The incidence of pediatric venous thromboembolism (VTE) has increased due to increased health care complexity, improved diagnostic techniques, and greater clinical awareness. Most episodes are associated with iatrogenic risk factors, particularly the use of central venous catheters, and occur in vulnerable populations such as neonates or children with cancer, congenital heart disease, and/or short bowel syndrome.
ObjectiveTo review special clinical scenarios of pediatric VTE and propose a practical approach to support decision-making in complex clinical settings.
MethodsNarrative review focused on clinical practice, addressing pathophysiological features, diagnosis, treatment, and follow-up, integrating recent guideline recommendations, observational case series, and clinical experience reports.
ResultsIn neonatology, developmental hemostasis, bleeding risk, and pharmacokinetics influence the indication, selection, and monitoring of anticoagulation therapy. The review discusses umbilical venous catheter-associated thrombosis, neonatal purpura fulminans, and renal and portal vein thrombosis, highlighting the criteria for anticoagulation and/or thrombolysis and the need for long-term follow-up to detect sequelae. In children with cancer, congenital heart disease, or short bowel syndrome, VTE is multifactorial and frequently catheter-related, requiring therapeutic adjustments (eg, thrombocytopenia, invasive procedures, preservation of vascular access). We summarize the current strategies for anticoagulation—including the emerging role of direct oral anticoagulants, with caution in selected subgroups—and thrombolysis.
ConclusionsIn special pediatric populations, VTE requires individualized and multidisciplinary management. Disease severity, residual risk, and the need to balance bleeding and thrombosis should guide decisions regarding treatment intensity/duration as well as prophylaxis, with emphasis on organ preservation, maintenance of venous capital, and prevention of long-term complications.
La enfermedad tromboembólica venosa (ETV) pediátrica ha aumentado por la complejidad asistencial, la mejora diagnóstica y la mayor sospecha clínica. La mayoría de los episodios se asocian a factores adquiridos en el ámbito hospitalario, especialmente al catéter venoso central (CVC), en grupos de pacientes vulnerables, como el recién nacido, el paciente con cáncer, cardiopatía congénita y/o síndrome de intestino corto.
ObjetivoRevisar situaciones clínicas especiales de ETV pediátrica y proponer un enfoque práctico para apoyar la toma de decisiones en contextos clínicos complejos.
MétodosRevisión narrativa orientada a la práctica clínica, centrada en particularidades fisiopatológicas, diagnóstico, tratamiento y seguimiento, integrando recomendaciones de las guías más recientes, series observacionales y experiencia clínica.
ResultadosEn neonatología, la hemostasia evolutiva, el riesgo hemorrágico y la farmacocinética condicionan indicación, elección y monitorización de anticoagulación. Se abordan trombosis asociada a catéter venoso umbilical (CVU), púrpura fulminans neonatal, trombosis de vena renal y de vena porta, destacando criterios de anticoagulación/trombólisis y la necesidad de seguimiento por secuelas. En cáncer, cardiopatías congénitas y síndrome de intestino corto, la ETV es multifactorial y frecuentemente asociada a CVC, requiriendo ajustes terapéuticos (trombocitopenia, procedimientos, preservación de accesos). Se resumen opciones de anticoagulación (incluyendo el papel emergente de los anticoagulantes orales de acción directa (ACOD), con cautelas en subgrupos) y trombólisis.
ConclusionesLa ETV en poblaciones pediátricas especiales exige manejo multidisciplinar e individualizado. La gravedad, el riesgo residual y el balance trombosis–hemorragia deben guiar intensidad/duración del tratamiento y la profilaxis, con foco en preservar órgano y capital venoso y prevenir secuelas a largo plazo.
