Thromboprophylaxis in Children: Navigating Uncharted Waters

Abstract

The rising incidence of pediatric thrombosis, increasing nearly 10% annually over the past decade, underlines a need for effective preventive strategies, particularly in hospitalized children. This narrative review explores existing literature on venous thromboembolism prevention in pediatric patients to clarify current strategies in children undergoing general, orthopaedic, and Fontan surgeries, and with conditions such as acute lymphoblastic leukemia and gastrointestinal disease. While recent studies have provided some insights into potential preventive strategies, real evidence is lacking on the best practices for thromboprophylaxis in these patient groups. In the absence of substantial studies, clinicians must rely on individual assessments weighting thrombotic and bleeding risk to effectively and safely manage these “uncharted waters.”

Zusammenfassung

Die steigende Inzidenz von Thrombosen bei Kindern, die in den letzten zehn Jahren jährlich um fast 10% zugenommen hat, unterstreicht den Bedarf an wirksamen Präventionsstrategien, insbesondere bei hospitalisierten Kindern. Diese narrative Übersicht untersucht die vorhandene Literatur zur Prävention von venösen Thromboembolien bei pädiatrischen Patienten, um aktuelle Strategien für Kinder zu beleuchten, die allgemeine, orthopädische oder Fontan-Operationen durchlaufen oder an Erkrankungen wie akuter lymphoblastischer Leukämie und Magen-Darm-Erkrankungen leiden. Während neuere Studien einige Einblicke in potenzielle Präventionsstrategien bieten, fehlen jedoch aussagekräftige Belege für bewährte Praktiken der Thromboseprophylaxe in diesen Patientengruppen. In Ermangelung umfassender Studien müssen sich Ärzte auf individuelle Bewertungen verlassen, bei denen thrombotische und Blutungsrisiken abgewogen werden, um diese „unbekannten Gewässer“ effektiv und sicher zu navigieren.

Keywords

thromboprophylaxis - pediatric - surgery - acute lymphoblastic leukemia - gastrointestinal disease

Schlüsselwörter

Thromboseprophylaxe - Pädiatrie - Chirurgie - akute lymphoblastische Leukämie - gastrointestinale Erkrankung

Introduction

Pediatric venous thromboembolism (VTE) is a rare condition, with an estimated incidence of 0.07 to 0.49 per 10,000 children under 18 years of age per year.[1] [2] [3] However, the prevalence of VTE in hospitalized children is notably higher, rising from 46 cases per 10,000 admissions in 2009 to 106 cases per 10,000 admissions in 2019 in the United States.[4] According to Virchow's triad, VTE results from intravascular vessel wall damage, static or abnormal blood flow, and hypercoagulability. Pediatric VTE is a serious condition: approximately 2% of pediatric patients with VTE die directly from the thrombotic event, nearly 10% experience recurrent thrombosis, and postthrombotic syndrome occurs in 26% of children following deep vein thrombosis.[2] [5]

In recent years, there has been growing attention on preventing thrombosis in high-risk children, particularly within hospital settings. This narrative review provides an overview of current knowledge from existing literature on strategies to prevent VTE in pediatric patients, with a specific focus on those undergoing general and orthopaedic surgery, after Fontan surgery, and with conditions such as acute lymphoblastic leukemia (ALL) and gastrointestinal disease.

