1. Introduction
Rates of pediatric venous thromboembolism (VTE) are rising, particularly among hospitalized children. A 2009 study from the Pediatric Health Information System database reported a 70% increase in the rates of VTE in hospitalized children from 2001 to 2007 [1]. A follow-up to this original study showed a continued rate increase of 130% from 2008 to 2019 [2]. Hospital-acquired venous thromboembolism (HA-VTE) increases not only the duration of hospitalization but also the cost, leading insurance payers to adopt policies by which they do not reimburse for preventable hospital-acquired conditions, including VTE [[3], [4], [5]]. VTE and its recurrence are associated with significant morbidity (eg, chronic venous insufficiency following deep vein thrombosis of the limbs) and potential mortality (fatal pulmonary embolism). This highlights the need for effective secondary VTE prevention strategies in pediatric patients.
Anticoagulation is the standard of care for secondary VTE prevention in high-risk adult patients, such as those with VTE provoked by a chronic risk factor [6]. In contrast, while pediatric guidelines recommend prolonged or episodic secondary anticoagulation for high-risk children, such as those with unresolved clinical risk factors or who require multiple doses of the prothrombotic chemotherapeutic agent asparaginase [7], our recent survey to assess practice patterns for secondary VTE prevention in pediatric patients found low use (<25%) of secondary anticoagulation in high-risk children [8]. In addition, most survey respondents reported discomfort in initiating secondary anticoagulation, particularly among children <12 years old [8]. A limitation of our survey was the use of hypothetical cases, and evidence for secondary anticoagulation in children is lacking.
To address this limitation, we designed the present multicenter, retrospective, case-control study of hospitalized children with a history of VTE to determine the frequency of and describe anticoagulation use for secondary VTE prevention.
2. Methods
We performed a retrospective analysis of the Children’s Hospital-Acquired Thrombosis (CHAT) Registry, described in detail elsewhere [9]. In summary, the registry contains demographic and clinical information of children aged 0 to 21 years who were diagnosed with imaging-confirmed HA-VTE and controls who did not develop HA-VTE from January 1, 2012, to June 14, 2021, across 8 participating pediatric hospitals in the United States. Cases comprised of retrospectively identified patients diagnosed with HA-VTE, and controls without HA-VTE were identified and frequency matched 1:1 to cases by admission year and institution [9].
Sites were provided access to REDCap along with detailed data dictionaries to ensure reproducible data collection. Missing data fields, outliers, and incorrect dates were sent to each site for review and verification through automated monthly data monitoring. For this analysis, variables analyzed included demographics (age, sex, race, and ethnicity), medical history, central venous catheter placement, and VTE location.
2.1. Definitions
HA-VTE was defined as any VTE diagnosed during hospitalization, not present on arrival, or within 48 hours of admission [9]. We defined secondary anticoagulation as anticoagulation use beyond the initial treatment period for purposes of VTE prevention, as previously described [8]. Pharmacologic prophylaxis refers to use of anticoagulation, whereas mechanical prophylaxis refers to use of a sequential compression device.
Data were summarized using descriptive statistics, including frequency and percentage for categorical variables. Median and observed ranges as well as IQRs were used for continuous variables. Clinical characteristics were compared between groups using the chi-square or Fisher exact test (categorical variables) and Mann–Whitney U-test (continuous variables). A P value of <.05 was considered significant. All statistical analyses employed SAS, version 9.4.
3. Results and Discussion
3.1. Participants with a history of VTE
There were 2198 participants enrolled in the CHAT Registry at the time of this analysis, of whom 48 had a history of VTE, detailed in Table 1. Historical details of the prior VTE were obtainable for 38% (18/48) of these participants with a VTE history, demonstrating that prior VTE was also hospital acquired in 14 (78%) participants.
Table 1.
