPI-oxLig1 ( P = 0.002) and to IMT of carotid arteries (common carotid P = 0.02, bifurcation P = 0.007). Naïve CD4+/CD45RA+ T cells inversely correlated with β2GPI-oxLDL ( P = 0.009). The relation between IgG anti-β2GPI-oxLig1 and IMT of carotid arteries with memory CD45RO + T lymphocytes suggests a role for the latter in PAPS related atherogenesis.

Objective The effects of a short intervention on behavioral risk factor modification in patients with coronary artery disease (CAD) on Type A behavior, vital exhaustion, and depression were studied in a randomized controlled trial. Methods Acute myocardial infarction patients or patients who underwent coronary artery bypass grafting (CABG) were randomly assigned to an 8-week multiple risk modification group program ( n =94) or to a control group ( n =90) that received usual care with standard physical exercise training. Patients were assessed before intervention, directly after intervention, and at 9-month follow-up. Results The intervention was effective in reducing hostility and total Type A behavior at postintervention ( P =.01) and at 9-month follow-up ( P =.03). The intervention had no overall impact on vital exhaustion and depression, measured by the Beck Depression Inventory (BDI), whereas we unexpectedly found that the percentage of patients with major depression was reduced in the control group but not in the intervention group. Conclusion The results indicate that a short behavioral intervention for coronary patients can result in relatively large and persistent reductions in cognitive aspects of Type A behavior and hostility, in particular. In view of the unwanted findings on the diagnosis of depression, however, we do not unequivocally advise the intervention to the general population of AMI and CABG patients.

Background and study aims Portal vein thrombosis is a rare event in patients with liver cirrhosis in the absence of a related neoplasm. Endoscopic sclerotherapy of esophageal varices has been anecdotally associated with the development of portal vein thrombosis. We tested the hypothesis that genetic thrombophilia plays a role in the development of portal vein thrombosis in patients with liver cirrhosis undergoing endoscopic sclerotherapy. Patients and methods From June 1998 to December 1999, 61 consecutive patients underwent multiple sessions of endoscopic sclerotherapy for bleeding esophageal varices. Doppler ultrasound of the portal vein was performed before sclerotherapy and every 3 months thereafter. Antiphospholipid antibodies, factor V Leiden (FVL) mutation, prothrombin mutation G20210A (PTHRA20210) and mutation TT677 of methylenetetrahydrofolate reductase (MTHFR C677T) were evaluated in all patients. Results Portal vein thrombosis developed in 16 % of the patients (10 of 61) after a mean follow-up period of 16 months. A genetic cause for thrombosis was found in 70 % of patients with liver cirrhosis who developed portal vein occlusion, but only in 8 % of patients without this complication. Conclusions Endoscopic sclerotherapy of esophageal varices may represent a trigger factor for portal vein thrombosis in cirrhotic patients with genetic thrombophilia.

Background Recently, a considerable amount of evidence suggested that anxiety, depression and other psychosocial variables might influence the outcomes of cardiac surgery. This study investigated the relationship between length of stay at the intensive care unit (ICU) and hospital after surgery and different psychosocial variables (e.g. depression, anxiety, self rated health, happiness, satisfaction). Methods We enrolled prospective patients who were waiting for elective cardiac surgery (N = 267) and consented to take part in the study. We collected data of sociodemographic, medical and perioperative factors as well as psychosocial questionnaires completed 1.56 days (standard deviation [SD] = 0.7) before surgery. The primary clinical endpoint was an ICU stay of at least 3 days and the secondary was hospital stay of at least 10 days. Results Two hundred sixty-seven patients participated in this study. Four patients (1.5%) died in the hospital and 38 patients (14.5%) spent more than 3 days in the ICU and 62 patients (23.2%) spent more than 10 days in the hospital. After controlling for medical and sociodemographic factors, lower self rated health (Adjusted Odds Ratio [AOR]: 0.51, 95% confidence interval [CI]: 0.28-0.95; p = 0.03), lower rate of happiness (AOR: 0.76, 95% CI: 0.59-0.97, p = 0.03), postoperative cardiac failure (AOR: 7.09, 95% CI:1.21-41.54; p = 0.03) and postoperative complications (AOR: 9.52, 95% CI: 3.76-24.11; p

