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Pediatric-Onset Rehabilitation

Thromboembolic Function

Pediatric venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism has a relatively low incidence compared with adults, estimated at 0.07 to 0.14 per 10 000 children (Andrew et al. 1994; Stein et al. 2004). The incidence is considerably higher in hospitalized children, reaching values of ≥58 per 10 000 admissions (Andrew et al. 1994; Gibson B 2003; Sabapathy et al. 2016; van Ommen CH 2001). Preventing episodes of VTE is essential for minimizing the significant morbidity and mortality associated with its occurrence, namely post-thrombotic syndrome, recurrence of thromboembolism, and death (Goldenberg et al. 2012; Monagle et al. 2000; Rajpurkar M 2015; Revel-Vilk et al. 2012).

While the literature is extensive when it comes to risk factors, diagnosis, and prevention of VTE in adults (Heit 2015; Phillippe 2017), there is substantially less knowledge about pediatric VTE (Branchford et al. 2018; Monagle et al. 2018). Identified risk factors for VTE include presence of central vein catheters, trauma and associated injury severity score, spinal fractures and associated SCI, ventilator dependency, chest injuries, BMI/obesity, family/personal history of clots, age (bimodal distribution, more frequent in neonates and teenagers, with the latest possibly influenced by hormones (intrinsic or exogenous – contraceptive pills) (Monagle et al. 2018; Witmer & Takemoto 2017). The easiest construct when assessing VTE risk in pediatric population appears to be Virchow’s triad activation: stasis of blood flow, injury to the endothelial lining, and hypercoagulability of blood components. The most common precipitating factor is the presence of a central venous catheter, which is related to almost 90% of VTE in neonates and >60% in older children (Tran et al. 2018). More than 90% of cases of pediatric VTE have >1 risk factor, with venous access devices being the most common single risk factor and accounting for >90% of neonatal VTE and >50% of pediatric VTE (Carrillo et al. 2019). VTE has been found to be the most likely cause of preventable death in hospitalized populations (Paiement 1995). And VTE, pediatric or adult, has the potential for significant morbidity and mortality (Witmer C 2016).

The natural history of VTE in children remains unclear in many circumstances. The reported VTE mortality from registry data is ∼3%, in the context of ∼16% of children dying from their underlying illness (Witmer & Takemoto 2017). Finally, as there are no anticoagulant drugs approved for use in children, with very little specific research on children, the European Society for Vascular Surgery issued clinical guidelines about venous thrombosis treatment in February 2021 advising that management of pediatric deep vein thrombosis should be guided by clinicians with specific expertise in pediatric thrombosis and hemostasis (Kakkos et al. 2021). In this context, an increased VTE likelihood in children with traumatic spinal cord injuries and the interest in its prevention and management can easily be explained. And while there is substantially more information about pediatric trauma-related VTE (Thompson et al. 2013), this section attempts to summarize the data pertinent to the traumatic SCI diagnosis.

Author, Year

Country

Study Design

Sample Size

Study Characteristics

Results

(Blevins & Raffini, 2015)

USA

Case Report

N=2

Case Report 1:

Population: Age: 17 yr; Gender: male; Injury etiology: SCI; Mechanism: MVC; Severity of injury: triplegia.

Intervention: Prophylactic, non-retrievable IVC filter and 40 mg enoxaparin daily for 12 mo.

Outcome Measures: VTE incidence and outcome.

Case Report 2:

Population: Age: 15 yr; Gender: male; Injury etiology: SCI; Mechanism: gunshot; Severity of injury: paraplegia.

Intervention: Prophylactic, removeable IVC filter with removal scheduled.

Outcome Measures: VTE incidence and treatment.

Case Report 1:

1.         Presentation: Occlusive thrombi extending from the IVC filter bilaterally down to the popliteal veins within two months of stopping enoxaparin.

2.        Treatment: Catheter- directed thrombolysis with recombinant tissue plasminogen activator and balloon venoplasty were performed to restore vascular patency.