Although pediatric venous thromboembolism (VTE) is a rare condition, an increasing number of health care professionals are involved in its management due to the rise in its incidence over the past two decades.1 This increase is associated with more aggressive treatments in unstable patients, improved diagnostic methods, and a higher index of suspicion, which, in turn, are closely related to the particular characteristics of VTE in the early stages of life. Its incidence follows a bimodal distribution, with one peak in the neonatal period and another in adolescence. In more than 80% of cases, VTE is associated with acquired risk factors. The presence of a central venous catheter (CVC) is the most frequent one.2 That said, the term “pediatric thrombosis” encompasses a broad range of clinical conditions, some of which are extremely rare, and all of which require an individualized and multidisciplinary approach. The evidence available for the pediatric population is scarce, and most recommendations are based on studies in adults, small case series, and expert opinion, which results in a low level of certainty.3,4 The consensus document published in Anales de Pediatría has addressed the management of pediatric patients with VTE, but it does not cover the neonatal period or delve into more complex clinical scenarios.5
This article reviews special situations in the context of pediatric VTE which, due to their high morbidity and mortality, diagnostic and therapeutic complexity, and lack of solid evidence, pose a significant clinical challenge. The aim of this article is to provide a practical and up-to-date overview to facilitate decision-making in the management of VTE in the neonatal period and other complex clinical situations.
Material and methodsThis document is divided into four sections covering thrombosis in the neonatal period, oncological patients, patients with congenital heart disease, and patients with short bowel syndrome.
We conducted a review of the literature, based on which we developed an initial draft. The draft underwent an internal consensus-building process among the authors, using the most recent international guidelines as reference. The study did not require review by an ethics committee, as it did not include any new research involving human subjects.
Thrombosis in the neonatal periodDevelopmental hemostasis explains the changes in the hemostatic system throughout life. The differences are most pronounced during intrauterine life and in the first few months of life6:
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Neonates have lower levels of vitamin K-dependent and contact factors; the rest have similar or higher concentrations compared to adults (Table 1).
Table 1.Hemostasis and thrombotic risk factors in neonates.
Particular characteristics of neonatal hemostasis Primary hemostasis Platelet counts similar to adult levels Platelet hyporeactivity Higher VWF levels Higher level of VWF large multimers Presence of very high molecular weight VWF multimers Coagulant factors Factors II, VII, IX, X, XI, XII ● Preterm neonates: 10%–30% of reference adult values ● Full-term neonates: 30%–50% of reference adult values Factor VIII: 150% of normal adult levels Factors V and XIII, fibrinogen: at least 80% of normal adult levels Qualitative differences in fibrinogen that result in a clot structure different from that of adults Anticoagulant factors Antithrombin ● 50%–60% of normal adult levels Protein C ● 10%−25% of normal adult levels ● Levels remain low until puberty Protein S ● Total protein S antigen levels: 15%–30% of normal adult levels ● Free form of protein S: predominant form due to absence of C4BP ● Functional protein S levels only slightly reduced Lower level of heparin cofactor II Lower level of TFPI Alpha-2-macroglobulin ● Double concentration compared to adults ● Levels remain high until the third decade of life Fibrinolysis Plasminogen: 50% of adult concentrations Plasminogen tissue activator: lower levels Plasminogen activator inhibitor: slightly increased levels Alpha-2-antiplasmin: 80% of normal adult levels Elevated d-dimer levels Risk situations associated with neonatal thrombosis Maternal/Placental Perinatal Neonatal Infection/Fever Urgent/emergency cesarean section Low birth weight or intrauterine growth restriction Metabolic syndrome, diabetes, dyslipidemia Premature or prolonged rupture of membranes Preterm birth Preeclampsia, eclampsia, hypertension Perinatal asphyxia Congenital or acquired thrombophilia Congenital or acquired thrombophilia Thick amniotic fluid or meconium aspiration Central venous catheter Placental thrombosis Treatment with corticosteroids Dehydration Placental abruption Fetal bradycardia Parenteral nutrition Abdominal surgery Mechanical ventilation Other comorbidities: Congenital heart disease, congenital nephrotic syndrome Abbreviations: C4BP, complement component C4b-binding protein; HTN, hypertension; TFPI, tissue factor pathway inhibitor; VWF, von Willebrand factor.
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The levels of most physiological anticoagulants are low at birth, with the exception of a2-macroglobulin, whose concentration is twice that of adults.7
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The neonatal fibrinolytic system has a reduced capacity to generate plasmin, and d-dimer levels are physiologically elevated.7
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Most coagulants and anticoagulants reach adult levels by six months of age, although slightly lower levels may persist until adolescence.
