Abstract
The aim of this study is to evaluate quality of life (QOL) in patients with rare bleeding disorders (RBDs). In this cross-sectional study, 52 consecutive children aged between 4 and 18 years old with RBDs registered at the Haemophila Center of Fars province in Southern Iran were investigated from January to April 2015. Quality of life was evaluated using Haemo-QOL questionnaire. Final score is defined between 0 and 100, and higher score of QOL shows worse condition. P value less than .05 was considered statistically significant. Mean age of the patients was 13.96 ± 4.50 and ranged from 4 to 18 years old including 28 males and 24 females. Family and friends were the 2 most impaired domains of Haemo-QOL in these patients. In univariate analysis, bleeding severity based on bleeding score, health status, and being bothered by the disease showed statistically significant correlations with QOL of the patients (P < .05). In multiple linear regression models, only degree of being bothered by the disease was determined as an independent influencing factor on QOL. Taking together, Haemo-QOL of children with RBDs was better than what was reported in patients with hemophilia in our region, but it was worse than that reported in patients with hemophilia in other developing and developed countries. Due to chronic feature of bleeding disorders, more attention to different aspects of the disease, especially in 2 dimensions of family and friends through considering educational and psychological program for the patients and their family, are recommended to improve QOL of the patients with RBDs.
Introduction
The rare bleeding disorders (RBDs) are a group of inherited disorders transmitted as autosomal recessive traits in both sexes. Different types of RBDs consist of deficiencies of fibrinogen; factor (F) II, FV, FVII, FX, FXI, FXIII; and combined FV and FVIII. 1 This group represents 3% to 5% of all inherited coagulation disorders. The prevalence of homozygous type of the disease in general population varies from 1 in 2 million for factor II (prothrombin) and FXIII deficiency to 1 in 500 000 for FVII deficiency. 2 –4 In regions with more prevalence of consanguineous marriages such as Middle Eastern countries and Southern India, the homozygous form of these autosomal recessive traits occur more frequently. 5 Due to the rarity of the disease, data on genetic, clinical, and laboratory characteristics of the patients with RBDs remains limited. 6 However, several national and international registries were established to collect accurate data on RBDs. 7 In Iran, a registry of bleeding disorders was established in 1970, and at the beginning of 1996 collaboration was defined between Iran and Milan based upon exchanging information, technology, and samples. Mannucci et al in 2004 reported a frequency of 750 patients with RBDs in Iran. 5 The most common clinical symptoms in patients with RBDs are excessive hemorrhage at the time of invasive procedures including dental extractions and circumcision followed by mucosal bleeding, especially epistaxis and menorrhagia. Depending on the type and severity of factor deficiency, other bleeding symptoms that might occur range from mild to life-threatening bleeding. However, patients with rare bleeding disorders may show various bleeding phenotypes due to molecular heterogeneity of the disease. 5 Due to the chronic feature of the disease, these patients face several problems because of bleeding symptoms as well as side effects of treatment. So it is important to evaluate the mental and physical health status in these patients. There are several studies evaluating health-related quality of life (QOL) in patients with hemophilia and von Willebrand disease. 8 –11 To our knowledge, this is the first study evaluating QOL and related factors in patients with RBDs in southern Iran, where consanguineous marriage is common.
Materials and Methods
Patients
In this cross-sectional study, all children with RBDs and age range of 4 to 18 years (n = 52) participated from January to April 2015. All patients were registered in Hemophilia Center affiliated to Shiraz University of Medical Sciences, a tertiary referral center for coagulation disorders in southern Iran. Diagnosis of patients was based on clinical history, physical examination, and laboratory analysis for diagnosis of specific coagulation factor deficiency. All patients were using on-demand therapy, and none of them were on prophylaxis treatment. Patients with congenital or acquired neurological disorders, systemic disease, or psychiatric disorders were excluded from the study. Also families with more than 1 affected child with RBDs were excluded from the study.
Informed written consent form was obtained from all patients or their parents. The protocol of the study was approved by the Ethics Committee of Shiraz University of Medical Sciences (Grant number = 6300). The purpose of study was explained to the patients and their parents.
Data Collection
Demographic and clinical characteristics as well as laboratory data were collected from medical records of the patients. Data included age, sex, type of factor deficiency, factor activity level, and bleeding severity. Bleeding severity was determined using Tosetto et al questionnaire which had been designed for evaluation of bleeding severity in patients with von Willebrand disease. In this questionnaire, frequency and severity of bleeding symptoms are assessed by summation of all scores in each item of bleeding symptom. 12 Severity of factor deficiency was defined based on the factor activity level: severe (<1% IU/dL), moderate (1%-5% IU/dL), and mild (>5% IU/dL).
