Review

Prothrombotic Risk Factors and Preventive Strategies in Adolescent Venous Thromboembolism

Clinical and Applied Thrombosis/Hemostasis 1-8 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029616631428 cat.sagepub.com

Lakshmi Srivaths, MD1 and Jennifer E. Dietrich, MD, MSc2,3

Abstract Venous thromboembolism (VTE) in adolescents is a serious condition that requires prompt recognition and optimal management to prevent mortality and long-term morbidity. Adolescents account for a large proportion of cases of VTE in children. As teenagers transition from childhood to adulthood, they are at risk of developing medical conditions and exposure to risky habits that predispose them to VTE. This review focuses on the variety of risk factors and comorbidities seen in adolescent VTE and takes a quick look into risk-based preventive strategies for primary and secondary prevention. Keywords venous thromboembolism, adolescent, risk factors, thrombophilia, thromboprophylaxis

Introduction The incidence of venous thromboembolism (VTE) in the pediatric population is rising in parallel with, and likely due to, increased awareness and advances in diagnostic modalities, therapeutic approaches, technologic support, and supplemental care for illnesses, both simple and complex. Several studies have shown 3- to 10-fold increases in the frequency of VTE diagnosed in hospitalized children during the past 2 decades.1 Most studies also show a bimodal peak distribution, with neonates and adolescents reported to be at the greatest risk of development of VTE. Although reports have addressed risk factors for VTE among adolescents with individual medical conditions, the overall prevalence and risk factor profile in adolescent VTE has not been clearly delineated. This review is an attempt to summarize the available literature about risk factors in adolescent VTE. The epidemiology of adolescent VTE and its prevalence in various medical conditions are discussed, emphasizing the need for increased awareness among health-care professionals and patient families about the panel of health disorders that predispose adolescents to the development of VTEs. This review also highlights the need for a comprehensive approach to consider timely prophylactic measures in high-risk scenarios in adolescents in order to prevent this serious complication.

Epidemiology of Adolescent VTE Several recent analyses of nationally representative data for pediatric VTE in the United States have shown an increased rate and risk of VTE in the adolescent population. The Pediatric

Hospital Information System (PHIS) database report from 2001 to 2007 showed that of 13,449 VTE admissions among 2,920,000 hospitalized children, teenagers, and neonates accounted for the majority of VTE admissions.2 Adolescents in the age-group of 13 to 18 years accounted for 30% of all VTE admissions (n ¼ 4003/13,449). The rate of admissions for VTE increased 49% among teenagers during this study period. In addition, the proportion of patients with recurrent VTE was significantly higher among teenagers. The report from Kid’s Inpatient Database 2006 evaluating children aged 18 years and younger with in-hospital VTE in a large array of pediatric and community hospitals found adolescents older than 15 years of age form the greatest proportion (37.8%) of this population.3 When standardized against the entire database of discharges, a greater risk of developing VTE was noted in both early teenagers aged 10 to 14 years (relative risk [RR] 1.62; 95% confidence interval [CI] 1.45-1.80) and late adolescents aged 15 to 18 years (RR 1.89; 95% CI 1.73-2.07) when compared to younger children. The Nationwide Inpatient Sample Data

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Department of Pediatrics, Section of Hematology/Oncology, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX, USA 2 Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA 3 Department of Pediatric and Adolescent Gynecology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA Corresponding Author: Lakshmi Srivaths, Department of Pediatrics, Section of Hematology/Oncology, Texas Children’s Hospital/Baylor College of Medicine, 6701, Fannin Street, Suite 1580.00, Houston, TX 77030, USA. Email: [email protected]

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Table 1. Published Results on the Epidemiology of Adolescent VTE. Publications

Database

Patient Population

Andrew et al6 Canadian registry of VTE 7/ 137 consecutive children 1990-12/1991 aged 1 month-18 years with VTE 75,000 children with VTE National Hospital Stein et al5 Discharge Survey Database 1979-2001 Raffini et al2 PHIS 2001-2007 11,337 hospitalized patients 35) Antiphopholipid antibody syndrome

4-12 3-4 6-10 20-25 35 10

50-100 8 11.3 32.4 17.5 2 4

Otherwise, several safe progestin-only options that do not increase the risk of thrombosis are available to manage conditions related to menses or functional ovarian cyst activity. Pregnancy with multiple physiologic prothrombotic changes, including hypercoagulable state, decreased mobility, mechanical obstruction of vessels, and vascular injury, is a well-recognized risk factor for thrombosis (Table 2). In a patient who already has risk of developing a VTE, an unplanned pregnancy could result in a compounded thrombotic risk.39 A recent analysis of Nationwide Inpatient Sample from 1994 to 2009 showed increasing trend in VTE diagnosis in pregnant adolescent and adult women, likely contributed by a rise in comorbid conditions such as obesity and hypertension.40 The occurrence of cerebral sinovenous thrombosis in adolescents with iron deficiency anemia caused by heavy menstrual bleeding and other causes is an interesting association.41,42 The pathophysiology of this association has not been fully elucidated, although thrombocytosis and decreased red cell deformability in iron deficiency have been proposed as contributing to thrombogenesis.

