term mental wellbeing of adolescents and ... - Wiley Online Library

Journal of Thrombosis and Haemostasis, 15: 2333–2343

DOI: 10.1111/jth.13873

ORIGINAL ARTICLE

Long-term mental wellbeing of adolescents and young adults diagnosed with venous thromboembolism: results from a multistage mixed methods study A . A . H Ø J E N , * † ‡ E . E . S Ø R E N S E N , † § P . S . D R E Y E R , ¶ * * M . S Ø G A A R D * ‡ and T . B . L A R S E N * ‡ *Department of Cardiology, Aalborg University Hospital; †Clinical Nursing Research Unit, Aalborg University Hospital Science and Innovation Center, Aalborg University Hospital; ‡Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University; §Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg; ¶Department of Anesthesiology and Intensive Care, Aarhus University Hospital; and **Institute of Public Health, Section of Nursing, Aarhus University, Aarhus, Denmark

To cite this article: Højen AA, Sørensen EE, Dreyer PS, Søgaard M, Larsen TB. Long-term mental wellbeing of adolescents and young adults diagnosed with venous thromboembolism: results from a multistage mixed methods study. J Thromb Haemost 2017; 15: 2333–43.

Essentials • Long-term mental wellbeing of adolescents and young adults with venous thromboembolism is unclear. • This multistage mixed methods study was based on Danish nationwide registry data and interviews. • Mental wellbeing is negatively impacted in the longterm and uncertainty of recurrence is pivotal. • The perceived health threat is more important than disease severity for long-term mental wellbeing. Summary. Background: Critical and chronic illness in youth can lead to impaired mental wellbeing. Venous thromboembolism (VTE) is a potentially traumatic and life-threatening condition. Nonetheless, the long-term mental wellbeing of adolescents and young adults (AYAS) with VTE is unclear. Objectives: To investigate the long-term mental wellbeing of AYAS (aged 13– 33 years) diagnosed with VTE. Methods: We performed a multistage mixed method study based on data from the Danish nationwide health registries, and semistructured interviews with 12 AYAS diagnosed with VTE. An integrated mixed methods interpretation of the findings was conducted through narrative weaving and joint displays. Results: The integrated mixed methods interpretation showed that the mental wellbeing of AYAS with VTE had a chronic perspective, with a persistently higher

Correspondence: Anette Arbjerg Højen, Aalborg Thrombosis Research Unit, Aalborg University Hospital, Sdr. Skovvej 15, DK9000, Denmark Tel.:+45 2 929 9114 E-mail: [email protected] Received: 7 June 2017 Manuscript handled by: C. McLintock Final decision: F. R. Rosendaal, 5 October 2017 © 2017 International Society on Thrombosis and Haemostasis

risk of psychotropic drug purchase among AYAS with a first-time diagnosis of VTE than among sex-matched and age-matched population controls and AYAS with a firsttime diagnosis of insulin-dependent diabetes mellitus. Impaired mental wellbeing was largely connected to a fear of recurrence and concomitant uncertainty. Therefore, it was important for the long-term mental wellbeing to navigate uncertainty. The perceived health threat played a more profound role in long-term mental wellbeing than disease severity, as the potential life threat was the pivot which pointed back to the initial VTE and forward to the perception of future health threat and the potential risk of dying of a recurrent event. Conclusion: Our findings show that the long-term mental wellbeing of AYAS diagnosed with VTE is negatively affected, and highlights these patients’ need for adequate support. Keywords: adolescent; anxiety; psychology; pulmonary embolism; venous thromboembolism; young adult.

Background Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), remains a major cause of mortality and morbidity, affecting 1–2 per 1000 persons annually [1]. The physical consequences of VTE have been extensively assessed and discussed within the scientific context of VTE, but subsequent mental wellbeing has received less attention. Increased levels of anxiety and depression symptoms have been reported among VTE patients in the immediate period following VTE [2,3], and in the long term [4,5]. Studies examining the quality of life (QOL) of VTE patients have also provided information about subjective mental and physical health, revealing a decline in QOL following VTE and a subsequent improvement over time, although

2334 A. A. Højen et al

this is less pronounced when only the mental component of QOL is considered [6–9]. Furthermore, patients have been reported to experience symptomatic PE as a lifechanging distressing event, leading to behavior modification, which, in some cases, may be characteristic of posttraumatic stress disorder [10]. Thus, the existing evidence suggests that the mental wellbeing of patients with VTE is negatively affected. This could play an important role in disease management and the long-term prognosis in patients with VTE. Results from the thrombEVAL study program recently showed that symptoms of anxiety and depression among patients treated with oral anticoagulation with vitamin K antagonists were associated with increased mortality and impaired quality of anticoagulant treatment [11]. The incidence of VTE increases with age, and is lowest among the young [12]. However, adolescents and young adults (AYAS) may be particularly vulnerable to psychological distress, as they are in a phase of life during which they are creating identities and making decisions regarding educational path, career, and family [13]. Accordingly, chronic physical illnesses, e.g. diabetes in adolescence or young adulthood, have been associated with significant long-term psychological, emotional and behavioral problems [14,15]. Nonetheless, the long-term mental wellbeing of AYAS diagnosed with VTE has been insufficiently explored. The aim of this multistage mixed methods study was to investigate the long-term mental wellbeing of AYAS Quantitative

between the ages of 13 years and 33 years with a firsttime diagnosis of VTE. Methods Design

