Thrombolytic Therapy for Venous Thromboembolism in the Pediatric Population: A Systematic Review and Meta-Analysis

Introduction: VTE in pediatric patients is usually managed with anticoagulation (AC), however, thrombolytic therapy may be necessary to rapidly restore venous patency in cases of life- or limb-threatening VTEs. The available evidence on the benefits and outcomes of thrombolysis in pediatric VTE is limited. We performed a systematic review and meta-analysis of the literature to evaluate the outcomes of thrombolytic therapy in pediatric patients with VTE.

Methods: As part of the American Society of Hematology/International Society on Thrombosis and Haemostasis guidelines on the management of VTE, we searched the published literature in PubMed, Embase, and The Cochrane Central Register of Controlled Trials, from inception till February 2024. Two reviewers independently screened the studies to assess their eligibility using Covidence systematic review software (Australia). A study was included if it addressed thrombolytic therapy outcomes in pediatric patients (<21 years old) with VTE. We statistically pooled estimates using Review Manager (5.4) using a random effect model. Reviewers assessed the risk of bias using Risk of Bias in Non-randomized Studies - of Interventions (ROBINS-I) tool and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Results: After screening 8925 references, we found a total of 9 eligible studies: 2 for submassive pulmonary embolism (PE) (n=31), 3 for massive PE (n=35), and 5 for deep vein thrombosis (DVT, n=108).When comparing thrombolytic therapy to standard AC in patients with submassive PE,thrombolytic therapy might decrease the risk of progression from submassive to massive PE with an absolute risk (95% confidence interval [CI]) of 40 fewer per 1,000 (from 106 fewer to 892 more). Thrombolysis has no effect on the rates of thrombus resolution with an absolute risk (95% CI) of 0 per 1,000 (from 360 fewer to 560 more). There were no events of chronic pulmonary hypertension or bleeding in either group. Out of 19 patients, there was one death in the standard AC group compared to 0 out of 14 in the thrombolysis group.In patients with massive PE, thrombolytic therapy may decrease mortality rates with an absolute risk (95% CI) of 60 fewer per 1,000 (from 290 fewer to 425 more) and may increase the risk of thrombosis recurrence with an absolute risk (95% CI) of 228 more per 1000 (from 86 fewer to 1000 more). Bleeding was not estimable with 1 event out of 7 patients in the thrombolysis group versus no bleeding on 1 patient in the standard AC group.

In patients with DVT, when compared to standard AC, thrombolytic therapy has little to no effect on mortality, recurrence of thrombosis, and major bleeding with an absolute risk (95% CI) of 3 fewer per 1,000 (from 76 fewer to 346 more), 3 fewer per 1,000 (from 76 fewer to 346 more), and 22 fewer per 1,000 (from 82 fewer to 444 more), respectively. For CRNMB, 1 event out of 42 occurred in the AC group. Thrombolytic therapy might increase the rate of thrombus resolution, and risk of PTS when compared to standard AC, with an absolute risk (95% CI) of 200 more per 1,000 (from 7 fewer to 469 more), and 333 more per 1,000 (from 88 fewer to 1,000 more), respectively.

The certainty of evidence for all estimates is very low due to concerns related to risk of bias and imprecision because of the small number of patients.

Conclusion:The certainty of the evidence is very low (very small sample size and high risk of bias) which limits our ability to make definitive conclusions on the benefits and short-term and long-term outcomes of thrombolysis in children.

Betensky:Zoll: Honoraria; Abbot: Honoraria; Aziyo: Honoraria; Boston Scientific: Honoraria; NHLBI K23: Research Funding. Brandao:AstraZeneca: Other: Ad board meeting on andexanet alfa (Feb. and Jun. 2023/ISTH - Montreal/QC, Canada; Pfizer/Bristol Myers Squibb: Research Funding. Chan:Bayer: Honoraria, Other: clinical trials, Research Funding; C17: Research Funding; Canadian Hemophilia Society: Research Funding; CIHR: Research Funding; Novo Nordisk: Honoraria, Other: clinical trials, Research Funding; Daiichi: Other: clinical trials; Pfizer: Other: clinical trials; Sanofi: Honoraria, Other: clinical trials; Sobi: Other: clinical trials; Takeda: Honoraria, Other: clinical trials; Roche: Honoraria. Kerlin:Aurinia: Research Funding. Kucine:Protagonist Therapeutics: Consultancy; PharmaEssentia: Consultancy; AOP Health: Other: Conference Presenter. Raulji:Abbvie: Current holder of stock options in a privately-held company; Vertex Pharmaceuticals: Current holder of stock options in a privately-held company. Sartain:Alexion Discovery Partnerships: Research Funding. Takemoto:Merck: Consultancy, Honoraria; Novartis: Other: DSMB; Pfizer: Research Funding; Novo Nordisk: Research Funding. Tarango:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wilson:Octapharma: Consultancy. Zia:Star Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; COR2ED GmbH: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Membership on an entity's Board of Directors or advisory committees.