Because no standard questionnaire has been designed for evaluation of QOL in patients with RBDs in the literature, and due to the similarity of clinical manifestations of hemophilia and RBDs, in this study, the Persian version of Haemo-QOL questionnaire (long version) was used to evaluate QOL of patients with RBDs. This Persian version has been tested and validated by Bagheri et al 13 in a group of Iranian children affected by hemophilia. Haemo-QOL questionnaire is a specific designed self-reported questionnaire to measure QOL in children and adolescents with hemophilia in the age ranges of 4 to 7 (I: 21 items), 8 to 12 (II: 64 items), 13 to 16, and 17 to 18 years (III: 77 items). 14 For the 4- to 7-year age-group, the questionnaire consisted of 8 dimensions (physical health, feeling, view of yourself, family, friends, other people, nursery school/kindergarten, and treatment) and 21 questions; for the 8- to 12-year age-group, it was expanded with 2 additional dimensions (perceived support and coping) and 64 questions; and for the 13- to 18-year age-group, the questionnaire contained 12 dimensions (2 additional domains included relationships and future) and 77 questions. 14,15 Raw scores were converted to a scale from 0 to 100 to make them comparable between different dimensions and different age-groups. Higher score determined more impairment and poorer QOL. 14 At the end of questionnaire, patients were asked about global health from their viewpoint which should be answered by 5 grades from excellent to poor health status. Also, they were asked about degree of being bothered by the disease in 5 scales from not at all to very much.
Statistical Analysis
Data were analyzed by SPSS v 21. Descriptive data were presented as mean, standard deviation (SD), and percentage. Student t test and Kruskal-Wallis test were used to compare quantitative variables between the 2 and 3 or more groups of patients, respectively. Pearson correlation test was used to assess the correlation between the 2 quantitative variables. Multiple linear regression was used to determine the independent influencing factors on QOL. P value less than .05 was considered statistically significant.
Results
The mean age of the patients was 13.96 ± 4.50 years old and ranged from 4 to 18 years old. The most common type of factor deficiencies in the studied population were deficiencies of FVII (28.8%) and fibrinogen (17.3%) followed by FXIII (15.4%), FXI (15.4%), and FX (13.5%). More than half (63.4%) of the patients reported that their global health status is good or higher. Of all patients, 26.9% reported that they were bothered by the affected disease very much and considerably. The mean of bleeding severity based on bleeding score was determined as 5.21 ± 3.62 and ranged between 0 and 13.
The results of Haemo-QOL score of the participants are presented in Table 1. Total Haemo-QOL score in all age-groups was determined as 41.15 ± 14.27. The worst total QOL scores were determined in 2 domains including family (54.56 ± 27.58) and friends (50.52 ± 29.46). Four evaluated age-groups were well matched relative to basic demographic characteristics including sex (P = .430), type of factor deficiency (P = .095), and severity of factor deficiency (P = .827). In comparison, of the total Haemo-QOL scores among different age-groups, the worst condition was related to the age-group of 4 to 7 years old (45.40 ± 17.38); however, the differences among 4 age-groups were not statistically significant (P = .344). The poorest Haemo-QOL scores of different dimensions in different age-groups were recognized as follows: family in 4- to 7-year-old group (90.62 ± 11.08), friends in 8- to 12-year-old group (66.47 ± 33.10), future in 13- to 16-year-old group (52.40 ± 19.01), and feeling in 17- to 18-year-old group (56.09 ± 22.75). In comparison, of the Haemo-QOL scores of each dimension among 4 age-groups, the differences were only significant in 3 dimensions including feeling, view, and family (<.05).
The results of Haemo-QOL Scores Overall and in Each Dimensions in Patients With Rare Bleeding Disorders Presented as Mean and Standard Deviation.
The relationships of total Haemo-QOL score with demographic and clinical characteristics of the patients are summarized in Table 2. Total Haemo-QOL score was 38.31 ± 12.91 in male patients and 44.46 ± 15.33 in female patients, the difference was not statistically significant (P = .122). In both sex groups, family and friends were the most affected subscales. Of all other evaluated variables, only health status (P = .011), being bothered by the disease (P < .001), and bleeding severity (P = .032) showed statistically significant association with Total Haemo-QOL score.
Univariate Analysis of Association of Covariates With Total Haemo-QOL Score in Patients With Rare Bleeding Disorders.
aStatistically significant.
Finally, variables with P value less than <.20 in the previous analysis were entered into the multiple linear regression model (Table 3). Only degree of being bothered by the disease remained in this model and was determined as the predictor variable for the total Haemo-QOL score (β = .624, P < .001).
Multiple Linear Regression of Associated Factors with Total Haemo-QOL Score in Patients With Rare Bleeding Disorders.a
a R 2 = .389, Stepwise method; β: Standardized coefficients.
bStatistically significant.
Discussion
To our knowledge, this is the first study to evaluate QOL and related factors in a large cohort of children and adolescents with RBDs.