In its broadest sense, the definition of mental wellbeing encompasses natural and physical dimensions as well as social and psychological dimensions [16], which necessitated the adoption of a study framework taking this into account. We therefore applied a mixed methods research approach. A keystone of this approach is the collection and analysis of both quantitative and qualitative data, thereby drawing on the strengths of both approaches in order to gain a better understanding of the mental wellbeing of AYAS than is achievable from either data source alone [17,18]. Our multistage mixed methods framework included three stages of data collection (Fig. 1). In the first quantitative stage of the study, we used registry data on psychotropic drug use as a proxy to describe the long-term mental wellbeing of AYAS diagnosed with VTE as compared with age-matched and sex-matched population controls. The second qualitative stage was aimed at gaining an in-depth understanding of the long-term mental wellbeing by exploring the essential meaning of the lived experiences of AYAS diagnosed with VTE. The third, final, quantitative stage was a follow-up to the qualitative

Qualitative

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Fig. 1. Multistage mixed method framework. [Color figure can be viewed at wileyonlinelibrary.com] © 2017 International Society on Thrombosis and Haemostasis

Mental wellbeing of young VTE patients 2335

results, in which we used registry data on psychotropic drug prescriptions to compare the long-term mental wellbeing of AYAS with VTE with that of chronically ill young persons with insulin-dependent diabetes mellitus (IDDM). In this way, our study drew on a combination of explanatory and exploratory approaches [19]. Integration at the method level was achieved by linking the methods of data collection and analysis through a building approach [19]; the results of study 1 informed the data collection approach of study 2, and the results of study 2 informed the data collection approach of study 3. To obtain valid and trustworthy findings during the whole research process, the three study stages were performed, analysed and described in their own logic in three individual substudies: (i) a Danish nationwide registrybased cohort study describing the long-term mental wellbeing of AYAS with incident VTE as compared with sex-matched and age-matched controls, using psychotropic drug purchase as a proxy [20]; (ii) a qualitative study with 12 semistructured interviews exploring AYAS’ lived experiences following VTE [21]; and (iii) a Danish nationwide registry-based cohort study comparing the long-term mental wellbeing of AYAS with VTE with that of chronically ill AYAS with IDDM, using psychotropic drug purchase as a proxy. In accordance with Danish law, no ethical approval is required for non-biomedical studies. The study was approved by the Danish Data Protection Agency (study 1 and study 3, File No. 2012-41-0633; study 2, File No. 2012-41-1134). Participants and data collection

In study 1 and study 3, we used the unique civil identification number assigned to all Danish residents to link data from four Danish nationwide registries: the Danish Civil Registration System [22], the Danish National Patient Registry [23], the Danish National Prescription Registry [24], and the Danish Medical Birth Registry [25]. Using the registries, we identified all patients aged 13– 33 years with a first-time primary diagnosis of DVT or PE. In study 1, we used a risk-set sampling approach to randomly select five VTE-free population controls per case, matched by birth year and sex. In study 3, we additionally identified all AYAS with IDDM defined by a first-time hospital diagnosis of diabetes mellitus and a concomitant prescription claim for insulin within 90 days after the diabetes diagnosis. In both studies, we excluded patients with a psychiatric diagnosis or psychotropic drug purchase within 2 years before the date of the VTE or IDDM diagnosis. The baseline characteristics of study 1 and study 3 are shown in Tables 1 and 2. The primary endpoint was psychotropic drug prescription purchase, including antidepressants, sedatives, anxiolytics, and antipsychotics. Table S1 provides information on the codes used in the studies. Statistical analysis included © 2017 International Society on Thrombosis and Haemostasis

Table 1 Baseline characteristics of the study population of study 1 Variable

VTE

Control cohort*

N Females, n (%) Recent pregnancy† Age group (years), n (%) 13–25 26–33 Risk factor for VTE present, n (%) DVT, n (%) PE, n (%)

4132 3126 (68.7) 725 (17.5)

19 292 13 472 (69.8) 2237 (11.6)

1598 2534 684 3280 852

7655 (39.7) 11 637 (60.3) 311 (1.6) – –

(38.7) (61.3) (16.5) (79.4) (20.6)

DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism. *Population controls matched on sex and birth year. †Childbirth at up to 8 weeks before and up to 42 weeks after the index date of cases.

Table 2 Baseline characteristics of the study population of study 3 Variable

VTE

IDDM

N Age (years), mean (SD) Females, n (%) Age group (years), n (%) 13–25 26–33 Risk factor for VTE present, n (%) Provoked VTE, n (%) DVT, n (%) PE, n (%)

5409 25.7 (5.3) 3695 (68.3)

6609 23.7 (6.5) 2516 (38.1)

2439 3627 1232 1140 4230 1179

2970 (54.9) 2982 (45.1) 449 (6.8) – – –

(45.1) (54.1) (22.8) (21.1) (78.2) (21.8)

DVT, deep vein thrombosis; IDDM, insulin-dependent diabetes mellitus; PE, pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism.

