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Keywords:

  • Haemophilia;
  • HIV ;
  • incidence;
  • mortality;
  • viral hepatitis

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

Sweden has been a pioneer in the treatment of haemophilia, with the first concentrate available in the 1950s. Treatment has improved over the years to its current state-of-the art. The aim of the current study was to evaluate the long-term outcome of haemophilia in terms of incidence, morbidity and mortality. Patients diagnosed with haemophilia A or B registered at the national haemophilia centres and/or the Patient Registry and born before 2009 and alive in 1968 were enrolled and linked to the Cause of Death-, Migration- and Medical Birth registries. Five age- and sex-matched controls were selected for each patient. A total of 1431 patients with haemophilia A or B were compared with 7150 controls. The 3-year moving average incidence rate per 100 000 population varied between 21 and 36. The hazard ratio for all-cause mortality compared with controls was 2.2, 95% CI: [1.8; 2.7], < 0.001 for the entire group of patients and 1.7, 95% CI: [1.3; 2.2], < 0.001 when patients with HIV and/or viral hepatitis were excluded. The corresponding figures for the severe haemophilia subgroup were 6.6, 95% CI: [4.5; 10.0], < 0.001 and 8.2, 95% CI [3.2; 20.8], < 0.001 respectively. The most common causes of death were related to malignancies and the haemostatic defect. People with haemophilia were 57% less likely to die from ischaemic heart disease than controls. People with haemophilia in Sweden demonstrate higher mortality over time, independent of HIV and viral hepatitis, despite relatively advantageous access to clotting factor concentrates.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

Haemophilia is an X-linked recessive disorder affecting males and characterized by the deficiency of coagulation factors VIII (haemophilia A) or IX (haemophilia B) [1]. The reported incidence is one in 10 000 male births.

Sweden was a pioneer in the treatment of the disease with the first concentrate available in the 1950s. Therapy has considerably improved over the years to the current use of prophylaxis to prevent bleeds in all patients with a severe phenotype. Despite the fact that prophylaxis is the state-of-the-art treatment, a large proportion of patients worldwide still lacks this preventive treatment due to its high cost. Instead, they rely on less effective methods of substituting the deficient factor. Life expectancy of persons with haemophilia has dramatically increased from a median age of 10–15 years one hundred years ago to more or less normal for a newborn today [2]. The use of plasma-derived products was, until the mid-1980s, associated with the transmission of blood borne viruses such as hepatitis C and human immunodeficiency virus (HIV) [3]. Viral inactivating procedures were then introduced and recombinant products developed, minimizing this risk.

To date, due to the lack of national registries, there have been few reports on the long-term outcome of patients with haemophilia compared with the general population [2, 4-8].

To address this issue, we have taken advantage of the unique national registries available in Sweden in the so-called HUMAZ study to evaluate the incidence of the disease over time as well as mortality and morbidity in patients with all severities of haemophilia, and in the subgroup with severe haemophilia with and without HIV and viral hepatitis. These findings have then been compared with controls without a bleeding disorder matched by age and gender.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

Registers

Sweden has a long tradition of high quality national record keeping made possible because all Swedish citizens have a unique personal identification number. As the national medical health care system is of a high standard and available for all citizens, it is possible to link complete information from the different registers on an individual level.

This current observational study is based on the linkage of local- and population-based registries held by the three coagulation centres in Göteborg, Malmö and Stockholm, the National Board of Health and Welfare and Statistics Sweden (SCB; Fig. 1). The Population Registry in Sweden has contained information on personal data since 1968. The In-Patient Registry contains data for complete hospital admissions since 1987 and the Out-Patient Registry has existed from 2001 – both of these registers can be found in the national Patient Registry. The Cause of Death Registry contains data from 1961 providing information on date and cause of death. The Medical Birth-Registry contains information for all deliveries in Sweden from 1973 including information on the newborn and the pregnancy itself. The Patient-, the Cause of Death- and the Medical Birth Registers all use the International Classification of Disease (ICD) codes. To calculate background standardized incidence/prevalence data, the number of newborn males (from 1968) and the male population (from 1969) were collected from SCB.

image

Figure 1. Swedish national registries used in the study.

