Cancer-associated thrombosis in children

Venous thromboembolism (VTE) is one of the leading causes of death in adult cancer patients and represents a challenge in pediatric cancer patients.

In children, cancer-associated thrombosis (CAT) has a prevalence of up to 16% for symptomatic to 40% for asymptomatic cases and increases the risk of death and VTE-related morbidity [1]. VTE rates are higher in children with cancer than without. A population-based cohort study estimated the absolute VTE rate to be  1.52 per 1,000 person-years (95% CI: 0.57–4.06) in children with cancer compared to 0.06 per 1,000 person-years (95% CI: 0.02–0.15) in children without cancer [2].

As with adults, VTE occurrence depends on the cancer type. The rate of VTE per 1,000 person-years was 0.9 (95% CI: 0.1–6.1) in leukemia/lymphoma patients, 8.1 (95% CI: 2.0–33.0) in soft tissue sarcoma/bone tumors patients and 4.0 (95% CI: 0.6–29.0) in patients with cancer in other sites [2]. Although adults with brain cancer have a high risk of developing VTE throughout the course of the disease, children with brain cancer seem to have a low VTE risk [3].

The etiology of VTE in children with cancer is multifactorial and involves genetic predisposition, disease-related factors, and treatment-related factors. These include the use of a central venous catheter (CVC), surgery, and chemotherapy.

 

Pediatric VTE risk factors: cancer-related hypercoagulability

Every tumor causes a prothrombotic state due to the ability of tumor cells to activate the coagulation system. Many prothrombotic factors have been recognized in cancer: procoagulant/fibrinolytic substances and inflammatory cytokines secretion, physical interaction between the tumor cell and blood or vascular cells, generation of acute phase reactants, necrosis, abnormal protein metabolism, and hemodynamic compromise [4].

Cancer cells shed procoagulant microparticles, which also contribute to the patient’s hypercoagulable state. Tumor cells present tissue factor on their surface that, together with the coagulation factors in the peritumor surround, causes thrombi formation. Moreover, tumor cells can downregulate the antithrombotic factors and anticoagulant pathways [5].

For more information on the molecular mechanism of VTE in cancer patients, read “Interplay between the hematologic system and solid tumor progression.”

 

Pediatric VTE risk factors: the mass effect

Any tumor with mass effect can impair blood flow and increase the risk of VTE. For example, a mediastinal mass in children with lymphoma increases the risk of VTE by compressing the upper extremity veins. VTE increased the rate of adverse events to 41% in children with thrombosis compared to 21.2% in children without thrombosis [1]. In another study, 92.7% of children with Hodgkin lymphoma that developed VTE had a mediastinal mass [6].

 

Pediatric VTE risk factors: CVC

Children with cancer require intravenous administration of chemotherapy and other therapies for a considerable period. For this reason, children with cancer often carry a CVC to easily administer those therapies and avoid repeated venipunctures. Although CVC greatly improves pediatric patients’ quality of life, it is also associated with mechanical, infectious and thrombotic complications.

The rate of symptomatic catheter-related VTE ranges from 2.6% to 36.7%, and for asymptomatic catheter-related VTE, the incidence is even higher, from 5.9% to 43% [7]. Another study highlighted that that the risk of CVC occlusion is strongly associated with a family history of thrombosis, type of CVC, place (e.g., angiography suite), and placement of the tip. The insertion of peripherally inserted central catheters and an angiography suite significantly increased the risk of symptomatic CVC‐related deep vein thrombosis [8].

 

Pediatric VTE risk factors: treatment

Cancer treatments are a VTE risk factor themselves. Chemotherapy agents influence hemostatic proteins and cause endothelial damage and secondary infections that increase the risk of VTE. Chemotherapy can activate platelets and induce tissue factor release, which is further increased by apoptosis resulting from chemotherapy [9].

Other risk factors for VTE are l-asparaginase, used for acute lymphoblastic leukemia treatment, one of the most common cancer in children, and steroids. l-asparaginase affects coagulation in many ways, such as reducing antithrombin, and steroids increase factor VIII and von Willebrand factor, contributing to prothrombotic risk [7].