descriptive data presented as count and percentages, absolute risk calculations performed with the Kaplan–Meier estimator, and risk difference assessments performed with pseudovalue regression [26]. We adjusted the analysis for the effects of risk factors for VTE of potential importance for long-term mental wellbeing (see Table S1 for detailed information). STATA/MP version 13 was used for the statistical analysis. For study 2, we recruited 12 patients aged 13–33 years with a confirmed inpatient or outpatient diagnosis of VTE in the period 1 November 2012 to 30 June 2013. Participant characteristics are shown in Table 3. In order to achieve maximum variation in sampling, we consecutively included nine participants, and purposefully included three participants to ensure maximum variation in experiences related to timespan, duration of anticoagulant treatment, and parental status. Data collection consisted of two stages: first, participant observation at admission or outpatient visit to facilitate the development of interview guides; and second, open semistructured interviews performed by the first author 6–11 months after recruitment. The interviews were analyzed with a method influenced by Ricoeur’s interpretation theory, and consisted of three levels: a naive reading; a structural

2336 A. A. Højen et al Table 3 Baseline characteristics of the study population of study 2 Characteristic

VTE

N Age at study (years), mean (SD)* Age at first VTE (years), mean (SD)† Living conditions, n (%) With parents With partner Alone Has children, n (%) VTE type, n (%) DVT DVT and PE Indefinite anticoagulant treatment, n (%)

12 24.8 (4.9) 20.9 (5.2) 3 6 3 3

(25) (50) (25) (25)

3 (25) 9 (75) 6 (50)

DVT, deep vein thrombosis; PE, pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism. *Range 17–33 years. †Range 14–30 years.

analysis; and a critical analysis and discussion [27,28]. Detailed information on the substudy methods and findings is described elsewhere [20,21]. Integration

In the present study, we integrated the findings of the three substudies through narrative weaving and joint displays in an integrated mixed method interpretation in order to achieve knowledge beyond what can be gained from each of the substudies individually [19]. In the narrative weaving, the findings of studies 1, 2 and 3 were structured and described thematically, with a weaving back and forth of quantitative and qualitative findings by the integrated theme. Joint displays (Figs 2, 3 and 4) were used as a facilitator and a way to represent the integrated themes visually [29]. Integration at the interpretation and reporting levels raised the potential question of coherence of the quantitative and qualitative findings [19]. Therefore, the integration of findings from studies 1, 2 and 3 was inspired by the notion of ‘fit of integration’, with the following three outcomes: (i) confirmation – findings from the studies confirm each other; (ii) expansion – the findings expand insights into long-term mental wellbeing, by addressing different aspects thereof; and (iii) discordance – the findings of the studies contradict each other, conflict with each other, or disagree with each other. Results Integrated mixed method interpretation

A chronic perspective – fear of recurrence and striving for normalization Narrative weaving—The long-term mental wellbeing of AYAS with VTE was impaired, and had a chronic perspective. In the description of mental wellbeing (study 1), AYAS with VTE had a substantially higher risk of

psychotropic drug purchase than sex-matched and agematched population controls over time. Among AYAS with VTE, the adjusted 1-year risk of psychotropic drug purchase was 7.1% (95% confidence interval [CI] 6.3–7.9) and the adjusted 5-year risk was 22.1% (95% CI 20.7– 23.5), corresponding to 1-year and 5-year risk differences relative to the controls of 4.1% (95% CI 3.3–4.9) and 9.6% (95% CI 8.1–11.1), respectively. Exploration of the lived experience of AYAS following VTE (study 2) confirmed this finding. VTE was perceived as something persisting, and caused psychological distress. The exploration also expanded the finding of a chronic perspective. The chronic perspective was widely connected to the fear of recurrence and the concomitant incessant uncertainty, whereby mortality manifested and entailed a heightened body awareness. Thus, the feeling of immortality was lost and replaced by a salient feeling of mortality. This was based on the initial VTE, but showed in the uncertainty of recurrence and in a body that was highly aware of signs and symptoms, causing anxiety and psychological distress. In addition to the fear of recurrence, the integrated theme of a chronic perspective was also evident in the impact on everyday life. Management of anticoagulant treatment, compression stockings and physical symptoms related to the post-thrombotic syndrome restricted the ability to feel normal. The comparison of long-term mental wellbeing (study 3) confirmed the chronic perspective. Psychotropic drug purchase among AYAS with VTE was comparable to that among chronically ill AYAS with IDDM, with a slightly higher risk in AYAS with VTE (1year risk difference of 2.5% [95% CI 1.6–3.3]; 5-year risk difference 3.6% (95% CI 2.0–5.2]). However, in discordance with this, the exploration (study 2) showed that AYAS perceived VTE as something persisting but did not necessarily consider themselves to be chronically ill. Everyday life was affected, and a feeling of being different both among peers and as a VTE patient was prominent, which introduced another dimension to the restricted ability to feel normal. This was perceived to be particularly challenging as they strived for normalization (Fig. 2). Navigating uncertainty Narrative weaving—Navigating uncertainty related to VTE was central for long-term mental wellbeing. The exploration of the lived experience of AYAS following VTE (study 2) showed that the level of uncertainty depended on whether the VTE was provoked or unprovoked. It was essential to know where the VTE came from and whether it would return. Finding a cause for the VTE was linked to the chance of determining the risk of recurrence, whereas not having a cause was related to greater uncertainty and concomitant psychological distress. This was in part confirmed in the comparison of long-term mental wellbeing (study 3), as we noted a slightly higher risk of psychotropic drug purchase among patients with unprovoked VTE than among patients with © 2017 International Society on Thrombosis and Haemostasis


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VTE perceived as something persisting related to the fear of recurrence. ‘This will stick to me for the rest of my life, like a little cloud that floats in your mind, that this is how it is.’ Fear of recurrences entailed heightened body awareness. ‘I feel everything in my body now. I have to be more alert of what my body does, what it complains about, so I can be more observant next time.’

