Enric Castellet, Míriam Basagaña-Farrés.
Response/Recommendation: Gender does not influence the choice of venous thromboembolism (VTE) prophylaxis. However, high-risk pediatric patients ³ 13-years old may benefit from the administration of VTE prophylaxis.
Strength of Recommendation: Strong.
Rationale: Several clinical practice guidelines (CPG) have repeatedly identified adolescence as an independent risk factor for the development of VTE. Conversely, patient gender has not been recognized as a risk factor for the development of VTE. Most studies refer to skeletal maturity as chronologic age. Terminology such as “puberty” and “adolescence” is also used by some authors1-6. Unlike in adults, there is a scarcity of evidence on the risks and benefits of VTE prophylaxis in children. In addition, most of the existing studies were carried out in pediatric patients who sustained traumatic injuries21-24, with very few evaluating patients undergoing elective orthopaedic procedures25-28.
Interventions to prevent VTE include early postoperative ambulation, mechanical prophylaxis, and pharmacologic prophylaxis. The VTE risk threshold for administration of prophylaxis must evaluate both the harm of a VTE event, as well as the possible adverse side effects brought on by the prophylactic agent itself29-38.
Most studies evaluating the incidence of VTE in pediatric patients showed no difference in risk with respect to gender39-47. Some isolated studies identified female gender as a contributing factor; however, the level of risk contribution was negligible compared to other risk factors48-49.
The precise age at which pediatric patients are at highest risk of VTE remains unknown. The evidence to date currently suggests that in pediatric patients undergoing orthopaedic procedures, children ³ 13-years old are at the highest risk of VTE development50-51.
Due to the low incidence of VTE in the pediatric orthopaedic surgical patients, and the considerable risks associated with thromboprophylaxis administration, universal thromboprophylaxis cannot be recommended44. The age at which a pediatric patient is considered at significant risk for VTE development remains a contentious issue. Age cut-offs for VTE risk tend to range from 9 to 15. The ambivalence towards age and risk is best reflected in a national multidisciplinary consensus study on VTE in pediatric trauma. They found that the risk of VTE appears augment in early adolescence and continues to increase into young adulthood44.
A survey of pediatric trauma practices indicated that 13% of trauma centres described their utilization of low-molecular-weight heparin (LMWH) prophylaxis in patients aged 11 to 15 as “often” or “always.” Additionally, the incidence increased to 57% in patients aged 16 to 204.
In 2017 the Pediatric Trauma Society (PTS), in conjunction with the Eastern Association of Surgery for Trauma (EAST), conducted a systematic review and published CPG on prophylaxis against VTE in pediatric trauma53. They recommended that pharmacologic and/or mechanical thromboprophylaxis be considered in all pediatric trauma patients ³ 15 years-old who are at low risk of bleeding. However, due to the inadequacies of available data, the significance of these CPG was limited. Additionally, there is no evidence to support routine surveillance with ultrasound screening for VTE in injured children54.
In one study, Hanson et al.51, concluded that despite the low incidence of VTE, emerging data indicates that critically injured adolescent patients are at significant risk of developing VTE. As the risk of bleeding with prophylactic doses of LMWH is quite low, critically injured adolescent patients is one population that stands to benefit greatly from the implementation of a protocol for VTE prophylaxis. In conjunction with mechanical prophylaxis, LMWH is appropriate for many critically injured adolescent patients who have a low risk of bleeding. CPG on early and aggressive postoperative mobilization have helped drastically reduce VTE occurrence and must continue to be part of the standard of care.
In a recent meta-analysis of studies on VTE risk factors and VTE risk-assessment models, Mahajerin et al.53, found that in children with a low risk of bleeding who are hospitalized for a traumatic injury, pharmacologic prophylaxis should be considered for those > 15 years old and in younger post-pubertal children with injury severity score (ISS) > 25. Furthermore, we recommend against the use of routine pharmacologic prophylaxis in pre-pubertal children, even those with ISS >25. Similarly, current EAST guidelines state that pharmacologic prophylaxis should only be used in either children ³ 15-years old, or post-pubertal children under the age of 15 with an ISS greater than 25. However, these guidelines are not definitive due to the lack of supportive data and overall low quality of evidence.
Despite the paucity of evidence supporting reliable treatment algorithms, CPG on the management of VTE in pediatrics have been established. In general, they have all identified adolescence and older age as independent risk factors and identified particular age cut-offs for the administration of specific VTE prophylactic agents55-56. While the overall incidence of VTE in pediatric patients remains low, the identification of a prophylactic agent that is both safe and effective remains a challenge. Currently, a reliable treatment algorithm for the management of VTE in pediatric patients is non-existent, further clinical trials with innovative study designs are required to aid in its development.