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Subjects

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

The cohort of this study comprises all Swedish patients alive in 1968 and born before 2009 with a registered diagnosis of haemophilia. Five randomly chosen controls without haemophilia matched on gender and age identified from the Population Registry (Table 1). Patients with haemophilia A or B were identified either from the national Patient registry or from any of the registers at the three coagulation centres in Sweden (Gothenburg, Malmö or Stockholm) by the following ICD-codes: ICD-8 (286); ICD-9 (286); ICD-10 (D66) and (D67). Until 2001, the mild form of the disorder was defined as an upper clotting factor level of 0.25 IU mL−1, after which it was redefined by the FVIII and FIX subcommittee of the ISTH to 0.40 IU mL−1 [9]. Moderate and severe haemophilia, however, have been consistently defined. At the local coagulation centres, the severities of haemophilia could be identified from written documentation. In general, the coagulation centres are able to keep more complete and comprehensive information. When the cohort of patients and controls was identified, it was then linked to the Patient-, Cause of Death-, Medical Birth- and Migration Registries.

Table 1. Characteristics of the entire study population
 Total study groupAfter exclusion of subjects with HIV infectionAfter exclusion of subjects with HIV infection and/or viral hepatitis
Haemophilia n (%)Controls n (%)Haemophilia n (%)Controls n (%)Haemophilia n (%)Controls n (%)
All
Number1431 (100)7150 (100)1335 (100)6671 (100)1067 (100)5331 (100)
Mean birth year, range1960, 1884–20081960, 1884–20081961, 1884–20081961, 1884–20081962, 1884–20081962, 1884–2008
HIV infection96 (7)2 (0)0 (0)1 (0)0 (0)1 (0)
Viral hepatitis337 (24)35 (1)268 (20)32 (1)0 (0)16 (0)
Emigration22 (2)432 (6)22 (2)386 (6)21 (2)293 (6)
Death382 (27)1351 (19)324 (24)1294 (19)274 (26)1100 (21)
Follow-up ≤ 60 years
Emigration22 (2)422 (6)22 (2)376 (6)21 (2)284 (5)
Death147 (10)337 (5)97 (7)308 (5)77 (11)229 (0)

Comorbidities

HIV infection was identified using ICD-9 (042, 279.6 and 279.5) and ICD-10: (B20–B24). Corresponding ICD-codes for viral hepatitis were as follows: ICD-7 (092), ICD-8 (070), ICD-9 (070) and ICD-10 (B18). HIV- and hepatitis virus status was also identified using information from the local registries in Malmö, Gothenburg and Stockholm. If HIV infection or viral hepatitis was not recorded as being present, then the person was considered to not have the disease.

Statistical analyses

The follow-up time was from date of birth until date of emigration, date of death or end of study (Dec 31, 2008). Cox proportional-hazards regression models, stratified on birthdate, were used to estimate hazard ratios (HR) with corresponding 95% confidence intervals (CI). This was done with and without the exclusion of patients with haemophilia with known HIV infection and/or viral hepatitis. To meet model assumptions, age was censored at 60 years. In the case of viral hepatitis, a few could have been diagnosed after the age of 60 because of missing information on diagnosis date of viral hepatitis. The incidence was presented with a 3-year moving average calculated by taking the average incidence of a 3-year period. A P-value less than 0.05 were considered significant. For all analyses, version 19.0 of SPSS was used.

Ethics

The study was approved by the regional ethics committee of Lund, Sweden on the 9th of January, 2009 with registration number 706/2008. For study purposes, all data have been de-identified and analysed at the group level.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

As shown in Table 1, 8581 persons were enrolled, of whom 1431 were diagnosed with haemophilia A or B and registered at one of the three coagulation centres in Sweden and/or the national Patient Registry. The severities of haemophilia were known for 934 patients registered at any of the three centres. Of those, 405 (43%) patients had mild, 145 (16%) moderate and 384 (41%) severe haemophilia. The mean year of birth was 1960 and ranged from 1884 to 2008.

