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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. publishersversion published

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.

Background The prevalence of heart failure with preserved ejection fraction (HFpEF) in patients with antiphospholipid syndrome (APS) is unknown. Methods Prospective multicenter cohort study including 125 patients: 91 primary APS (PAPS), 18 APS-SLE, and 16 carriers. HFpEF was diagnosed according to the 2019 European Society of Cardiology criteria: patients with ≥5 points among major and minor functional and morphological criteria including NT-ProBNP >220 pg/ml, left atrial (LA) enlargement, increased left ventricular filling pressure. Results Overall, 18 (14.4%) patients were diagnosed with HFpEF; this prevalence increased from 6.3% in carriers to 13.2% in PAPS and 27.8% in APS-SLE (Figure). Patients with HFpEF were older and with a higher prevalence of hypertension and previous arterial events. At logistic regression analysis, age, arterial hypertension, anticardiolipin antibodies IgG >40 GPL (odds ratio [OR] 3.43, 95% Confidence Interval [CI] 1.09–10.77, p=0.035), anti β-2-glycoprotein-I IgG >40 GPL (OR 5.28, 1.53–18.27, p=0.009), lupus anticoagulants DRVVT >1.25 (OR 5.20, 95% CI 1.10–24.68, p=0.038), (OR 3.56, 95% CI 1.11–11.47, p=0.033) and triple positivity (OR 3.56, 95% CI 1.11–11.47, p=0.033) were associated with HFpEF after adjustment for age and sex. Discussion HFpEF has a clinically relevant prevalence in patients with APS. The role of antiphospholipid antibodies in the pathogenesis and prognosis of HFpEF needs to be investigated. Funding Acknowledgement Type of funding sources: None.

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