2.2-2.5 1.6-3.2

Abbreviations: BMI, body mass index; RR, relative risk. a RRs are compared to baseline population of women of all ages without risk for thrombosis.

medical conditions affecting the use of hormonal therapy and other contraceptive methods, dividing them into categories 1 to 4 in the order of increasing health risk. In general, estrogen containing hormonal therapy is to be avoided in patients with VTE. The MEC category 2 is assigned for the use of various progestin-only methods in patients with past history of VTE or underlying inherited thrombophilia. In the setting of acute VTE, the use of progestin-only therapy falls into the higher risk category 3. Another contraceptive option for such patients is the copper intrauterine device (IUD), as it is placed in the lowest risk category of 1. Several long-acting reversible contraceptives are available and include levonoregestrel IUD, copper IUD, etonogestrel implant, and depo medroxyprogesterone acetate injections, which have been shown to be safe, not to increase the risk of thrombosis, and to be reasonable options to prevent unintended pregnancy, a condition which escalates the risk of thrombosis even further beyond baseline.30,36 The current literature suggests that it is not cost effective to mass screen females for underlying inherited thrombophilia prior to initiating hormonal therapy.37 Screening is recommended only in the settings of active VTE, strong family history of VTE, and when the screening results could affect the management.38 Other factors to consider include the patient’s age and the baseline risks of thrombosis for certain populations as well as the risk in the setting of hormone use. In patients with a known thrombophilic condition, estrogen therapy generally is contraindicated. However, in certain situations that require estrogen therapy (eg, delayed puberty occurring with Turner Syndrome),38 it should be initiated only after careful patient counseling about the risks and benefits of such therapy.

Obesity Obesity in children and adolescents is a public health concern in Western societies and has been linked to cardiovascular disease and increased risk for thrombosis.43 Hypercoagulable state in an obese individual is evidenced by the presence of elevated factor VII level, thrombin and thrombin–antithrombin complexes, tissue factor procoagulant activity, g-fibrinogen concentration, and increased platelet activation.43,44 In the pediatric population, studies have shown increased risk for development of VTE in patients with cardiovascular and cerebrovascular diseases because of enhanced atherogenesis and thrombogenesis in the setting of obesity.45-47 The combination of obesity with other risk factors such as inflammatory mediators and estrogen therapy in young women has been shown to further heighten the risk of developing a VTE. Further elucidation of the complex interactions between obesity and thrombogenesis will help to identify potential therapeutic targets in the future.

Sedentary Causes Due to the evolving behavior of extreme, continuous video and/ or computer gaming for several hours, youth are facing an emerging threat of developing ‘‘Gamer’s thrombosis’’ caused by venous stasis resulting from extended periods of sitting.48-50 Information in the medical literature is scarce, with only a few case reports citing extreme cases in otherwise healthy adolescents with VTE, including bilateral and recurrent DVT and PE requiring aggressive surgical interventions in addition to medical management. These case reports raise the concern that continuous gaming may be a thrombotic risk factor of clinical significance. Although few educational Web sites address physical and social issues related to extreme gaming, increased awareness is needed among the medical personnel about the

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potential risk for developing VTE in this population.51 Further research is also required to understand the true frequency of Gamer’s thrombosis, as preventive strategies, such as taking frequent breaks and doing leg exercises similar to those advised for air travelers, may help to avert this ‘‘e-thrombosis.’’

Sickle Cell Disease An example for cross-talk between inflammation and coagulation is perhaps the increased propensity for development of VTE in patients with sickle cell disease (SCD). Although it is not exclusive to adolescents, the heightened association of PE in acute chest syndrome and increased incidence of DVT in pregnant patients with SCD encompasses adolescents, with the risk increasing in association with other coexisting factors such as hormonal therapy, indwelling catheters, and infections.52,53 Whether VTE plays a role as cause or effect in sickle-cellrelated pulmonary disorders has not been fully elucidated and remains an under-recognized complication. A recently published retrospective cohort study54 analyzing data from the Cooperative Study of Sickle Cell Disease has shown that patients older than 15 years who have SCD are at increased risk for VTE and those with VTE are at higher risk for death than those without. Increased awareness of VTE associated with SCD is important and further studies to unravel the pathophysiology of TE in these patients are needed to institute timely interventions.