Demographics of Children’s Hospital-Acquired Thrombosis Registry participants with a history of venous thromboembolism (N = 48).
| Covariate | N (column %) |
|---|---|
| Age at admission (y), median (range; IQR) | 10 (0.1-20; 3-17) |
| Age stratum (y), n (%) | |
| Infant (birth to <1) | 7 (14.6) |
| Child (≥1 to <13) | 20 (41.7) |
| Teenager (≥13 to <21) | 21 (43.8) |
| Sex, n (%) | |
| Male | 25 (52.1) |
| Female | 23 (47.9) |
| Race, n (%) | |
| White | 24 (50) |
| Asian | 2 (4.2) |
| Black or African American | 5 (10.4) |
| Native Hawaiian or Pacific Islander | 0 (0) |
| American Indian or Native Alaskan | 0 (0) |
| Unknown | 12 (25) |
| Other | 5 (10.4) |
| Ethnicity, n (%) | |
| Hispanic/Latino | 19 (39.6) |
| Non-Hispanic | 27 (56.3) |
| Not listed | 2 (4.2) |
We compared clinical characteristics of participants in the CHAT Registry with a history of VTE to those without a history of VTE. Those with a VTE history were older, with a median age of 10.1 years (IQR, 3.0-16.5 years) as compared to a median age of 3.9 years (IQR, 0.4-12.6 years) in participants without a history of VTE (P < .001). Otherwise, no statistically significant or clinically meaningful differences in demographic or disease characteristics were found between the 2 groups.
3.2. Participants with HA-VTE
Participants with a history of VTE had increased odds of developing recurrent VTE during their hospitalization (odds ratio, 3.84; 95% CI, 1.79-8.24). As shown in Table 2, the majority of the recurrent VTEs were deep vein thromboses of the upper extremity (63%), central venous catheter related (57.5%), and occurred in an intensive care unit setting (65%). There were no cases of cerebral sinus venous thrombosis. Of 2150 participants with no history of VTE, 1216 (56.6%) experienced HA-VTE. Participants with a history of VTE were older, with a median age of 9.1 years (IQR, 2.4-16.0 years), than participants without a VTE history, with a median age of 1.8 years (IQR, 0.1-12.3 years; P < .001).
Table 2.
Characteristics of participants with hospital-acquired venous thromboembolism within the Children’s Hospital-Acquired Thrombosis Registry.
| Covariate | VTE history N = 40 |
No VTE history N = 1216 |
P valuea |
|---|---|---|---|
| Age at admission (y), median (range; IQR) | 9 (0.1-20; 2-16) | 2 (0-20; 0.1-12) | <.001 |
| Age stratum (y) | .002 | ||
| Infant (birth to <1) | 7 (17.5) | 538 (44.2) | |
| Child (≥1 to <13) | 17 (42.5) | 393 (32.3) | |
| Teenager (≥13 to <21) | 16 (40) | 285 (23.4) | |
| Sex | .43 | ||
| Male | 20 (50) | 684 (56.3) | |
| Female | 20 (50) | 532 (43.8) | |
| Race | .71 | ||
| White | 20 (50) | 502 (41.3) | |
| Asian | 2 (5) | 71 (5.8) | |
| Black or African American | 4 (10) | 89 (7.3) | |
| American Indian or Native Alaskan | 0 (0) | 4 (0.3) | |
| Unknown | 11 (27.5) | 453 (37.3) | |
| Other | 3 (7.5) | 97 (8.0) | |
| Ethnicity | .23 | ||
| Hispanic/Latino | 16 (40) | 394 (32.4) | |
| Non-Hispanic | 22 (55) | 655 (53.9) | |
| Unknown | 2 (5) | 167 (13.7) | |
| Diagnosesb | |||
| Autoimmune/inflammatory | 1 (2.5) | 16 (1.3) | .43 |
| Cancer | 6 (15) | 139 (11.4) | .49 |
| Congenital heart disease | 16 (40) | 251 (20.6) | .003 |
| Other | 24 (60) | 599 (49.3) | .18 |
| Unknown/none | 0 (0) | 370 (30.4) | |
| VTE prophylaxis | .002 .88 |
||
| No | 20 (50) | 933 (78.0) | |
| Yes | 20 (50) | 263 (22.0) | |
| Mechanical only | 7 (35) | 95 (36.1) | |
| Pharmacologic only | 10 (50) | 133 (50.6) | |
| Both | 3 (15) | 35 (13.3) | |
| Days after admission to HA-VTE (d) | N = 40 | N = 1206 | .09 |
| Mean (SD) | 14 (22.2) | 20 (39.6) | |
| Median (range; IQR) | 7 (1-129; 3-16) | 9 (0-495; 4-20) | |
| Hospital location at VTE diagnosis | .45 | ||
| Non-ICU | 14 (35) | 498 (41.0) | |
| ICU | 26 (65) | 716 (60.0) | |
| Line related | .36 | ||
| No | 16 (40) | 379 (31.3) | |
| Yes | 23 (57.5) | 808 (66.7) | |
| Unknown | 1 (2.5) | 25 (2.1) | |
| VTE locationb | |||
| DVT upper extremity | 25 (62.5) | 556 (45.8) | .04 |
| DVT lower extremity | 11 (27.5) | 512 (42.1) | .07 |
| Cardiac | 2 (5) | 43 (3.5) | .65 |
| PE | 1 (2.5) | 31 (2.6) | 1.00 |