Perioperative Thromboprophylaxis

Surgery is an important risk factor for the development of hospital-acquired VTE. In the Children's Hospital-Acquired Thrombosis (CHAT) study, 43% of 621 included patients had surgery prior to VTE diagnosis.[6] The absolute incidence of surgery-associated VTE in children, however, is low. A large population-based study in England estimated an overall rate of VTE following general surgery to be 0.4 per 1,000 person-years (95% confidence interval [CI]: 0.15–0.88) compared to 0.04 per 1,000 person-years in the general population.[7] VTE was not diagnosed after inguinal hernia repair and 1-day surgery. In the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P) dataset from 2012 to 2015, 0.20% of the inpatient pediatric surgical patients developed VTE.[8] Median time to VTE was 9 days. Most VTEs developed predischarge. The highest VTE rates were found after cardiothoracic (0.72%) and general surgery (0.28%). In orthopaedic surgery, the median VTE incidence for all subtypes was on average 0.16%.[9] [10] A higher median VTE incidence of about 0.3 to 0.4% was calculated for orthopaedic surgery in trauma patients. Musculoskeletal infections were associated with the highest thrombotic risk (3.5%, 95% CI: 0.0–13.8%).[10] Several other studies have identified specific predictors for VTE development after surgery. The CHAT registry revealed the highest thrombotic risk in patients with a central venous catheter (odds ratio [OR]: 14.69; 95% CI: 7.06–30.55), intensive care unit stay (OR: 5.31; 95% CI: 2.53–11.16), and hospitalization in the month preceding surgery (OR: 2.75; 95% CI: 1.24–6.13).[11] Central venous catheters may elevate the risk of thrombosis by causing endothelial injury, altering blood flow, and inducing a hypercoagulable state as a result of the infused solutions. American Society of Anesthesiologists class ≥3, preoperative sepsis, ventilator dependence, enteral/parenteral feeding, steroid use, preoperative blood transfusion, gastrointestinal disease, hematologic disorders, longer operative time, and older age were independent predictors for VTE in the NSQIP-P database.[8]

In children, the risk of perioperative VTE is low, but the impact of affected children on the health care system may be significant.[12] Additionally, perioperative VTE may be preventable in children, as it is in adults. In adults, perioperative thromboprophylaxis is widely recommended, as VTE is a major comorbidity in this population.[13] Numerous trials have demonstrated that pharmacological prophylaxis is superior to placebo in reducing VTE incidence in high-risk adult groups.[13] Unfortunately, evidence supporting the effectiveness and safety of thromboprophylaxis in children remains limited.[14] There is general consensus that universal thromboprophylaxis is unnecessary for hospitalized children undergoing surgery; however, mechanical and/or pharmacologic prophylaxis may benefit certain pediatric patients. Despite the limited evidence, several hospital-driven initiatives have been implemented to prevent VTE in pediatric surgical patients. All these initiatives rely on risk stratification tools that weigh both the risks of thrombosis and bleeding. The tools differ in the specific risk factors for thrombosis, the number of factors required to classify a patient as intermediate or high risk for VTE, and the age cut-off for considering prophylaxis. Moreover, some tools are designed specifically for surgical patients, while others are more general and include surgery as just one of several risk factors.[15] [16] [17] [18] [19] [20]

Prophylactic strategies include early mobilization, mechanical prophylaxis, and /or pharmacologic prophylaxis. Mechanical prophylaxis includes graduated compression stockings and intermittent pneumatic compression devices. These devices wrap around the legs or feet and periodically inflate and deflate to promote blood flow in the veins. In adults, they have shown to prevent VTE.[21] [22] No studies have been performed in children. Mechanical prophylaxis is limited to teenagers, weighting >40 kg, as pediatric compression boots are not available. Contraindications include acute VTE, massive leg edema, neuropathy, local conditions such as burns, fracture or wounds, leg deformity, and ill-fitting devices. Low-molecular-weight heparin (LMWH) is the preferred anticoagulant drug for pharmacologic prophylaxis. The major bleeding rate for prophylactic use of LMWH is low.[23]

In 2018, the Association of Paediatric Anaesthetists of Great Britain and Ireland published recommendations for perioperative VTE prophylaxis in pediatric patients over 13 years of age, based on a systemic literature review.[17] In adolescents with an expected immobilization of more than 48 hours, adequate hydration, early mobilization, and reduction of risk factors, such as removal of central venous catheter, are recommended. Additionally, for adolescents at low risk (no additional risk factors) or intermediate risk (more than 1 risk factor), mechanical prophylaxis should be considered. For high-risk adolescents (more than two risk factors), bleeding risk should be evaluated, and LMWH may be considered ([Table 1]). Padhye et al developed a perioperative thromboprophylaxis algorithm specifically for pediatric orthopaedic surgery patients.[16] In this tool, age ≥14 years is one of the risk factors. For low-risk patients with 0 to 2 risk factors, early mobilization and passive range-of-motion exercises are encouraged. Mechanical prophylaxis is recommended for patients with three or more risk factors. For patients with a personal or first-degree family history of VTE, severe thrombophilia, or four or more risk factors, a hematology consult is recommended to evaluate the need for pharmacologic anticoagulation. ([Table 1]). After the implementation of this algorithm, there was a 47.9% reduction in the use of pharmacological thromboprophylaxis (pre: 28/656 patients; post: 14/643 patients) in one tertiary care center for pediatric orthopaedic surgery. VTE and significant bleeding complications did not occur before and after implementation of the algorithm.[24]