Overall score for the studied population was determined as 41.15 ± 14.27, and the worst scores were found in 2 subscales of family and friends. Bagheri et al 13 investigated QOL of children with hemophilia using Haemo-QOL in southern Iran and reported a mean overall QOL score of 54.1 ± 7.3 that is poorer than our patients. So it seems patients with RBDs have a better QOL than patients with hemophilia in our region. Possible cause could be explained by less severity and frequency of bleeding episodes in patients with RBDs compared with hemophiliacs. However, in the literature there are some reports of better Haemo-QOL scores in children with hemophilia in both developed and developing countries such as 33.8 ± 15.5 in 8- to 16- and 35 ± 16.1in 4- to 7-year-old children in the United States, 16 and 39.6 ± 15.0 in 4- to 16-year-old children in Turkey, 17 indicating higher impairments in QOL of our patients with RBDs as well as our patients with hemophilia compared to those in other countries. Also, health-related QOL was reported as satisfactory in 4- to 16-year-old children with severe hemophilia residents in 6 countries of Western Europe. This difference could be due to advanced diffusion of home treatment as well as prophylaxis therapy in developed countries. 15 Based on the results of our study, health-related QOL in our patients with RBDs is more impaired compared to children affected by severe hemophilia in developed countries. It seems advanced supportive care can be helpful to a large extent in the promotion of health status of patients with bleeding disorders.
In our study, the worst QOL score was found in 4- to 7-year-old children (45.40 ± 17.38); however, the difference was not statistically significant. This result was in contrast with the results of Dekoven et al 16 who reported significant higher impairments of QOL in children with hemophilia with increasing age. Also, in adult patients with hemophilia, increasing age induced more impairment in health status of the patients evaluated by both the Short Form (SF-36) and the Euro QOL (Euro QOL). 18 More attention toward our younger children with RBDs should be taken into account.
Family and friends were the 2 most impaired dimensions of Haemo-QOL in our patients. Similarly, Bagheri et al reported the greatest impairment in the friends, perceived support, and family dimensions in children with hemophilia. 13 Also, friends and perceived support were the most impaired dimensions in other reports in children with hemophilia in some developed countries. 15,19 Physical health, family, and treatment were found to be the most impaired dimensions in Egyptian children and adolescents with hemophilia. 20 Moreover, in different age-groups in our study, the greatest impairments were observed in the dimension of family in 4- to 7-year-old, friends in 8- to 12-year-old, future in 13- to 16-year-old, and feeling in 17- to 18-year-old children. More attention is warranted to consider appropriate educational intervention for all the families with children affected by RBDs to improve both family and friends dimensions of QOL. Also, psychological interventions are especially needed in adolescences with RBDs to improve future and feeling dimensions.
In our study, boys showed better scores of QOL compared to girls, but the difference was not significant. Also, severity of factor deficiency and type of coagulation factor deficiency were not significantly associated with QOL. Unexpectedly, in RBDs, there is a heterogeneous association between disease severity based on factor activity level and clinical bleeding symptom. 7,21 In contrast to our results, significant correlation between QOL and disease severity have been reported in patients with hemophilia and von Willebrand disease. 10,13,22,23
On the other hand, QOL of the studied population was significantly affected by bleeding severity indicating that poorer medical situation results in lower health-related QOL of the patients. This was in agreement with the results of other reports evaluating the patients with hemophilia and von Willebrand disease. 8,11,13 However, in multiple regression model, the only predictive variable influencing on QOL was determined as being bothered by the disease. Possibly, the cause of no significance of the bleeding severity in this model is that the amount of suffering from disease is also affected by bleeding severity and phenotype of the disease.
Our study was limited due to the lack of control group. Also, there was no similar study in the literature evaluating QOL of children with RBDs, and no specifically designed questionnaire for RBDs, so Haemo-QOL questionnaire was used, and our results were compared to population with hemophilia. On the other hand, availability of a large cohort of children with RBDs and accuracy in data gathering by expert nurses were the strong points of our study. Further studies with control groups including healthy individuals or other specific diseases are recommended.
Conclusion
Based on our results, Haemo-QOL of children with RBDs was better than what was reported in patients with hemophilia in our region, but it was worse than what was reported in patients with hemophilia in other developing and developed countries. In univariate analysis, QOL of patients was significantly associated with health status, being bothered by the disease and bleeding severity. After removal of confounding variables by multiple linear regression model, being bothered by the disease was the only predictor of QOL. It seems suffering from the disease is affected by bleeding severity as well. Due to chronicity and feature of bleeding disorders, more attention to different aspects of the disease, especially in 2 dimensions of family and friends through considering educational and psychological programs for patients and families are necessary to improve QOL of the patients with RBDs.
Footnotes
Acknowledgement
We would like to express our deep thanks to our patients and their families for their cooperation and participation in our study. Also, we should express our great thanks to the Research Vice Chancellor of Shiraz University of Medical Sciences for approval and financial support of this project (This article is relevant to the thesis of H. Mohtadi with Project no. 6300). We thank Sheryl Nikpoor for editing and improving the use of English in the manuscript.
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.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.