The prevalence of antiphospholipid antibodies (aPL) and thrombophilic genotypes was compared and their reciprocal interactions assessed in consecutive patients with venous thrombosis (n = 101; 58 male, 43 female; mean age, 56 +/- 16 years) and in blood donors (n = 121; 55 male, 46 female; mean age, 43 +/- 12 years). Multiple aPL were detected by enzyme-linked immunosorbent assay (ELISA) and factor V Leiden (FVL), methylenetetrahydrofolate reductase (MTHFR) C677

The prevalence of prothrombin (PT) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677-- T was assessed in 40 patients with primary antiphospholipid syndrome (APS) (14 male, 26 female; mean age, 37 +/- 14 years) and in 27 persistent carriers of antiphospholipid antibodies (aPL) (five male, 22 female; mean age, 40 +/- 16 years) without underlying diseases. Non-APS thrombotic patients (n = 100; 47 female, 53 male; mean age, 40 +/- 10 years) and healthy subjects (n = 100; 46 female, 54 male; mean age, 56 +/- 16 years) served as control groups. Plasma homocysteine (HC) (enzyme-linked immunosorbent assay) was measured in all aPL patients and in 51 subjects from the healthy control group (mean age, 38 +/- 16 years). Heterozygous prothrombin PT G20210A was more frequent in the thrombotic group without APS (18%) than in the control (4%), APS (12%) or aPL (11%) groups, whereas homozygous MTHFR C677-- T was equally distributed. After genotype sub-grouping, plasma HC was higher in APS patients with homozygous MTHFR C677-- T compared with non-homozygous APS patients (22 +/- 5.4 versus 11 +/- 1.3 micromol/l; P0.01) and with homozygous MTHFR C677-- T controls (22 +/- 5.4 versus 15 +/- 2.0 micromol/l). In the APS group, mean age at first event was lower in homozygous MTHFR C677-- T patients than in non-homozygous patients (26 +/- 7.5 versus 36 +/- 13 years; P = 0.008). In the same group, homozygous MTHFR C677-- T patients suffered an increased average number of events per person than non-homozygous patients (1.9 versus 1.3; P = 0.04). Heterozygous PT G20210A contributes little to the thrombotic tendency of primary APS whereas plasma HC may influence age at first event and number of events. Measurement of plasma HC in aPL subjects may identify patients at increased thrombotic risk requiring HC lowering.

Detection of a lupus anticoagulant (LA) is of major importance to detect a thrombotic tendency. Confirmation of its phospholipid dependency may represent a tricky step in the diagnostic algorithm for LA, as several tests may yield borderline results of little diagnostic help. To improve on this point, we had previously employed a procedure comparing sensitive [rabbit brain kaolin (RBK)] and insensitive [soy bean phosphatides (SBP)] reagents to LA to screen and confirm LA at the same time in activated partial thromboplastin systems (aPTT). Here we compared its performance against a platelet neutralization procedure (PNP). To allow comparisons of our procedures with the PNP, a percentage ratio correction was calculated according to the following formula: [(RBK ratio - SBP ratio) x 100]/ RBK ratio. Similarly for the PNP: percentage ratio correction = [(buffer ratio - platelet phospholipid ratio) x 100]/buffer ratio. On 44 known LA plasmas, the PNP, expressed in seconds, yielded 15 (34%) negative or borderline results. After ratio transformation, the PNP still yielded 10 of 15 (66%) uncertain results, whereas the RBK/SBP procedure did not give any uncertain results (P = 0.0002). The mean percentage ratio correction was far superior for the RBK/SBP procedure than for the PNP (53.24 +/- 15.93 versus 20.28 +/- 12.15%, P0.0001). The use of sensitive and insensitive reagents to the lupus anticoagulant increases the confirmatory yield of LA in aPTT systems and may deserve inclusion amongst the confirmatory procedures for its diagnosis.

