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1.  Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM) 
Systematic Reviews  2014;3:69.
Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications.
We conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy.
The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin.
Systematic review registration
PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249
PMCID: PMC4094595  PMID: 24969227
Pregnancy; Placenta-mediated pregnancy complications; Low-molecular-weight heparin; Meta-analysis; Individual patient data meta-analysis; Pre-eclampsia; Small-for-gestational age; Placental abruption; Pregnancy loss; Systematic review
2.  Identification of genetic risk variants for deep vein thrombosis by multiplexed next-generation sequencing of 186 hemostatic/pro-inflammatory genes 
Next-generation DNA sequencing is opening new avenues for genetic association studies in common diseases that, like deep vein thrombosis (DVT), have a strong genetic predisposition still largely unexplained by currently identified risk variants. In order to develop sequencing and analytical pipelines for the application of next-generation sequencing to complex diseases, we conducted a pilot study sequencing the coding area of 186 hemostatic/proinflammatory genes in 10 Italian cases of idiopathic DVT and 12 healthy controls.
A molecular-barcoding strategy was used to multiplex DNA target capture and sequencing, while retaining individual sequence information. Genomic libraries with barcode sequence-tags were pooled (in pools of 8 or 16 samples) and enriched for target DNA sequences. Sequencing was performed on ABI SOLiD-4 platforms. We produced > 12 gigabases of raw sequence data to sequence at high coverage (average: 42X) the 700-kilobase target area in 22 individuals. A total of 1876 high-quality genetic variants were identified (1778 single nucleotide substitutions and 98 insertions/deletions). Annotation on databases of genetic variation and human disease mutations revealed several novel, potentially deleterious mutations. We tested 576 common variants in a case-control association analysis, carrying the top-5 associations over to replication in up to 719 DVT cases and 719 controls. We also conducted an analysis of the burden of nonsynonymous variants in coagulation factor and anticoagulant genes. We found an excess of rare missense mutations in anticoagulant genes in DVT cases compared to controls and an association for a missense polymorphism of FGA (rs6050; p = 1.9 × 10-5, OR 1.45; 95% CI, 1.22-1.72; after replication in > 1400 individuals).
We implemented a barcode-based strategy to efficiently multiplex sequencing of hundreds of candidate genes in several individuals. In the relatively small dataset of our pilot study we were able to identify bona fide associations with DVT. Our study illustrates the potential of next-generation sequencing for the discovery of genetic variation predisposing to complex diseases.
PMCID: PMC3305575  PMID: 22353194
Deep vein thrombosis; venous thromboembolism; next-generation sequencing; target capture; multiplexing; FGA; rs6025; heamostateome; DVT; VTE
3.  Exposure to Particulate Air Pollution and Risk of Deep Vein Thrombosis 
Archives of internal medicine  2008;168(9):920-927.
Particulate air pollution has been linked to heart disease and stroke, possibly resulting from enhanced coagulation and arterial thrombosis. Whether particulate air pollution exposure is related to venous thrombosis is unknown.
We examined the association of exposure to particulate matter of less than 10 µm in aerodynamic diameter (PM10) with DVT risk in 870 patients and 1210 controls from Lombardia Region, Italy examined between 1995–2005. We estimated exposure to particulate matter of less than 10 µm in aerodynamic diameter (PM10) in the year before DVT diagnosis (cases) or examination (controls) through area-specific average levels obtained from ambient monitors.
Higher average PM10 level in the year before the examination was associated with shortened Prothrombin Time (PT) in DVT cases (beta=−0.12; 95% CI −0.23, 0.00; p=0.04) and controls (beta=-0.06; 95% CI −0.11, 0.00, p=0.04). Each PM10 increase of 10 µg/m3 was associated with a 70% increase in DVT risk (OR=1.70; 95% CI, 1.30–2.23; p=0.0001) in models adjusting for clinical and environmental covariates. The exposure-response relationship was approximately linear over the observed PM10 range. The association between PM10 and DVT was weaker in women (OR=1.40; 95% CI, 1.02–1.92; p=0.02 for the interaction between PM10 and sex), particularly in those using oral contraceptives or hormone replacement therapy (OR=0.97; 95% CI 0.58–1.61; p=0.048 for the interaction between PM10 and hormone use).
