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The spreading of recreational opium use pose new health related concerns. In some areas of Asia its use is believed to protect from cardiovascular disorders, such as coronary artery disease (CAD). However, whether opium use has an association with CAD is unclear. We aimed to investigate the association between opium use and CAD. We set up a case-control analysis, i.e., the premature CAD Milano-Iran (MIran) study by enrolling consecutive young patients who underwent a coronary angiography at the Tehran Heart Center, between 2009 and 2012. Incident cases with CAD were contrasted with controls for recreational opium use. Relative risks were calculated in terms of odds ratios (ORs) by logistic regression models adjusted for age, sex, cigarette smoking, body mass index, hypertension, hyperlipidaemia, and diabetes. Interaction analyses were performed between opium and major cardiovascular risk factors. 1011 patients with CAD (mean age 43.6 years) and 2002 controls (mean age 54.3 years) were included in the study. Habitual opium users had a 3.8-fold increased risk of CAD (95%CI 2.4–6.2) compared with non-users. The association was strongest for men, with a fully adjusted OR of 5.5 (95%CI 3.0-9.9). No interaction was observed for the combination of opium addiction and hypertension, or diabetes, but an excess in risk was found in opium users with hyperlipidaemia (OR 16.8, 95%CI 8.9–31.7, expected OR 12.2), suggesting supra-additive interaction. In conclusion, despite common beliefs, we showed that recreational opium use is associated with an increased risk of CAD, even when other cardiovascular risk factors are taken into account.

Background Red cell distribution width (RDW) is a marker of cardiovascular diseases and venous thromboembolism, but its role in cerebral vein thrombosis (CVT) is unknown. Aims To investigate whether high values of RDW are associated with an increased risk of CVT. Methods A case–control study of CVT patients (≥ 18 years-old) referred to our center contrasted with healthy individuals. Odds ratios (ORs) were calculated for RDW values > 90th percentile by multivariable logistic regression and adjusted for demographic characteristics, hemorheological parameters, renal function, fibrinogen and CRP. Quartiles based on the distribution of RDW values were used in an additional model to assess a dose–response relationship. The risk of CVT associated with the combined presence of high RDW and either thrombophilia abnormalities or oral contraceptive use was also estimated. Results 143 cases (median age 36 years, 18–79) and 352 controls (42 years, 18–80) were investigated. RDW values > 90th percentile (> 14.6%) were associated with an increased risk of CVT (OR 2.44, 95% CI 1.39–4.28). The association remained after further adjustment for hemorheological parameters (OR 3.73, 95% CI 1.72–8.09), inflammatory markers (OR 3.77, 95% CI 1.72–8.25) and renal function (OR 3.62, 95% CI 1.53–8.55). The risk appeared restricted to these extreme levels (> 14.6%), as there was no graded association between values of RDW and CVT risk over quartiles. There was a synergistic effect on the risk of CVT for the combination of high RDW and thrombophilia abnormalities (OR 33.20, 95% CI 6.95–158.55) or oral contraceptive use (OR 37.99, 95% CI 8.78–164.45). Conclusions Values of RDW > 90th percentile are associated with CVT.