All severities of haemophilia

For the haemophilia cohort, the total mean follow-up time was 44.2 years, the minimum and maximum 0–97.7 years. The 3-year moving average incidence rates are presented in Fig. 4, the prevalence rates for the haemophilia cohort are presented in Fig. 2.

image

Figure 2. The prevalence (per 100 000 persons) for the total study cohort of patients with haemophilia and for the subgroup with severe haemophilia.

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The lowest 3-year moving average incidence, 21, 95% CI: [15; 30] patients per 100 000, was seen in 2004–2006 and the highest, 36, 95% CI: [27; 47] per 100 000, in 1998–2000. The lowest prevalence, 21, 95% CI: [21; 23] patients per 100 000, was found in 1969 and the highest, 25, 95% CI: [23; 26] per 100 000, in the year 1988. Twenty-two (2%) of the patients with haemophilia and 432 (6%) of the controls emigrated during the follow-up period. The mean ages of death for the periods 1981–1990, 1991–2000 and 2001–2008 for all patients were 58.5, 59.9 and 69.4, respectively, and the corresponding ages for the controls 66.4, 69.6 and 75.5 as shown in Fig. 3.

image

Figure 3. The mean age of death for the entire population with haemophilia as well as for controls and the subgroup of patients with severe haemophilia for the periods 1981–1990, 1991–2000 and 2001–2008.

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There were 96 (7%) patients diagnosed with HIV and 337 (24%) with viral hepatitis. Among the controls, only two (0.03%) patients were diagnosed with HIV and 35 (0.5%) with viral hepatitis.

In the haemophilia and control cohorts, 382 (27%) and 1351 (19%) died during the period of observation. The hazard ratio for all-cause mortality for those with haemophilia A or B compared with their matched controls was estimated to be 2.2, 95% CI: [1.8; 2.7], < 0.001. When haemophilia patients with HIV infection were excluded, the hazard ratio declined to 1.6, 95% CI: [1.2; 2.0], P < 0.001. When HIV and/or viral hepatitis were excluded, the hazard ratio was estimated to be 1.7, 95% CI: [1.3; 2.2], P < 0.001 (Table 4). The most frequently reported cause of death for the haemophilia cohort was malignancies (22%) and haemorrhage related (14%) without further characterization, whereas cerebrovascular diseases were reported in 23 cases (6%), the majority of these (65%) specified as intracerebral bleeds. The haemophilia cohort was 57% less likely to die from ischaemic heart disease than the control cohort. For the controls, the comparative figures for malignancies and haemorrhage-related deaths were 306 (23%) and 0. The most frequent causes of death for haemophilia A or B with comparative numbers for the control cohort are presented in Table 2.

Table 2. The most frequent causes of death for the total study group of haemophilia patients, for patients without HIV, for patients without HIV and/or viral hepatitis. The most frequent causes of death for patients with severe haemophilia, for severe haemophilia patients without HIV and for patients without HIV and/or viral hepatitis. The comparative numbers for their matched controls are also presented
Causes of deathTotal study groupAfter exclusion of subjects with HIV infectionAfter exclusion of subjects with HIV infection and/or viral hepatitis
Haemophilia, n (%)Control, n (%)Haemophilia, n (%)Control, n (%)Haemophilia, n (%)Control, n (%)
  1. a

    ICD-9 (279).