Table 1 Guidelines for thromboprophylaxis in general surgery and orthopaedic pediatric patients

Guideline	Target population	Risk categories	Criteria	Interventions	Risk factors
Morgan et al[17]	Pediatric surgical patients of ≥13 years with expected reduced mobility >48 h	Low	No other risk factor	Adequate hydration Early mobilization Reduce risk factors Consider mechanical prophylaxis	CVC Active cancer Dehydration Thrombophilia BMI ≥ 30 One medical comorbidity Personal history of VTE, first-degree relative with VTE <40 years Estrogen Pregnancy Severe trauma ISS >9 Spinal cord injury with paralysis Anesthetic time >90 minutes Sepsis Pelvis/lower limb surgery with anesthetic time >60 minutes ICU stay Severe burns
		Moderate	>1 risk factor	Adequate hydration Early mobilization Reduce risk factors Consider mechanical prophylaxis
		High	>2 risk factors	Adequate hydration Early mobilization Reduce risk factors Consider mechanical prophylaxis If no bleeding risk: consider LMWH
Padhye et al[16]	Pediatric orthopaedic surgical patient	Low	0–2 risk factors	Early ambulation PROM	CVC Age ≥ 14 years BMI ≥ 30 Active cancer Active inflammatory disease Limited mobility > 48 h Cardiovascular flow anomalies Estrogen ICU stay Pregnancy Dehydration Surgery >120 minutes Complicated/repeat surgery Major trauma Severe infection Smoking Metabolic conditions
		Moderate	3 risk factors	Early ambulation PROM Mechanical prophylaxis
		High	4 or more risk factors Personal or first-degree relative with history of VTE/severe thrombophilia	Consult hematology Early ambulation PROM Mechanical prophylaxis If no bleeding risk: consider LMWH

Abbreviations: BMI, body mass index; CVC, central venous catheter; h, hour; ICU, intensive care unit; ISS, injury severity score; LMWH, low-molecular-weight heparin; PROM, passive range of motion; VTE, venous thromboembolism.

None of these guidelines or other hospital-driven initiatives have undergone extensive external validation, nor do any comparative studies exist. However, these tools may aid in patient management and help reduce variability in care. Additional prospective evaluations of compliance, VTE, and bleeding rates will enable further assessment of these tools' safety and effectiveness in future.

Thromboprophylaxis after Fontan Surgery

The Fontan procedure is used to treat patients with congenital heart disease and a single functional ventricle. In the Fontan circulation, the systemic venous blood flow is directly connected to the lungs, whereas the single ventricle supports the systemic circulation. Unfortunately, patients with a Fontan circulation have an increased risk for thromboembolic events. The reported thromboembolic event rate varied between 0.74 and 5.2% per patient-year.[25] Various studies have shown a time-related thrombosis risk with an initial peak during the first 6 to 12 months after surgery, followed by a plateau phase and a second peak after 10 years post-surgery.[26] [27] [28] Multiple factors contribute to the increased risk of thromboembolic events in Fontan circulation, including abnormal blood flow, endothelial dysfunction, and hypercoagulability.[25] [29] Late post-Fontan thromboembolic events may result from decreased cardiac function and protein-losing enteropathy, which can occur years after the Fontan procedure and lead to serum protein loss and hemostatic imbalance. As thromboembolic events account for significant morbidity and mortality following Fontan surgery, antithrombotic prophylaxis is suggested in all Fontan patients.[30] [31] Both antiplatelet and anticoagulation agents are used.