Despite these differences, hemostasis in healthy newborns is balanced or tends slightly toward a hypercoagulable state. On the other hand, in neonates with VTE, the particular characteristics of hemostasis, variations in the volume of distribution and renal clearance of drugs, and the risk of bleeding—especially in preterm infants—determine the indication of pharmacotherapy, choice of agent, dose, and frequency of monitoring.8
Umbilical venous catheterUmbilical venous catheters (UVCs) are essential for the management of critically ill newborns because of their ease of insertion and dwell time.9 Prolonged use or malposition of the catheter and transfusion of blood components increase the risk of VTE.10
The correct position for the UVC tip is at the junction of the inferior vena cava (IVC) and the right atrium. If the tip is placed too high or too low, the risk of complications increases. Thrombosis can occur at any point along the route; the most common locations are the heart and the liver.9
Although these events may be asymptomatic, there is a risk of serious complications such as infection, pulmonary embolism, or liver necrosis. The recommendations for the management of UVC-related thrombosis are the same as for other forms of CVC-related thrombosis (Fig. 1).
Neonatal purpura fulminans
Purpura fulminans is a medical emergency that occurs in neonates with severe protein C or protein S deficiency. It has onset in the first hours of life with the development of ecchymotic or purpuric lesions on the extremities, buttocks, and abdomen that grow in a radial fashion and progress to necrosis. In addition to the skin, involvement of the central nervous system, eyes, and kidneys is common.10 Without treatment, it progresses to disseminated intravascular coagulation. Ocular or neurologic sequelae due to prenatal or perinatal thrombosis are common.
It is diagnosed by measuring protein C/S levels and parental testing. Treatment is urgent: administration of fresh frozen plasma or protein C11 (Table 2).
Neonatal purpura fulminans.
| Presentation | Ecchymotic or purpuric lesions progressing to necrosis and DIC in the first 72h of life. |
| Less common: large vessel thrombosis or neonatal stroke in absence of cutaneous manifestations. | |
| Diagnosis | Measurement of protein C and S levels* |
| Measurement of levels of protein C or S, as applicable, in the parents. | |
| Genetic testing | |
| Treatment | Until diagnosis is confirmed or protein S deficiency |
| ● Fresh-frozen plasma 10−15mL/kg every 8−12h; increase to 20mL/kg if the patient's condition does not improve. | |
| Protein C Deficiency | |
| ● Loading dose: 120IU/kg | |
| ● Maintenance dose: 50−60IU/kg every 6−12h. | |
| Anticoagulation | |
| ● During acute phase, consider risks/benefits, especially in the context of DIC. | |
| ● UFH or LMWH: indicated in large vessel thrombosis. |
Abbreviations: DIC, disseminated intravascular coagulation; LMWH, low molecular weight heparin; UFH, unfractionated heparin.
It is the most common form of non-catheter-related neonatal VTE. It manifests within the first 72h of life, although the diagnosis may be made prenatally or at a later stage. Its incidence is low, but its clinical significance is high due to the risk of complications in 70% of cases (renal atrophy, portal hypertension, renal failure, and proteinuria).12 The classic triad consists of a palpable flank mass, gross hematuria, and thrombocytopenia. It can be unilateral (70% of cases) or bilateral, with involvement of the IVC.
The goal of treatment is to rapidly restore renal blood flow and prevent severe kidney injury. After assessing the individual risk of bleeding (prematurity, thrombocytopenia), anticoagulation is recommended in all cases, including those of unilateral thrombosis. Thrombolysis followed by anticoagulation is recommended for cases with bilateral involvement, extension to the IVC, cases nonresponsive to anticoagulation, or imminent risk of kidney loss3 (Fig. 2).
The duration of treatment depends on the severity of the event and the patency of the affected vessel. There is no explicit recommendation in relation to the anatomical site (Figs. 1 and 2). Regardless of the duration, guidelines emphasize that these patients require long-term clinical and nephrological follow-up due to the risk of hypertension or chronic kidney disease.3
Portal vein thrombosisPortal vein thrombosis (PVT) is an increasingly recognized condition with a higher incidence in the neonatal intensive care setting. It typically manifests within the first 7–10 days of life, mainly in association with central venous catheters (CVCs), invasive procedures, and the prothrombotic state of critically ill patients. Other relevant factors include sepsis, prematurity, and low birth weight.13
Its management depends on the extent and impact of the thrombosis (Fig. 2). There is no clear evidence that anticoagulation accelerates resolution or reduces the risk of complications such as portal hypertension, so its routine use is therefore not recommended. Current guidelines suggest anticoagulation only for occlusive PVT, post-liver transplantation PVT or idiopathic PVT.3
Although 30%–70% of cases resolve spontaneously without anticoagulation over a variable period of days or months, a proportion of patients may develop complications such as liver lobe atrophy, portal hypertension, cavernous transformation of the portal vein, and esophageal varices, which warrant long-term multidisciplinary follow-up (pediatric hepatology, hematology).14
TreatmentThe management of neonatal VTE includes three main approaches: watchful waiting (observation), anticoagulation, and fibrinolysis (selected severe cases). The available evidence is limited and of low certainty, with recommendations based on observational studies and extrapolations from pediatric and adult data. Table 3 summarizes the recommendations for the dosage and adjustment of anticoagulant agents.
