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
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
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
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
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.
