Immune thrombocytopenia: improving quality of life and patient outcomes

Figures & data

Table 1 Studies of HRQoL in adults with ITP

Study	Assessment tool(s)	Population	Analysis	Use of MID	Reliability and validity assessment	Findings
Zhou 2007^Citation17	SF-36 (Chinese mainland version)	236 adults with ITP	Cross-sectional study. HRQoL compared with a survey of 1,688 healthy individuals. Also asked about fear of bleeding	No	No. Tested in other medical conditions, including hemophilia, another bleeding disorder	In 6/8 SF-36 subscores (dimensions), HRQoL was significantly worse in patients with ITP vs healthy individuals (not energy/vitality). Significantly worse HRQoL was found in 3 domains for those with a lower platelet count and chronic vs acute ITP. In regression analysis, treatment cost, increasing age and fear of bleeding were predictors of worse HRQoL
Bussel 2007^Citation42	SF-36v2	Trial of 118 adults with chronic ITP randomized to eltrombopag or placebo	Evaluation of impact of treatment on HRQoL as a secondary endpoint	No	No	HRQoL by SF-36v2 was similar at baseline and end of study. There was a significant decrease from baseline in the mean emotional-role score for the group receiving 75 mg of eltrombopag
Mathias 2007^Citation24	ITP-PAQ	73 adult patients with ITP	Development and validation of the ITP-PAQ. Administered twice	No	Yes	Test–retest reliability judged acceptable. Internal consistency reliability, measured by Cronbach’s alpha was acceptable for all scales except reproductive health. Construct validity was demonstrated by moderate to strong correlation between ITP-PAQ and SF-36 and CES-D scores with the exception of the reproductive health scale. In known groups validity testing, a significant difference was identified between those on treatment vs those who were not
Mathias 2007^Citation25	ITP-PAQ	34 adult patients with chronic ITP receiving romiplostim in an open-label trial	Assessment of responsiveness, reliability and validity of the ITP-PAQ. Administered at baseline and weeks 4, 12 and 24.	No	Yes	5/10 of the ITP-PAQ scales were sensitive to clinical (platelet) response. Internal consistency reliability and test–retest reliability were acceptable for most scales. Construct validity was supported by correlation between ITP-PAQ and SF-36 scales with the exception of menstrual symptoms and fertility subscales. In known groups validity testing, durable platelet responders had significantly better scores than nonresponders for symptoms, bother, psychological and overall QoL scales
McMillan 2008^Citation18	SF-36	73 adult patients with chronic ITP	Evaluation of HRQoL in ITP patients compared with the general US population and six other common disorders. Consenting patients completed the survey then repeated it 2 weeks later	No	Reliability assessed in ITP population. Found acceptable internal reliability (Cronbach’s alphas) and test–retest reliability	Scores of ITP patients were lower than the US general population in all 8 domains and both summary scores (statistically significant in all except mental health). ITP patients on active treatment had significantly lower scores in 6/8 domains vs those not receiving treatment. When ITP patients were compared with other medical conditions, physical but not mental component scores were significantly worse than in patients with hypertension, arthritis or cancer (not controlled for disease severity)
Snyder 2008^Citation19	ITP-PAQ, SF-36 and EQ-5D	Cross-sectional web-based survey of 1,002 adult ITP patients and 1,031 controls	SF-36 and EQ-5D scores in ITP patients compared with controls. The impact of splenectomy status, duration of illness and platelet count on HRQoL was assessed in ITP patients	No	No	Significantly worse scores in ITP patients on 7/8 SF-36 domains (not bodily pain), SF-36 physical and mental summary scores, and on the EQ-5D visual analog scale vs controls. SF-36 and EQ-5D scores not significantly different in ITP patients who had undergone splenectomy vs those that had not, but they scored significantly worse on 5/10 ITP-PAQ scales. On the ITP-PAQ, patients diagnosed within the past 5 years had worse bother and overall QoL scores than less recently diagnosed patients. A lower platelet count was consistently associated with worse ITP-PAQ scores and had weaker associations with SF-36 and EQ-5D scores. Differences between ITP patients and controls were noted to be generally small, despite their statistical significance. Also noted that ITP group generally well controlled and 44% had platelet counts >150×10^9/L
Mathias 2009^Citation14	ITP-PAQ	125 adults with chronic ITP participating in two randomized placebo-controlled trials of romiplostim	Estimation of the MID for 9/11 ITP-PAQ scores using a combination of anchor and distribution-based methods	Yes	No	Each ITP-PAQ scale had all its item scores transformed to a 0 (worst) to 100 (best) continuum. MIDs ranged from 8 to 12 points for symptoms, bother, psychological, overall QoL, social activity, menstrual symptoms and fertility. MID was 10–15 points for the fatigue and activity scales. Recommended further work to finalize these estimates