| ASVT | 1 (2.5) | 27 (2.2) | .60 |
| CSVT | 0 (0) | 68 (5.6) | .16 |
ASVT, abdominal site venous thrombosis; Cardiac, R atrium + cardiac ventricle; CSVT, cerebral sinus venous thrombosis; DVT, deep vein thrombosis; HA-VTE, hospital-acquired venous thromboembolism; ICU, intensive care unit; PE, pulmonary embolism; VTE, venous thromboembolism.
The parametric P value was calculated using analysis of variance for numerical covariates and the chi-square test for categorical covariates. The nonparametric P value was calculated using the Kruskal–Wallis test for numerical covariates and Fisher exact test for categorical covariates.
Each line represents a yes/no response, with only “yes” selections summarized as n (%) and P value.
3.3. Use of VTE prophylaxis
Among all CHAT Registry participants, 23% received some method of VTE prophylaxis. Fifty percent (20/40) of participants with a history of VTE received secondary VTE prophylaxis. Thirteen (65%) participants were prescribed pharmacologic prophylaxis alone (n = 10) or in combination with mechanical prophylaxis (n = 3). Anticoagulant data were able to be obtained for 7 of these subjects: 2 received aspirin, 4 received enoxaparin, and 1 was treated with warfarin. The remaining 7 (39%) participants with a history of VTE received mechanical prophylaxis only.
Of the remaining 28 participants with a history of VTE who did not receive VTE prophylaxis, 8 (29%) had documented contraindications to pharmacologic (n = 3) and mechanical (n = 5) prophylaxis, respectively. The most frequent contraindication to pharmacologic prophylaxis was increased risk of bleeding, including uncorrected coagulopathy, ongoing/uncontrolled hemorrhage, and/or thrombocytopenia. The sole reason recorded for contraindication to mechanical prophylaxis was incorrect fit/lack of appropriate size.
The results of this analysis from the multicenter CHAT Registry confirm prior findings that demonstrated prior VTE to be a risk factor for recurrent VTE [10]. However, we found a higher rate of recurrent VTE than has been previously reported in hospitalized children. Limitations of this study include its retrospective design and the relatively small sample size. Additionally, we lacked details of prior VTE in those with a history of VTE. Despite these limitations, these data clearly highlight the need for prospective studies to confirm the incidence of recurrent VTE, research to define high-risk populations for recurrent VTE, clinical trials to provide additional evidence to define the best strategies for secondary VTE prevention, and implementation science to address approaches to improve adoption of secondary anticoagulation in this high-risk population.
In conclusion, there is a high rate of VTE in hospitalized children who have a history of VTE, particularly if the prior VTE was also hospital acquired. Nevertheless, in this real-world experience, the use of secondary anticoagulation for prevention of recurrent VTE during hospitalization was infrequent. These findings identify a critical opportunity for future risk-stratified clinical trials of secondary anticoagulation for VTE prevention in hospitalized children with a history of VTE.
Acknowledgments
We acknowledge the following 8 Children’s Hospital-Acquired Thrombosis Consortium sites and personal investigators who contributed to the Children’s Hospital-Acquired Thrombosis Registry: Julie Jaffray, MD, MS, Children’s Hospital Los Angeles and the Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; Brian Branchford, MD, Children’s Hospital Colorado, Aurora, CO, and Versiti Blood Research Institute, Milwaukee, WI, USA; Nihal Bakeer, MD, Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA; James D. Cooper, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA; Stacy E. Croteau, MD, MMS, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA; John H. Fargo, DO, Akron Children’s Hospital, Akron, OH, USA; Arash Mahajerin, MD, CHOC, Children’s Hospital, Orange, CA, USA; and Michael Silvey, DO, Children’s Mercy Hospital, Kansas City, MO, USA.