Thromboprophylaxis The American College of Chest Physicians evidence-based clinical practice guidelines for antithrombotic therapy in neonates and children55 recommends primary prophylaxis for VTE in patients with certain underlying conditions including cardiac catheterization, specific cardiac surgeries, cardiomyopathy, primary pulmonary hypertension, long-term total parenteral nutrition, hemodialysis with central venous access device (CVAD) or arteriovenous fistula, and Kawasaki disease with moderate or giant coronary artery aneurysm. Secondary prophylaxis is recommended for patients with CVAD or with other ongoing risk factors for TE until they resolve. No uniform practice exists for thromboprophylaxis in adolescents managed in pediatric hospitals, although it is strongly recommended for hospitalized critically ill adults without a contraindication for anticoagulation. A multinational study of thromboprophylaxis practice (including pneumatic/sequential compression devices or graduated compression stockings as mechanical prophylaxis and aspirin, clopidogrel, lowmolecular-weight heparin, subcutaneous unfractionated heparin, intravenous unfractionated heparin >10U/h, or coumadin as pharmacoprophylaxis) in critically ill children showed that even though 86.9% of children in the pediatric intensive care unit studied had  1 risk factor for thrombosis, only 12.4% of the patients received pharmacoprophylaxis, and only 23.8% received mechanical prophylaxis. The study documented high variations and lower rates of practice of both mechanical and

pharmacologic prophylaxis in critically ill children when compared to adults, which were seen more often but not consistently in teens older than 13 years of age.56 Raffini and colleagues undertook the implementation of a patient-safety and quality-improvement project in adolescents older than 14 years of age in their institution to use risk-based pharmacologic (enoxaparin or unfractionated heparin) and/or mechanical thromboprophylaxis (pneumatic compression device and/or graduated compression stockings).57 Hospitalized teens were risk stratified depending on their mobility status and VTE risk factors, including acute and chronic medical conditions and past and/or family history of VTE. For ambulatory patients without additional VTE risk factors, early ambulation was recommended, whereas the interventions for patients at high risk (VTE risk factor and altered mobility) and at risk (at least 1 risk factor for VTE) included pharmacologic and/or mechanical thromboprophylaxis, the former administered to patients without contraindications for anticoagulation. This initiative resulted in no patient developing noncatheterrelated VTE, with low incidence of bleeding overall.58 In addition, from a baseline of 22%, the rate of VTE prophylaxis at their institution increased to an average rate of 82%, with intermittent improvements up to 100%. Similar strategy for VTE prevention has been proposed by Meier and colleagues59 based on their recent review of pediatric literature on VTE prophylaxis in adolescents. There is a need for multi-institutional studies to better define the role of pharmacologic and/or mechanical thromboprophylaxis in the prevention of adolescent VTE in hospitalized patients. Studies incorporating risk stratification of hospitalized adolescents based on underlying thrombotic risk factors and institution of measures such as early ambulation, pneumatic/sequential compression devices, or graduated compression stockings in patients at lower risk for VTE and pharmacologic prophylaxis with low-molecular-weight or unfractionated heparin for high risk patients will enable assessment of clot prevention benefits and bleeding risks in hospitalized children and help reach a consensus guideline for adolescent thromboprophylaxis. Risk-stratified approaches can then be applied uniformly in pediatric institutions to identify and provide thromboprophylaxis for at-risk hospitalized adolescents. Further work is required to understand the true epidemiology and risk association in adolescent thrombosis in order to develop effective risk-adapted strategies. These approaches might not only lead to recognition and management of at-risk adolescents with VTE prophylaxis but also help identify adolescents who may benefit from minimal intervention such as early ambulation. In the out-patient setting, increased awareness among providers of high-risk situations for adolescent VTE may lead to teen education to avoid or modify risk factors to prevent VTE.

Conclusion The prevalence of VTE in adolescents is high and has been increasing in recent years. Focused evaluation and

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management of teenagers with VTE is needed, as often the etiology is multifactorial requiring specific measures to manage the underlying risk factors for VTE and preventing recurrence. Further research focusing on adolescents with VTE will help us to better understand the true epidemiology and risk association and enable us to develop effective riskadapted strategies for at-risk adolescents. This approach can in turn lead to routine risk-based institution of mechanical and/or pharmacologic prophylaxis in adolescents with acute illness and chronic health conditions. In addition, educating teens about the various risk factors and life-style modification strategies can lead to a positive impact in the future in reducing the rate of VTE in these youngsters, who have a long life ahead of them.

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Authors’ Note LS drafted, reviewed, edited, and revised the manuscript. JED drafted, reviewed, edited, and revised the manuscript.

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Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 17.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Prothrombotic Risk Factors and Preventive Strategies in Adolescent Venous Thromboembolism.

Venous thromboembolism (VTE) in adolescents is a serious condition that requires prompt recognition and optimal management to prevent mortality and lo...
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