Abstract: Three RCTs and three CCTs (including 1291 children) investigated the prevention of VTE (low molecular weight heparin (LMWH) n = 134, antithrombin (AT) supplementation n = 37, low-dose warfarin n = 31, cryoprecipitate and/or fresh frozen plasma (FFP) supplementation n = 240, AT supplementation and LMWH n = 41). AT, cryoprecipitate and FFP were supplemented only in cases of AT or fibrinogen deficiency. Of the six included RCTs/CCTs, five investigated the prevention of VTE compared with no intervention (n = 737), and one CCT compared AT supplementation and LMWH with AT supplementation (n = 71). All studies had methodological limitations, and clinical heterogeneity between studies was noted. We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE and no differences in adverse events (such as major and/or minor bleeding; none of the studies reported thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia with thrombosis (HITT), death as a result of VTE, removal of CVC due to VTE, CVC-related infection, and post-thrombotic syndrome (PTS)) between experimental and control groups. Two studies with comparable participant groups and interventions were included for meta-analyses (n = 182). In the experimental group, 1/68 (1.5%) children were diagnosed with symptomatic VTE, as were 4/114 (3.5%) in the control group (best case scenario: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.09 to 4.78). These studies also evaluated asymptomatic CVC-related VTE: In the experimental group, 22/68 (32.4%) were diagnosed with asymptomatic VTE, as were 35/114 (30.7%) in the control group (best case scenario: RR 1.02, 95% CI 0.40 to 2.55). Heterogeneity was substantial for this analysis: I2 = 73%. The attribution of LMWH to AT supplementation resulted in a significant reduction in symptomatic VTE (Fisher's exact test, two-sided P = 0.028) without bleeding complications; asymptomatic VTE, thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection and PTS were not assessed. Four cohort studies were included for the evaluation of adverse events. Three studies provided information on bleeding episodes: One participant developed an ischaemo-haemorrhagic stroke. One study provided information on other adverse events: None occurred. We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE in paediatric oncology patients with CVCs. However, this could be a result of the low number of included participants, which resulted in low power. In one CCT, which compared one systemic treatment with another systemic treatment, we identified a significant reduction in symptomatic VTE with the addition of LMWH to AT supplementation. All studies investigated the prevalence of major and/or minor bleeding episodes, and none found a significant difference between study groups. None of the studies reported thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection or PTS among participants. On the basis of currently available evidence, we are not able to give recommendations for clinical practise. Additional well-designed international RCTs are needed to further explore the effects of systemic treatments in preventing VTE. Future studies should aim for adequate power with attainable sample sizes. The incidence of symptomatic VTE is relatively low; therefore, it might be necessary to select participants with thrombotic risk factors or to investigate asymptomatic VTE instead.

Plain-language summary: In this review, we investigated whether systemic treatments can prevent thrombosis. We identified six studies; two studies investigated low molecular weight heparins, one antithrombin supplementation and one cryoprecipitate and/or fresh frozen plasma supplementation; one study compared antithrombin supplementation with low molecular weight heparin and antithrombin supplementation, and another investigated warfarin. The addition of low molecular weight heparins to antithrombin supplementation did result in a lower number of symptomatic thromboses. This was statistically significant. We could not detect an effect of systemic preventive treatments in comparison with no treatment, and no difference was noted in the number of participants who suffered from major or minor bleeding. However, the overall number of participants was very small; a similar study with a larger population of participants might yield different results.