A creeping loss of youth immortality A perception of lost immortality prominent in life after VTE. ‘Yor are aware that nothing lasts forever’ ‘Yor have become aware of how little it takes’

The perception of being different The participants did not consider themselves to be chronically ill, but everyday life was affected, which restricted their ability to feel normal. ‘I think that was the hardest, that I suddenly wasn’t like the others anymore’

Fig. 2. Joint display, chronic perspective – fear of recurrence and striving for normalization. IDDM, insulin-dependent diabetes mellitus; VTE, venous thromboembolism. aPopulation controls matched on sex and birth year.

provoked VTE as compared with patients with IDDM. The 5-year risk difference for unprovoked VTE versus IDDM was 6.4% (95% CI 3.6–9.2), as compared with 3.9% (95% CI 2.3–5.8) for provoked VTE versus IDDM. In the exploration of the lived experience of AYAS following VTE (study 2), the integrated theme of navigating uncertainty was present in relation to anticoagulant © 2017 International Society on Thrombosis and Haemostasis

treatment, which was perceived as a protective factor of paramount importance for preventing recurrence. Anticoagulant treatment was a key aspect in relieving uncertainty about recurrence along with concomitant psychological distress. However, expanding on this, the exploration also showed that anticoagulation therapy did not completely relieve uncertainty. Especially in situations


of increased risk, uncertainty resurfaced and was often enhanced. For example, pregnancy, which was expected to be a positive experience, made the risk of thrombosis highly apparent and contributed to greater uncertainty. Furthermore, the exploration showed how the navigation of uncertainty was complicated by a delay in the initial diagnosis of VTE. The delay resulted in a breach of trust in the doctors’ ability to correctly interpret future

symptoms of VTE. This enhanced the uncertainty and made it vital to be in control. Thus, navigating uncertainty, when the ability to be in control was limited, required the use of different strategies to ensure that VTE recurrence would be recognized, including a form of salient negotiation and exaggeration of symptoms. Consequently, this resulted in many visits to the general practitioner and hospital admissions (Fig. 3).

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To live with a body in a state of alert To relieve uncertainty of recurrence it was essential to find a course for the VTE. ‘If you don’t know where it came from you cannot know whether it will come back again.’ It was important to be well-medicated. However, this did not relieve the feeling of uncertainty completely. ‘Even though I was told that it can’t happen again as long as I take my medicine, it’s still just not enough, It is the anxiety, I think, the fear of knowing this could happen again.’ Feeling of uncertainty was enhanced and resurfaced in situations of increased risk. ‘I could feel how it [pregnancy] kicked me right back into it; I found it to be really really tough.’ Symptom management insecurity Initial delay in diagnosis enhanced uncertainty and made control vital. ‘Suddenly it has become super imporatant to me, that everything is under control, and I am best in control if I control it myself. The control in knowing, that I know what it is all about.’ Different strategies were used to ensure VTE recurrence would be recognized. “Sometimes I can hear myself make matters worse, just to make sure they will take a look at me, and to make sure they will listen to me and to what I am telling them.’

Fig. 3. Joint display, navigating uncertainty. IDDM, insulin-dependent diabetes mellitus; VTE, venous thromboembolism. © 2017 International Society on Thrombosis and Haemostasis


Perceived health threat versus disease severity Narrative weaving—Disease severity played a less significant role in long-term mental wellbeing than the perceived health threat. In the description of long-term mental wellbeing, the 5-year risk difference for psychotropic drug purchase as compared with age-matched and sex-matched population controls did not differ among patients with DVT (9.8%, 95% CI 8.2–11.5) and patients with PE (9.4%, 95% CI 6.1–12.7). The exploration of the lived experience of AYAS following VTE (study 2) expanded this finding. The initial experience of VTE was characterized as uncritical, also by patients who had experienced a near-fatal PE. However, retrospectively, the patients came to think and reflect on what happened and could have happened, often initiated by the confrontation with the reaction of their parents. The potential life-threatening aspect of the disease became pivotal, and pointed both back to the initial VTE and also forward to the perception of future health threat and the potential risk of dying of a recurrent event. Thus, the retrospective appraisal of health threat and perception of future health threat appeared to be more important than the actual disease severity (Fig. 4).