3.        Follow-up: Warfarin as an outpatient for long-term anticoagulation.

Case Report 2:

4.        Presentation: IVC filter was never removed due to loss of follow-up. Occlusive thrombi extending from the IVC filter bilaterally down to the popliteal veins within 7 months of injury.

5.        Treatment: Catheter- directed thrombolysis with recombinant tissue plasminogen activator and balloon venoplasty were performed to restore vascular patency.

6.        Follow-up: Warfarin as an outpatient for long-term anticoagulation.

(Jones et al., 2005)

USA

Observational

N=16,240

(N=1,585 <20 yr)

Population: Age: 44.5±21.0 yr; Gender: males=11,777, females=4,463; Level and severity of injury: complete paraplegia=1017, complete tetraplegia=1218

Intervention: None

Outcome Measures: Incidence of venous thromboembolism (VTE).

1.         In total, 70 of 1,585 (4.4% pediatric patients (aged 8-19 yr) with SCI developed a VTE within one year of hospitalization.
(Vogel et al., 2002b)

USA

Observational

N=216

Population: Age at injury: 14.1±4.0 yr; Age at interview: 28.6±3.4 yr; Gender: males=150, females=66; Time since injury: 14.2±4.6 yr; Level of injury: tetraplegia=123, paraplegia=93. Severity of injury: C1-4 ABC=41, C5-8 ABC=67, T1-S5 ABC=82, tetra/para D=26.

Intervention: None. Survey.

Outcome Measures: Prevalence of

thromboembolism.

1.         Forty-one subjects experienced thromboembolism after the immediate postinjury period.

2.        Among all the study variables, thromboembolism was only significantly associated with older age at interview (p=0.044) and longer duration of injury (p=0.004).

Author, Year

Country

Study Design

Sample Size

Study Characteristics

Results

(Bigelow et al., 2018)

USA

Observational

N=692

Population: Median Age (IQR): 4.0 (0.8-11.0) yr; Gender: 358 male, 180 female; Setting: Pediatric Intensive Care Units; Etiologies: intracranial head injury, thoracic injury, abdominal/pelvic injury, burn injury, blood vessel injury, lower extremity fracture, upper extremity fracture, crush injury, SCI, coagulation disorder, hemorrhagic condition.

Intervention: Mechanical (pneumatic compression device), Pharmacologic (heparin, LMW heparin, direct thrombin inhibitor, oral Xa inhibitor, warfarin) or dual (mechanic and pharmacologic) DVT prophylaxis.

Outcome Measures: Factors associated with prophylaxis.

1.         There was no significant association between injury diagnoses, without the corresponding procedure (aside from head injury), which was inversely associated with any prophylaxis.
(Leeper et al., 2017)

USA

Observational

N=753 (N=57 SCI)

Population: Median Age (IQR): 4 (1-13) yr for DVT group, 9 (3-14) yr for no DVT group; Gender: 503 males, 250 females. Setting: Pediatric Intensive Care Unit.

Intervention: None.

Outcomes: Incidence of DVT and PE.

1.         Just 5 of 57 individuals with SCI developed a DVT and none developed PE.
(Faustino et al., 2014)

USA

Observational

N=2,484

Population: Age <1 yr: 1,025; Age 1-13 yr: 1,191; Age >13 yr: 268; Gender: 1,389 males, 1,095 females; Setting: 59 Pediatric Intensive Care Units in Australia, Canada, New Zealand, Portugal, Singapore, Spain, and the United States.
Intervention: None.
Outcome Measures: Predictors of pharmacological and mechanical thromboprophylaxis.
1.         The presence of cyanotic congenital heart disease (OR, 7.35; p<0.001) and SCI (OR, 8.85; p=0.008) strongly predicted the use of pharmacologic and mechanical thromboprophylaxis, respectively.

2.        The presence of SCI had the highest likelihood of mechanical thromboprophylaxis (OR, 8.85; 95% CI, 1.79–43.82; p=0.008).

