The ASH ISTH 2026 guideline addresses the prevention of venous thromboembolism (VTE) in high-risk pediatric populations. A multinational panel of 22 experts worked on the development of this document using the GRADE methodology. The expert group united specialists from various fields, including hematologists, cardiologists, and patient representatives. The presented recommendations represent a systematic analysis of randomized controlled trials (RCTs) and observational studies.
Cases of hospital-acquired VTE in pediatric patients are increasing at an alarming rate. Since this problem ranks second among the causes of preventable harm, the new guidelines shift strategy: instead of a universal approach, the focus is now placed on risk-stratified decisions.
The goal of the guideline is to find a reasonable balance between reducing the risk of VTE and the threats of bleeding. In making this decision, taking the interests of the patient and the family into account is paramount. These fundamental principles extend to categories such as oncology patients, individuals with central venous access devices (CVADs), traumatic injuries, and critical conditions.
However, it must also be considered that prophylaxis is usually selectively administered to more severely ill patients, which inherently leads to risks of bias and data inaccuracy. Consequently, all recommendations are assigned a low or very low degree of certainty, which reflects the reality of VTE prophylaxis research in the pediatric population rather than a flaw in the guideline.
Prevention of Thromboembolism in Oncology Patients
In children undergoing asparaginase therapy for acute lymphoblastic leukemia or lymphoblastic lymphoma, the panel issues a conditional recommendation for either administering or withholding anticoagulant prophylaxis. This decision is based on the results of two RCTs and three non-randomized studies. However, despite a significant reduction in symptomatic VTE in these data, a benefit in terms of preventing overall VTE was still not recorded.
Prophylactic therapy demonstrates particular effectiveness in high-risk patients. This group primarily unites adolescents over 10 years of age, as well as individuals with obesity, T-cell immunophenotype, high-risk ALL, or a history of thrombosis. In such cases, conducting prophylaxis is justified only during the stage of asparaginase treatment. However, if the patient develops thrombocytopenia or requires surgical intervention, maintaining procedural intervals is essential.
In contrast, the panel does not support replacement therapy with antithrombin concentrate. Although very low-certainty data showed a reduced risk of VTE, this benefit was neutralized by a worsening of the event-free survival rate. It was precisely the negative clinical outcome that led to the rejection of the routine use of the preparation.
In the case of solid tumors and Hodgkin lymphoma, an analysis of four non-randomized studies showed a negligible effect on VTE prevention. Since the positive impact proved minimal, the guideline issues a conditional recommendation against prophylaxis.
Nevertheless, clinicians should still consider individual high-risk factors in adolescents. When making a decision, special attention is assigned to the use of oral contraceptives, tumor compression, and surgical intervention. Additionally, CVADs, prolonged immobilization, and genetic thrombophilia must also be taken into account.
Prophylaxis in Parenteral Nutrition and CVAD Cohorts
In children who are on home parenteral nutrition for more than 60 days, the guideline assigns preference to conducting prophylaxis. In this case, low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKA) are considered safe therapeutic alternatives. However, the mentioned approach does not extend to the neonatal age group or to cases of short-term treatment. This is due to the circumstance that the loss of venous access represents a vital threat to this category of patients.
In contrast, during the short-term use of a central venous access device (CVAD) (≤7 days), the guideline issues a conditional recommendation against prophylaxis. The mentioned approach relies on the results of the CRETE RCT and four observational studies. In these scientific materials, the therapeutic benefit proved inconsistent, while bleeding and mortality rates increased at least slightly. Exceptions are made only for children one year of age and older who are on mechanical ventilation, if they exhibit a low risk of bleeding.
An analogous approach extends to medium- and long-term CVADs (≥8 days) in non-oncology and non-TPN patients, where a recommendation for prophylaxis is not issued. The very low certainty of evidence is linked to one RCT subgroup, which failed to confirm an effect on VTE prevention. Consequently, in such cases, decisive importance is assigned to the individual risk assessment of each patient.
Individual Approaches in Antiphospholipid Syndrome
In pediatric patients who exhibit antiphospholipid syndrome (APS) and a history of thromboembolism (VTE), the guideline assigns conditional preference to secondary prophylaxis. The mentioned recommendation is based on the synthesis of four non-randomized studies. In these studies, the recurrence rate without treatment reached 21.3%, while the risk was significantly reduced against the background of anticoagulant therapy.
This approach is also reinforced by subgroup data from the DIVERSITY study. In these cases, the risk of bleeding proved minimal, although a fact of recurrent thrombosis was still recorded after the cessation of therapy. Furthermore, as a result of an expert survey involving 157 patients, it was established that major bleeding was revealed in only 1.27% of cases, while clinically relevant non-major bleeding (CRNMB) was found in 7.6%.
Taking adult data into account, the use of direct oral anticoagulants (DOACs) is contraindicated during triple-positive APS or arterial complications. Consequently, low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) remain the primary therapeutic choices. The selection of their dosage occurs individually in each case, based on the risks of recurrence and bleeding, as well as the patient’s lifestyle. Regarding antiplatelet-only schemes, they remained outside of consideration due to pre-defined methodological criteria.