George 2009^Citation22	ITP-PAQ	125 adults with chronic ITP participating in two randomized placebo-controlled trials of romiplostim	Comparison of HRQoL in ITP patients receiving romiplostim vs placebo. ITP-PAQ was self-administered at baseline and weeks 4, 12 and 24	No	No	In patients receiving placebo, 0/10 ITP-PAQ scales improved between baseline and 24 weeks. Patients receiving romiplostim had statistically significant improvements over placebo in 4/10 ITP-PAQ scales (splenectomized patients) and 1/10 scales (nonsplenectomized). A post-hoc pooled analysis found statistically significant improvement in 7/10 scales. No analysis found a difference in the fatigue scale between treatment and placebo. Significantly better scores were associated with a durable platelet count response in 2/10 scales (bother and psychological health). At baseline, splenectomized patients had significantly lower scores in 7/10 scales vs nonsplenectomized patients
Newton 2011^Citation35	FIS	585 adults (UK), 93 adults (USA) with active ITP or a prior history of ITP	Comparison of fatigue in ITP patients with normal subjects. Multivariate analysis of patient characteristics associated with fatigue	No	Validated in other fatigue-associated diseases (PBC, CFS). In a prior study, 40 normal adults had a mean FIS score of 13. Assuming a normal distribution and that the patients were representative of the normal population, 2.5% of the normal population would be expected to have a fatigue score ≥40 (2 SD above the mean)	Significantly more patients in the UK cohort (39%) and US cohort (22%) had fatigue compared to normal subjects (P<0.0001 in both groups). In multivariate analysis, for patients with bleeding symptoms, fatigue was associated with a platelet count <100×10^9/L and female gender. In patients without bleeding symptoms, fatigue was associated with a platelet count <30×10^9/L, presence of other medical conditions, daytime sleepiness and orthostatic symptoms. Fatigue was not associated with duration of ITP or splenectomy status
Cheng 2011^Citation21	SF-36v2, FACIT fatigue subscale, FACT-Th6 and MEI-SF	197 adults with chronic ITP randomized to eltrombopag or placebo (RAISE trial)	HRQoL was assessed at baseline and weeks 6, 14 and 26 or at discontinuation of study drug. Assessment of change in HRQoL from baseline, difference in HRQoL between treatment arms and association between HRQoL and bleeding symptoms or platelet count	No	No	No HRQoL improvement from baseline in placebo arm. Statistically significant improvement from baseline in eltrombopag arm for FACT-Th6 and SF-36v2 (2/2 summary scores and 5/8 domains). Statistically significant greater improvement from baseline for the eltrombopag arm vs placebo was seen in FACT-Th6 and SF-36v2 (1/2 summary scores and 3/8 domains) but not MEI-SF and FACIT fatigue subscale. Increased platelet count and reduced WHO bleeding score were associated with statistically significant improvements in HRQoL
Signorovitch 2011^Citation66	SF-36v2, FACIT fatigue subscale and FACT-Th6	Patients from two eltrombopag trials: a placebo-controlled RCT (RAISE, n=197) and an open-label extension (EXTEND, n=154)	Assessment of the reliability and validity of these HRQoL scales in adult patients with chronic ITP	No	Yes	Acceptable internal consistency reliability, with all Cronbach’s alphas >0.70. Acceptable test–retest reliability, with all intraclass correlation coefficients >0.70. Construct validity was supported by moderate (0.35<r<0.50) to strong (r>0.50) intermeasure correlations for baseline and change scores. The mean FACIT fatiguescore at baseline in RAISE was not significantly lower than the reference value reported for the general US population (<1 SD). Both mean summary scores and 7/8 domains of the SF-36v2 were within 1 SD of the US population standardized mean
Kuter 2012^Citation23	ITP-PAQ	234 adult nonsplenectomized ITP patients in a randomized open-label 52-week study of romiplostim vs SOC	Comparison of HRQoL changes in both treatment groups and by responder status and splenectomy status, and after rituximab	Yes	No	Over 52 weeks, statistically significant improvements in HRQoL occurred in both romiplostim and SOC arms for 9/10 ITP-PAQ scales. MID estimates were available for 7 scales and the improvement from baseline exceeded the MID in both arms, for 4/7 scales for SOC and for romiplostim only in a further 2/7. No significant improvement in fatigue was found in either arm. On comparing the change in scores between arms, statistically significant improvements in HRQoL in those receiving romiplostim vs SOC were found in 7/10 scales but in no scale did this exceed the MID. Receiving rituximab or splenectomy did not influence HRQoL but numbers were small (n=16 and 13, respectively). Statistically significant improvement was seen in 8/10 scales in responders vs nonresponders regardless of treatment group. HRQoL improvements seen in responders exceeded the MID for most scales, including fatigue
Efficace 2016^Citation16	SF-36 and MFS	424 adults with primary ITP	Cross-sectional study comparing HRQoL and fatigue with the general population and by disease phase (newly diagnosed, persistent and chronic)	Yes	No	SF-36 scores ranged from 0 (worst) to 100 (best) and the MID was set at 8 points based on previous studies. Compared with the normal population, ITP patients had lower HRQoL that was clinically significant in 2/8 domains of SF-36. When analyzed by disease phase, those with persistent ITP (3–12 months) had the worst HRQoL, with reductions reaching MID in 5/8 domains. With MFS, ITP patients had significantly worse fatigue than normal controls (P<0.001). The greatest burden of fatigue occurred in those with persistent ITP. Greater fatigue by MFS was associated with worse mental and physical HRQoL, especially limitation in daily activity due to physical problems. Only weak correlations were found between general fatigue and platelet count or bleeding score