(O’Brien & Candrilli, 2011)

USA

Observational

N=135,032

(N=3,172 SCI)

Population: Mean Age (SE): 13.6 (0.1) yr; Gender: 94,204 males, 40,828 females; Setting: Pediatric Critical Care Unit.

Intervention: None.

Outcomes: Incidence and risk factors of VTE.

1.         Among 3,172 patients SCI, 68 (8.2%) developed a VTE.

2.        SCI was a significant risk factor for developing a VTE in this pediatric trauma population (OR 1.77, p<0.0001).

(Hanson et al., 2010)

USA

Observational

N=144

Population: Age: 8.6 (2.3-17.9) yr for VTE group, 11.5 (0.4-17.8) yr for non-VTE group; Setting: Pediatric Intensive Care Unit.

Intervention: None.

Outcomes: Risk factors for developing VTE.

1.         SCI was not a significant risk factor for VTE.
(Cyr et al., 2006)

Canada

Observational

N=3,291

Population: Age: <18 yr; Setting: Pediatric Intensive Care Unit.

Intervention: None.

Outcomes: Incidence of VTE.

1.         SCI was a significant risk factor VTE (OR 23.4; 95% CI 3.2-170.8).
(Azu et al., 2005)

USA

Observational

N=13,894

Population: Age: <13 yr, 13-17 yr, >17 yr; Setting: Trauma Registry.

Intervention: None.

Outcomes: Incidence of VTE.

1.         SCI was not a significant risk factor VTE.
(Cook et al., 2005)

USA

Observational

N=116,357

Population: Age 0-13 yr: 72,279; Age 14-17 yr: 44,078; Gender: 75,743 males, 40,511 females; Database: National Trauma Databank (Pediatric): head injury, severe SCI, vertebral fracture, severe pelvic fracture, severe femur fracture, and tibia fracture.

Intervention: None.

Outcome Measures: Risk factors associated with vena cava filtration placement.

1.         SCI was a significant risk factor associated with vena cava filtration (p<0.001).
(Vavilala et al., 2002)

USA

Observational

N=58,716

Population: Age: >16 yr; Setting: Trauma Registry.

Intervention: None.

Outcomes: Incidence of VTE.

1.         Individuals with SCI had a VTE rate of 6.0 per 1,000 patients.

2.        SCI was significantly associated with VTE (RR 7.9, CI 1.9-32.7).

(McBride et al., 1994)

USA

Observational

N=28,692 (N=290 SCI)

Population: Mean Age: 9 yr; Setting: National Pediatric Trauma Registry. SCI Severity: 108/290 with paraplegia or tetraplegia.

Intervention: None.

Outcomes: Incidence of DVT and PE.

1.         Just 6 of 28,692 patients had a DVT.

2.        Just 2 of 28,692 patients had a PE (no DVT); both patients had sustained a SCI resulting in paraplegia.

3.        Among those with a PE, one patient had a vena cava filter placed prior to the PE and died; the other patient had a vena cava filter placed after the PE and survived.

(Radecki & Gaebler-Spira, 1994)

USA

Observational

N=532
(N=87 SCI, N=4 transverse myelitis)

Population: Mean Age: <18 yr; Setting: Pediatric Rehabilitation Unit.

Intervention: None.

Outcomes: Incidence of DVT and PE.

1.         Just 1 of 87 patients with SCI and 1 of 4 patients with transverse myelitis each had a PE.

2.        DVT was confirmed in 8 of 87 patients with SCI; just 1 patient with confirmed DVT in SCI was under age 13 yr.

Author, Year

Country

Study Design

Number of Studies Included for Review

Method

Databases Search

Level of Evidence

Research Question

Results

(Thompson et al., 2013)

USA

Systematic Review

N=18 articles

Databases:  English-language articles identified through Pubmed published from 1995 until November 2012, and from bibliographies of relevant articles.

