Acute lymphoblastic leukemia (ALL), the most common type of childhood cancer, has cure rates exceeding 90% among pediatric patients. Asparaginase or its prolonged formulations, polyethylene glycol (PEG)-asparaginase and, more recently, calaspargase pegol (Vrooman et al., 2021), have been part of the backbone of ALL therapy for over 40 years. Omitting asparaginase doses is associated with inferior disease-free survival (DFS) in patients with high-risk ALL (Gupta et al., 2020). However, venous thromboembolism (VTE) is a frequently observed and severe side effect of asparaginase therapy. Asparaginase may increase platelet aggregation and enhance endothelial activation by increasing the levels of soluble P-selectin, high molecular weight von Willebrand factor antigen and plasminogen activator inhibitor-1 (Goyal and Bhatt, 2015). Asparaginase reduces the naturally occurring anticoagulation proteins: protein C, protein S, and antithrombin (Beinart and Damon, 2004, Truelove et al., 2013). The nadir of antithrombin depletion occurs within 10 days following the initial dose of asparaginase and the decline of antithrombin level can be sustained for 3 weeks following administration of PEG-asparaginase (Zwicker et al., 2020). Asparaginase (ASP), especially PEG-ASP, can induce hypertriglyceridemia (Lee et al., 2022) and higher hypertriglyceridemia is associated with severe VTE (Barzilai-Birenboim et al., 2020). Additionally, steroids and inflammatory states may cause elevation of factor VIII, plasminogen activator inhibitor-1, and von Willebrand factor which may contribute to thrombosis development (van Zaane et al., 2010, Majoor et al., 2016).

The incidence of VTE in patients with ALL is approximately 3.7–43%, varying by detection method and age (Truelove et al., 2013, Mitchell et al., 2003a, Rank et al., 2018, Fulcher and Carrier, 2020, Grace et al., 2011).The physiological concentration of coagulation factors gradually increases over age. The risk of VTE has an exponential increase with age (Previtali et al., 2011). Younger healthy populations have decreased potential to generate thrombin and decreased tendency for fibrin formation (Ignjatovic et al., 2015). Age is the most significant predictor for VTE in patients with ALL following the similar trend in other cancer and non-cancer counterparts (Cushman, 2007). The incidence of VTE significantly increased to above 20% in patients older than 10 years (Grace et al., 2011, Athale et al., 2022). VTE often involves upper extremity veins, particularly when a central venous catheter is used. Central nervous system thrombosis and other major VTE may cause significant morbidity including long-term neurological consequences.

Several thrombosis treatment guidelines are available (Monagle et al., 2012, Monagle et al., 2018, Stevens et al., 2021), but the VTE-preventive strategies, especially during ALL treatment, are not uniformly defined. Thus, evaluating the mechanisms of VTE in leukemia may direct VTE prophylaxis strategies. Having a leukemia diagnosis combined with treatment with asparaginase and corticosteroids are some of the many thrombotic risk factors in patients with ALL. Other factors include having central venous catheters, a mediastinal mass, surgical procedures, prolonged immobility, infections, nephrotic syndrome, and trauma.

The common treatment options for VTE include unfractionated heparin, low molecular weight heparin (LMWH) derivatives, and vitamin K antagonists like warfarin. Other alternatives could include direct factor Xa or thrombin inhibitors such as bivalirudin, argatroban, apixaban, and fondaparinux, and the new direct oral anticoagulants (DOAC). Only antithrombin, LMWH, at earlier time fresh frozen plasma (FFP), and lately some direct Xa or thrombin inhibitors have been tested for primary thromboprophylaxis (O'Brien et al., 2019, Lassen et al., 2010, Tun and Oo, 2013, Adam et al., 2013). Antithrombin is a cofactor of heparin and LMWH, and naturally works to inhibit factors IIa and Xa, the prothrombotic factors. It is refractory to treat thrombosis with heparin unless antithrombin levels are restored. Because antithrombin reduction is one of the major mechanisms for thrombosis risk in ALL patients, many investigators have studied the role of antithrombin replacement in VTE prophylaxis and confirmed increased plasma antithrombin activities after administration of antithrombin concentrates (Mattioli Belmonte et al., 1991, Mazzucconi et al., 1994, Nowak-Gottl et al., 1996, Matsuzaki et al., 2002). The data about whether replacing antithrombin can prevent ASP-induced VTE in patients with ALL are conflicting (Chen et al., 2019, Farrell et al., 2016).

LMWH has been used widely in both the treatment and prevention of VTE in different conditions. Some studies demonstrated promising outcomes of using LMWH to prevent VTE development (Sibai et al., 2020). Others were unable to confirm the benefit of LMWH to reduce the risk of thromboses in ALL patients (Klaassen et al., 2017). FFP, which contains antithrombin, did not significantly ameliorate antithrombin or fibrinogen levels, and its supplementation was not beneficial in the prevention of VTE in pediatric ALL patients (Klaassen et al., 2019, Halton et al., 1994).

The most recent systematic review for prophylaxis of thromboembolism during asparaginase therapy in ALL was focused on adults in 2020 (Rank et al., 2020). In pediatrics, there are few large-scale randomized prospective studies (Orvain et al., 2020) that definitively support one regimen over another. To fill this gap, we conducted a meta-analysis aiming to offer a comprehensive literature review on the efficacy of LMWH, antithrombin, and other methods in preventing VTE in patients with newly diagnosed ALL. Our approach expanded the scope of previous reviews by encompassing all age groups and subsequently conducting subgroup analyses based on age. Utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, this study meticulously evaluates the certainty and quality of evidence associated with each thromboprophylactic management method, thereby augmenting the accessibility and reliability of the results.