Risk Factors for Venous Thrombo-Embolism in Children with Sickle Cell Disease: a Multicenter Cohort Study

Background: A hypercoagulable state resulting in increased venous thrombo-embolism (VTE) has been described in adults with sickle cell disease (SCD). Similar data for children is lacking. Previously, in a single-institution, retrospective study of 414 pediatric patients with SCD followed at Nationwide Children's Hospital (NCH) between 2009 and 2015, we identified central venous catheters (CVC) as an independent risk factor for VTE [OR (± 95%CI): 10.3 (1.1-92.2)]. 12/414 (2.9%) subjects developed VTE over the course of the study¹. The objective of this retrospective, multicenter cohort study was to describe risk factors associated with VTE in children with SCD across children's hospitals in the United States (US).

Methods: This study was deemed to be exempt by the Institutional Review Board at NCH. Data source for this multicenter cohort study was the Pediatric Health Information Systems (PHIS), an administrative database that contains clinical and resource utilization data for inpatient, ambulatory surgery, emergency department and observation unit patient encounters for 49 free standing children's hospitals in the US. Data quality and reliability are assured through a joint effort between Children's Hospital Association and participating institutions². ICD-9-CM codes were used to identify subjects. Eligible subjects were <21 years of age, were admitted to one of the PHIS hospitals between 01/01/2009 and 12/31/2013 and had at least 2 SCD specific ICD-9 discharge codes. VTE and comorbid conditions of interest (congenital heart disease, cancer, chronic renal disease, obesity, inflammatory bowel disease etc) were also identified using ICD-9 codes. Supply codes were used to identify CVC placement and pharmaceutical billing codes to identify oral contraceptive use. Logistic regression analysis was used to study association between unique patient characteristics and VTE. Due to the low event rate of VTE, logistic regression models were corrected using the Firth method. Variables found to be significant (p-value < 0.05) on univariate analysis were entered into a multivariable model. All data were summarized and presented using descriptive statistics. All statistical analyses were performed using SAS software, version 9.3 (SAS Institute, Cary, NC).

Results: A total of 8941 unique subjects (4359 female) met inclusion criteria with a mean age (± 95%CI) of 7.28 (7.14-7.42) years. 159 subjects (96 female) developed VTE during the study period. Mean age (± 95%CI) at VTE diagnosis was 14.73 (13.84-15.63) years. No increase in VTE diagnosis was appreciated over the course of the study. On multivariable analysis, any CVC placement [OR (± 95%CI): 8.9 (6.45-12.3); p<0.0001], chronic renal disease [5.19 (1.48-18.19); p=0.01], female gender [1.59 (1.15-2.20); p=0.005), and older age at admission [1.10 (1.07-1.12); p<0.0001] were identified as risk factors associated with VTE diagnosis. Patients with SCD and VTE were more likely to be admitted to the intensive care unit (1.61 (0.99-2.62); p=0.05), though VTE diagnosis had no impact on mortality [1.49 (0.44-5.10); p=0.5].

Conclusion: Rate of VTE in children with SCD admitted to children's hospitals in the US is around 1.8%. CVC use is associated with a nearly 9-fold increased risk of VTE diagnosis. Additionally, chronic renal disease, female gender and older age at admission were also associated with VTE diagnosis. Prospective cohort studies are needed to confirm these findings and develop risk prediction models for VTE in children with SCD. Such studies will help develop and validate evidence based VTE prophylactic regimens for children with SCD.

Reference:

1. Woods G, Sharma R, Creary S, et al. Venous thrombo-embolism (VTE) in children with sickle cell disease (SCD): an institutional experience. Journal of Thrombosis and Haemostasis. 2015;13:58-58.

2. Witmer CM, Lambert MP, O'Brien SH, Neunert C. Multicenter Cohort Study Comparing U.S. Management of Inpatient Pediatric Immune Thrombocytopenia to Current Treatment Guidelines. Pediatr Blood Cancer. 2016;63(7):1227-1231.