  2. Malignancies: ICD-8 and ICD-9 (140–208). ICD-10 (C00–C97).

  3. Haemorrhage-related deaths: ICD-8 and ICD-9 (280–289). ICD-10 (D65–D69).

  4. Ischaemic heart disease: ICD-8 and ICD-9 (410–414). ICD-10 (I20–I25).

  5. Immunodeficiency including HIV/AIDS: ICD-9 (279, 042). ICD-10 (B20–B24).

  6. Cerebrovascular disease: ICD-8 and ICD-9 (430–438). ICD-10 (I60–I69).

  7. Viral hepatitis: ICD-8 and ICD-9 (070) ICD-10: B15–B19.

All severities
Number of deaths382 (100)1351 (100)324 (100)1294 (100)274 (100)1100 (100)
Malignancies83 (22)306 (23)77 (24)296 (23)62 (23)254 (23)
Haemorrhage related54 (14)0 (0)47 (15)0 (0)35 (13)0 (0)
Ischaemic heart disease48 (13)391 (29)48 (15)378 (29)45 (17)322 (29)
Immunodeficiency including HIV/AIDS29 (8)0 (0)4 (1)0 (0)4 (2)0 (0)
Cerebrovascular disease23 (6)111 (8)22 (7)106 (8)18 (7)91 (8)
Severe haemophilia
Number of deaths78 (100)102 (100)31 (100)63 (100)14 (100)24 (100)
Immunodeficiency including HIV/AIDS24 (31)01a (3)01a (7)0
Haemorrhage-related deaths/cerebrovascular disease18 (23)6 (6)13 (42)2 (3)8 (57)1 (4)
Malignancies9 (12)13 (13)5 (16)8 (13)1 (7)3 (13)
Viral hepatitis5 (6)03 (10)000
Ischaemic heart disease3 (4)25 (25)3 (10)18 (29)1 (7)8 (33)

Severe haemophilia

The severity of haemophilia was known for 934 patients; of those a total of 384 had severe disease (Table 3). The lowest 3-year moving average incidence was 5, 95% CI: [2; 9] patients per 100 000, the years 1978–1980 and the highest 18, 95% CI: [12; 26] per 100 000, in 1997–1999 (Fig. 4). The lowest prevalence, 4, 95% CI: [3, 4] patients per 100 000, was found in 1969 and the highest 7, 95% CI: [6, 7] per 100 000, in the year 2005 (Fig. 2).

Table 3. Characteristics of the study population with severe haemophilia and their matched controls
 Total study groupAfter exclusion of subjects with HIV infectionAfter exclusion of subjects with HIV infection and/or viral hepatitis
Haemophilia, n (%)Controls, n (%)Haemophilia, n (%)Controls, n (%)Haemophilia, n (%)Controls, n (%)
All
Number384 (100)1918 (100)306 (100)1529 (100)196 (100)979 (100)
Mean birth year, range1975, 1903–20081975, 1903–20081980, 1903–20081980, 1903–20081990, 1903–20081990, 1903–2008
HIV infection78 (20)1 (0)0 (0)0 (0)0 (0)0 (0)
Viral hepatitis167 (44)9 (1)110 (36)7 (1)0 (0)1 (0)
Emigration2 (1)129 (7)2 (1)90 (6)2 (1)42 (4)
Death78 (20)102 (5)31 (10)63 (4)14 (7)24 (3)
Follow-up ≤ 60 years
Emigration2 (1)128 (7)2 (1)89 (6)2 (1)42 (4)
Death66 (17)61 (3)23 (8)37 (2)12 (6)11 (1)
image

Figure 4. Three-year moving average incidence (per 100 000 persons) for the total study group of patients with haemophilia and for the subgroup of patients with severe haemophilia.

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The subgroup with severe haemophilia was compared with 1918 age- and sex-matched controls. The mean follow-up time of those with severe haemophilia was 30.7 years, minimum and maximum 0–91.9 years, from birth to emigration, death or end of study. Only two (0.5%) patients with haemophilia emigrated during the study period whereas 128 (7%) controls moved to another country.

There were 78 (20%) patients with haemophilia with known HIV infection and 167 (43%) with viral hepatitis. The corresponding numbers among the controls were 1 (0%) and 9 (0.5%). During the study period, 78 (20%) patients and 102 (5%) controls died. When patients with HIV were excluded, the number of deaths decreased to 31 (10%) in the haemophilia group and 63 (4%) deaths in the control group, and when those with viral hepatitis were excluded 14 (7%) and 24 (2.5%) respectively.

The mean ages of death for the periods 1981–1990, 1991–2000 and 2001–2008 in the entire subgroup of patients with severe haemophilia were 45.6, 40.5 and 56.0 (Fig. 3).

The hazard ratio for all-cause mortality for haemophilia patients compared with controls was 6.6, 95% CI: [4.5; 10.0], < 0.001. When patients with HIV were excluded, the hazard ratio was 3.3, 95% CI: [1.9; 5.6], < 0.001. Exclusion of both HIV and/or viral hepatitis for the patients yielded a hazard ratio of 8.2, 95% CI: [3.2; 20.8], < 0.001 (Table 4). The most frequent cause of death for those with severe haemophilia was immunodeficiency including HIV/AIDS, 24 (31%), followed by haemorrhage-related deaths/cerebrovascular-related deaths, 18 (23%). None of the controls died from immunodeficiency including HIV/AIDS and 6% of the controls died from cerebrovascular disease.