References:
1. Euling SY, Herman-Giddens ME, Lee PA, Selevan SG, Juul A, SØrensen TIA, et al. Examination of US Puberty-Timing Data from 1940 to 1994 for Secular Trends: Panel Findings. Pediatrics. 2008 Feb 1;121(Supplement 3):S172–91.
2. Ishola T, Kirk SE, Guffey D, Voigt K, Shah MD, Srivaths L. Risk factors and co-morbidities in adolescent thromboembolism are different than those in younger children. Thromb Res. 2016 May;141:178–82.
3. Meier KA, Clark E, Tarango C, Chima RS, Shaughnessy E. Venous Thromboembolism in Hospitalized Adolescents: An Approach to Risk Assessment and Prophylaxis. HospPediatr. 2015 Jan 1;5(1):44–51.
4. O’Brien SH, Haley K, Kelleher KJ, Wang W, McKenna C, Gaines BA. Variation in DVT Prophylaxis for Adolescent Trauma Patients. J Trauma Nurs. 2008 Apr;15(2):53–7.
5. Sherrod BA, McClugage SG, Mortellaro VE, Aban IB, Rocque BG. Venous thromboembolism following inpatient pediatric surgery: Analysis of 153,220 patients. J Pediatr Surg. 2019 Apr;54(4):631–9.
6. Van Arendonk KJ, Schneider EB, Haider AH, Colombani PM, Stewart FD, Haut ER. Venous Thromboembolism After Trauma. JAMA Surg. 2013 Dec 1;148(12):1123.
7. Andrew M, Michelson AD, Bovill E, Leaker M, Massicotte MP. Guidelines for antithrombotic therapy in pediatric patients. J Pediatr. 1998 Apr;132(4):575–88.
8. Branchford BR, Mourani P, Bajaj L, Manco-Johnson M, Wang M, Goldenberg NA. Risk factors for in-hospital venous thromboembolism in children: a case-control study employing diagnostic validation. Haematologica. 2012 Apr 1;97(4):509–15.
9. Chalmers E, Ganesen V, Liesner R, Maroo S, Nokes T, Saunders D, et al. Guideline on the investigation, management and prevention of venous thrombosis in children*. Br J Haematol. 2011 Jul;154(2):196–207.
10. Cunningham AJ, Dewey E, Hamilton NA, Schreiber MA, Krishnaswami S, Jafri MA. Validation of a venous thromboembolism prediction algorithm for pediatric trauma: A national trauma data bank (NTDB) analysis. J Pediatr Surg. 2020 Jun;55(6):1127–33.
11. Cunningham AJ, Dewey E, Lin S, Haley KM, Burns EC, Connelly CR, et al. Pediatric trauma venous thromboembolism prediction algorithm outperforms current anticoagulation prophylaxis guidelines: a pilot study. PediatrSurg Int. 2020 Mar 3;36(3):373–81.
12. Faustino EVS, Raffini LJ. Prevention of Hospital-Acquired Venous Thromboembolism in Children: A Review of Published Guidelines. Front Pediatr. 2017 Jan 26;5.
13. Hanson SJ, Punzalan RC, Arca MJ, Simpson P, Christensen MA, Hanson SK, et al. Effectiveness of clinical guidelines for deep vein thrombosis prophylaxis in reducing the incidence of venous thromboembolism in critically ill children after trauma. J Trauma Acute Care Surg. 2012 May;72(5):1292–7.
14. Jackson PC, Morgan JM. Perioperative thromboprophylaxis in children: development of a guideline for management. PediatrAnesth. 2008 Jun;18(6):478–87.
15. Landisch RM, Hanson SJ, Cassidy LD, Braun K, Punzalan RC, Gourlay DM. Evaluation of guidelines for injured children at high risk for venous thromboembolism. J Trauma Acute Care Surg. 2017 May;82(5):836–44.
16. Mahajerin A, Webber EC, Morris J, Taylor K, Saysana M. Development and Implementation Results of a Venous Thromboembolism Prophylaxis Guideline in a Tertiary Care Pediatric Hospital. HospPediatr. 2015 Dec 1;5(12):630–6.
17. Morgan J, Checketts M, Arana A, Chalmers E, Maclean J, Powis M, et al. Prevention of perioperative venous thromboembolism in pediatric patients: Guidelines from the Association of PaediatricAnaesthetists of Great Britain and Ireland (APAGBI). PediatrAnesth. 2018 May;28(5):382–91.
18. SharathkumarA, Mahajerin A, Heidt L, Doerfer K, Heiny M, Vik T, et al. Risk-prediction tool for identifying hospitalized children with a predisposition for development of venous thromboembolism: Peds-Clot clinical Decision Rule. J ThrombHaemost. 2012 Jul;10(7):1326–34.
