Biomarkers for venous thromboembolism in children with central venous catheters

Abstract Background The incidence of venous thromboembolism (VTE) in children has been increasing by about 10% per year for the past decade. More than 50% of venous thromboses in children and more than 90% of thromboses in neonates are catheter-related thromboses (CRTs), making central venous catheter (CVC) placement the single most significant risk factor for thrombosis in children. Low serum albumin has been proposed as a biomarker for increased risk of VTE in pediatric patients with CVCs. We therefore initiated a prospective study to determine the relative risk of CVC-associated venous thrombosis in pediatric patients with hypoalbuminemia and other biomarkers at the time of CVC placement. Methods In this prospective cohort study of pediatric patients who were undergoing a CVC placement, we followed the patients for 12 months to determine if they did or did not develop a CRT during their enrollment period, and collected patient demographics, clinical status of patients, type of CVC placed and laboratory biomarkers including serum albumin, factor VIII activity, D-dimer, antithrombin, protein C activity, free protein S activity and thrombin generation assay parameters within 4 days of CVC placement. Thrombin generation was performed by CAT-TM using 5 pM tissue factor and thrombomodulin (TM) to determine endogenous thrombin potential (ETP) and reduction after addition of TM to obtain % ETP reduction. We determined differences in continuous and categorical variables between patients who developed a CRT and those who did not develop CRT by t-test and chi-squared test, respectively. We also used multivariable logistic regression modeling to determine if albumin level was independently associated with developing CRT. Results A total of 148 patients aged 1-18 years were enrolled between Mar 2017 and Oct 2020. The median age of our cohort was 6.45 years. The mean BMI was 18.5 (SD 4.7). One hundred fifty-three CVCs were placed including 75 non-tunneled catheters, 77 tunneled catheters and 1 dialysis catheter. Most of patients receiving CVCs were in the ICU (40%) or had a malignancy (51%) and 20% had active infections. Thirteen patients (8.8%) developed a CRT during the 12-month enrollment period. CVCs placed in these 13 patients included 8 peripherally inserted central catheters (PICC), 4 femoral vein catheters, 2 port-a-caths and 1 internal jugular vein catheter. Patients who developed a CRT were older than those who did not develop a CRT (p=0.001, OR 1.23). There was no difference in body mass index between the two groups. Albumin levels were significantly lower in patients who developed CRTs compared to those who did not using the multivariate logistic regression for age and antithrombin levels (p=0.04, OR 0.35). Antithrombin activity was lower in the CRT group than the non-CRT group (p =0.026, OR 0.97), however, it was not significant using multivariate logistic regression (p=0.32, OR 0.99). %ETP reduction was lower in patients who developed a CRT compared to those who did not but was not statistically significant (p =0.06, OR 0.94). Factor VIII activity, fibrinogen, D-dimer, protein C and free protein S activity levels were not different between the two groups. Conclusions We conclude that hypoalbuminemia is a significant predictor of CRT in children with CVCs. Given that protein loss can lead to low antithrombin which creates a thrombophilia state, the association between hypoalbuminemia and low antithrombin activity needs to be further explored in hospitalized patients at risk for thrombosis.