In 2011, a meta-analysis of 20 observational studies showed that prophylaxis with vitamin K antagonists (VKAs) was not associated with a lower incidence of thromboembolic events than antiplatelet therapy in patients undergoing extracardiac conduit Fontan procedure (5 vs. 4.5%, respectively).[32] In addition, an underpowered randomized controlled trial (RCT) could not find a significant difference in thromboembolic events between heparin/VKA (target international normalized ratio [INR]: 2.0–3.0) and antiplatelet therapy (acetylsalicylic acid [ASA]: 5 mg/kg/day) for 2 years, suggesting both anticoagulants and antiplatelet agents can be effective for thromboprophylaxis.[33] Primary endpoint in this study was thrombosis, and transesophageal echocardiography (TEE) was performed to screen for asymptomatic thrombosis. In the heparin/VKA group, 13 thromboses (13/54; 24%) were diagnosed (3 clinical, 10 with TEE), and 12 thromboses (12/57; 21%) in the ASA group (4 clinical, 8 with TEE). Major bleeding occurred in one patient in each treatment group. Two years after Fontan surgery, overall thrombosis-free survival was 19%, despite thromboprophylaxis. A secondary analysis of this RCT revealed an increased thrombosis risk for patients with poorly controlled VKA therapy.[27] Especially for this patient group, direct oral anticoagulants (DOACs) might be a solution.

The UNIVERSE study compared a prophylactic dose of rivaroxaban (equivalent to rivaroxaban 10 mg once daily in adults) and ASA (≈5 mg/kg/day) in 112 children between 2 and 8 years of age who had undergone Fontan surgery, for a period of 12 months.[34] One major bleeding occurred in one patient on rivaroxaban (1/64; 2%), and none in the ASA group (0/34; 0%). Clinically relevant nonmajor (CRNM) bleeding occurred in 6% of the rivaroxaban patients and in 9% of the ASA patients. In the rivaroxaban group, one patient (2%) developed a pulmonary embolism, and in the ASA group, one patient had ischemic stroke and two patients had VTE (9%). The SAXOPHONE study evaluated the safety and efficacy of therapeutic doses of apixaban for prevention of thromboembolism in 192 children between 28 days and 17 years of age with a broader range of acquired or congenital heart disease.[35] Most participating children were between 2 and 12 years of age (70%). Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). The pediatric apixaban dose was similar to the adult apixaban dose of 5 mg twice daily. One of the 126 patients (0.8%) in the apixaban group had one major and one CRNM bleeding, whereas, 3 of the 62 patients (4.8%) in the heparin/VKA group had one major and two CRNM bleedings. None of the patients developed thromboembolic events or died during the 1-year follow-up. The ENNOBLE-ATE study aimed to obtain safety and efficacy data for edoxaban in 167 children (>38 weeks of gestation to <18 years of age) with cardiac diseases at risk for thromboembolic complications, including Fontan surgery (44%), Kawasaki disease (22%), heart failure (4%), and other heart disease (30%).[36] Pediatric edoxaban dose was equivalent to the adult edoxaban dose of 60 mg once daily. In the first 3 months, CRNM bleedings occurred in one patient of the edoxaban group (1/109; 0.9%) and one patient of the heparin/VKA group (1/58; 1.7%). One patient in the heparin/VKA group had a thromboembolic event (1.7%). Thrombosis did not occur in the edoxaban group. During the extension period up to 12 months, 144 patients were treated with edoxaban. Two patients had major or CRNM bleeding (1.4%), and three patients had a thromboembolic event (2.1%).

In 2023, a network meta-analysis revealed that ASA (incidence rate ratio [IRR]: 0.24; 95% CI: 0.15–0.39), VKA (IRR: 0.23; 95% CI: 0.14–0.37), and DOACs (IRR: 0.11; 95% CI: 0.03–0.40) were associated with lower risk of thromboembolic events compared to no thromboprophylaxis.[37] DOACs appeared to be the most effective in preventing thromboembolic events when compared to ASA and VKA. However, ASA demonstrated the most favorable overall profile, offering a significantly reduced risk of thromboembolic events and a trend toward a lower risk of major bleeding. This meta-analysis only included the UNIVERSE trial, and two small adult DOAC trials, leading to a low number of included patients treated with DOACs (1.2% of the total patient-years).