Anticoagulant drugs, dosages, clinical scenarios of use, and monitoring.
| Agent | Dose | Objective | Clinical use | Dose adjustment | |||
|---|---|---|---|---|---|---|---|
| aPTT ratio | Anti-Xa | Approach | |||||
| Unfractionated heparin | Loading bolus: 50−100IU/kg IV. | Anti-Xa 0.35–0.7 or aPTT 1.5−2.5 ratio | Critically ill patient, post-cardiac surgery, severe kidney failure, high risk of bleeding | < 1.2 | < 0.1 | 50IU/kg bolus ↑ infusion 10% | |
| Maintenance dose: 28IU/kg/h IV | 1.2−1.4 | 0.1−0.34 | ↑ infusion 10% | ||||
| 1.5−2.5 | 0.35−0.7 | no change | |||||
| 2.6−3.0 | 0.71−0.89 | ↓ infusion 10% | |||||
| 3.1−3.5 | 0.9−1.2 | stop infusion for 30min and ↓ by 10% | |||||
| >3.5 | >1.2 | stop infusion for 60min and ↓ by 10% | |||||
| Low molecular weight heparin | Enoxaparin | Preterm: 2mg/kg/12h SC | Anti-Xa 0.5−1.0 | First-line in noncritical patients | Anti-Xa | Approach | New evaluation |
| Full-term: 1.7mg/kg/12h SC | < 0.35 | ↑ 25% | 4h after the next dose | ||||
| 0.35−0.5 | ↑10% | 4h after the next dose | |||||
| 0.5−1 | No changes | 24h, 1 week, and 1 month | |||||
| 1−1.5 | ↓20% | Before the next dose | |||||
| 1.6−2 | Defer 3h and ↓30% | Before the next dose and at 4h | |||||
| > 2 | Suspend until anti-Xa 0.5 and ↓40% | Before the next dose; if > 0.5, repeat every 12h | |||||
| Tinzaparin | < 2 months: 275IU/kg/day SC | Anti-Xa 0.5−1.0 | |||||
| Dalteparin | < 2 months: 150IU/kg per dose every 12h SC | Anti-Xa 0.5−1.0 | |||||
| Bemiparin | < 2 months: 197IU/kg every 24h | Anti-Xa 0.5−1.0 | |||||
| Direct thrombin inhibitors | Bivalirudin | Bolus 0.125mg/kg IV | |||||
| Maintenance | aPTT 1.5−2.5 times the baseline value | Resistance to UFH, HIT | aPTT 1.5−2.5 times the baseline value | ||||
| 0.125−0.25mg/kg/h IV | |||||||
| Argatroban | 0.75μg/kg/min by continuous infusion | ||||||
| 0.2μg/kg/min (if there is liver impairment) | |||||||
| Fibrinolytics | Low-dose regimen: 0.06−0.1mg/kg/h IV | Extreme situations: life-threatening, risk of loss of organ or limb. | Management in intensive care unit | ||||
| rtPA (Alteplase) | Duration: 6−12h | Monitor complete blood count, aPTT, PT, fibrinogen, and D-dimer every 6−12h | |||||
| High-dose regimen: 0.1−0.5mg/kg/h for 6h | Maintain fibrinogen > 1g/dL and platelets > 50 000×109 | ||||||
| Imaging every 6−12h to assess response | |||||||
| Rule out intracranial bleeding every 24h | |||||||
| Concomitant low-dose UFH infusion (10IU/kg/h) monitored with anti-Xa (target 0.1−0.3) | |||||||
| Vitamin K antagonists | Acenocoumarol | 0.2mg/kg/day | INR 2−3 (as indicated/based on risk) | Medium- and long-term oral treatment | According to INR: Avoid sudden dose changes (in general, avoid dose increases/decreases > 0.5−1mg per week) | ||
| 0.3mg/kg/day | Avoid administering vitamin K when INR is elevated but there are no clinical signs of bleeding (skipping a dose may suffice) | ||||||
| Warfarin | |||||||
| Direct oral anticoagulants | Rivaroxaban | 2.6−2.9 kg: 0.8mg/8h orally | Does not require monitoring | GA > 37 weeks and weight > 2600g | Monitoring may be considered in special situations, such as when malabsorption is suspected, to assess levels in cases of clinical bleeding, or when urgent surgery is required. | ||
