Immune thrombocytopenic purpura: epidemiology and implications for patients

Abstract

The age-adjusted prevalence of immune thrombocytopenic purpura (ITP) is estimated to be 9.5 per 100 000 persons in the USA while its annual incidence is estimated to be 2.68 per 100 000 in Northern Europe (at a cut-off platelet count of <100 × 10⁹/L). The mean age of adults at diagnosis in Europe is 50 yrs and the incidence of ITP increases with age. Both the treatments used to treat patients with ITP and the disease itself can impact on patient health-related quality of life (HRQoL). As the incidence of ITP in Europe rises, especially in the elderly, the number of patients with a decreased HRQoL is increasing. Literature searches and focus groups have aided the development of a conceptual model to assess HRQoL. In this model, low platelet counts and the associated symptoms of ITP in addition to the side effects of treatment are proposed as the main determinants of a negatively impacted HRQoL. Primary conceptual domains of HRQoL, affected in patients with ITP, include emotional health, functional health, work, social and leisure activities and reproductive health. As treatment benefits are likely to improve these domains, the conceptual model could be used for better management of patients, taking into account HRQoL. The short-form 36-item questionnaire (SF-36) and the ITP Patient Assessment Questionnaire (ITP-PAQ) are validated measures of HRQoL which can provide a comprehensive assessment of numerous factors to help evaluate decisions about patient management. Future clinical trials investigating treatment options for ITP should assess HRQoL using these validated questionnaires.

Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder in which antiplatelet autoantibodies bind to antigens on the surface of platelets and cause accelerated destruction (1). ITP affects both children and adults with an overall female to male ratio of 2 : 1. Patients with ITP and low platelet counts (i.e. <30 × 10⁹/L) have an increased risk of bleeding, including spontaneous bruising, mucosal bleeding, and prolonged bleeding with injury (2). Symptoms depend on the severity of thrombocytopenia but are highly variable from one patient to another (3). Some patients may have few symptoms apart from mild bruising, whilst others can present with haemorrhage from any site, the most serious of which is intracranial (4). ITP remains a diagnosis of exclusion whereby other possible causes of thrombocytopenia are ruled out (1, 5). Following diagnosis, the aim of the physician treating a patient with ITP is to increase platelet counts to a level that reduces the patient’s risk of severe haemorrhage (3).

However, besides the bleeding symptoms, patients with ITP often complain of other symptoms such as fatigue, and the treatments used to treat ITP may also have an impact on a patient’s health-related quality of life (HRQoL) (3). In this paper, the epidemiological data available in the published literature are described first, followed by a discussion focusing on the tools that have been recently developed to assess HRQoL in patients with ITP.

Incidence and prevalence of ITP

Until recently in Europe and the USA, there were few well-designed epidemiological studies providing robust data focusing on adults with ITP and ITP was often considered a disease affecting predominantly young or middle-aged (<50) women. In Europe, the incidence of ITP in adults has been estimated to be between 1 and 4 per 100 000 persons (6–8) without any obvious seasonal variation. When a cut-off platelet count of <50 × 10⁹/L was applied, the annual incidence of ITP was estimated to be 2.25 per 100 000 in Denmark (6) and 1.6 per 100 000 in the UK (7). Interestingly in both studies, the median age of patients at time of ITP diagnosis (56 yrs) was identical. US data have indicated the estimated incidence of ITP to between 6.0 and 10 per 100 000 persons (2). More recently, in an epidemiological study carried out in a single US state, the age-adjusted prevalence was estimated to be 9.5 per 100 000 persons (9).

As shown in European studies and in contrast to what was previously thought, the incidence of ITP tends to increase with age (6–8). As life expectancy in Europe increases, the number of elderly patients with ITP and subsequent comorbidities is also set to increase. In the Danish study, the incidence rate more than doubled in those individuals aged over 60 yrs compared with younger patients (6) (Fig. 1). This observation was confirmed by the results from a UK cohort study, where patients aged over 60 yrs had the highest incidence of ITP (7). Incidence statistics may also be affected by sex as women have been shown to have a higher incidence of ITP compared with men (6, 8, 9). However in the Danish survey, this sex difference was only apparent in patients younger than 65 yrs (6) while in the UK cohort study, the absolute incidence was similar for both sexes (7).

Figure 1.  Incidence of ITP with age (6). This research was originally published in Blood. © The American Society of Hematology.

Health-related quality of life

ITP has long been perceived by physicians to be only a bleeding disorder. If avoiding serious bleeding remains the main medical objective of ITP treatment, this is evidence that ITP may have an important impact on the patient’s quality of life. Patients with chronic ITP, representing more than two thirds of all adults diagnosed with ITP, have reported concerns not only about bleeding, but also about restrictions on lifestyle, fear of splenectomy, and the side effects of corticosteroid therapy (3, 10). Corticosteroids are the current standard first-line treatment for patients with ITP, but there is evidence that the long-term or repeated administration of corticosteroids may cause many side effects such as weight gain, facial swelling, hyperglycaemia, hypertension, diabetes mellitus and osteoporosis (11, 12).