In summary, anticoagulation is currently recommended for 3 to 12 months after the Fontan procedure due to the increased thrombotic risk postsurgery ([Fig. 1]).[25] [30] In the past, LMWH and VKA were the only available options. Therapeutic doses of DOACs seem to be a safe and effective alternative in this time period. Long-term prophylaxis may consist of ASA, if no risk factors are present. In the presence of risk factors, such as atrial arrythmia, history of thromboembolism, severe protein-losing enteropathy, and presence of pulmonary artery stump, anticoagulation (VKA or DOAC) is recommended.[25] [38] In patients with mechanical valves and in pregnant patients, DOACs are contraindicated.

Fig. 1 Suggested algorithm for children after Fontan surgery.

Thromboprophylaxis in Acute Lymphoblastic Leukemia

The survival rate of children with ALL has increased impressively to almost 90% due to intensive research collaborations and improved supportive care. Unfortunately, ALL patients have the highest risk for thrombosis compared to other malignancies in childhood. The reported incidences of thrombosis varied widely between 1 and 43% due to differences in disease surveillance (asymptomatic vs. symptomatic VTE), study design (retrospective and prospective), and the various chemotherapy regimens.[39] Several factors contribute to the development of VTE in ALL, including the disease itself, chemotherapy, in particular asparaginase, supportive care, including central venous catheters, and associated complications such as infections. Age is an important risk factor: thrombotic risk increases with increasing age.[40]

Despite the high thrombotic risk, especially in adolescents with ALL, primary thromboprophylaxis is not standard of care. Some studies have investigated the efficacy and safety of primary thromboprophylaxis, including replacement therapy and anticoagulant therapy, in children with ALL ([Table 2]). Replacement therapy is mostly used during asparaginase exposure. Asparaginase changes the levels of both coagulation factors and anticoagulant proteins, especially antithrombin. Fresh frozen plasma (FFP) and antithrombin concentrate have been administered to correct antithrombin deficiency. Unfortunately, several studies have shown that FFP supplementation has no impact on altering plasma antithrombin levels or preventing VTE.[41] [42] [43] Additionally, FFP has multiple drawbacks, including the risk of allergic reactions, volume overload, and the presence of asparagine, which may counteract the effects of asparaginase.

Table 2 Studies investigating thromboprophylaxis in acute lymphoblastic leukemia

Study (first author)	Study type	Patients	Intervention	Patients with VTE		Patients with bleeding
				Intervention	SOC	Intervention	SOC
Klaassen[41]	Retrospective	205	FFP	11/82 (13%)	7/123 (6%)	–	–
Nowak-Göttl[45]	Retrospective	27	AT	0/15 (0%)	0/12 (0%)	–	–
Abbott[42]	Retrospective	719	FFP/Cryo	0/249 (0%)	7/470 (1.5%)	–	–
Zaunschirm[43]	Prospective	13	FFP	0/13 (0%)	–	–	–
Hongo[44]	Retrospective	127	FFP AT	0/84 (0%) 0/48 (0%)	1/43 (2.3%) 1/79 (1%)	0/84 (0%) 0/48 (0%)	1/43 (2.3%) 1/79 (1%)
Mitchell[70]	RCT	85	AT	7/25 (28%)	22/60 (37%)
Mitchell[71]	Prospective cohort	19	LMWH	1/8 (12%)	8/11 (73%)	0/8 (0%)	0/11 (0%)
Greiner[47]	RCT	949	AT LMWH	6/320 (1.9%) 11/317 (3.5%)	25/312 (8%) 25/312 (8%)	3/320 (0.9%) 1/317 (0.3%)	0/312 (0%) 0/312 (0%)
Ruiz-Llobet[48]	Retrospective	652	LMWH	4/71 (5.6%)	53/581 (9.2%)	0/71 (0%)	0/581 (0%)
O'Brien[49]	RCT	512	Apixaban	31/256 (12%)	45/256 (18%)	11/256 (4%)	3/256 (1%)

Abbreviations: AT, antithrombin; Cryo, cryoprecipitate; FFP, fresh frozen plasma; LMWH, low-molecular-weight heparin; RCT, randomized controlled trial; SOC, standard of care; UFH, unfractionated heparin; VTE, venous thromboembolism.