Background: The spreading of opium addiction, especially in Asian countries, pose new health related concerns. In some areas its use is still believed to protect from cardiovascular disorders, such as coronary artery disease (CAD). However, whether opium use has an association with CAD is unclear. Methods: We set up a case-control analysis, i.e., the premature CAD Milano-Iran (MIran) study. We enrolled consecutive young patients who underwent a coronary angiography at the Tehran Heart Center, between 2009 and 2012. Incident cases with CAD were contrasted with controls for habitual opium use. Relative risks were calculated in terms of odds ratios (ORs) by logistic regression models adjusted for age, sex, cigarette smoking, body mass index, hypertension, hyperlipidaemia, and diabetes. We performed interaction analyses between opium use and hypertension, hyperlipidaemia and diabetes. Findings: 1011 patients with CAD (mean age 43.6 years) and 2002 controls (mean age 54.3 years) were included in the study. Habitual opium users had a 3.8-fold increased risk of CAD (95%CI 2.4-6.2) compared with non-users. The association was strongest for men, with a fully adjusted OR of 5.5 (95%CI 3.0-9.9). No interaction was observed for the combination of opium addiction and hypertension, or diabetes. On the contrary, an excess in risk was found in opium users with hyperlipidaemia (OR 16.8, 95%CI 8.9-31.7, expected OR 12.2), suggesting supra-additive interaction. Interpretation: Despite common beliefs, our study showed that opium addiction is associated with an increased risk of CAD, even when other cardiovascular risk factors are taken into account. Funding Statement: the Tehran Heart Center and the Universita degli Studi di Milano. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was approved by the Ethical committee Board of Tehran Heart Center, and all patients and controls signed informed consent before inclusion in the study.

An increased von Willebrand factor propeptide (VWFpp) to VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) indicates an enhanced clearance of VWF. This finding has been described in von Willebrand disease (VWD) and in acquired von Willebrand syndrome (AVWS). A distinction between these two diseases, one congenital and the other acquired, is primarily based on family and personal history of bleeding. However, if this information is scanty, the diagnosis might be challenging due to the lack of an effective diagnostic biomarker. In this cross-sectional study, we assessed the ability of VWFpp/VWF:Ag for the differential diagnosis between VWD and AVWS. VWFpp/VWF:Ag was measured in a group of 153 patients (125 with VWD and 28 with AVWS). Most patients with AVWS and VWD showed an increased VWFpp/VWF:Ag, although to variable degrees. A marked increase of VWFpp/VWF:Ag was mainly associated with the diagnosis of AVWS and VWD type 1 Vicenza. A receiver operating characteristic curve was used to identify the optimal cutoff of VWFpp/VWF:Ag for discrimination of patients with a modestly increased (most VWD cases) versus those with a markedly increased clearance (AVWS and VWD type 1 Vicenza), and this cutoff was identified at the value of 3.9 (sensitivity: 0.70, specificity: 0.97). The ROC curve sorting from a logistic model containing VWFpp/VWF:Ag, age, and sex had an area under the curve (AUC) of 0.88 (95% confidence interval: 0.80–0.95). A subsequent molecular evaluation discriminated VWD type 1 Vicenza from AVWS. In conclusion, VWFpp/VWF:Ag appears helpful to discriminate patients with a markedly increase VWF clearance (AVWS or VWD type 1 Vicenza) from those with a modestly increased clearance (most VWD patients).

Background An association between high red cell distribution width (RDW) and venous thromboembolism (VTE) has been observed. However, it is not known whether this association differs within various manifestations of VTE, nor if there is an interaction between RDW and thrombophilia abnormalities on the risk of VTE. Aims To investigate whether RDW is a marker of the risk of VTE; to identify subgroups of patients in which the association between RDW and VTE is stronger; to investigate a possible interaction between RDW and thrombophilia abnormalities. Methods Case–control study on 730 patients with a first objectively-confirmed VTE episode (300 unprovoked and 430 provoked) consecutively referred to our Center between 2007 and 2013, and 352 healthy controls. Blood was taken for a thrombophilia work-up and a complete blood count, including RDW, at least three months after VTE. Results Individuals with RDW above the 90 th percentile (> 14.6%) had a 2.5-fold increased risk of VTE compared to those with RDW ≤ 90 th percentile, independently of age, sex, body mass index, other hematological variables and renal function (adjusted odds ratio: 2.52 [95%CI:1.42-4.47]). The risk was similar for unprovoked and provoked VTE, and slightly higher in patients with pulmonary embolism (adjusted odds ratio 3.19 [95%CI:1.68-6.09]) than in those with deep vein thrombosis alone (2.29 [95%CI:1.22-4.30]). No interaction between high RDW and thrombophilia abnormalities on the risk of VTE was observed. Conclusion Our findings confirm RDW as an independent and easily available marker for stratification of the risk of VTE.