OBJECTIVES: Mesenteric vein thrombosis is a rare but severe abdominal emergency, often requiring intestinal resection. New genetic prothrombotic defects such as factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype have been described in association with venous thrombosis. Our goal was to assess prevalence and clinical significance of genetic thrombophilia in mesenteric vein thrombosis. METHODS: Twelve patients with acute mesenteric vein thrombosis were compared with 431 healthy people from the same geographical area. The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype were identified by polymerase chain reaction and restriction analysis. RESULTS: A thrombophilic genotype was present in 9 patients (75%): the methylenetetrahydrofolate reductase TT677 genotype was present in 6 (50%), the factor V Leiden in 3 (25%), and the prothrombin transition G20210A in 3 (25%). Combined mutations were present in 4 (33%) patients. CONCLUSIONS: The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype are important predisposing factors in the pathogenesis of mesenteric vein thrombosis. Their identification bears strong clinical implications for management of patients with mesenteric vein thrombosis.

The pathogenesis of antiphospholipid antibody (aPL) related thrombosis is multifactorial and includes, amongst others, enhanced coagulation activation measured as prothrombin fragment 1 / 2 (F1 / 2), elevated plasma levels of von Willebrand factor (vWF), plasminogen activator inhibitor (PAI) and endothelin-l (ET-1) as well as heightened thromboxane generation and lipid peroxidation. To evaluate the antioxidant susceptibility of some of the above pathways, probucol (500 mg/d orally, a cholesterol lowering agent bearing antioxidant properties) was administered for a three week period to 14 subjects with aPL and to seven healthy controls. At baseline aPL participants showed higher plasma levels of vWF (P ‘ 0.006), ET-1 (P ‘ 0.0002) and enhanced urinary excretion of 11-dehydro-thromboxane-B2(TXB2)(P ‘ 0.0004), F2-isoprostanes (marker of lipid peroxidation) (P ‘ 0.02) and albumin (P ‘ 0.04) than controls. In the aPL group baseline IgG anticardiolipin (aCL) titre positively related with urinary TXB2(r2‘ 0.43, P ‘ 0.01) and inversely with urinary NOx(r2‘ÿ0.6, P ‘ 0.005) whereas urinary NOxand TXB2were negatively correlated (r2‘ÿ0.42, P ‘ 0.01). After the treatment period significant decreases from baseline values were noted for PAI (P ‘ 0.01), ET-1 (P ‘ 0.006), TXB2(P ‘ 0.02), F2-isoprostanes (P ‘ 0.01) and albuminuria (P ‘ 0.01) in aPL participants but not in controls. These pilot data support oxidative sensitive mechanisms and a potential role for antioxidant treatment in the pathogenesis of aPL induced vasculopathy.

The prevalence and pathogenesis of portal vein thrombosis (PVT) in patients with cirrhosis without hepatocellular carcinoma are not clearly defined. The role of thrombophilic genetic factors is well established in other venous thrombotic diseases, as well as in noncirrhotic portal thrombosis. Recently, new, inherited thrombophilic disorders (factor V Leiden [FVL], mutation G20210A of prothrombin [PTHR A(20210)], and mutation TT677 of methylenetetrahydrofolate reductase [MTHFR C677-->T]) have been identified and associated with increased risk of venous thrombosis. The aim of our study was to investigate the role of these thrombophilic disorders in the pathogenesis of PVT in cirrhotic patients. Twenty-three cirrhotic patients with PVT and 40 cirrhotics without PVT were included. A group of 184 patients with deep vein thrombosis (DVT) and 431 healthy persons served as controls. The FVL, PTHR A(20210), and MTHFR C(677)-->T genotypes were identified by a polymerase chain reaction and restriction analysis. The frequencies of FVL, PTHR A(20210) mutation, and homozygous MTHFR C(677)-->T were 13%, 34.8%, and 43.5% in cirrhotic patients with PVT and 7.5%, 2.5%, and 5% in cirrhotic patients without PVT, respectively. Five patients in the former group had associated defects. A thrombophilic genotype was detected in 69.5% of the patients with PVT. Identification of this high-risk group may have implications in patients who are candidates for major surgery or liver transplantation, and may influence the duration of oral anticoagulation.