Antithrombin supplementation in 48 of the 127 patients did not affect VTE occurrence in the study of Hongo et al.[44] In the study of Nowak-Göttl et al, antithrombin concentrate was administered in 15 of the 27 patients during the induction phase when antithrombin plasma levels decreased below 60% of normal in combination with increased D-dimer levels. Antithrombin concentrate normalized thrombin generation and decreased D-dimer formation, but the number of children was too low to investigate a clinical benefit.[45] The PARKAA study was an open, RCT investigating the effect of antithrombin concentrate in 85 children with asparaginase therapy in the induction phase.[46] Antithrombin concentrate was administered once weekly for 4 weeks to increase antithrombin plasma levels to approximately 30 U/L. Thrombosis was diagnosed by bilateral venography, ultrasonography, echocardiography, and magnetic resonance imaging after the induction phase. Thrombotic events were diagnosed in 7 of the 25 patients with antithrombin (28%, 95% CI: 10–46%) and in 22 of the 60 patients without antithrombin (37%, 95% CI: 24–49%). The effect and safety of antithrombin concentrate was investigated in the THROMBOTECT study, as well.[47] This study was a RCT investigating the efficacy of antithrombin concentrate or prophylactic LMWH (enoxaparin) versus low-dose unfractionated heparin (2 U/kg/h) in 949 children aged 1 to 18 years with ALL treated in the leukemia trials ALL BFM 2000 and AIEOP-BFM ALL 2009. Thromboembolic events occurred in 42 patients (4.4%). Patients randomized to antithrombin had a lower VTE risk (6/320, 1.9%) than those randomized to unfractionated heparin (25/312, 8.0%). Major bleeding occurred in four patients in the induction phase while receiving antithrombotic prophylaxis, with no differences between the three groups. Unfortunately, antithrombin concentrate might have an impact on leukemia outcome, as 5-year cancer-free survival was less in the antithrombin group (80.9 ± 2.2%) than in the unfractionated heparin (85.9 ± 2.0%) group and LMWH (86.2 ± 2.0%). The reason for this finding was not clear.

In the TROMBOTECT trial, patients with LMWH prophylaxis had a significantly lower thrombotic risk (11/317, 3.5%) than those with unfractionated heparin (25/312, 8.0%), as well. The study, however, showed an important drawback in practical use of LMWH: 33% of the patients refused allocation to the LMWH treatment arm and were assigned to another treatment arm. Rejection of the LMWH arm was more frequent in patients below 6 years of age than in older patients (62/157 [39%] vs. 42/160 [27%]), respectively. A decreased thrombotic risk by using LMWH prophylaxis in ALL patients was also found in the retrospective study of Ruiz-Llobet et al.[48] They performed a retrospective multicentric study in ALL patients 1 to 18 years old following SEHOP-PETHEMA-2013 treatment and investigated the safety and usefulness of LMWH administration as primary thromboprophylaxis. Generally, VTE incidence was lower in patients receiving prophylactic LMWH (5.6%) than in those who did not receive prophylaxis (9.2%). This difference was statistically significant in patients with inherited thrombophilia and in patients with T-cell ALL phenotype.

DOACs might be more convenient and acceptable to patients with ALL and their families. They can be administered orally, are antithrombin-independent, and do not require laboratory monitoring. The PREVAPIXX-ALL was an open-label, randomized, controlled trial investigating the efficacy and safety of apixaban in reducing VTE in children with ALL or lymphoma during induction compared to no anticoagulation.[49] The used apixaban dose was equivalent to the adult prophylactic dose of apixaban 2.5 mg twice daily. Unfortunately, no statistically significant treatment benefit was observed in patients receiving apixaban. During a median follow-up period of 27 days, 31 (12%) of 256 patients on apixaban had a composite VTE compared with 45 (18%) of 256 patients receiving no anticoagulation. Composite VTE included nonfatal clinically unsuspected and symptomatic deep venous thrombosis, pulmonary embolism, cerebral sinus venous thrombosis, and VTE-related death. Only four patients (2%) in the apixaban group and six patients (2%) in the no anticoagulation group had symptomatic deep venous thrombosis. Major and CRNM bleedings were infrequent, but patients with apixaban (n = 11, 4%) had a higher incidence of CRNM bleeding than those with no anticoagulation (n = 3, 1%). Those CRNM bleedings were primarily epistaxis in younger children. The short duration of the study (4 weeks) and the limited exposure to apixaban were likely contributing factors to the lack of statistically significant results. A longer timeframe and increased exposure may be necessary to observe significant effects.