Abbreviations: CES-D, Center for Epidemiologic Studies Depression Scale; CFS, chronic fatigue syndrome; EQ-5D, Euro-Qol 5 Dimensions; FACIT, Functional Assessment of Chronic Illness Therapy; FACT-Th6, Functional Assessment of Cancer Therapy thrombocytopenia subscale; FIS, Fatigue Impact Score; HRQoL, health-related quality of life; ITP, immune thrombocytopenia; ITP-PAQ, ITP Patient Assessment Questionnaire; MEI-SF, Motivation and Energy Inventory Short Form; MFS, Multidimensional Fatigue Score; MID, minimal important difference; PBC, primary biliary cirrhosis; QoL, quality of life; RCT, randomized controlled trial; SF-36, 36-Item Short Form Health Survey; SF-36v2, 36-Item Short Form Health Survey version 2; SOC, standard of care.

Table 2 Studies of HRQoL in children with ITP

Study	Assessment tool(s)	Population	Analysis	Use of MID	Reliability and validity assessment	Findings
von Mackensen 2006^Citation47	ITP-QoL	17 children with acute and chronic ITP, and their parents	Design and pilot testing of an ITP-specific HRQoL tool for children age 3–7 and 8–18 and parents in Italian, German and Swedish	No	Not reported	Description of design process and patients’ feedback from the pilot
Klaassen 2007^Citation51	KIT and PedsQL	41 children with acute ITP, 49 children with chronic ITP, and their parents	Design and testing of KIT. Measure administered twice alongside PedsQL	No	Both assessed	KIT was valid, showing moderate correlation with PedsQL. Reliability was comparable to PedsQL but KIT was more responsive to change. Patients with acute ITP had significantly lower KIT scores (lower HRQoL) than those with chronic ITP
Neunert 2009^Citation53	KIT	41 children with acute ITP, 49 children with chronic ITP, and their parents	Secondary analysis of the 90 children enrolled into the KIT study (Klaassen 2007^Citation51)to determine the relationship between platelet count, bleeding severity and HRQoL	No	As per Klaassen 2007^Citation51	Platelet count and bleeding score did not correlate with HRQoL as measured by the KIT score
Klaassen 2012^Citation55	KIT	22 children with chronic ITP and their parents, treated in a Phase I/II trial with romiplostim or placebo	KIT assessments at baseline, week 5 and week 13 of treatment	No	Acceptable test– retest reliability	Significant improvement in HRQoL for parents of children receiving romiplostim vs placebo (P=0.008), but no significant difference for the children themselves (child self-assessment and parent-proxy assessment)
Grainger 2013^Citation50	KIT	217 children with newly diagnosed, persistent and chronic ITP	Secondary analysis of data obtained during validation of the North American and International KIT	No	Yes, reported elsewhere^Citation45	HRQoL was significantly lower in newly diagnosed patients vs those with chronic ITP (P=0.005). Patients who were treated (prednisone, IVIg, rituximab, anti-D, splenectomy) had no significant difference in platelet count, bleeding score or HRQoL compared with those observed. In newly diagnosed patients, proxy KIT was significantly lower vs those observed
Strullu 2013^Citation48	PedsQL 4.0 Generic Core Scale	73 children with acute ITP age 2–18 and their parents	Testing was at diagnosis, 1, 3 and 6 months (longitudinal and prospective). Parent-proxy used in children age <5 years	Yes	Reliability and validity testing in other conditions	No difference in scores to healthy population reference at presentation. No difference at 6 months. 54.5% had an improved HRQoL as measured by MID between presentation and 6 months. Around two-thirds had a normal platelet count at 6 months, although platelet count (> or <100×10^9/L) at presentation or 6 months and bleeding scores or initial treatment did not influence scores of patients or parents