Funding
This work was supported by the National Institutes of Health from the National Center for Advancing Translational Sciences (grant number UL1TR001855 to J.J.) and the Hemostasis and Thrombosis Research Society Mentored Research Award, supported by an independent educational grant from Takeda Pharmaceuticals USA (to J.J.).
Ethics statement
The Registry was approved by the institutional review board at each of the participating hospitals and a waiver of consent was granted.
Author contributions
J.J., B.B., and N.A.G. conceived the Children’s Hospital-Acquired Thrombosis Consortium Registry. H.P.W. designed the subanalysis under the mentorship and guidance of N.A.G., M.M., and J.L. conducted the data analysis. All other authors contributed to patient and data entries. H.P.W. wrote the initial draft of the manuscript. All authors edited and approved the final manuscript version of the paper.
Relationship Disclosure
There are no competing interests to disclose.
Footnotes
Handling Editor: Dr Lana Antoinette Castellucci
References
- 1.Raffini L., Huang Y.S., Witmer C., Feudtner C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics. 2009;124:1001–1008. doi: 10.1542/peds.2009-0768. [DOI] [PubMed] [Google Scholar]
- 2.O’Brien S.H., Stanek J.R., Witmer C.M., Raffini L. The continued rise of venous thromboembolism across US children’s hospitals. Pediatrics. 2022;149 doi: 10.1542/peds.2021-054649. [DOI] [PubMed] [Google Scholar]
- 3.Boulet S.L., Amendah D., Grosse S.D., Hooper W.C. Health care expenditures associated with venous thromboembolism among children. Thromb Res. 2012;129:583–587. doi: 10.1016/j.thromres.2011.08.006. [DOI] [PubMed] [Google Scholar]
- 4.Branchford B. Clinical and financial impact of HACs: a commentary on clinical and financial costs of hospital-acquired conditions. Transl Pediatr. 2015;4:331–333. doi: 10.3978/j.issn.2224-4336.2015.10.06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Deitelzweig S., Thompson S., Lin J., McMorrow D., Johnson B. Impact of CMS VTE hospital acquired conditions (HAC) policy on hospital cost and revenue associated with major surgical hip and knee procedures. Blood. 2010;116:3824. doi: 10.1182/blood.V116.21.3824.3824. [DOI] [Google Scholar]
- 6.Ortel T.L., Neumann I., Ageno W., Beyth R., Clark N.P., Cuker A., et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4:4693–4738. doi: 10.1182/bloodadvances.2020001830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Monagle P., Chan A.K.C., Goldenberg N.A., Ichord R.N., Journeycake J.M., Nowak-Göttl U., Vesely S.K. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e737S–e801S. doi: 10.1378/chest.11-2308. Published correction appears in Chest 2014;146:1694. Published correction appears in Chest 2014;146:1422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wilson H.P., Capio R., Aban I., Lebensburger J., Goldenberg N.A. Secondary thrombosis prevention practice patterns in pediatrics: results of an international survey. Res Pract Thromb Haemost. 2022;6 doi: 10.1002/rth2.12693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Jaffray J., Mahajerin A., Young G., Goldenberg N., Ji L., Sposto R., et al. A multi-institutional registry of pediatric hospital-acquired thrombosis cases: the Children’s Hospital-Acquired Thrombosis (CHAT) project. Thromb Res. 2018;161:67–72. doi: 10.1016/j.thromres.2017.11.019. [DOI] [PubMed] [Google Scholar]
- 10.Mahajerin A., Webber E.C., Morris J., Taylor K., Saysana M. Development and implementation results of a venous thromboembolism prophylaxis guideline in a tertiary care pediatric hospital. Hosp Pediatr. 2015;5:630–636. doi: 10.1542/hpeds.2014-0241. [DOI] [PubMed] [Google Scholar]