In summary, based on available evidence, thromboprophylaxis is not recommended in all patients with ALL. DOACs or LMWH might be considered during asparaginase therapy in ALL patients at high risk for VTE, such as patients with previous VTE, T-cell ALL phenotype, and known congenital thrombophilia.

Thromboprophylaxis in Gastrointestinal Disease

Several gastrointestinal diseases can be complicated by the development of VTE in children, with those having intestinal failure (IF) and inflammatory bowel disease (IBD) being at the greatest risk.

Intestinal Failure

VTE is a common complication in patients with IF. In those patients, long-term parenteral nutrition is needed to satisfy the body's nutrient and fluid requirements for adequate growth, development, and homeostasis.[50] Parenteral nutrition is preferably administered via a central venous catheter. Reported incidences of VTE are highly variable, ranging from 2 to 75%, mainly depending on study design and diagnostic methods used.[51] In 2019, a meta-analysis reported thrombosis in 328 of 1,277 (25.7%) patients, resulting in an incidence of 750 per 10,000 person-years.[52] Risk factors for VTE in this patient group are mainly related to the presence of the central venous catheter. Thrombotic risk seemed to be higher with triple-lumen catheters than double-lumen catheters, and when the catheter is placed on the left side of the body (OR: 2.5; 95% CI: 1.0–6.4) and in the subclavian vein (OR: 3.1; 95% CI: 1.2–8.5) than on the right side and in the jugular vein.[53] In addition, VTE is associated with repeated catheter insertions and repeated catheter-related blood stream infections.[54]

An international survey among 59 specialized pediatric IF teams across Europe in 2018 revealed the use of primary thromboprophylaxis in 46% of the teams.[55] Prophylactic anticoagulation was used significantly more frequently in the teams with >10 patients than in teams with ≤10 patients (59 vs. 28%, p = 0.019). Reasons for not giving anticoagulation were no evidence (17%), not necessary/no thrombosis seen (7%), and potential side effects (3%). Current guidelines on pediatric parenteral nutrition do not advocate the use of prophylactic anticoagulation to reduce catheter-related VTE as there is insufficient evidence. Indeed, only few cohort studies have investigated the efficacy and safety of prophylactic anticoagulation in children with home parenteral nutrition. Newall et al were the first to report the use of warfarin in eight children on home parenteral nutrition for short bowel syndrome.[56] Warfarin increased the duration of catheter patency from 161 days prior to start of warfarin to 351 days after start. Most patients received therapeutic doses of warfarin with target INR between 2 and 3. New VTE and major bleeding complications did not occur. Vegting et al investigated a small cohort study of 32 children: 14 children had no thromboprophylaxis, 13 switched from no thromboprophylaxis to prophylaxis with LMWH (target level: 0.1–0.3 IU/mL) or VKA (target level: INR: 2–3), and 5 children started thromboprophylaxis with LMWH directly after insertion of the catheter.[54] Cumulative 5-year thrombosis-free survival was 48 and 93% in the nonprophylaxis and prophylaxis groups, respectively (p = 0.047). Bleeding complications did not occur. The long-term follow-up of these patients was reported in the study of Nagelkerke et al.[57] Their study included 55 patients with primary thromboprophylaxis with LMWH (target level: 0.1–0.3 IU/mL) or VKA (target level INR: 2–3). The incidence of catheter-related VTE on prophylactic anticoagulation was 0.2 per 1,000 catheter-days. The incidence of clinically relevant bleeding, including major bleeding and CRNM bleeding, was 0.1 per 1,000 catheter-days. Cumulative thrombosis-free survival was 96 and 78% after 2 and 5 years, respectively. DOACs might be a good alternative to LMWH or VKA. In adults, a pharmacokinetic study showed some absorption of both rivaroxaban and dabigatran in patients with short bowel syndrome, although lower than reference values.[58] The absorption of rivaroxaban seemed to be better than that of dabigatran. This might be due to absorption of rivaroxaban in the stomach and more proximally in the small bowel than dabigatran, and co-administration of proton pump inhibitors, which reduce absorption of dabigatran.