| 3−3.9 kg: 0.9mg/8h orally | Enteral feeding | ||||||
| 4−4.9 kg: 1.4mg/8h orally | GFR > 30mL/min | ||||||
| 5−6.9 kg: 1.6mg/8h orally | Medium- and long-term oral treatment | ||||||
| Dabigatran | 2.5 to <5 kg: 2mL/12h | Does not require monitoring | GA > 37 weeks and weight > 3rd percentile in WHO growth standards | ||||
| 5 to <7 kg: 3mL/12h | Enteral feeding | ||||||
| GFR > 50mL/min | |||||||
| Medium- and long-term oral treatment | |||||||
Low-molecular-weight heparin (LMWH) is considered the first-line treatment for noncritical patients due to its predictable pharmacokinetics, subcutaneous administration, reduced need for monitoring, and a lower risk of heparin-induced thrombocytopenia (HIT) compared to unfractionated heparin (UFH). Unfractionated heparin has a very short half-life (30−60min), the dose depends on age (faster clearance in neonates), and requires close monitoring. It is the treatment of choice for critically ill patients, patients recovering from major surgery, those at high risk of bleeding, and those with severe kidney failure.3
Of the available fibrinolytic agents (recombinant tissue plasminogen activator [rtPA], streptokinase, and urokinase), rtPA is the most widely used; it has a higher affinity for fibrin-bound plasminogen, which reduces the risk of bleeding.15 A study found a percentage of complete or partial thrombus resolution of 88%, but also a 23% risk of bleeding.15 Given this risk, the routine use of thrombolysis is not recommended, but it can be considered in emergencies with critical organ or limb compromise, subject to multidisciplinary consultation.
Vitamin K antagonists (VKAs) (acenocoumarol/warfarin) exhibit high pharmacokinetic and pharmacodynamic variability in association with enzymatic immaturity, in addition to multiple interactions with food and other medications, which limits their use in newborns. Direct-acting oral anticoagulants (DOACs), such as dabigatran and rivaroxaban, are a safe and effective alternative in the pediatric population; however, preterm infants were excluded from clinical trials.16 Direct thrombin inhibitors (bivalirudin and argatroban) are used off-label in neonates as an alternative to UFH in situations where UFH is ineffective or contraindicated (heparin resistance, HIT), with stronger evidence supporting the use of bivalirudin in the context of extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass. Their main advantages are that they do not depend on antithrombin (AT) and exhibit less variability during ECMO.17
Thrombosis in pediatric cancer patientsIts etiology is multifactorial (Fig. 3) and its incidence varies between 2.1% and 16%.18–21 The risk is higher in acute lymphoblastic leukemia (3%–15%), lymphoma (5%–12%) and Ewing sarcoma (12%–19%).21 Forty percent of cases are asymptomatic, and up to 75% are CVC-related.
The clinical manifestations and diagnosis of VTE are no different from those in patients without cancer. However, a high index of suspicion should be maintained in high-risk situations, as the symptoms can be confused with the manifestations of the disease or adverse effects of treatment.