Research Questions: In the pediatric traumatic injury population: (1) What is the overall incidence of VTE? (2) Is age (adolescence versus pre-adolescence) associated with higher VTE incidence? (3) Which risk factors are associated with higher VTE incidence? (4) Does mechanical and/or pharmacological prophylaxis impact outcomes?

1.  N=18; In the spinal cord injury population, patients aged 14–19 yr had significantly more VTE (4.4% compared to 1.1% of younger patients; p = .035).

2. In multivariate logistic modeling, the younger age group (b 14 yr) had a decreased risk of VTE (odds ratio 0.2, 95% confidence interval 0.1 to 0.9). Most episodes (90%) of VTE occurred within 91 days of injury.

3. Patients with a SCI represent a subset of the trauma population with a higher risk for VTE, although data in children younger than 15 yr are sparse.

Discussion

Among the studies identified in the literature search, three focused exclusively on the pediatric SCI population (Blevins & Raffini 2015; Jones et al. 2005; Vogel et al. 2002b). Most of the papers were retrospective in nature, and the data were heterogeneously presented, with variations amongst assessed outcomes, analysis of co-existing or pre-existing VTE risk factors, and diagnosis, usually based on clinical symptoms. Nevertheless, the studies generally revealed a low prevalence of VTE (deep vein thrombosis and pulmonary embolism) in hospitalized children and adolescents with SCI, ranging from 0.6% to 10% (Faustino et al. 2014; Hanson et al. 2010; Jones et al. 2005; Leeper et al. 2017; McBride et al. 1994; O’Brien & Candrilli 2011). In addition, in a study investigating the prevalence of various medical complications, such as UTI, pressure ulcers, thromboembolism, and AD,  in 216 adults with pediatric-onset SCI, VTE was amongst the least reported medical complications in that sample (Vogel et al. 2002b).

Of those with pediatric-onset SCI, older age was found to be associated with higher likelihood of developing VTE (Jones et al. 2005; Radecki & Gaebler-Spira 1994; Thompson et al. 2013). In a sample of 1,585 hospitalized children and adolescents with SCI from Jones and colleagues (2005) study, the incidence of VTE was considerably higher in adolescents between ages 14-19 (4.4%) compared to that in children between ages 8-13 (1.1%). Similar results were revealed in several other studies examining the prevalence of VTE across different age groups in the pediatric SCI population (Cyr et al. 2006; McBride et al. 1994; Thompson et al. 2013). According to Cyr et al. (2006), those with higher level of injury severity may also be more likely to develop VTE than those with less severe injuries.

Concerning the relation between gender and occurrence of VTE, the research findings are mixed. Furthermore, there is conflicting evidence regarding whether SCI is associated with heightened risk of developing VTE in the pediatric population. While the majority of the studies suggested that having SCI was a significant risk factor for VTE (Cyr et al. 2006; O’Brien & Candrilli 2011; Thompson et al. 2013; Vavilala et al. 2002), some did not demonstrate such link (Azu et al. 2005; Hanson et al. 2010; Leeper et al. 2017).

Jones et al. (2005) found that boys aged 8-13 years were just slightly more likely than girls to experience VTE; in the 14-19 age group, adolescent boys were 3.5 more likely than females to be diagnosed with thromboembolic events. There were just 181 VTE cases age 13 or under, and only 8 of those were coded as having complete paraplegia or quadriplegia, thus a relationship between injury severity and likelihood of VTE was not established in the pediatric population.

In terms of VTE prophylaxis, both mechanical (applied in children 8 years or older) and pharmacological prophylaxis were common in the younger children and becomes more common in adolescents, especially those admitted to adult trauma centers (Azu et al. 2005; Bigelow et al. 2018; Faustino et al. 2014). Because of the low incidence of VTE in pediatric patients with SCI, some have suggested that VTE prophylaxis may not be necessary for this population (Azu et al. 2005). Among pediatric patients with various trauma etiology who received VTE prophylaxis, both Bigelow et al. (2018) and Faustino et al. (2014) found that pediatric SCI was predominantly associated with initiation of mechanical prophylaxis.

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