Table 4. Estimated hazard ratios for haemophilia patients compared with matched controls for all causes of death
GroupHR95% CIP-value
Patients with all severities
All
Haemophilia control2.2[1.8; 2.7]< 0.001
HIV-infected excluded
Haemophilia control1.6[1.2; 2.0]< 0.001
HIV-infected and viral hepatitis excluded
Haemophilia control1.7[1.3; 2.2]< 0.001
Patients with severe haemophilia
All
Haemophilia control6.6[4.5; 10.0]< 0.001
HIV-infected excluded
Haemophilia control3.3[1.9; 5.6]<0.001
HIV-infected and/or viral hepatitis excluded
Haemophilia control8.2[3.2; 20.8]<0.001

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

This cohort study was conducted to examine long-term follow-up of the Swedish cohort diagnosed with haemophilia. All patients registered in the local haemophilia databases at the three haemophilia centres, or at any time registered in a national patient registry, were enrolled and compared with age- and sex-matched controls. The strength of this type of study is that it allows linkage of registries which enables evaluation of the long-term course of the patient cohort, and provides opportunities to address disease- and family-related issues. However, the design also has weaknesses. First, we found that the severity of haemophilia is not consistently or uniformly captured in the national Patient database, which hampers the ability to evaluate phenotypic aspects of the entire cohort, particularly those patients with a milder disease. For this reason, analyses were completed in the subset of patients with severe haemophilia – a group more likely to be completely ascertained. This finding also underlines the importance of having a well-designed national registry database for follow-up. In a previous report [2] of the Swedish cohorts of patients with haemophilia, the percentages of mild, moderate and severe haemophilia were comparable for the entire study group, but somewhat different when only the data from the patient registries at the haemophilia centres were considered. The reason for this is not clear, but could be due to incomplete registration of patients with a milder disease at the centres. Second, the occurrence of missing data is greater in the initiation phase of a new registry. Twenty-two (2%) of the patients with haemophilia emigrated during the study period and 432 (6%) of the controls, likewise for the subgroup of patients with severe haemophilia: (1%) and their controls (7%). These findings indicate that people with haemophilia are less likely to move to another country than those without a severe bleeding disorder, probably due to treatment advantages offered in Sweden over the years – treatment introduced in the 1950s and 1960s and then continuously improved by dedicated pioneers in the field.

As seen in Fig. 4, the incidence for all severities of haemophilia varied over the years examined between 21 and 36 per 100 000. Prenatal diagnosis was introduced in Sweden in the early 1970s, but this does not seem to have influenced the decision to give birth to a child with haemophilia. Moreover, the haemophilia population worldwide was severely affected by HIV infection in the 1980s, and it might be expected that the prevalence of haemophilia was affected by this catastrophe. Despite this, however, there were an increasing number of people with the disease until the beginning of the 1990s, after which there was a clear downward trend. As seen in Fig. 3, the mean age of death has increased over the years concomitantly with an improved therapy, but with a decline in the period of 1991–2000. This will, at least partly, be due to an increasing mortality rate for patients infected with HIV and hepatitis C. In a report [6] from Austria covering the years 1983–2006 investigators reported that the death rate reached a peak in 1991–1993, and declined thereafter. The prevalence of people with haemophilia in the population increased until about 1991 followed by a decrease likely explained by HIV-related deaths.