Other treatment options for treating chronic ITP include splenectomy, and/or immunosuppressive agents, which are also associated with substantial side effects (13). It is therefore not surprising that both the symptoms of ITP and its treatment have a considerable impact on the patient’s HRQoL, affecting day-to-day functioning as well as having psychological effects (3). A proportion of patients will be refractory to ITP treatment and for these individuals the impact of the disease on HRQoL is likely to be even greater than for patients who respond to treatment (14). Therefore, maintaining HRQoL is an important issue in the management of patients with ITP and should be considered carefully when making decisions about treatment (15).

Conceptual model of HRQoL

To understand the impact of ITP and its treatment on HRQoL, various literature searches have been conducted and these combined with the feedback from focus groups of adults with ITP, have helped identify common themes in ITP. Mathias et al. (10) created a comprehensive list of the issues affecting the HRQoL in patients with ITP, and placed these issues into a primary conceptual category, where appropriate subcategories were then applied (10). This research led to the development of a conceptual model for HRQoL (Fig. 2), which determined that a low platelet count and the associated symptoms of ITP in addition to the side effects of treatment, have a negative impact on patients’ HRQoL. The main determinants of HRQoL in patients with ITP were recognized to be ‘signs and symptoms’ and ‘treatment effects’. Primary conceptual domains of HRQoL comprised emotional health, functional health, work, social and leisure activities and reproductive health. Benefits of a treatment for ITP, such as a stable platelet count, increase in energy and vitality, or a decrease in anxiety, were likely to improve the domains of the HRQoL.

Figure 2.  Conceptual model for health-related quality of life (HRQoL) (10). Reprinted from Health Qual Life Outcomes. Published by BioMed Central 2008.

Focus group discussion

Discussions in focus groups regarding the signs and symptoms of ITP revealed that platelet counts are of particular concern to patients (10). Indeed it has been reported previously that HRQoL is substantially affected by the fear of a bleeding episode caused by low platelet count (16). Platelet counts are a particularly important consideration as they can have an impact on the treatment of ITP, and the level of anxiety caused due to transient fluctuation in platelet counts is similar to that caused by the symptoms of the disease itself (10).

More than 90% of patients in focus groups were adversely affected by fatigue, which was thought to considerably hinder the ability to perform daily activities. Bruising and bleeding, commonly noted signs and symptoms of ITP, also contribute to a decreased HRQoL. With regard to treatment modalities, focus group data suggest that the most commonly reported adverse effects were attributed to the administration of corticosteroids (10). Numerous side effects were reported including anger, insomnia, mood swings and weight gain, all of which negatively impacted upon the HRQoL. In addition, the long-term complications of corticosteroids such as steroid-induced diabetes mellitus and osteoporosis can also have a detrimental effect on the HRQoL (11). Splenectomy as a treatment option was linked to concerns about the associated susceptibility to infection and uncertainty about disease remission (10).

HRQoL domains

Table 1 shows the main findings from patient focus groups arranged according to the impact on the various domains of HRQoL (10). When questioned about the domain of emotional health, more than 70% of patients in the focus group rated anxiety, stress and fear above the symptoms of the disease. Personal relationships were affected in approximately half of patients, together with mental health issues and self-consciousness. In the functional health domain, a strong relationship was apparent between the symptoms of ITP and functional health limitations, with particular emphasis on fatigue hindering daily activities. Focus group feedback also reported that ITP had interfered with the ability to work in 87% of the patients. Over two thirds of patients commented that they had been absent from work due to the symptoms or treatment of ITP and one third of patients felt their career progression was slowed down by the disease. Reported feelings included social embarrassment due to visible bruising and limited involvement in social and leisure activities, such as sport, exercise, gardening and travel. Patients also mentioned reproductive health issues such as a loss of libido due to the symptoms of ITP and side effects of treatment. Female patients were concerned about the potential inability to bear children as well as exacerbation of menstrual bleeding.

Table 1.   HRQoL domains affected and issues identified via patient focus group discussion (10). Reprinted from Health Qual Life Outcomes. Published by BioMed Central 2008

Quality of life domain	Patients affected (%)
Emotional health	93
Fear, stress and anxiety	73
Relationships	47
Depression, isolation and loss of control	47
Mood and self consciousness	47
Functional health	87
Daily activities	73
Sleep	60
Changes in lifestyle	47
Work	87
Absences	67
Changes in attitudes	33
Career advancement	33
Productivity	27
Social and leisure	67
Sports/exercise/physical activity	33
Leisure activities	33
Social stigma	27
Travel	20
Reproductive health	67
Sex	60
Women’s reproductive issues	53

Patient assessment

Measures of HRQoL can provide a comprehensive assessment of multiple factors, including social functioning and emotional functioning, and may help to evaluate decisions about patient management. Furthermore, instruments that measure patient-reported outcomes can be designed to impose a minimal burden on the patient. Among the instruments used to assess HRQoL are the short-form 36-item questionnaire (SF-36) and the ITP Patient Assessment Questionnaire (ITP-PAQ).