The influence of thrombosis on the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT) and the role of the commonest inherited thrombophilia abnormalities factor V Leiden and prothrombin G20210A in the development of thrombosis are unknown. We investigated a cohort of patients who underwent LT for HCC with the aim to estimate the incidence rate (IR) of thrombosis, its influence on mortality and re-transplantation rates and, in the frame of a nested case-control study, the role of thrombophilia in donors and recipients for the development of thrombosis. Four-hundred and thirty patients underwent LT and were followed for a median of 7.2 years. Twenty-six recipients (6%) developed thrombosis (IR 1.06 [95%CI: 0.71-1.53] per 100 pts-yr). Mortality rate after LT was 3.95 (95%CI: 3.22-4.79) per 100 pts-yr and was not influenced by thrombosis. Re-transplantation was planned for 33 patients and was more common in patients with thrombosis than in those without (HR 2.50 [95%CI: 0.87-7.17]). The risk of thrombosis was 4 times higher in recipients with thrombophilia than in those without (OR 4.23 [95%CI: 0.99-18.04]) and 6 times higher when the analysis was restricted to venous thrombosis (OR 6.26 [95%CI: 1.19-32.85]). The presence of inherited thrombophilia in the donors did not increase the risk of thrombosis of the recipient. In conclusion, thrombosis is a complication of 6% of patients transplanted for HCC and increases the risk of re-transplantation but not of mortality. The risk of thrombosis, particularly venous, is increased in the presence of thrombophilia abnormalities in the recipients.

Throughout the past decade, a possible role of eosinophils in blood coagulation and thrombosis has been suggested. We conducted a Pubmed (MEDLINE) search of case and series referring to any kind of thrombotic events described in three conditions characterised by persistent blood eosinophilia, i.e. the hypereosinophilic syndrome (HES), the Churg Strauss syndrome (CSS), and parasitic infestations from 1966 to date. One hundred and ninety-two articles were found regarding thrombotic events in HES and CSS, and 209 cases of thrombosis were extracted. One hundred and seventy- seven articles dealing with parasitic diseases and thrombosis were found, but only 15 manuscripts reporting thrombosis of unknown origin in 22 patients were selected. In HES, arterial thromboses were more frequent than in CSS (p=0.006), representing almost half of the cases (45%), while venous and mixed artero-venous thrombosis were respectively 28% and 27%. In contrast, in CSS there was a predominance of venous thrombosis (56%, p=0.006), with arterial thrombosis representing 38% of total thrombotic events, and mixed thrombosis being the least frequent (4%). The higher incidence of arterial thrombosis in HES patients can be explained by the common cardiac involvement (64% of patients). In the 22 patients with parasitoses and thrombosis, 15 had arterial thrombosis (68%) and 7 had venous thrombosis (32 %). Literature analysis shows that there are numerous reports of thrombotic events in patients with eosinophil-related disorders supporting a role for eosinophils in thrombosis. This observation raises the problem of prevention and treatment of thromboembolism particularly in HES and CSS patients.

SummaryBackground Low ADAMTS-13 levels have been repeatedly associated with an increased risk of ischemic stroke, but results concerning the risk of myocardial infarction are inconclusive. Objectives To perform an individual patient data meta-analysis from observational studies investigating the association between ADAMTS-13 levels and myocardial infarction. Methods A one-step meta-analytic approach with random treatment effects was used to estimate pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for confounding. Analyses were based on dichotomous exposures, with the 5th and 1st percentiles of ADAMTS-13 antigen levels as cut-off values. Quartile analyses, with the highest quartile as a reference category, were used to assess a graded association between levels and risk (‘dose’ relationship). Additionally, we assessed the risk of the combined presence of low ADAMTS-13 and high von Willebrand factor (VWF) levels. Results Five studies were included, yielding individual data on 1501 cases and 2258 controls (mean age of 49 years). Low ADAMTS-13 levels were associated with myocardial infarction risk, with an OR of 1.89 (95% CI 1.15–3.12) for values below the 5th percentile versus above, and an OR of 4.21 (95% CI 1.73–10.21) for values below the 1st percentile versus above. Risk appeared to be restricted to these extreme levels, as there was no graded association between ADAMTS-13 levels and myocardial infarction risk over quartiles. Finally, there was only a minor synergistic effect for the combination of low ADAMTS-13 and high VWF levels. Conclusions Low ADAMTS-13 levels are associated with an increased risk of myocardial infarction.

