Discussion
Our experience in children demonstrates that CDT, in combination with systemic anticoagulation, is a safe and effective treatment modality for life- or limb-threatening thrombosis. Of the 29 patients that were included in the analysis there was only one major19and three non-major bleeding events that were described. The major bleed involved a precipitous drop in the hemoglobin of a neonate following the interventional procedure that required multiple blood transfusions, while the minor bleeds only required temporary cessation of CDT and anticoagulation to resolve. This review also provides descriptive information that may help pediatric hematologists and IRs prepare the post-procedural expectations of staff and patients, including post-procedural decline in hemoglobin (2.3 g/dL), and platelets (50,000 cells/dL), with ~25% of patients requiring a transfusion after the procedure.
The rate of complete thrombus resolution of 34.5% in our patient cohort compares favorably to other studies evaluating outcomes of LE DVT in children. Specifically, the findings by Avila et al. noted a complete resolution rate between 19.6 and 30.9% in neonates and non-neonates at the end of therapy images.21 Our thrombosis resolution rate is notable due to the extent of thromboses that were included in our study, with 93% having multiple segments of occlusion, and those patients who are selected for thrombolysis at our institution have increased vascular compromise, secondary to extensive thrombosis, compared to those treated with anticoagulation alone. Our findings also add to the evidence that Hispanic patients affected with vascular disease have worse outcomes (in our case, thrombus resolution) than those patients that identify as non-Hispanic,22-24with no Hispanic identifying patients experiencing thrombus resolution compared to 45.5% of non-Hispanic patients. This may suggest the need for more aggressive interventional and medical approaches in Hispanic children with LE or IVC DVT.
Patients that received the anticoagulant rivaroxaban during their treatment course had a 6-fold increase in the rate of thrombus resolution, which remained significant after controlling for ethnicity. The direct oral anticoagulant rivaroxaban is becoming increasingly used for VTE in children,25 with the advantages of not requiring laboratory monitoring and the ease of oral administration. While we cannot conclude on reasons for the enhanced efficacy of this drug, it may be secondary to better compliance over other agents in our population. Our data suggests that the medication should be considered for anticoagulation in children affected with extensive LE and IVC thrombosis, especially in the adolescent age range due to ease of dosing regimen. It is important to note, however, that rivaroxaban is not currently approved by the FDA for use in children. The risk factor of estrogen-containing oral hormonal therapy (a reversable thrombosis risk factor upon cessation of the medication) was also associated with thrombus resolution.
In general, most devices used in pediatrics are considered “off-label,” as they do not have specific pediatric approval. The use of Angiojet for patients less than 18 years of age has not received approval via the FDA, and studies are not available in the pediatric population. A thorough review of the literature does not suggest a detrimental safety profile for device use in the less than 18-year-old population, and multiple studies have documented use of the Angiojet in this population without significant incident.26,27 It is important to note that patients can have temporary bradyarrhythmia as a result of the use of this device, regardless of which vascular territory it is being used in.28
Based on the analysis of our data, the use of Angiojet as part of interventional therapy during pediatric thrombolysis trends to improved resolution of the thrombus burden. While this might be a part of the impact of aggressive utilization of tPA, as this trend was also noted with relatively better thrombus clearance and less progression in our “on-table” tPA administration only cohort, the use of the thrombolytic function of the Angiojet with “lace and lyse” delivery of tPA may be a superior modality for interventional thrombolysis. The use of tPA in this cohort can assist with thrombus clearance and potentially avoid mandated ICU stays associated with CDT. Furthermore, these results will lead us to consider changing our practice to using the Angiojet device with “on-table” tPA when the circumstances permit.
In addition, as has been noted in multiple adult studies, the use of tPA for venous thrombolysis carries a relatively low risk profile in the pediatric population.29-32 One does need to be careful in this population as pediatric patients process tPA differently than adults. It is known that neonates and young infants have lower plasminogen levels than older children and adults33which may lead to inadequate fibrinolysis unless plasminogen is supplemented.34
There is a valid concern with respect to intra-procedural blood loss with the use of thrombectomy or thrombolysis devices. All utilized devices carry some risk of direct or indirect blood loss with their utilization; e.g. the hemolytic side effect of the Angiojet and the potential for blood loss with other aspiration devices. We did note that our patients experienced decrease in their hemoglobin (>2g/dL) regardless of whether it required intervention.
Limitations of this study include its retrospective nature and limited sample size. As treatment decisions were not randomized but at the discrepancy of the treating physicians, it is difficult to make direct comparisons of treatment approaches between patients. This review does, however, provide a baseline understanding for this important and growing population and allows our institution and others the ability to develop systematic and uniform approaches to pediatric patients with extensive LE and IVC thrombosis. We will continue to evaluate outcomes and adverse events with pediatric thrombolysis moving forward, including the use of a dedicated outcomes survey.
In conclusion, the experience at our pediatric institution demonstrates that tPA administration, whether by CDT or as an intra-procedural bolus, in combination with anticoagulation is an effective and safe approach to extensive pediatric LE and IVC thrombosis. The improved thrombosis resolution rate with rivaroxaban needs additional future investigation, though is encouraging for pediatric patients requiring thrombolysis for acute thrombosis. Future prospective and multi-institutional studies are needed to develop a widely accepted and optimized approach to pediatric thrombolysis.
Conflict of Interest Statement: The authors of this manuscript have no conflicts to disclose; no funding was received for this work.
Data sharing statement : The data that support the findings of this study are available from the corresponding author upon reasonable request.