The prevalence rate for patients with severe haemophilia began to increase in the year 1999, probably due to improved treatment resulting in a longer survival. For the total study group, the prevalence began to decrease around 1994. This could in part be due to incomplete registration of patients with milder form of haemophilia. The most common causes of death in the haemophilia population over the years were, not surprisingly, related to haemorrhages and HIV infection [4-8, 13, 14]. As treatment improves, these causes will become less significant. Other causes, including malignancies, will be more important. Regarding malignancies there were no difference between patients and controls. Whether different types of malignant diseases are more or less prevalent among the Swedish population with haemophilia compared with the general male population remain to be evaluated. People with haemophilia, irrespective of severity, are considered to have a low risk for cardiovascular thromboembolic events. In our haemophilia cohort, 48 (12%) patients died from ischaemic heart disease compared with 391 (29%; < 0.001) in the control group, and patients with haemophilia were 57% less likely to die from ischaemic heart disease than males in the control cohort. These findings are consistent with previous reports [4, 15, 16]. Although less frequently affected than the controls, data show that cardiovascular events have been and will continue to be a significant problem in a substantial number of patients with haemophilia and that improved and evidence-based guidelines on how to manage these patients are warranted. However, opposite findings have also been shown [10] reporting a standardized mortality ratio (SMR) of 3.0, 95% CI: [1.5; 5.8], for death from acute myocardial infarction for males with haemophilia compared with males without haemophilia in six US states, 1993–1995.

The hazard ratio of 2.2 shows a higher overall mortality for the haemophilia cohort compared with controls. Similar results, measured by a SMR of 2.3 between 1992 until 2001, have been reported from the Netherlands [4]. For the subgroup with severe haemophilia in our study, the hazard ratio was 6.6 compared with controls, a figure similar to that of Plug and co-workers who reported an SMR of 5.1 [4]. Moreover, a study from Greece [11] demonstrated a mortality rate for patients with severe haemophilia 7.9 times that for the general population between 1972 and 1993. In our study, the hazard ratio for patients with severe haemophilia A and B compared with controls was estimated to be 3.3, 95% CI: [1.9; 5.6] when patients with HIV were excluded. In the United Kingdom, an all-cause mortality rate of 2.69, 95% CI: [2.37; 3.05] from 1977 to 1999 was reported [5] for patients not infected by HIV. This is slightly lower and may be due to an age-related difference between the cohorts. Exclusion of both HIV and/or viral hepatitis in our cohort greatly decreased the number of deaths, but the difference remained significant.

The current study is unique in its design and shows that the haemophilia population in Sweden, a country with one of the highest per capita use of factor concentrates in the world [9], still has a higher mortality from all causes of death than those without a bleeding disorder. In addition, and perhaps not so surprising, emigration appeared to be less frequent among the people with haemophilia than others. Due to increased life expectancy other age-related diseases, including malignancies and cardio- and cerebrovascular comorbidities, will become more common in the future not least in patients with milder forms of haemophilia. More data to guide the clinical management of these patients are warranted. Further analyses of the causes of death and various comorbidities are ongoing, and these data will hopefully provide additional valuable contributions towards understanding of the long-term outcome of the haemophilia disease and the treatment provided.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

The authors acknowledge Sharyne Donfield for valuable comments on the manuscript. The study was funded by AstraZeneca.

Author contributions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

S Lövdahl has designed and performed the research, interpreted and analysed data, written the manuscript and given her final approval of the version to be published. K M Henriksson has designed and performed the research, interpreted and analysed data, written the manuscript and given her final approval of the version to be published. M Holmström has contributed data, interpreted and analysed data, revised the manuscript and given her final approval of the version to be published. F Baghaei has contributed data, interpreted and analysed data, revised the manuscript and given her final approval of the version to be published. J-Å Nilsson has designed and supervised the statistical part of the study, interpreted and analysed data, and revised part of the manuscript and given his final approval of the version to be published. E Berntorp has designed and performed the research, interpreted and analysed data, written the manuscript and given his final approval of the version to be published. J Astermark has designed and performed the research, interpreted and analysed data, written the manuscript and given his final approval of the version to be published.

Disclosures

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References

K M Henriksson is an employee of AstraZeneca. E Berntorp has received research funds and honorarium for consultancy from AstraZeneca.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Subjects
  6. Results
  7. Discussion
  8. Acknowledgement
  9. Author contributions
  10. Disclosures
  11. References
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    Rosendaal FR, Briet E, Stibbe J et al. Haemophilia protects against ischaemic heart disease: a study of risk factors. Br J Haematol 1990; 75: 52530.
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    Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briet E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med 1995; 123: 82327.