Prof. Gili Kenet is a Pediatric Hematologist, Professor and Chair of the Haematology Department at the Sackler Medical School, Tel Aviv University; Chair of the Amalia Biron Research Institute of Thrombosis and Hemostasis at Tel Aviv University; and the Director of the Israel National Hemophilia Center and Thrombosis Institute in the Sheba Medical Center, Israel.
During the 10th ICTHIC, she talked about cancer-associated thrombosis in the pediatric setting, and we had the opportunity to have an interview with her in this regard.
In the last 30 years, Prof. Kenet has dealt with children with hemostatic problems, either bleeding or thrombosis. Cancer is associated with children’s thrombosis, and children with cancer develop thrombotic complications.
What is the incidence of venous thromboembolism in pediatric cancer patients?
Cancer is found in 20% of children with venous thromboembolism (VTE). The most common malignancy is acute lymphoblastic leukemia (ALL), which has an important impact on the pathogenesis and development of VTE in children .
In a recent population-based cohort study, the absolute rate of VTE in children with cancer was 1.52 per 1000 person-years versus only 0.06 per 1000 person-years in controls .
Compared to the general pediatric population, children with cancer who develop thromboembolism (TE) have an increased risk of death, TE recurrence, TE-related morbidity, and a higher potential for utilization of healthcare resources .
The incidence of VTE in cancer pediatric patients can vary, depending on how it is calculated and the type of study, retrospective or prospective. Prospective studies find higher incidence than retrospective ones, and studies that screened for asymptomatic VTE reported higher prevalence than studies addressing symptomatic cases only .
The reported prevalence ranges from up to 16% of symptomatic to 40% of asymptomatic TE in children with cancer. However, the prevalence in children with ALL, including asymptomatic cases, may reach up to 73% in some studies .
Finally, hematological malignancies have a higher incidence of VTE compared with solid tumors.
What are the main risk factors of VTE in pediatric patients?
The risk factors can be patient-dependent, disease-dependent and treatment-dependent.
Patients with cancer may have inherited and acquired thrombophilic risk factors, which can increase their risk of VTE. Factor V Leiden, deficiency of protein C, protein S and antithrombin are some of the inherited risk factors that can play a role in the risk of VTE in pediatric cancer patients.
ALL therapies can also exacerbate the inherited deficiency of antithrombin, protein C and protein S. In contrast, factor V Leiden combined with asparagine therapy may increase the effects of the suppression of protein C and protein S.
Among the disease-dependent factors, tumor mass may impair blood flow and cause stasis, increasing the risk for VTE. In children with lymphoma, the presence of mediastinal mass may compress the upper extremity veins .
In addition, by invading vessels, cancer cells may increase thrombosis risk, which may be later augmented by surgery .
Cancer cells produce and release procoagulant, fibrinolytic proteins and proinflammatory cytokines, which increase the risk of VTE. They can adhere to the host cells and shed procoagulant microparticles that contribute to the patient’s hypercoagulable state. Other tumor-related elements that can facilitate thrombi formation are the presence of the tissue factor on the surface of tumor cells and the availability of coagulation factors in the peritumor .
For more information, read “Interplay between the hematologic system and solid tumor progression” and “The role of microparticles in VTE.”
What is the use of direct oral anticoagulants in pediatric cancer patients?
Most children with cancer-associated thrombosis are still treated with low-molecular-weight heparin. Unlike adults, direct oral anticoagulants (DOACs) have not been approved in the pediatric population until recently, when rivaroxaban was approved for pediatric use by the EMA and the FDA.
The phase III Einstein Jr multicenter randomized controlled study (NCT02234843) showed that rivaroxaban is safe and effective in children with VTE. It involved 500 children, 10–12% of which were pediatric active cancer patients, with the purpose to evaluate comparative efficacy and safety of rivaroxaban to the standard of care in children with acute VTE [8,9].
Another study, the DIVERSITY (NCT01895777), compared the efficacy and safety of dabigatran etexilate to the standard of care in pediatric patients with VTE. The results indicate that dabigatran was non-inferior to the standard of care in terms of efficacy and might be a suitable alternative to care standards. However, in this study, there was not a represented population for cancer patients .
Therefore, the use of DOACs in children will certainly increase in the future, but it will take time since many drugs are not registered yet for pediatric cancer patients.
What strategies could be used to increase the awareness of the risk of thrombosis in the pediatric population?
Thrombosis in children results from the interaction of individual- and tumor-related risk factors and greatly impacts children’s lives. Early diagnosis and treatment may prevent future morbidity and mortality. We need to increase awareness and prevention of modifiable risk factors. The ongoing studies on the use of DOACs in pediatric cancer patients may help in the future for VTE prevention.
To raise awareness, information should be provided to pediatric patients, and caregivers and media should be involved.
“If you are aware of the risks, then you can diagnose, if you can diagnose then you can treat, if you can treat, then you can reduce the rate of complications,” concluded Prof. Kenet.
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- Barg AA, Kenet G. Cancer-associated thrombosis in pediatric patients. Thromb Res. 2020;191(Suppl 1):S22-S25.
- Forbrigger Z, Kuhle S, Brown MM, Moorehead PC, Digout C, Kulkarni K. The association of venous thromboembolism with survival in pediatric cancer patients: a population-based cohort study. Ann Hematol. 2018;97(10):1903-1908.
- Athale U. Thrombosis in pediatric cancer: identifying the risk factors to improve care. Expert Rev Hematol. 2013;6(5):599-609.
- Levy-Mendelovich S, Barg AA, Kenet G. Thrombosis in pediatric patients with leukemia. Thromb Res. 2018;164(Suppl 1):S94-S97.
- Athale UH, Nagel K, Khan AA, Chan AK. Thromboembolism in children with lymphoma. Thromb Res. 2008;122(4):459-465.
- Bordbar M, Karimi M, Shakibazad N. Thrombosis in pediatric malignancy: a review and future perspectives with focus on management. Blood Coagul Fibrinolysis. 2018;29(7):596-601.
- Falanga A, Russo L, Milesi V, Vignoli A. Mechanisms and risk factors of thrombosis in cancer. Crit Rev Oncol Hematol. 2017;118:79-83.
- Thom K, Lensing AWA, Nurmeev I, et al. Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE). Blood Adv. 2020;4(19):4632-4639.
- Male C, Lensing AWA, Palumbo JS, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2020;7(1):e18-e27.
- Halton J, Brandão LR, Luciani M, et al. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021;8(1):e22-e33.