Background and Purpose: Hypercoagulability increases the risk of arterial thrombosis; however, this effect may differ between various manifestations of arterial disease. Methods: In this study, we compared the effect of coagulation factors asmeasures of hypercoagulability on the risk of ischaemic stroke (IS) and myocardial infarction (MI) by performing a systematic review of the literature. The effect of a risk factor on IS (relative risk for IS, RRIS) was compared with the effect on MI (RRMI) by calculating their ratio (RRR = RRIS/RRMI). A relevant differential effect was considered when RRR was >1+ its own standard error (SE) or 1+1SE) was found in 49/343 (14%) markers. Of these, 18/49 (37%) had an RRR greater than 1+2SE. On the opposite side, a larger effect on MI risk (RRR

Background and Scope. Early etiologic diagnosis of ischemic stroke subtype guides acute management and treatment. We aim to evaluate if plasma biomarkers can predict stroke subtypes in the early phase from stroke onset.Methods. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP), D-dimer, C-reactive protein, serum albumin, and globulin levels have been investigated in 114 consecutive patients presenting at the emergency room within 6 hours of the ischemic stroke onset. Plasma levels of biomarkers have been correlated with stroke aetiology (based on TOAST criteria) by multivariable logistic regression analysis, adjusted for several covariates.Results. Of the 114 patients, 34 (30%) had cardioembolic stroke, 27 (23%) atherothrombotic stroke, 19 (17%) lacunar stroke, and 34 (30%) stroke of undetermined origin. Patients with cardioembolic stroke had significantly higher levels of NT-proBNP and lower globulin/albumin (G/A) ratio compared with the other subgroups. At multiple logistic regression NT-proBNP>200 pg/mL, G/A ratio>0.70,and NIHSS score were independent predictors of cardioembolic stroke with high accuracy of the model, either including (AUC, 0.91) or excluding (AUC, 0.84) atrial fibrillation.Conclusions. A prediction model that includes NT-proBNP, G/A ratio, and NIHSS score can be useful for the early etiologic diagnosis of ischemic stroke.

BACKGROUND: The prevalence of platelet primary secretion defects (PSD) among patients with bleeding diathesis is unknown. Moreover, there is paucity of data on the determinants of bleeding severity in PSD patients. OBJECTIVE: To determine the prevalence of PSD in patients with clinical bleeding and to study the relationships between the type of platelet defect and bleeding severity. METHODS: Data on patients referred for bleeding to the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan (Italy) in the years between 2008 and 2012 were retrieved to study the prevalence of PSD. Demographic, clinical and laboratory information on 32 patients with a diagnosis of PSD was used to compare patients with or without associated medical conditions and to investigate whether or not the type and extension of platelet defects were associated with the bleeding severity score (crude and age-normalized) or with the age at first bleeding requiring medical attention. RESULTS: The estimated prevalence of PSD among 207 patients with bleeding diathesis and bleeding severity score above 4 was 18.8% (95% confidence interval [CI]: 14.1-24.7%). Patients without associated medical conditions had earlier age of first bleeding (18 vs 45 years; difference: -27 years; 95% CI: -46 to -9 years) and different platelet functional defect patterns (Fisher's exact test of the distribution of patterns, P = 0.007) than patients with accompanying medical conditions. The type and extension of platelet defect was not associated with the severity of bleeding. CONCLUSIONS: PSD is found in approximately one fifth of patients with clinical bleeding. In patients with PSD, the type and extension of laboratory defect was not associated with bleeding severity.