The management is similar to that of VTE in the general population,5 but requires an individualized approach. Chemotherapy-induced thrombocytopenia, the risk of bleeding, the risk of thrombus progression and recurrence, and the complexity of concomitant treatments pose challenges in its management.18–20 It is important to bear in mind that the current recommendations are based on small case series and data extrapolated from studies conducted in children without cancer and in adults with cancer.3,19,22
There are some peculiarities regarding treatment in these patients:
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Low molecular weight heparins (LMWHs) are the treatment of choice. Treatment should be discontinued 24h before invasive procedures (eg, lumbar puncture or surgery). It can be resumed 12–24h after most minor invasive procedures.19,22
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Direct oral anticoagulants have shown promise as an alternative in pediatric cancer patients enrolled in clinical trials, but real-world experience is still limited.3,18–23
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Treatment should be adjusted according to the platelet count. During the first two to four weeks of treatment, platelet transfusions are recommended to maintain counts of ≥50×109/L. Thereafter, adjustment of the anticoagulation dose is recommended: (1) platelet count>50×109/L: full dose; (2) count between 25×109/L and 50×109/L: half dose; count<25×109/L: discontinue anticoagulation.22
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In the case of VTE associated with the use of asparaginase, treatment should be suspended until symptoms improve. Subsequently, treatment may be resumed at the full dose (consider thromboprophylaxis) and, if possible, any missed doses should be administered.3,19
It is worth noting that Wilms tumor may present at diagnosis with a mural thrombus in the vena cava (4%–10%). Its management is complex and multidisciplinary. Preoperative chemotherapy is recommended to reduce the size of the thrombus and the tumor and thus facilitate surgery. Consider anticoagulant therapy if the VTE is symptomatic or progressive.24–26
There is no clear consensus on the indications for prophylaxis in pediatric cancer patients. The latest guidelines suggest considering prophylaxis (after assessing individual bleeding risk) in patients with lymphoblastic leukemia or lymphoma who have specific risk factors (age>10 years, obesity, T-cell phenotype, with high-risk treatment regimens, or with a family or personal history of thrombosis). Prophylaxis is recommended during treatment with asparaginase (especially during induction therapy).22
Thrombosis in pediatric patients with congenital heart diseaseCongenital heart defects are present in 1% of live births. Up to 80% of these children undergo surgery before the age of five. In this context, VTE can be a significant complication, especially during the perioperative period (11%–40%; 60% in the neonatal period), and is associated with an increased length of stay, higher morbidity, and a thrombosis-related mortality of 7%–12%.27
Its etiology is multifactorial. The risk factors include age, the need for vascular devices, including CVCs, the type of defect, and the underlying hemodynamic disturbance, as well as specific characteristics of the hemostatic system in this context (Fig. 4).27,28 The clinical presentation varies and depends on the location (most frequently in the extremities) and the extent of the thrombosis. However, up to 50% of cases are clinically unsuspected, and their detection results from chance findings of imaging tests performed for screening or for an unrelated reason.29
Thrombosis in patients with congenital heart disease.
Risk Factors associated with thrombosis in pediatric patients with congenital heart disease. Indications for treatment and primary and secondary prophylaxis.
Abbreviations: CHD, congenital heart disease; DOAC, direct-acting oral anticoagulants; ECMO, extracorporeal membrane oxygenation; EF, ejection fraction; HIT, heparin-induced thrombocytopenia; LMWH, low-molecular-weight heparin; RACHS-4, risk stratification in cardiac surgery; UFH, unfractionated heparin; VKA, vitamin K antagonist.
The treatment recommendations are no different from the general recommendations3–5,30 (Fig. 1), although there are some particularities:
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Management must be multidisciplinary, especially in life-threatening situations, such as intracardiac thrombosis with hemodynamic compromise or thrombosis following certain palliative surgeries, such as the modified Blalock-Taussig-Thomas shunt, which may require aggressive treatment (thrombectomy, thrombolysis).
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In the absence of contraindications, the use of anticoagulation is reasonable, even in cases of clinically unsuspected thrombosis. In addition to preventing potential long-term complications, it helps preserve the venous capital in patients who may need a CVC in the future.29,31 Anticoagulation is associated with high resolution rates (up to 70%), with few hemorrhagic events, and favorable outcomes (>80% of patients do not develop post-thrombotic syndrome).32
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There are no differences in the dosage and monitoring of UFH, but it is important to watch for the development of HIT, which is rare but is associated with a mortality rate of up to 20%.33
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Patients with congenital heart disease require significantly higher doses of LMWH, likely due to a larger volume of distribution.34
Direct oral anticoagulants have been found to be safe and effective in the pediatric population. Although the experience is limited, favorable outcomes have been reported with the use of rivaroxaban, dabigatran, apixaban, and edoxaban.35 Rivaroxaban and dabigatran are approved for the treatment and secondary prevention of VTE in children.
