Venous Thromboembolism in Pediatric Cystic Fibrosis

Background: Pediatric venous thromboembolism (VTE) is a rare but serious medical condition resulting in significant morbidity, mortality and healthcare costs. In the recent decade, the rate of general pediatric VTE has dramatically increased across all age ranges, from neonates to adolescents. This increase is likely multi-factorial, including more aggressive management of critically ill patients, improved survival of children with chronic disease and the increased use of central venous catheters (CVCs). Cystic fibrosis (CF) is a chronic, inflammatory disease process often managed with courses of intravenous antibiotics administered through CVCs, both peripherally inserted central catheters (PICC) and implantable venous ports. There are limited data documenting an increased risk of VTE in CF patients with ports. However, there are no published data on PICC line-associated VTE or overall VTE incidence specifically in the pediatric CF population.

Methods: A retrospective cohort study was conducted in CF patients, ages 0 to 21 years, followed at the CF Care Center at Children's Hospital Colorado between 2003 and 2016, who were enrolled in the national CF Foundation Patient Registry. VTE cases were identified by informatics, including anticoagulation administration, documentation of VTE in radiographic reports and nursing flowsheets, and use of VTE ICD-9 and ICD-10 codes. All identified cases were confirmed by manual chart review and data including personal and family history of VTE, use of prophylaxis and VTE type, diagnosis date, diagnostic modality and line-association were entered into a secured REDCap longitudinal database. Data including CF mutation, CF co-morbidities, microbiology history, pulmonary function testing, disease modifying medications, thrombophilia testing and central line specifications and duration were collected for every admission on all study participants to allow for future risk factor analysis.

Results: The cohort consisted of 488 participants with a total of 2,590 admissions (mean 5.34 per participant, range 1-56). Two hundred and forty-nine individuals were male (51%) and the majority were Caucasian (463, 95.3%) with a normal BMI (average 19.7, range 14.8-25.4). A total of 1,157 CVCs were placed over the study period including 981 PICCs (84.8%), 93 ports (8%) and 83 unspecified (7.2%). Thirty-one VTEs were diagnosed in 23 participants (4.3%) on 29 admissions (1.12%). Twelve of the 23 participants with VTE were male (52%) and the average age of those with VTE was 15.3 years (range 4-21). Twenty-two of the VTEs were deep vein thromboses, including 4 pulmonary emboli, and 9 were in superficial veins. The average day of VTE diagnosis was hospital day 4.9 (range 0-14). At the time of diagnosis, 11 had ports, 15 had PICCs and 5 had no CVC. The majority of VTEs were associated with the CVC (19, 61.3%) and of those CVC-associated VTEs, the majority were seen with PICCs (14, 73.7%). On average, PICC-associated VTE occurred on line day 5.2 (range 2-14) and port-associated VTE occurred on line day 897.5 (range 37-1496). Of the 23 participants with VTE, 14 were tested for Factor V Leiden mutation and 2 were heterozygous. Similarly, for the prothrombin mutation, 13 were tested and two were heterozygous. While the majority of participants had minimal to no thrombophilia evaluation, notably, an elevated factor VIII was associated with 11 of 12 VTE diagnoses (91.7%, average 215.47, range 61-341.3).

Conclusion: In this large pediatric cohort of patients with CF, there was an increased number of VTE when compared to previously published general pediatric populations. Consistent with known risk factors, the average participant with VTE was in their teenage years and had a CVC, although 16% occurred without a line in place. Gender and obesity did not appear to contribute dramatically as the male/female distribution was roughly equal and the average BMI was within normal range. If a CVC was placed, the vast majority of CF patients received PICCs. PICCs also made up the majority of CVC-associated VTE with the average thrombosis occurring on day 5 following line placement. Few participants with VTE had complete thrombophilia evaluations but of those that did, factor VIII was elevated in all but one individual.