A recent study carried out in the USA using the SF-36, evaluated the HRQoL of 73 adult patients with ITP by measuring eight domains that impact upon HRQoL; namely physical functioning, physical and emotional roles, bodily pain, general health, vitality, social functioning, and mental health (3). The results were compared with the general population and also with patients who had other relatively common chronic disorders such as arthritis and cancer. The results of this survey demonstrated a significantly reduced HRQoL in patients with ITP compared with the general US population, in every domain except mental health. More surprisingly, the data showed that the impact of chronic ITP on the HRQoL of a patient is similar to that presented by diabetes and greater than that of hypertension, arthritis or cancer.

The results obtained using the SF-36 identified diminished HRQoL in patients with ITP, but this questionnaire did not assess ITP-specific issues such as how much of the reduced HRQoL was related to the disease itself rather than to the effects of treatment. To address this, the ITP-PAQ was developed and validated to assess disease-specific QoL in adults with ITP (14). The ITP-PAQ questionnaire takes 10–15 min to complete and contains 44 items assessing 10 scales: physical health (symptoms, fatigue/sleep, bother and activity), emotional health (psychological and fear), QoL (overall, social and work) and women’s reproductive health.

The ITP-PAQ was evaluated as part of an open-label extension study of romiplostim in adult patients with ITP (15). Romiplostim was self-administered by subcutaneous injection once-weekly at baseline and then at weeks 4, 12 and 24. Platelet response was defined as a platelet count of ≥50 × 10⁹/L and a doubling of the baseline value at week 24. A durable platelet response was a platelet count of ≥50 × 10⁹/L and a doubling of baseline values on ≥6 occasions during weeks 17–24. The change scores of patients who responded to romiplostim treatment were compared with patients who did not respond. Nine out of 10 scales and two subscales used in the ITP-PAQ significantly improved (Guyatt’s statistic ≥ 0.20), in particular, the physical health scale (symptoms, fatigue/sleep, bother and activity). Significantly better ITP-PAQ scores were observed in patients who had a durable platelet response for symptoms (P = 0.022; t-test), bother (P = 0.008), psychological (P = 0.033) and overall QoL (P = 0.032) scales compared with patients who did not respond to treatment. Additionally, the results of the ITP-PAQ showed that on the women’s reproductive health scale, women who had not undergone splenectomy had significantly higher scores than their splenectomized counterparts.

A recent cross-sectional, descriptive study used the SF-36 and the ITP-PAQ (as well as the EQ-5D) to compare the HRQoL of patients with ITP with control subjects matched for age and sex (17). Altogether 1002 patients recruited from the Platelet Disorder Support Association completed a one-time, web-based survey that included all three HRQoL assessment tools – the control subjects (n = 1031) completed only the SF-36 and EQ-5D. Patients with ITP scored worse on seven of eight SF-36 domains (all P < 0.05; Cochran-Mantel-Haenszel test). The results of the ITP-PAQ showed that patients who had undergone splenectomy scored significantly worse on five of the 10 scales (bother, psychological, fear, social activity and work; all P < 0.05) compared with non-splenectomized patients. Women who had not undergone splenectomy had significantly better scores on the fertility scale compared with splenectomized women (P = 0.008). Platelet count was strongly associated with HRQoL while duration of ITP appeared to have little effect. These data support the clinical validity of the ITP-PAQ in identifying differences in HRQoL based on disease severity and ITP treatments, and advocates its use in future clinical studies.

Conclusion

The epidemiological data reported in the literature have shown that, at least in some European countries, the annual incidence of ITP (1.6–2.6 per 100 000) was lower than expected, but these data need to be confirmed by more extensive studies which include more European countries. It is now well known that, in adults, the incidence of ITP increases with age and that in patients aged over 60, the female-to-male ratio tends toward 1. As life expectancy is increasing in Europe, the number of patients with ITP is likely to increase in the future. Consequently, the management of elderly patients, with comorbidities and receiving concurrent medication that may increase the risk of bleeding, will be challenging. Lastly, as it is now acknowledged that the symptoms of ITP and the side effects of treatment negatively affect the HRQoL of patients with ITP, future clinical trials investigating new treatments for ITP should also assess HRQoL by using specially adapted tools such as SF-36 and/or the recently developed ITP-PAQ. This will help identify the extent to which new treatments may improve the HRQoL of the patient, and hopefully make the management of ITP more optimal for both patient and physician.

Conflicts of interest

Professor M. Michel is a consultant and has been a member of scientific advisory boards for Amgen and GlaxoSmithKline. M. Michel has presented data at scientific conferences on behalf of Amgen and GlaxoSmithKline.