Haemophilia (2014), 1–8
DOI: 10.1111/hae.12474
REVIEW ARTICLE
The burden and management of FXIII deficiency T . D E J A G E R , * L . P E R I C L E O U S , † M . K O K O T - K I E R E P A , ‡ M . N A D E R I § and M . K A R I M I ¶ *Pharmerit International, AV Rotterdam, the Netherlands; †Novo Nordisk A/S, Bagsværd, Denmark; ‡Novo Nordisk Health Care AG, Zurich, Switzerland; §Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran; and ¶Haematology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
Summary. Factor XIII congenital deficiency (FXIII CD) is a serious bleeding disorder resulting in a lifelong bleeding tendency, defective wound healing and recurrent miscarriage. The aim of this study was to review available literature on the burden and management of FXIII CD. To this end, Medline, Embase and Cochrane databases were searched. In current literature, FXIII CD is described as one of the most severe forms of a congenital coagulation disorder, primarily due to a high risk of severe bleeding events. The published literature suggests that over 50% of untreated FXIII CD patients experience severe bleeding symptoms. Intracranial haemorrhage (ICH) – a major cause of death and morbidity – is reported to occur in up to one-third of patients. Nonetheless, data on the social and financial burden in patients with FXIII CD are sparse. Identified reports on the effectiveness and safety of
Introduction Factor XIII congenital deficiency (FXIII CD) is a severe rare bleeding disease caused by an impaired production of clotting factor XIII; the last protein to become activated in the blood coagulation cascade. The lack of FXIII can introduce a wide range of severe bleeding events in patients, may significantly affect their quality of life, and can increase mortality [1,2]. The prevalence of this inherited rare coagulation disorder is estimated to be 1 in 1–3 million, although there is some variability in reported prevalence. Also an acquired form of FXIII deficiency exists; however, only around 60 cases have been reported to date [3,4].
Correspondence: Tim de Jager, Pharmerit International, Marten Meesweg 107, 3068 AV Rotterdam, the Netherlands. Tel.: +31 (0)88 440 01 24; fax: +31 10 4421158; e-mail: [email protected] Accepted after revision 27 April 2014 © 2014 John Wiley & Sons Ltd
recommended treatments support that patients with FXIII CD should receive prophylactic treatment as early as possible in their lives to prevent the occurrence of bleeds, including potentially life-threatening ICHs. In conclusion, limited data on the social and economic consequences related specifically to FXIII CD have been published to date. However, it is widely acknowledged that the high risk of severe bleeds and ICH results in a high level of burden in patients with bleeding disorders. To inform future clinical decision-making and reimbursement decisions, further research is required to gain insight in how specifically FXIII CD affects quality of life and to fully understand associated economic consequences. Keywords: burden of illness, cost of illness, disease management, factor XIII deficiency, review
Although FXIII CD is one of the most severe bleeding disorders, the knowledge of the burden of disease is limited and no clear international consensus on management exists. Thus, a literature review was performed with a two-fold objective. First, to obtain insight in the frequency and severity of bleeding events, their effect on Health-Related Quality of Life (HRQoL), and potential financial consequences. Second, to summarize published evidence on the effectiveness, safety and economics of recommended treatment options.
Methods This is a systematic review study of Medline, Embase and Cochrane databases using the key disease-related terms ‘Factor XIII deficiency’, ‘F13 deficiency’, ‘FXIII deficiency’, ‘Factor 13 deficiency’ and ‘Fxiii deficiency’ in the title or abstract. To avoid losing relevant information, no limitations were set in the search. Articles reporting on the occurrence of bleedings in FXIII CD patients, outcomes of HRQoL or financial 1
2
T. DE JAGER et al.
consequences were included for full-text reading. In addition, clinical evidence (either randomized controlled trials, or open-label and observational studies) on the effectiveness and safety of treatments was included in the final selection. The evaluation of clinical evidence was limited to treatments that are recommended in published consensus papers; highly purified plasma-derived FXIII concentrate (pd-FXIII) and recombinant FXIII concentrate (rFXIII) [5,6]. References included in the full-text papers were manually searched if they were not identified in the original search. As the literature on ICH in FXIII CD patients was anticipated to be sparse, a broader, non-indication specific topline search was performed to collect evidence on the effect of ICH on HRQoL, as well as data on the economic consequences of having an ICH. These data were deemed relevant as it could provide an indication of how FXIII patients are affected by this severe complication.