Discussion Our mixed methods interpretation of the three individual substudies revealed that the long-term mental wellbeing of AYAS with VTE involved three integrated themes: (i) chronic perspective – fear of recurrence and striving for normalization; (ii) navigating uncertainty; and (iii) perceived health threat versus disease severity. Chronic timeline perspective – fear of recurrence and striving for normalization

Our findings showed a chronic timeline of mental wellbeing, with increased risks of psychotropic drug purchase and psychological distress persisting over time. These findings support previous studies showing that time since VTE diagnosis was not associated with less anxiety and depression or better mental QOL [4,7–9,30,31], indicating that the psychological impact of VTE does not disappear over time. The persisting impairment of mental wellbeing was largely connected to the fear of recurrence and concomitant uncertainty, whereby mortality had manifested and entailed heightened body awareness. The patients experienced what has been described as ‘the Damocles syndrome’ [32]. The patients were glad to be alive, but now lived with the risk of VTE recurrence and death. Interestingly, this mirrors findings in young cancer survivors, in whom uncertainty and lack of control related to fear of recurrence have been identified as important causes of psychological distress, and lower QOL [33,34]. © 2017 International Society on Thrombosis and Haemostasis

According to the uncertainty in illness theory of Mishel [35], enduring uncertainty can dismantle the existing cognitive structures that give meaning to everyday events, throwing the person into a state of confusion and disorientation. Thus, our finding of enduring uncertainty related to the risk of recurrence may help to explain the persisting and long-term impairment of mental wellbeing. This could support previous notions suggesting that VTE should be considered a chronic illness because of the risk of recurrence [36,37]. According to Oxford Dictionaries, chronic illness is defined as an illness persisting for a long time or constantly recurring [38]. Considering the perpetual risk of recurrence, this definition could apply to VTE, in particular among AYAS, in whom the risk of VTE recurrence is highest [12]. On the other hand, our findings revealed that, whereas young patients perceived VTE as something persisting, they did not necessarily consider themselves to be chronically ill. Thus, the perpetual risk of recurrence and concomitant uncertainty constitute a chronic element, without VTE necessarily being generally considered to be a chronic illness. The chronic perspective of mental wellbeing also appeared in striving for normalization. The ability to feel normal was affected by the impact on everyday life and the perception of being different. In line with Fiandaca et al. [30], who reported high impairment in social activities among young patients with thrombosis, our findings demonstrated how the social ability to fit in was challenged. According to Brown et al. [39], the ability to fit in is important to obtain acceptance from desired peer groups and for identity development. Therefore, the ability to fit in is a key component in the developmental transition and challenges of adolescence and young adulthood. The results from the present study identified peer support from fellow VTE patients as an opportunity to feel understood. A meeting with a fellow VTE patient was experienced as reassuring, and moderated the perception of feeling different and alone, suggesting that peer support could be a way to enhance mental wellbeing in young patients [40]. Navigating uncertainty

Navigation of uncertainty was central for the understanding of the long-term mental wellbeing of AYAS with VTE. The provoked or unprovoked status of VTE was related to the level of uncertainty and concomitant psychological distress, which is in line with Klok et al. [8], who reported better QOL in patients with PE caused by a transient risk factor than in patients with unprovoked PE or PE caused by permanent risk factors. Our study elaborated on previous research into the experience of VTE, which has shown worry and anxiety in relation to not knowing the cause of VTE [10,41]. In our study, knowing the cause of VTE was linked to the perceived chance of determining the risk of recurrence. According to Mishel


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A creeping loss of youth immortality The participants ruminated on what happend and could have happened, initiated by the confrontation with the reaction of their parents. ‘My mother told me, my face turned blue, and could see how my body desperately needed oxygen, and this really frightened them, I don’t remember it being that bad, but now afterwards, when you think about it, well, it scares me, because it was probably a closer call than I just thought.’ ‘I was scared sh**less and had nightmares, dreamt I burned alive. Well, at that point all the emotional stuff began to emerge, that I actually could have died.’ To live with a body in a state of alert Regardless of type or severity of VTE, symptoms that were difficult to interpret caused anxiety, because of the potential risk of a fatal outcome of a recurrent event. ‘If I am in pain and can’t understand what is wrong, it really makes me cry, and actually I would sat that the physical pain during this has not been the worst, it is the mental pain that came after that was the worst.’

Fig. 4. Joint display, perceived health threat versus disease severity. DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism. aPopulation controls matched on sex and birth year.

[35], the hallmark of illness uncertainty is the risk of dying, which often cannot be relieved by prognostic information. In continuation thereof, Bennet et al. [4] have previously found that worries about future health risk related to VTE were not moderated by beliefs about the effectiveness of medical treatment. In contrast, and in line with the findings of Casais et al. [42], anticoagulant treatment was perceived as a protective factor in our study. However, this did not cover situations of increased risk, in which uncertainty was described as being salient even

years after the initial event. Our findings are in agreement with those of Etchegary et al. [43], who described how travel and surgery made VTE highly salient. In a transition theory perspective, times of increased risk will be considered to be critical points entailing heightened vulnerability, reactivating a latent transition experience and disconnection [44]. Thus, our findings indicate that uncertainty may resurface and be enhanced at times of increased risk of recurrence. This also true in the long term, as the intensity of uncertainty may diminish during © 2017 International Society on Thrombosis and Haemostasis