In cases where a patient exhibits a solid positive indicator of antiphospholipid antibodies without thrombosis, conducting primary prophylaxis is not expedient. As a result of a survey of 88 patients, it was established that the risk of VTE without prophylaxis amounted to only 2%, whereas under conditions of prophylactic therapy, this figure increased to 20%, to which an analogous frequency of CRNMB was added. The mentioned data point to the accompanying difficulties and side effects of LMWH/VKA therapy. Accordingly, during autoimmune diseases, multi-positivity, high titers, or microvascular manifestations, the selection of management tactics requires a strictly individual approach.
Risk-Benefit Assessment in Trauma, Hospitalization, and Surgery
In pediatric patients with trauma, the guideline does not recommend routine prophylaxis. An analysis of ten studies involving 254,947 individuals showed that the average prevalence rate of VTE amounts to only 0.3%. Interestingly, a paradoxically high frequency of mortality and complications was recorded in the prophylaxis groups. This is likely the result of an error (selection bias) determined by clinical indications rather than the therapy itself. However, in high-risk subgroups (shock, age over 12, immobilization, intubation, CVAD), the complication rate reached 5.5–24%. The mentioned data support conducting early prophylaxis in specific cases, in accordance with internal institutional protocols.
The guideline maintains an analogous approach for hospitalized children as well. One randomized study confirmed that the use of LMWH does not essentially change the frequency of VTE (12% vs. 10%) compared to standard care. Observational data also showed that the benefit versus possible harm of therapy in this population is mostly negligible. Although pediatric recommendations do not always coincide with adult practice, high-risk adolescents (immobilization, estrogen intake, obesity, infection, inflammation) still require individual prophylaxis.
In patients with non-cardiac surgical profiles, the guideline does not recommend routine prophylaxis. According to data from five observational studies, the frequency of VTE practically did not differ between groups (1.0% vs. 0.9%), although a significant exception (7.4% vs. 32.5%) emerged in cases of esophageal atresia. While facts of bleeding were not recorded in the studies, prolonged surgery, long-term immobilization, CVAD (>7 days), obesity, thrombophilia, or the use of oral contraceptives still necessitate an individual assessment of each patient’s condition.
Critical Conditions: High Risks and Heterogeneity
In the case of children in critical condition, despite the presence of a central venous access device (CVAD), the guideline does not recommend routine prophylaxis. The mentioned approach is based on one randomized study (Faustino et al.) and five non-randomized scientific works. According to these materials, against the background of a high VTE prevalence rate (35%) and imprecise bleeding risks (median 3.7%), the total benefit of therapy is called into question.
High mortality rates and the exclusion of patients with a high risk of bleeding from studies point toward the necessity of treating only selected subgroups. Specifically, prophylaxis may be prescribed for patients (≥1 year) with non-tunneled CVADs or those on invasive mechanical ventilation who exhibit a low risk of bleeding.
Establishing the recommendation in practice still involves certain difficulties. Frequent refusal of treatment on the part of medical personnel or parents and the low compliance revealed in studies highlighted the need for additional resources. However, despite these challenges, the implementation of the mentioned approach into daily activity is still possible.
Anticoagulant Regimens
The sharp diversity of anticoagulant regimens made the development of a unified, standardized manual practically impossible. Low-molecular-weight heparin (LMWH) predominated in most studies (72%), the dosage of which fluctuated within the range of 0.5–1.5 mg/kg once or twice a day. Along with this, monitoring of the anti-Xa factor with different target indicators was carried out in only a third of patients. The use of unfractionated heparin (16%) primarily corresponded to patients with a high risk of bleeding or traumatic injuries (for example, with a dosage of 10.4 U/kg/h). When long-term therapy was required, the choice was made for vitamin K antagonists (VKA), where the INR target range amounted to 2–3. As for direct oral anticoagulants (DOACs), their weight-based use was rarely encountered (12%) in clinical practice.
Despite existing data, the implementation of standardized reporting and the determination of optimal dosage and treatment duration remain the primary challenges. Along with this, the in-depth study of the safety profile of direct oral anticoagulants (DOACs) in various subgroups represents a most important priority for future research.
Methodological Limitations and Research Priorities
The transparency of the panel’s work, which implies the management of conflicts of interest, external revision, and the use of GRADE EtD frameworks, significantly increases the reliability of the decisions made. Nevertheless, the low certainty of evidence is determined by the scarcity of randomized trials, observational biases, and those expert opinions that filled the existing scientific vacuum. The universal, conditional nature of the recommendations reflects the heterogeneity of pediatric patients.
Future research priorities require the development of valid risk scores, the conduct of adequately powered studies in high-risk subgroups, and the optimization of DOAC use. Furthermore, the study of the effectiveness of mechanical prophylaxis and the evaluation of the long-term impact on quality of life are on the agenda. This strategy restricts unnecessary medical interventions and ensures the safety of vulnerable patients through practice based on evidence and general consensus.
Source: ASH Publications