Long-term exposure to particulate air pollution is associated with altered coagulation function and DVT risk. Other risk factors for DVT may modulate the effect of particulate air pollution.
PMCID: PMC3093962  PMID: 18474755
4.  Living Near Major Traffic Roads and Risk of Deep Vein Thrombosis 
Circulation  2009;119(24):3118-3124.
Particulate air pollution has been consistently linked to increased risk of arterial cardiovascular disease. Few data on air pollution exposure and risk of venous thrombosis are available. We investigated whether living near major traffic roads increases the risk of deep vein thrombosis (DVT), using distance from roads as a proxy for traffic exposure.
Methods and Results
Between 1995-2005, we examined 663 patients with DVT of the lower limbs and 859 age-matched controls from cities with population>15,000 inhabitants in Lombardia Region, Italy. We assessed distance from residential addresses to the nearest major traffic road using geographic information system methodology. The risk of DVT was estimated from logistic regression models adjusting for multiple clinical and environmental covariates.
The risk of DVT was increased (Odds Ratio [OR]=1.33; 95% CI 1.03-1.71; p=0.03 in age-adjusted models; OR=1.47; 95%CI 1.10-1.96; p=0.008 in models adjusted for multiple covariates) for subjects living near a major traffic road (3 meters, 10th centile of the distance distribution) compared to those living farther away (reference distance of 245 meters, 90th centile). The increase in DVT risk was approximately linear over the observed distance range (from 718 to 0 meters), and was not modified after adjusting for background levels of particulate matter (OR=1.47; 95%CI 1.11-1.96; p=0.008 for 10th vs. 90th distance centile in models adjusting for area levels of particulate matter <10 μm in aerodynamic diameter [PM10] in the year before diagnosis).
Living near major traffic roads is associated with increased risk of DVT.
PMCID: PMC2895730  PMID: 19506111
Deep vein thrombosis; air pollution; risk factors; coagulation
5.  Air Pollution, Smoking, and Plasma Homocysteine 
Environmental Health Perspectives  2006;115(2):176-181.
Mild hyperhomocysteinemia is independently associated with an increased risk of cardiovascular disease. Air pollution exposure induces short-term inflammatory changes that may determine hyperhomocysteinemia, particularly in the presence of a preexisting proinflammatory status such as that found in cigarette smokers.
We examined the relation of air pollution levels with fasting and postmethionine-load total homocysteine (tHcy) in 1,213 normal subjects from Lombardia, Italy.
We obtained hourly concentrations of particulate matter < 10 μm in aerodynamic diameter (PM10) and gaseous pollutants (carbon monoxide, nitrogen dioxide, sulfur dioxide, ozone) from 53 monitoring sites covering the study area. We applied generalized additive models to compute standardized regression coefficients controlled for age, sex, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long-term trends.
The estimated difference in tHcy associated with an interquartile increase in average PM10 concentrations in the 24 hr before the study was nonsignificant [0.4%; 95% confidence interval (CI), −2.4 to 3.3 for fasting; and 1.1%, 95% CI, −1.5 to 3.7 for postmethionine-load tHcy]. In smokers, 24-hr PM10 levels were associated with 6.3% (95% CI, 1.3 to 11.6; p < 0.05) and 4.9% (95% CI, 0.5 to 9.6; p < 0.05) increases in fasting and postmethionine-load tHcy, respectively, but no association was seen in nonsmokers (p-interaction = 0.005 for fasting and 0.039 for postmethionine-load tHcy). Average 24-hr O3 concentrations were associated with significant differences in fasting tHcy (6.7%; 95% CI, 0.9 to 12.8; p < 0.05), but no consistent associations were found when postmethionine-load tHcy and/or 7-day average O3 concentrations were considered.
Air particles may interact with cigarette smoking and increase plasma homocysteine in healthy subjects.
PMCID: PMC1831519  PMID: 17384761
air pollution; cardiovascular risk; generalized additive models; homocysteine; particulate matter; smoking

Results 1-5 (5)