periods of relative predictability, but never completely resolve [45]. Our findings showed that the navigation of uncertainty was enhanced and complicated by a delay in the initial VTE diagnosis, entailing a breach of confidence in the healthcare professionals, and their ability to recognize symptoms of a recurrence. This is in accordance with Mishel’s [45] description of how a lack of confidence in the healthcare providers leads to higher levels of uncertainty. In a social constructivist frame of reference, Luhmann [46] argues that loss of confidence increases the complexity of social systems. We found that the increased complexity manifested in the way in which AYAS with VTE prospectively had to relate to both the information given by the healthcare professionals, and to the veracity of the information and the decisions made. This entailed uncertainty about whether VTE-related issues would be taken seriously. Therefore, self-reliance and control became essential. However, in accordance with previous research, the ability to be in control of the future risk of VTE was considered to be low [3,4], and self-reliance was not perceived to be possible when symptoms indicative of recurrence were experienced. Consequently, the patients used different strategies to ensure that their symptoms would be taken seriously, including a form of salient negotiation and exaggeration of symptoms. This finding demonstrates an interesting paradox. On the one hand, the exaggeration of symptoms upholds trust for the young VTE patients that a possible recurrent event will be discovered. On the other hand, the healthcare professionals will be making their assessments on the basis of a distorted symptomatology, possibly resulting in overutilization of healthcare services. Perceived health threat versus disease severity

The perception of health threat played a more profound role than actual disease severity in the long-term mental wellbeing of AYAS with VTE. According to Mishel [47], uncertainty is a defining experience of serious illness, regardless of the specific illness characteristics. This may explain our finding of psychological distress and an increased risk of psychotropic drug purchase both among AYAS with relatively innocuous DVT and among those with the more serious PE, as they all live with the risk of recurrence and concomitant uncertainty. This finding is in line with former studies reporting similar psychosocial outcomes for DVT and PE patients [3,4,7,10,41], and with observations in young breast cancer survivors, in whom initial cancer severity does not seem to affect the subsequent fear of recurrence [34]. Thus, our results emphasize the potential importance of illness perception for mental wellbeing, which has also been described for a number of other diseases, including diabetes, congenital heart disease, and cancer [48,49]. © 2017 International Society on Thrombosis and Haemostasis

Study strengths and limitations Integration is an important issue in mixed methods research. Integration is the move beyond the use of multiple methods and a dualistic perspective [18,19]. Thus, it is through integration that the strength and value of mixed methods research are achieved [18,19,29,50]. We used several measures to ensure thorough and meaningful integration. Overall, we used a visual diagram (Fig. 1) to join all components of the study and provide an overview to enhance the understanding [18], and thereby continually keep the study rationale in focus. To strengthen the integration of the substudy findings, our mixed methods interpretation consisted of narrative weaving descriptions and joint displays. Joint displays is a visual way of integrating and presenting mixed methods results by providing a structure to discuss the integrated analysis and compose the narrative weaving descriptions [18,29]. Integration in mixed methods studies creates the potential for conflicting findings, which may be seen as a legitimation issue [19,51,52]. To address the question of coherence, we assessed our findings through the ‘fit of integration’ [19]. As an example of an observed discordance, the findings of study 3 suggested a chronic timeline perspective when VTE and IDDM patients were compared, whereas study 2 revealed that the VTE patients did not consider themselves to be chronically ill. However, we do not consider such discordance to be a limitation of our study, owing to the complementary nature of the research. The purpose of our mixed methods design was not to validate the findings between the substudies, but rather to obtain a nuanced understanding of the long-term mental wellbeing of AYAS with VTE. We were unable to investigate the effects of socioeconomic factors. In general, low socioeconomic position is associated with increased mental health problems, and has previously been associated with higher depression rates among young patients with IDDM, and low healthrelated QOL in young women with pregnancy-related DVT [31,53]. Thus, further research exploring socioeconomic factors would be relevant. Furthermore, the use of psychotropic drug purchase as a proxy in study 1 and study 3 will probably have led to an underestimation of ‘true’ mental impairment, as other treatment options are recommended for milder cases, especially among adolescents [54]. Conclusion The mental wellbeing of AYAS with VTE has a chronic perspective, with a persistently higher risk of psychotropic drug purchase among AYAS with VTE than among sex-matched and age-matched population controls, and AYAS with IDDM. Impaired mental wellbeing is largely connected to fear of recurrence and concomitant uncertainty. Therefore, it is important for long-term


mental wellbeing to navigate uncertainty. Perceived health threat plays a more profound role in long-term mental wellbeing than disease severity, as the potential life threat is the pivot that points back to the initial VTE and forward to the perception of future health threat and the potential risk of dying of a recurrent event. In conclusion, our findings show that the long-term mental wellbeing of AYAS diagnosed with VTE is negatively affected, and emphasize these patients’ need for adequate support.

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Addendum A. A. Højen, E. E. Sørensen, P. S. Dreyer, and T. B. Larsen designed the study. A. A. Højen drafted the manuscript. E. E. Sørensen, P. S. Dreyer, M. Søgaard, and T. B. Larsen critically revised the manuscript. All authors obtained, analyzed and interpreted the data.

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Disclosure of Conflict of Interests T. B. Larsen has been an investigator for Janssen Scientific Affairs and Boehringer-Ingelheim, and has served on speaker bureaus for AstraZeneca, Bayer, BoehringerIngelheim, Bristol-Myers Squibb/Pfizer, Roche Diagnostics, Siemens Diagnostics, and Takeda, outside the submitted work. The other authors state that they have no conflict of interest.