A 23-year-old woman developed ischemic stroke (IS) 8 to 12 hours after ingestion of sumatriptan (ST) and then developed mucosal bleeding secondary to acute thrombocytopenia likely due to dipyridamole (DP) on the 10th day poststroke. Sumatriptan-associated IS and DP-induced thrombocytopenia are rare events in themselves and their sequential occurrence in the same patient is quite exceptional. We compare our case to other similar cases in the literature.

Objective. To evaluate the occurrence and clinical significance of lipid peroxidation (oxidative stress) in rheumatic diseases characterized by vascular involvement.Patients and methods. Plasma 8-epi-PGF(2 alpha) (oxidative stress marker) was measured by gas chromatography-mass spectrometry in 36 patients with systemic lupus erythematosus (SLE), 13 with systemic sclerosis (SSc), 13 with systemic vasculitis [Wegener's granulomatosis (WG), n = 4; Churg-Strauss syndrome (CSS), n = 3; Behcet syndrome, rr = 6], 12 with rheumatoid arthritis (RA) and in 23 healthy controls (n = 23).Results. 8-epi-PGF(2 alpha) levels were higher in patients with SLE (P = 0.007), SSc (P < 0.001) and vasculitis (P = 0.001) than in controls. In SLE, a positive Coombs' test and arterial hypertension independently predicted 8-epi-PGF(2 alpha) concentrations (P = 0.004 and P = 0.001, respectively). SLE patients not taking prednisolone showed higher 8-epi-PGF(2 alpha) concentrations than SLE patients on prednisolone (P = 0.02). In the latter group, a dose-response relationship was noted between 8-epi-PGF(2 alpha) and steroid dosage (I = 0.6, P = 0.0003). In WG and CSS, 8-epi-PGF(2 alpha) concentrations correlated with disease activity (r = 0.8, P = 0.01) and were higher than in patients with Behcet disease (P = 0.003).Conclusions. Oxidative stress may be pathogenetically relevant in some autoimmune rheumatic diseases with vascular involvement. Amelioration of some clinical manifestations of these diseases may be envisaged by targeting lipid peroxidation with dietary or pharmacological antioxidants.

SummaryIt was the aim of the present study to investigate factor II levels in liver cirrhosis (LC) patients with portal vein thrombosis (PVT) carrying the heterozygous G20210A prothrombin (PT) mutation. Plasma concentrations of factor II, VII, X, V, protein C (PC) total protein S (tPS) antithrombin (AT) and D-dimers (DD) were measured in 13 LC patients with PVT heterozygous for PT G20210A, in 13 LC patients with PVT without PT G20210A and in 13 LC controls matched by age, sex and Child-Pugh score. Crude factor II and factor II/DD ratio were highest in LC patients with PVT heterozygous for PT G20210A (p=0.03 and p=0.02 respectively). The factor II/PC ratio, expression of a procoagulant/anticoagulant imbalance was highest in the same group (p=0.0008). Plasma factor II levels are elevated in LC patients heterozygous for PT G20210A and may favour PVT.

The effect of β2glycoprotein I (β2GPI) and human monoclonal anticardiolipin antibody (aCL) on the protein S/C4b-binding protein (C4BP) system was evaluated. The binding of C4BP to protein S was assessed by ELISA in the presence of β2GPI with/without human monoclonal aCL. β2GPI downregulated the binding between S and C4BP significantly. Human monoclonal aCL abolished the β2GPI inhibitory effect in a calcium (Ca++) independent fashion. In separate experiments, the reactivity of aCL towards protein S in the presence or absence of β2GPI and cardiolipin was investigated. Monoclonal aCL bound to protein S only in the presence of a combination of β2GPI and cardiolipin. This binding was Ca++dependent. These findings suggest that human monoclonal aCL increases the affinity of C4BP for protein S, and that protein S may represent one of the targets for aCL when combined with β2GPI and cardiolipin. Both issues may explain acquired free protein S deficiency and the attendant risk of thrombosis in patients with aCL.