19. Leeper CM, Vissa M, Cooper JD, Malec LM, Gaines BA. Venous thromboembolism in pediatric trauma patients: Ten-year experience and long-term follow-up in a tertiary care center. Pediatr Blood Cancer. 2017 Aug;64(8):e26415.
20. Napolitano LM. Venous Thromboembolism Prevention in Pediatric Trauma—Time for National Guidelines. JAMA Surg. 2013;148(12):1130–1.
21. Hanson SJ, Punzalan RC, Christensen MA, Ghanayem NS, Kuhn EM, Havens PL. Incidence and Risk Factors for Venous Thromboembolism in Critically Ill Children With Cardiac Disease. PediatrCardiol. 2012;33(1):103–8.
22. Harris DA, Lam S. Venous thromboembolism in the setting of pediatric traumatic brain injury. J NeurosurgPediatr. 2014 Apr;13(4):448–55.
23. OʼBrien SH, Candrilli SD. In the absence of a central venous catheter, risk of venous thromboembolism is low in critically injured children, adolescents, and young adults: Evidence from the National Trauma Data Bank*. PediatrCrit Care Med. 2011 May;12(3):251–6.
24. Chima RS, Hanson SJ. Venous Thromboembolism in Critical Illness and Trauma: Pediatric Perspectives. Front Pediatr. 2017 Mar 13;5.
25. Murphy RF, Williams D, Hogue GD, Spence DD, Epps H, Chambers HG, et al. Prophylaxis for Pediatric Venous Thromboembolism. J Am AcadOrthop Surg. 2020 May;28(9):388–94.
26. Jain A, Karas DJ, Skolasky RL, Sponseller PD. Thromboembolic Complications in Children After Spinal Fusion Surgery. Spine (Phila Pa 1976). 2014 Jul;39(16):1325–9.
27. Odent T, de Courtivron B, Gruel Y. Thrombotic risk in children undergoing orthopedic surgery. OrthopTraumatolSurg Res. 2020 Feb;106(1):S109–14.
28. Georgopoulos G, Hotchkiss MS, McNair B, Siparsky G, Carry PM, Miller NH. Incidence of Deep Vein Thrombosis and Pulmonary Embolism in the Elective Pediatric Orthopaedic Patient. J PediatrOrthop. 2016 Jan;36(1):101–9.
29. Azu MC, McCormack JE, Scriven RJ, Brebbia JS, Shapiro MJ, Lee TK. Venous Thromboembolic Events in Pediatric Trauma Patients: Is Prophylaxis Necessary? J Trauma Inj Infect Crit Care. 2005 Dec;59(6):1345–9.
30. Badawy SM, Rychlik K, Sharathkumar AA. Current Practice of Pharmacological Thromboprophylaxis for Prevention of Venous Thromboembolism in Hospitalized Children: A Survey of Pediatric Hemostasis and Thrombosis Experts in North America. J PediatrHematolOncol. 2016 May;38(4):301–7.
31. Bidlingmaier C, Kenet G, Kurnik K, Mathew P, Manner D, Mitchell L, et al. Safety and Efficacy of Low Molecular Weight Heparins in Children: A Systematic Review of the Literature and Meta-Analysis of Single-Arm Studies. SeminThrombHemost. 2011 Oct 20;37(07):814–25.
32. Culbert MH, Hamidi M, Zeeshan M, Hanna K, Romero A, Joseph B, et al. Retrospective Analysis of Low-Molecular-Weight Heparin and Unfractionated Heparin in Pediatric Trauma Patients: A Comparative Analysis. J Surg Res. 2020 May;249:121–9.
33. Faustino EVS, Hanson S, Spinella PC, Tucci M, O’Brien SH, Nunez AR, et al. A Multinational Study of Thromboprophylaxis Practice in Critically Ill Children*. Crit Care Med. 2014 May;42(5):1232–40.
34. Faustino EVS, Patel S, Thiagarajan RR, Cook DJ, Northrup V, Randolph AG. Survey of pharmacologic thromboprophylaxis in critically ill children*. Crit Care Med. 2011 Jul;39(7):1773–8.
35. Hofmann S, Knoefler R, Lorenz N, Siegert G, Wendisch J, Mueller D, et al. Clinical Experiences with Low-Molecular Weight Heparins in Pediatric Patients. Thromb Res. 2001 Sep;103(5):345–53.
36. O’Brien SH, Klima J, Gaines BA, Betz S, Zenati MS. Utilization of Low-Molecular-Weight Heparin Prophylaxis in Pediatric and Adolescent Trauma Patients. J Trauma Nurs. 2012 Apr;19(2):117–21.
37. Raffini L, Trimarchi T, Beliveau J, Davis D. Thromboprophylaxis in a Pediatric Hospital: A Patient-Safety and Quality-Improvement Initiative. Pediatrics. 2011 May 1;127(5):e1326–32.