Inflammatory Bowel Disease

The incidence rate of VTE in children with IBD varies between 3.09 and 31.2 per 10,000 person-years.[59] [60] [61] [62] The prospective international Safety Registry, including almost 25,000 patients with IBD, reported a 14-fold higher VTE risk compared to the general pediatric population.[61] In this study, 20 VTE episodes were reported: 14 had a diagnosis of ulcerative colitis, whereas 6 patients had Crohn's disease with colonic involvement, highlighting that active colonic inflammation could be a potential risk factor for the development of VTE. Similar findings were observed in the German–Austrian IBD registry, which included 4,153 pediatric patients over a decade, identifying 12 cases of VTE: 8 patients with ulcerative colitis, 3 with Crohn's disease, and 1 with IBD-unclassified, all with colonic involvement.[63] Interestingly, about 50% of VTE patients in both registries were found to have sinovenous thrombosis.[62] [63] Similarly, a systematic review analyzing 92 venous and arterial thromboembolic events in 70 children with IBD from 51 studies identified sinovenous thrombosis as the most common type of VTE (31/67, 46%).[64] The reasons for this potential preference for certain locations (as observed in VTE patients with ALL) remain unclear. In contrast, a nested case–control study of pediatric IBD patients in Canada reported the extremities as the most frequent site of VTE, occurring in 12 out of 15 patients (80%).[65] Several risk factors may contribute to the higher VTE risk in children with IBD, including oral contraceptives, complete immobilization, central venous catheters, obesity, concurrent significant infection, known prothrombotic disorder, previous VTE, and family history of VTE.[64]

Robust studies investigating the safety and efficacy of thromboprophylaxis in children with active severe colitis are lacking. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPHAN) recommends the use of anticoagulation (LMWH) in adolescents with acute severe colitis when one or more of the abovementioned risk factors are present. Thromboprophylaxis by using LMWH may be considered in prepubertal children with acute severe colitis with at least two risk factors.[66] An international Research AND Development (RAND) panel consisting of 14 pediatric gastroenterologists considered thromboprophylaxis in all patients with new-onset acute severe colitis; all flares of known ulcerative colitis, irrespective of risk factors except in prepubescent patients with limited disease and no risk factors; and all Crohn's patients with risk factors.[67] Nevertheless, many pediatric gastroenterologists are reluctant to use thromboprophylaxis in children with IBD. In a survey, 92% of 153 pediatric gastroenterologists acknowledged the increased risk of VTE among children with IBD, but only one-third provided thromboprophylaxis to their patients.[68] The most common reasons for this discrepancy were limited pediatric data, patient resistance, and concerns for bleeding complications.

In conclusion, children with IF and IBD face a higher risk of VTE than the general pediatric population. Thromboprophylaxis could play a valuable role in preventing VTE in high-risk patients; however, limited evidence and bleeding risks make gastroenterologists hesitant to implement broader prophylactic measures.

Conclusion

The field of thromboprophylaxis in children remains a challenging yet essential aspect of pediatric health care. With increasing awareness of thromboembolic events in younger populations, pediatricians face the complicated task of balancing efficacy and safety in prophylactic anticoagulation therapies for children. Although recent studies have shed light on potential protocols, including the DOAC studies in patients with ALL and after Fontan surgery, the absence of large, age-specific research highlights a critical gap in understanding the optimal use of thromboprophylaxis in pediatric care. Addressing these gaps requires innovative solutions due to the low number of clinically apparent VTE in children. Disease registries have proven to be highly valuable sources of information, particularly for rare diseases. Following the implementation of specific antithrombotic prophylaxis protocols, systematically and prospectively collecting patient data in registries like the CHAT or Throm-PED registries could aid in identifying safe and effective strategies for VTE prevention.[6] [69] Until such research advances, clinicians must exercise caution, relying on individual assessments and interdisciplinary collaboration to navigate these “uncharted waters” effectively and safely.

Conflict of Interest

C. Heleen Ommen reports grants from Octapharma, Bayer BV, and Boehringer Ingelheim; consulting fees from Bayer BV; and payment from Xenios.

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Publication History

Received: 01 November 2024

Accepted: 26 December 2024

Article published online:
27 April 2025