Results The database search using key disease-related terms resulted in a total number of 603 hits. After the selection procedure, 17 studies met the inclusion criteria (See Fig. 1). Six of the studies related to registries or questionnaire-based studies reporting the occurrence of bleeding events in patients with FXIII CD; one publication included an outcome of HRQoL. The remaining 10 publications reported effectiveness and safety outcomes of treatment. No reports on the economic consequences of FXIII CD were identified. In addition to the 17 articles identified using disease-specific search terms, the non-indication specific search resulted in a total of 13 articles on the HRQoL of ICH and 18 articles on the economic consequences of ICH.
The occurrence of bleeding events The burden of FXIII CD is primarily related to the occurrence of severe bleeds. In the literature review,
Fig. 1. Flow diagram of study selection.
Haemophilia (2014), 1--8
six publications of registries and questionnaire-based studies were identified reporting data on the occurrence and severity of bleeding events (See Table 1). These studies confirm that the risk of severe bleedings in FXIII CD is relatively high when compared with other bleeding disorders. For example, in the European Network of Rare Bleeding Disorders registry, 48.5% of all registered bleedings in patients with FXIII deficiency were classified as spontaneous major bleeds (i.e. intramuscular, joint, central nervous system, gastrointestinal and umbilical cord bleeding) [7]. In comparison, the proportion of major bleeds was 42.3% in individuals with fibrinogen deficiency, 23.5% for patients with FX deficiency and < 15% in all other rare bleeding diseases. Furthermore, a high risk of severe bleeding events was observed in a registry by the European Thrombosis Research Organization; attending physicians reported 53% of the patients experienced a severe bleeding event before the initiation of FXIII replacement therapy [1]. Severe bleeds in FXIII CD can occur spontaneously or after minor trauma at all ages. Umbilical cord bleeding is reported in 56–83% of newborns with FXIII CD [1,8]. Also, severe bleedings have been observed after circumcision within 24 h after birth [9]. During life, FXIII CD patients have a severe bleeding tendency in various locations of the body. Bleeding events in the joint and muscles are observed in 27–49% of patients, introducing chronic pain and physical disability [7,10]. Moreover, patients have a relatively high risk of bleedings in the central nervous system, and an ICH is observed in 10–34% [1,10]. ICH is the main cause of death in FXIII CD, and surviving patients may be confronted with severe impairments in physical or cognitive functioning [11]. Furthermore, a small proportion of patients (3–10%) experience severe gastrointestinal bleeds. In women with FXIII CD, recurrent miscarriage is suggested to introduce significant burden [12]. Although no clarity on the risk of a miscarriage exists, the occurrence of spontaneous miscarriage was reported in several case reports and case series. Sharief et al. reported that out of 185 recorded pregnancies in a total of 60 women, 125 (67.5%) resulted in a miscarriage [13]. Moreover, 16 (27%) women reported recurrent miscarriage, defined as three or more pregnancy loss. Next to these disease manifestations, defective wound healing is reported in 14–29% of cases [1,8]. This may lead to chronic wounds and patients are at risk of entering a state of pathologic inflammation. Patients also have an increased risk of haemorrhage after surgery. This occurred in 40% of patients included in a European registry [1]. Moreover, Lak et al. reported 84% of 32 Iranian patients included in their registry who underwent surgery experienced a surgical bleed [14]. © 2014 John Wiley & Sons Ltd
FXIII DEFICIENCY – BURDEN AND MANAGEMENT
3
Table 1. Reported occurrence of bleeding events in patients with FXIII deficiency per location from six individual registries and questionnaire-based studies. References Region
[1]
[7]
[8]
[10]
[14]
[40]
13 European countries, Iran, Morocco Questionnaire 104 NA NR 69%
11 European countries Retrosp. database 42 2007–2010 NR NR
India
North-America
Iran
Iran
Retrosp. database 88 1975–2008 9.5 (
DOI: 10.1111/hae.12474
REVIEW ARTICLE
The burden and management of FXIII deficiency T . D E J A G E R , * L . P E R I C L E O U S , † M . K O K O T - K I E R E P A , ‡ M . N A D E R I § and M . K A R I M I ¶ *Pharmerit International, AV Rotterdam, the Netherlands; †Novo Nordisk A/S, Bagsværd, Denmark; ‡Novo Nordisk Health Care AG, Zurich, Switzerland; §Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran; and ¶Haematology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