38. Thompson AJ, McSwain SD, Webb SA, Stroud MA, Streck CJ. Venous thromboembolism prophylaxis in the pediatric trauma population. J Pediatr Surg. 2013 Jun;48(6):1413–21.
39. Atchison CM, Arlikar S, Amankwah E, Ayala I, Barrett L, Branchford BR, et al. Development of a New Risk Score for Hospital-Associated Venous Thromboembolism in Noncritically Ill Children: Findings from a Large Single-Institutional Case-Control Study. J Pediatr. 2014 Oct;165(4):793–8.
40. Faustino EVS. It’s Time to ROCKIT. PediatrCrit Care Med. 2016 May;17(5):458–9.
41. Guzman D, Sabharwal S, Zhao C, Sabharwal S. Venous thromboembolism among pediatric orthopedic trauma patients: a database analysis. J PediatrOrthop B. 2018 Mar;27(2):93–8.
42. Mahajerin A, Branchford BR, Amankwah EK, Raffini L, Chalmers E, van Ommen CH, et al. Hospital-associated venous thromboembolism in pediatrics: a systematic review and meta-analysis of risk factors and risk assessment models. Haematologica. 2015 May 22;
43. Mahajerin A, Croteau SE. Epidemiology and Risk Assessment of Pediatric Venous Thromboembolism. Front Pediatr. 2017 Apr 10;5.
44. MacNevin W, Padhye K, Alkhalife Y, Price V, El‐Hawary R, Branchford BR, et al. Optimizing pharmacologic thromboprophylaxis use in pediatric orthopedic surgical patients through implementation of a perioperative venous thromboembolism risk screening tool. Pediatr Blood Cancer. 2021 Feb 21;68(2).
45. Padhye K, El-Hawary R, Price V, Stevens S, Branchford B, Kulkarni K. Development of a perioperative venous thromboembolism prophylaxis algorithm for pediatric orthopedic surgical patients. PediatrHematolOncol. 2020 Feb 17;37(2):109–18.
46. Sharathkumar AA, Biss T, Kulkarni K, Ahuja S, Regan M, Male C, et al. Epidemiology and outcomes of clinically unsuspected venous thromboembolism in children: A systematic review. J ThrombHaemost. 2020 May 15;18(5):1100–12.
47. Yen J, Van Arendonk KJ, Streiff MB, McNamara L, Stewart FD, Conner KG, et al. Risk Factors for Venous Thromboembolism in Pediatric Trauma Patients and Validation of a Novel Scoring System. PediatrCrit Care Med. 2016 May;17(5):391–9.
48. Connelly CR, Laird A, Barton JS, Fischer PE, Krishnaswami S, Schreiber MA, et al. A Clinical Tool for the Prediction of Venous Thromboembolism in Pediatric Trauma Patients. JAMA Surg. 2016 Jan 1;151(1):50.
49. Carrillo LA, Kumar A, Harting MT, Pedroza C, Cox CSJ. Venous thromboembolism risk factors in a pediatric trauma population. PediatrSurg Int. 2019 Apr;35(4):487–93.
50. Petty JK. Venous thromboembolism prophylaxis in the pediatric trauma patient. SeminPediatr Surg. 2017 Feb;26(1):14–20.
51. Hanson SJ, Faustino EVS, Mahajerin A, O’Brien SH, Streck CJ, Thompson AJ, et al. Recommendations for venous thromboembolism prophylaxis in pediatric trauma patients. J Trauma Acute Care Surg. 2016 May;80(5):695–701.
52. Cunningham AJ, Tobias J, Hamilton NA, Schreiber MA, Azarow KS, Jafri MA. Significant practice variability exists in the prevention of venous thromboembolism in injured children: results from a joint survey of the Pediatric Trauma Society and the Trauma Center Association of America. PediatrSurg Int. 2020 Jul 2;36(7):809–15.
53. Mahajerin A, Petty JK, Hanson SJ, Thompson AJ, O’Brien SH, Streck CJ, et al. Prophylaxis against venous thromboembolism in pediatric trauma. J Trauma Acute Care Surg. 2017 Mar;82(3):627–36.
54. Landisch RM, Hanson SJ, Punzalan RC, Braun K, Cassidy LD, Gourlay DM. Efficacy of surveillance ultrasound for venous thromboembolism diagnosis in critically ill children after trauma. J Pediatr Surg. 2018 Nov;53(11):2195–201.
55. Braga AJ, Young AER. Preventing venous thrombosis in critically ill children: what is the right approach? PediatrAnesth. 2011 Apr;21(4):435–40.
56. Monagle P, Chan AKC, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Göttl U, et al. Antithrombotic Therapy in Neonates and Children. Chest. 2012 Feb;141(2):e737S-e801S.