Heitink-Pollé 2014^Citation28	KIT and PedsQL	107 children with newly diagnosed ITP, a platelet count <20×10^9/L and mild to moderate bleeding randomized to observation vs IVIg	HRQoL assessed at baseline, 1 week, 1 month, 3 months, 6 months and 12 months. Related HRQoL to type of treatment, bleeding severity and clinical course. Compared HRQoL to published data on Dutch school children	No	Not specifically in this study	PedsQL scores in patients with newly diagnosed ITP were not significantly different from the reference group of Dutch children. No difference in HRQoL in those who received IVIg vs those observed after 1 week and 1 month. No HRQoL difference in those with mild vs moderate bleeding at presentation and 1 week (insufficient data for analysis at 1 month). After 6 months, HRQoL was significantly worse in children with persistent disease vs those who had recovered by proxy report and parent self-report, but with no difference in child self-report
Bussel 2015^Citation54	KIT	67 children with chronic ITP randomized to observation vs eltrombopag	KIT assessment at baseline, 6 weeks, 12 weeks and treatment completion or study withdrawal	Yes	No	No significant improvement in HRQoL during treatment with eltrombopag
Zhang 2016^Citation15	KIT and PedsQL	42 children with chronic ITP and their parents	Cross-sectional study. Assessment of reliability and validity of Chinese version of KIT. Assessment of impact of clinical characteristics and treatment of ITP on HRQoL	No	Both assessed	Significant correlation between KIT and PedsQL. Internal consistency reliability was acceptable. Significant concordance between children’s self and parent-proxy reports. HRQoL was significantly lower in patients with a platelet count ≤30×10^9/L in the week prior to survey completion vs >30×10^9/L in both parent-proxy reports and the KIT child self-report
Mathias 2016^Citation49	KIT	62 children with chronic ITP treated in a Phase III RCT of romiplostim vs placebo	Longitudinal study. KIT assessment at baseline and weeks 8, 16 and 25. Assessment of change from baseline, comparison of treatment arms and estimation of MID	Yes	Both assessed	In mixed effects analysis, changes in child KIT scores were not significantly different between romiplostim and placebo arms. However, parent-impact scores were significantly better with romiplostim (P=0.015). Moderate evidence of reliability and validity demonstrated. Ranges for the MID were estimated as 9–13 points for the child self-report version and 11–13 points for the parent-impact version
Flores 2017^Citation32	KIT	99 children with newly diagnosed ITP	Longitudinal study. KIT assessment at baseline, 1 week, 6 months and 12 months	No	No, previously demonstrated	At diagnosis, no correlation between KIT scores and either age or platelet count. Oral bleeding negatively impacted proxy-reported disease burden at diagnosis. KIT scores significantly improved in the first year following diagnosis (P<0.001). Persistence of disease and lower platelet counts at 6 and 12 months had a significant, negative impact on HRQoL for both parents and children

Abbreviations: HRQoL, health-related quality of life; ITP, immune thrombocytopenia; ITP-QoL, ITP Quality of Life; IVIg, intravenous immunoglobulin; KIT, Kids’ ITP Tools; MID, minimal important difference; PedsQL, Pediatric Quality of Life Inventory; RCT, randomized controlled trial.

Figure 1 Conceptual model for health-related quality of life in patients with ITP.

Note: Reproduced from Mathias SD, Gao SK, Miller KL, et al. Impact of chronic Immune Thrombocytopenic Purpura (ITP) on health-related quality of life: a conceptual model starting with the patient perspective. Health Qual Life Outcomes. 2008;6:13. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.²⁶
Abbreviation: ITP, immune thrombocytopenia.

Figure 2 Model of the pathogenesis of ITP-associated fatigue.

Notes: *T cells can attack platelets directly, secrete proinflammatory cytokines and drive formation of autoreactive B cells. This results in antibody- and complement-mediated platelet destruction. Platelet microparticles are prothrombotic and able to activate the proinflammatory complement pathway. Reproduced from Hill QA, Newland AC. Fatigue in immune thrombocytopenia. Br J Haematol. 2015;170(2):141–149 with permission from the publisher, John Wiley and Sons. © 2015 John Wiley & Sons Ltd.³⁷
Abbreviations: ITP, immune thrombocytopenia; 2ry, secondary; B cell, autoantibody producing B lymphocytes; T cell (Th1), T lymphocyte with a T helper 1 polarization; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; MP, microparticle; CNS, central nervous system.

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