VTE can have serious consequences for cancer patients, including death. In children with leukemia, the central nervous system (CNS) is one of the most common venous thromboembolism locations. A prospective multicenter cohort of 20 children with acute lymphoblastic leukemia highlighted a cumulative incidence of cerebral sinus venous thrombosis of 2%, with 16 of the thromboses related to asparaginase and 16 to steroids. Cerebral sinus venous thrombosis directly or indirectly led to mortality in 10% of the cases [10].

 

Treatment

Anticoagulation therapy is used to prevent thrombosis; however, anticoagulants in cancer patients are a tricky matter, considering the high risk of bleeding among these patients. The American College of Chest Physicians guidelines recommends at least three months of anticoagulation for DVT associated with cancer, followed by extended therapy if no clot resolution has occurred. Prophylaxis with low-molecular-weight heparin (LMWH) should be continued if any of the following risk factors exist active cancer, CVC, and chemotherapy [11]. A  CVC should be left in place as long as it is functional and necessary for treatment.

Because children are less prone to thrombosis than adults, primary anticoagulant prophylaxis is not recommended [9].

Anticoagulant drugs in children can be divided into the older multitargeted agents – heparin, LMWH and warfarin – and the newer targeted agents – argatroban, bivalirudin and fondaparinux. These anticoagulants have several limitations for use in children, and their dose regimens are still extrapolated from adult guidelines because well-designed clinical trials were never performed in children.

Recently, a series of direct oral anticoagulants (DOACs) have been developed to prevent and treat thrombosis in adults. DOACs have several advantages for children: oral administration is easier, they have predictable pharmacokinetics, little food and drug interaction, and possibly no monitoring is required. There is not much information on the safety and efficacy of DOACs in children, and no guidelines are available, but several pediatric trials on all approved DOACs are currently ongoing. The first results of phase III trials indicate that DOACs are at least as efficient and safe as LMWH and vitamin K antagonists for the treatment and prevention of thrombotic events in children with different clinical conditions [12]

Much more study is needed on this topic, but DOACs are promising to treat VTE agents in children with or without cancer.

References

1. Athale U. Thrombosis in pediatric cancer: identifying the risk factors to improve care. Expert Rev Hematol. 2013;6(5):599-609.
2. Walker AJ, Grainge MJ, Card TR, West J, Ranta S, Ludvigsson JF. Venous thromboembolism in children with cancer – a population-based cohort study. Thromb Res. 2014;133(3):340-344.
3. Tabori U, Beni-Adani L, Dvir R, et al. Risk of venous thromboembolism in pediatric patients with brain tumors. Pediatr Blood Cancer. 2004;43(6):633-636.
4. Caine GJ, Stonelake PS, Lip GY, Kehoe ST. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia. 2002;4(6):465-473.
5. Schönning A, Karlén J, Frisk T, et al. Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden. Thromb Res. 2017;152:64-68.
6. Ko RH, Thornburg CD. Venous Thromboembolism in Children with Cancer and Blood Disorders. Front Pediatr. 2017;5:12.
7. Revel-Vilk S, Yacobovich J, Tamary H, et al. Risk factors for central venous catheter thrombotic complications in children and adolescents with cancer. Cancer. 2010;116(17):4197-4205.
8. Barg AA, Kenet G. Cancer-associated thrombosis in pediatric patients. Thromb Res. 2020;191 Suppl 1:S22-S25.
9. Ranta S, Tuckuviene R, Mäkipernaa A, et al. Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia – a multicentre study from the Nordic Society of Paediatric Haematology and Oncology. Br J Haematol. 2015;168(4):547-552.
10. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines [published correction appears in Chest. 2012 Dec;142(6):1698-1704]. Chest. 2012;141(2 Suppl):e419S-e496S.
11. Albisetti M. Use of direct oral anticoagulants in children and adolescents. Hamostaseologie. 2020;40(1):64-73.