THROMBOEMBOLISM: DEALING WITH POTENTIALLY CAUSAL AND CONFOUNDING RISK FACTORS USING DIRECTED ACYCLIC GRAPH (DAG) ANALYSIS

Introduction: Hospital-acquired venous thromboembolism (HA-VTE) in children comprises multiple risk factors that should not be evaluated separately due to collinearity and multiple cause and effect relationships. This is one of the first case-control study of pediatric HA-VTE risk factors using Directed Acyclic Graph (DAG) analysis. Material and Methods: Retrospective, case-control study with 22 cases of radiologically proved HA-VTE and 76 controls matched by age, sex, unit of admission, and period of hospitalization. Descriptive statistics was used to define distributions of continuous variables, frequencies, and proportions of categorical variables, with a comparison between cases and controls. Due to many potential risk factors of HA-VTE, a directed acyclic graph (DAG) model was created to identify confounding, reduce bias, and increase precision on the analysis. The final model consisted of a DAG-based conditional logistic regression. The study was approved by the Institutional Review Board (CAAE Results: In the initial univariable model, the following variables were selected as potential risk factors for HA-VTE: length of stay (LOS, days), ICU admission in the last 30 days, LOS in ICU, infection, central venous catheter (CVC), L-asparaginase, heart failure, liver failure and nephrotic syndrome. The final model (table 1) revealed LOS (OR=1.108, 95%CI=1.024-1.199, p=0.011), L-asparaginase (OR=27.184, 95%CI=1.639-450.982, p=0.021), and nephrotic syndrome (OR=31.481, 95%CI=1.182-838.706, p=0.039) as independent risk factors for HA-VTE. Conclusion: The DAG-based approach was useful to clarify the influence of confounders and multiple causalities of HA-VTE. Interestingly, CVC placement - a known thrombotic risk factor highlighted in several studies - was considered a confounder, while LOS, L-asparaginase use and nephrotic syndrome were confirmed as risk factors to HA-VTE. Large confidence intervals are related to the sample size, however the results were significant. therapy (heparin, vitamin K antagonist, vena cava filter, thrombolysis), the dosage of anticoagulant used, bleeding and its classification (according to ISTH(12)), and laboratory test used for anticoagulation monitoring: international normalized ratio (INR), Partial Thromboplastin Time (TTP), and anti-factor Xa. Outcome variables were death (cases and controls), pulmonary embolism (for patients with previous DVT), the extension of the VTE (radiology proved), and the transformation from non-occlusive to occlusive VTE. 22.3%) and warmness (2/22; 9.1%). Two patients (2/22; 9.1%) had PE and presented with the following symptoms: one with cough and hemoptysis and the other with dyspnea, tachypnea, cough, and tachycardia. Only one patient had cerebral venous sinus thrombosis (CVST) and presented with seizures. He had a diagnosis of acute lymphoblastic leukemia (ALL) and was treated with L-asparaginase. DVT cases were diagnosed using Doppler ultrasound and PE with a CT scan. The 22 patients had 38 sites of VTE which included lower limbs (26/38; intra-abdominal (4/38; 10.5%) inferior vena more frequent in cases (17/22; 77.27%) than controls (33/76; 43.42%) with no difference between local or systemic ones. L-asparaginase use was higher in cases (6/22; 27.27%) than controls (2/76; 2.63%). Nephrotic syndrome was seen in 22.72% (5/22) of cases compared to 1.32% (1/76) of controls. Liver failure was more common in cases (3/22; 13.63%) than controls (2/76; 2.63%). We did not observe any difference between cases and controls regarding obesity, surgery, immobility, mechanical ventilation, length of mechanical ventilation, corticosteroid use, inflammation/autoimmune disease, and neoplasia. contributing to a procoaguable state(29). Other reported risk factors for venous thromboembolism (VTE) in this population include infection, CVCs, diuretics, and intravascular volume depletion(30). In our study, 5 of 6 (83.33%) patients with nephrotic syndrome developed VTE. Infection (60%), CVC (40%), and ICU admission (20%) were also seen in most patients. Our study showed a higher percentage (83.33%) of nephrotic patients with VTE, considering a recent cohort study of 370 children with nephrotic syndrome admitted to 17 pediatric hospitals across North America from 2010 to 2012, where only 11 (3%) of patients developed VTE(30). was not final model but remained to better adjust confounding factors.