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Supporting Information Additional Supporting Information may be found in the online version of this article:

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Table S1. ICD-10 and ATC codes used in the study 17

References 1 ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Thromb Haemost 2014; 112: 843–52. 2 Liu C-P, Li X-M, Chen H-W, Cui J-Y, Niu L-L, He Y-B, Tian X-L. Depression, anxiety and influencing factors in patients with acute pulmonary embolism. Chin Med J (Engl) 2011; 124: 2438– 42. 3 Moore T, Norman P, Harris PR, Makris M. Cognitive appraisals and psychological distress following venous thromboembolic disease: an application of the theory of cognitive adaptation. Soc Sci Med 2006; 63: 2395–406. 4 Bennett P, Patterson K, Noble S. Predicting post-traumatic stress and health anxiety following a venous thrombotic embolism. J Health Psychol 2014; 21: 1–9. 5 Lukas PS, Neugebauer A, Schnyder S, Biasiutti FD, Krummenacher R. Ferrari M-LG, von K€anel R. Depressive symptoms, perceived social support, and prothrombotic measures in patients with venous thromboembolism. Thromb Res 2012; 130: 374–80. 6 Kahn SR, Shbaklo H, Lamping DL, Holcroft CA, Shrier I, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, Solymoss S, Desjardins L, Johri M, Ginsberg JS. Determinants of health-

18 19

20

21

22 23 24 25

related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost 2008; 6: 1105–12. Lukas PS, Krummenacher R, Biasiutti FD, Begre S, Znoj H, von K€anel R. Association of fatigue and psychological distress with quality of life in patients with a previous venous thromboembolic event. Thromb Haemost 2009; 102: 1219–26. Klok FA, van Kralingen KW, van Dijk APJ, Heyning FH, Vliegen HW, Kaptein AA, Huisman MV. Quality of life in long-term survivors of acute pulmonary embolism. Chest 2010; 138: 1432– 40. van Korlaar IM, Vossen CY, Rosendaal FR, Bovill EG, Cushman M, Naud S, Kaptein AA. The impact of venous thrombosis on quality of life. Thromb Res 2004; 114: 11–8. Noble S, Lewis R, Whithers J, Lewis S, Bennett P. Long-term psychological consequences of symptomatic pulmonary embolism: a qualitative study. BMJ Open 2014; 4: e004561. Michal M, Prochaska JH, Keller K, G€ obel S, Coldewey M, Ullmann A, Schulz A, Lamparter H, M€ unzel T, Reiner I, Beutel ME, Wild PS. Symptoms of depression and anxiety predict mortality in patients undergoing oral anticoagulation: Results from the thromb EVAL study program. Int J Cardiol Elsevier Ireland Ltd 2015; 187: 614–9. Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: A populationbased cohort study in patients without active cancer. Thromb Haemost 2014; 112: 255–63. Sigelman CK, Rider EA. Human development across the life span. 7. ed. Belmont Calif.: Wadsworth Cengage Learning; 2012. Zoffmann V, Vistisen D, Due-Christensen M. A cross-sectional study of glycaemic control, complications and psychosocial functioning among 18- to 35-year-old adults with type 1 diabetes. Diabet Med 2014; 31: 493–9. DeMaso DR, Martini DR, Cahen LA, Bukstein O, Walter HJ, Benson S, Chrisman A, Farchione T, Hamilton J, Keable H, Kinlan J, Schoettle U, Siegel M, Stock S, Ptakowski KK, Medicus J. Practice parameter for the psychiatric assessment and management of physically ill children and adolescents. J Am Acad Child Adolesc Psychiatry 2009; 48: 213–33. European Commission. Green Paper. Improving the Mental Health of the Population. Towards a Strategy on Mental Health for the European Union. Health & Consumer Protection Directorate General. 2005. Creswell JW, Plano Clark VL. Designing & Conducting Mixed Methods Research, 2nd edn. Los Angeles: SAGE Publications, 2010. Creswell JW. A concise introduction to mixed methods research. Thousand Oaks California: Sage, 2015. Fetters MD, Curry LA, Creswell JW. Achieving integration in mixed methods designsprinciples and practices. Health Serv Res 2013; 48: 2134–56. Højen AA, Gorst-Rasmussen A, Lip GYH, Lane DA, Rasmussen LH, Sørensen EE, Larsen TB. Use of psychotropic drugs following venous thromboembolism in youth. A nationwide cohort study. Thromb Res 2015; 135: 643–7. Højen AA, Dreyer PS, Lane DA, Larsen TB, Sørensen EE. Adolescents’ and Young Adults’ Lived Experiences Following Venous Thromboembolism: “It will always lie in wait”. Nurs Res 2016; 65: 455–64. Pedersen CB. The Danish Civil Registration System. Scand J Public Health 2011; 39: 22–5. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011; 39: 30–3. Kildemoes HW, Sørensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health 2011; 39: 38–41. Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull 1998; 45: 320–3.