The prescribing of antiplatelet agents or anticoagulants for primary prophylaxis must be individualized and agreed upon by a multidisciplinary team. To date, UFH, LMWHs, and VKAs have been the drugs of choice. In the case of Fontan surgery, rivaroxaban and apixaban have demonstrated safety and efficacy comparable to standard-of-care treatment in specific clinical trials; therefore, they offer an alternative that reduces the therapeutic burden (Fig. 4).35
Thrombosis in pediatric patients with short bowel syndromeChildren with short bowel syndrome lack the intestinal length required for adequate growth and development, which makes them dependent on parenteral nutrition (PN). This entails prolonged use of CVCs, which contributes significantly to the morbidity and mortality in these patients.
Venous thromboembolism is one of the main complications, with a variable incidence (1%–80%) that depends, among other factors, on the diagnostic method.36
The mechanisms involved in the development of VTE include endothelial damage secondary to catheter insertion and hypercoagulable states associated with chronic inflammation, recurrent infections, and the use of hyperosmolar solutions containing high levels of dextrose and/or calcium36,37 (Fig. 5).
Most cases of CVC-related thrombosis are clinically unsuspected. Some reviews recommend annual Doppler ultrasounds to rule it out, given the high incidence of asymptomatic cases.37
The goal of anticoagulation is to prevent the progression of thrombosis, systemic embolism, and the development of chronic thrombosis with loss of venous access (which is essential in this population). Anticoagulation is recommended even in clinically unsuspected cases. Low molecular weight heparins (LMWHs) are the treatment of choice (Fig. 1). Thrombolysis is reserved for cases that progress despite anticoagulation, are life threatening, or pose a risk of organ loss.3,36 Catheter-directed thrombolysis may also be considered if the benefits of restoring patency to the vein outweigh the risk of bleeding.
After the acute period, reducing the dose to prophylactic doses while the central venous catheter (CVC) remains in place is recommended (Fig. 5), but the target anti-Xa level is still under debate.38 Prophylactic doses (anti-Xa 0.2−0.5IU/mL) are typically recommended. In the case of recurrence, especially if a patient is already receiving prophylactic doses, maintenance of therapeutic doses is recommended.
The routine use of DOACs is not recommended in these patients, although recent studies with rivaroxaban have shown promising results.39 The use of rivaroxaban, with appropriate monitoring of drug levels, has been found to achieve low rates of rethrombosis and bleeding complications.40
Primary prophylaxis is not recommended due to a lack of solid evidence, although some studies suggest a possible reduction in the incidence of events.
DiscussionIn these special populations, while general treatment recommendations apply,3,5 multidisciplinary management should be considered on account of their specific characteristics.8,19,22,35 It is important to remember that complications can appear past the acute phase of disease. Monitoring for potential sequelae (hypertension, chronic kidney disease, portal hypertension, renal cavernoma, and/or loss of vascular access) is part of the comprehensive management of these patients.3,14
Thrombosis in these special populations is subject to ongoing debate on many aspects: whether to treat clinically unsuspected thrombosis, which can preserve the venous capital and prevent complications, but increases the risk of bleeding3,31,36; the duration of treatment3,36; the indication of prophylaxis: primary prophylaxis requires multidisciplinary decision-making and must be individualized, as there is no solid evidence to guide it; secondary prophylaxis may be warranted when residual risk persists, a common situation when the disease, treatments and CVC use persist35,38,39; the use of new therapies: DOACs are effective in children (cancer, congenital heart disease, etc), but there are limits to the extrapolation of the evidence (exclusion of preterm infants), and caution is recommended for some indications.16,19,23,35,40
In conclusion, the management of VTE in neonates, oncological patients, patients with congenital heart disease, and those with short bowel syndrome requires an individualized multidisciplinary evaluation and decision-making. The indication for primary prophylaxis is still under debate, so its use must be individualized; the severity and residual risk should guide the intensity and duration of treatment, as well as secondary prophylaxis; and the ultimate goal is to not only resolve the thrombosis but also preserve the organ and vascular access while minimizing bleeding complications.
FundingThis work did not receive any external funding.
The authors declare having no conflicts of interest.