Summary. Factor XIII congenital deficiency (FXIII CD) is a serious bleeding disorder resulting in a lifelong bleeding tendency, defective wound healing and recurrent miscarriage. The aim of this study was to review available literature on the burden and management of FXIII CD. To this end, Medline, Embase and Cochrane databases were searched. In current literature, FXIII CD is described as one of the most severe forms of a congenital coagulation disorder, primarily due to a high risk of severe bleeding events. The published literature suggests that over 50% of untreated FXIII CD patients experience severe bleeding symptoms. Intracranial haemorrhage (ICH) – a major cause of death and morbidity – is reported to occur in up to one-third of patients. Nonetheless, data on the social and financial burden in patients with FXIII CD are sparse. Identified reports on the effectiveness and safety of
Introduction Factor XIII congenital deficiency (FXIII CD) is a severe rare bleeding disease caused by an impaired production of clotting factor XIII; the last protein to become activated in the blood coagulation cascade. The lack of FXIII can introduce a wide range of severe bleeding events in patients, may significantly affect their quality of life, and can increase mortality [1,2]. The prevalence of this inherited rare coagulation disorder is estimated to be 1 in 1–3 million, although there is some variability in reported prevalence. Also an acquired form of FXIII deficiency exists; however, only around 60 cases have been reported to date [3,4].
Correspondence: Tim de Jager, Pharmerit International, Marten Meesweg 107, 3068 AV Rotterdam, the Netherlands. Tel.: +31 (0)88 440 01 24; fax: +31 10 4421158; e-mail: [email protected] Accepted after revision 27 April 2014 © 2014 John Wiley & Sons Ltd
recommended treatments support that patients with FXIII CD should receive prophylactic treatment as early as possible in their lives to prevent the occurrence of bleeds, including potentially life-threatening ICHs. In conclusion, limited data on the social and economic consequences related specifically to FXIII CD have been published to date. However, it is widely acknowledged that the high risk of severe bleeds and ICH results in a high level of burden in patients with bleeding disorders. To inform future clinical decision-making and reimbursement decisions, further research is required to gain insight in how specifically FXIII CD affects quality of life and to fully understand associated economic consequences. Keywords: burden of illness, cost of illness, disease management, factor XIII deficiency, review
Although FXIII CD is one of the most severe bleeding disorders, the knowledge of the burden of disease is limited and no clear international consensus on management exists. Thus, a literature review was performed with a two-fold objective. First, to obtain insight in the frequency and severity of bleeding events, their effect on Health-Related Quality of Life (HRQoL), and potential financial consequences. Second, to summarize published evidence on the effectiveness, safety and economics of recommended treatment options.
Methods This is a systematic review study of Medline, Embase and Cochrane databases using the key disease-related terms ‘Factor XIII deficiency’, ‘F13 deficiency’, ‘FXIII deficiency’, ‘Factor 13 deficiency’ and ‘Fxiii deficiency’ in the title or abstract. To avoid losing relevant information, no limitations were set in the search. Articles reporting on the occurrence of bleedings in FXIII CD patients, outcomes of HRQoL or financial 1
2
T. DE JAGER et al.
consequences were included for full-text reading. In addition, clinical evidence (either randomized controlled trials, or open-label and observational studies) on the effectiveness and safety of treatments was included in the final selection. The evaluation of clinical evidence was limited to treatments that are recommended in published consensus papers; highly purified plasma-derived FXIII concentrate (pd-FXIII) and recombinant FXIII concentrate (rFXIII) [5,6]. References included in the full-text papers were manually searched if they were not identified in the original search. As the literature on ICH in FXIII CD patients was anticipated to be sparse, a broader, non-indication specific topline search was performed to collect evidence on the effect of ICH on HRQoL, as well as data on the economic consequences of having an ICH. These data were deemed relevant as it could provide an indication of how FXIII patients are affected by this severe complication.