© 2017 International Society on Thrombosis and Haemostasis

Mental wellbeing of young VTE patients 2343 26 Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in time. Stat Med 2007; 26: 4505–19. 27 Dreyer PS, Pedersen BD. Distanciation in Ricoeur’s theory of interpretation: narrations in a study of life experiences of living with chronic illness and home mechanical ventilation. Nurs Inq 2009; 16: 64–73. 28 Ricoeur P. The Hermeneutical Function of Distanciation. Philos Today 1973; 2: 129–41. 29 Guetterman TC, Fetters MD, Creswell JW. Integrating Quantitative and Qualitative Results in Health Science Mixed Methods Research Through Joint Displays. Ann Fam Med 2015; 13: 554–61. 30 Fiandaca D, Bucciarelli P, Martinelli I, Tantardini F, Clemente C, Mannucci PM. Psychological impact of thrombosis in the young. Intern Emerg Med 2006; 1: 119–26. 31 Wik HS, Enden TR, Jacobsen AF, Sandset PM. Long-term quality of life after pregnancy-related deep vein thrombosis and the influence of socioeconomic factors and comorbidity. J Thromb Haemost 2011; 9: 1931–6. 32 Koocher G. The Damocles syndrome: psychosocial consequences of surviving childhood cancer. New York: McGraw-Hill, 1981. 33 Skaali T, Foss a SD, Bremnes R, Dahl O, Haaland CF, Hauge ER, Klepp O, Oldenburg J, Wist E, Dahl AA. Fear of recurrence in long-term testicular cancer survivors. Psychooncology 2009; 18: 580–8. 34 Lebel S, Beattie S, Ares I, Bielajew C. Young and worried: Age and fear of recurrence in breast cancer survivors. Health Psychol 2013; 32: 695–705. 35 Mishel MH, Padilla G, Grant M, Sorenson DS. Uncertainty in illness theory: a replication of the mediating effects of mastery and coping. Nurs Res 1990; 40: 236–40. 36 Piazza G, Ridker PM. Is venous thromboembolism a chronic inflammatory disease? Clin Chem 2015; 61: 313–6. 37 Mason C. Venous thromboembolism: a chronic illness. J Cardiovasc Nurs 2009; 24: 4–7. 38 Oxford University Press. Oxford Dictionaries Online. 2012. 39 Brown BB, Larson J. Peer relationships in adolescence. Handb Adolesc Psychol Vol 2 Context Influ Adolesc Dev 2009; 2: 74–103. 40 Dennis C-L. Peer support within a health care context: a concept analysis. Int J Nurs Stud 2003; 40: 321–32. 41 Haxaire C, Tromeur C, Couturaud F, Leroyer C. A Qualitative Study to Appraise Patients and Family Members Perceptions, Knowledge, and Attitudes towards Venous Thromboembolism Risk. PLoS One 2015; 10: e0142070.

© 2017 International Society on Thrombosis and Haemostasis

42 Casais P, Meschengieser SS, Sanchez-Luceros A, Lazzari MA. Patients’ perceptions regarding oral anticoagulation therapy and its effect on quality of life. Curr Med Res Opin 2005; 21: 1085– 90. 43 Etchegary H, Wilson B, Brehaut J, Lott A, Langlois N, Wells PS. Psychosocial aspects of venous thromboembolic disease: an exploratory study. Thromb Res 2008; 122: 491–500. 44 Meleis AI, Sawyer LM, Im EO, Hilfinger Messias DK, Schumacher K. Experiencing transitions: an emerging middle-range theory. ANS Adv Nurs Sci 2000; 23: 12–28. 45 Mishel MH. Uncertainty in illness. J Nurs Scholarsh 1988; 20: 225–32. 46 Luhmann N. Familiary, confidence, trust: Problems and Alternatives. Trust: Making and Breaking Cooperative Relations. 1988: 94–107. 47 Stewart JL, Mishel MH. Uncertainty in childhood illness: a synthesis of the parent and child literature. Sch Inq Nurs Pract 2000; 14: 299–319. 48 Petrie KJ, Jago LA, Devcich DA. The role of illness perceptions in patients with medical conditions. Curr Opin Psychiatry 2007; 20: 163–7. 49 Hagger MS, Orbell S. A Meta-Analytic Review of the CommonSense Model of Illness Representations. Psychol Health 2003; 18: 141–84. 50 Bryman A. Barriers to Integrating Quantitative and Qualitative Research. J Mix Methods Res 2007; 1: 8–22. 51 Burke JR, Onwuegbuzie AJ. Mixed Methods Research: A Research Paradigm Whose Time Has Come. Educ Res 2004; 33: 14–26. 52 Onwuegbuzie AJ, Johnson BR. Validity issue in mixed methods. Res Sch 2006; 13: 48–63. 53 Lind T, Waernbaum I, Berhan Y, Dahlquist G. Socioeconomic factors, rather than diabetes mellitus per se, contribute to an excessive use of antidepressants among young adults with childhood onset type 1 diabetes mellitus: A register-based study. Diabetologia 2012; 55: 617–24. 54 Walkup J, Bernet W, Bukstein O, Walter H, Arnold V, Benson S, Beitchnian J, Chrisman A, TR F, Hamilton J, Keable H, Kinlan J, Mcclellan J, Schoettle U, Shaw J, Siegel M, Stock S. Practice Parameter on the Use of Psychotropic Medication in Children and Adolescents. J Am Acad Child Adolesc Psychiatry 2009; 48: 961–73.