Results The database search using key disease-related terms resulted in a total number of 603 hits. After the selection procedure, 17 studies met the inclusion criteria (See Fig. 1). Six of the studies related to registries or questionnaire-based studies reporting the occurrence of bleeding events in patients with FXIII CD; one publication included an outcome of HRQoL. The remaining 10 publications reported effectiveness and safety outcomes of treatment. No reports on the economic consequences of FXIII CD were identified. In addition to the 17 articles identified using disease-specific search terms, the non-indication specific search resulted in a total of 13 articles on the HRQoL of ICH and 18 articles on the economic consequences of ICH.
The occurrence of bleeding events The burden of FXIII CD is primarily related to the occurrence of severe bleeds. In the literature review,
Fig. 1. Flow diagram of study selection.
Haemophilia (2014), 1--8
six publications of registries and questionnaire-based studies were identified reporting data on the occurrence and severity of bleeding events (See Table 1). These studies confirm that the risk of severe bleedings in FXIII CD is relatively high when compared with other bleeding disorders. For example, in the European Network of Rare Bleeding Disorders registry, 48.5% of all registered bleedings in patients with FXIII deficiency were classified as spontaneous major bleeds (i.e. intramuscular, joint, central nervous system, gastrointestinal and umbilical cord bleeding) [7]. In comparison, the proportion of major bleeds was 42.3% in individuals with fibrinogen deficiency, 23.5% for patients with FX deficiency and < 15% in all other rare bleeding diseases. Furthermore, a high risk of severe bleeding events was observed in a registry by the European Thrombosis Research Organization; attending physicians reported 53% of the patients experienced a severe bleeding event before the initiation of FXIII replacement therapy [1]. Severe bleeds in FXIII CD can occur spontaneously or after minor trauma at all ages. Umbilical cord bleeding is reported in 56–83% of newborns with FXIII CD [1,8]. Also, severe bleedings have been observed after circumcision within 24 h after birth [9]. During life, FXIII CD patients have a severe bleeding tendency in various locations of the body. Bleeding events in the joint and muscles are observed in 27–49% of patients, introducing chronic pain and physical disability [7,10]. Moreover, patients have a relatively high risk of bleedings in the central nervous system, and an ICH is observed in 10–34% [1,10]. ICH is the main cause of death in FXIII CD, and surviving patients may be confronted with severe impairments in physical or cognitive functioning [11]. Furthermore, a small proportion of patients (3–10%) experience severe gastrointestinal bleeds. In women with FXIII CD, recurrent miscarriage is suggested to introduce significant burden [12]. Although no clarity on the risk of a miscarriage exists, the occurrence of spontaneous miscarriage was reported in several case reports and case series. Sharief et al. reported that out of 185 recorded pregnancies in a total of 60 women, 125 (67.5%) resulted in a miscarriage [13]. Moreover, 16 (27%) women reported recurrent miscarriage, defined as three or more pregnancy loss. Next to these disease manifestations, defective wound healing is reported in 14–29% of cases [1,8]. This may lead to chronic wounds and patients are at risk of entering a state of pathologic inflammation. Patients also have an increased risk of haemorrhage after surgery. This occurred in 40% of patients included in a European registry [1]. Moreover, Lak et al. reported 84% of 32 Iranian patients included in their registry who underwent surgery experienced a surgical bleed [14]. © 2014 John Wiley & Sons Ltd
FXIII DEFICIENCY – BURDEN AND MANAGEMENT
3
Table 1. Reported occurrence of bleeding events in patients with FXIII deficiency per location from six individual registries and questionnaire-based studies. References Region
[1]
[7]
[8]
[10]
[14]
[40]
13 European countries, Iran, Morocco Questionnaire 104 NA NR 69%
11 European countries Retrosp. database 42 2007–2010 NR NR
India
North-America
Iran
Iran
Retrosp. database 88 1975–2008 9.5 (
