LETTERS TO THE EDITORS
caused by the chronic inflammatory eroding process due to chronic synovitis. Consistent with these articles that we had reviewed, severe articular cartilage destruction was confirmed by the histologic tests of the femoral head [1,4,6]. Additionally, chronic inflammation also excited at the surface and the inside of the subchondral bone and was eroding the subchondral bone, which was similar to the inflammatory bone loss in rheumatoid arthritis [7]. Although the diagnosis of osteonecrosis was wrong, but to this patient’s hip, the articular cartilage damage was so severe and only the THA can stop the hip pain and improve the joint function. So for hip haemophilic arthropathy patients, the cystic degeneration focus seen on the radiographic image may not be the result of osteonecrosis of the
References 1 Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8: 1895–902. 2 Kempton CL, Antun A, Antoniucci DM et al. Bone density in haemophilia: a single institutional cross-sectional study. Haemophilia 2014; 20: 121–8. 3 Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treat-
e83
femoral head but just a bone defect focus caused by inflammatory bone erosion. We sincerely recommend the orthopaedists to scrupulously analyse the imaging outcomes of haemophilic patient’s joint when it shows a cystic change.
Acknowledgements This work was supported by the program for Zhejiang Leading Team of S&T Innovation and the program for Key Laboratory of Zhejiang Province.
Disclosures The authors stated that they had no interest which might be perceived as posing a conflict or bias.
ment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535–44. 4 Jansen NW, Roosendaal G, Lafeber FP. Understanding haemophilic arthropathy: an exploration of current open issues. Br J Haematol 2008; 143: 632–40. 5 Rodriguez-Merchan EC. Effects of hemophilia on articulations of children and adults. Clin Orthop Relat Res 1996; 328: 7–13.
6 Jansen NW, Roosendaal G, Wenting MJ et al. Very rapid clearance after a joint bleed in the canine knee cannot prevent adverse effects on cartilage and synovial tissue. Osteoarthritis Cartilage 2009; 17: 433–40. 7 Karmakar S, Kay J, Gravallese EM. Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention. Rheum Dis Clin North Am 2010; 36: 385– 404.
Are there systemic comorbidities in haemophilia unrelated to bleeding and transfusion-transmitted infections? S . J A N C Z A R , * O . W E G N E R , * M . K O S T R Z E W S K A , * M . S T O L A R S K A , * A . J . W . P A I G E † and W. MLYNARSKI* *Department of Paediatrics, Oncology, Hematology and Diabetology Medical University of Lodz, Poland; and †Department of Life Sciences University of Bedfordshire, UK
For decades, life expectancy and quality of life of patients with haemophilia were poor due to bloodborne infections and bleeding complications. Currently, prophylactic administration of coagulation factors has significantly reduced the frequency and severity of haemophilic arthropathies as well as the
Correspondence: Wojciech Mlynarski, Department of Paediatrics, Oncology, Haematology & Diabetology, Medical University of Lodz, Sporna 36/50, 91-738 Lodz, Poland. Tel.: +48426177750; fax: +48426177798; e-mail: [email protected] Accepted after revision 19 September 2014 DOI: 10.1111/hae.12560 © 2014 John Wiley & Sons Ltd
extent of patient immobility. The use of recombined clotting factors, modern pathogen inactivation and surveillance against viral infections has practically eradicated transfusion-related infections. Nevertheless, there continues to be a significant haemophilia comorbidity that may be explained by recurrent subclinical microbleeds and their consequences, an unreported biological role for factor VIII or IX outside the clotting cascade, or additional effects of the genomic events disrupting factor VIII (F8) and IX (F9) genes. Comorbidities are better described for haemophilia A because of higher prevalence of the disease. Many studies lack analysis restricted to haemophilia B patients making it difficult to establish if there are significant differences between comorbidities in these Haemophilia (2015), 21, e70--e121
e84
LETTERS TO THE EDITORS
two diseases. We discuss the evidence for systemic abnormalities in haemophilia that cannot be easily attributed to bleeding or transfusion- transmitted infections. These include delayed growth and sexual development, reduced bone mineral density and hypertension. An extensive study of 333 children and adolescents including 60 subjects with a history of inhibitors published by the Hemophilia Growth and Development Study Group demonstrated that adolescents with haemophilia A and B, and a history of inhibitors (but without HIV infection, 20 patients) displayed 9 or more months delay in skeletal maturation as compared to patients without inhibitors. Furthermore, the patients with inhibitors had features of delayed sexual maturation: older age at particular Tanner stages (pubertal progression from stage 0 to stage 5 ), lower maximal growth velocity and lower maximal testosterone levels. The significance of these results was preserved after controlling for HCV status. The authors speculated on the possible explanation for these observations and considered lack of stimulatory effects of physical activity, chronic upregulation of inflammatory cytokines, or anaemia due to persistent clinical and subclinical bleeding [1]. Considering the higher prevalence of gross genomic changes, such as large deletions or inversions, in patients with inhibitors [2], it can also be speculated that sexual maturation of patients with haemophilia might be partly due to disruption or defective regulation of other genes in the vicinity of F8 or F9 on chromosome X. There are several reports of reduced bone mineral density (BMD) in males with haemophilia A [3]. This is typically explained by relative immobility due to destruction of the joints, periods of symptomatic musculoskeletal bleeding, and lifestyle limitations. Nevertheless, there is accumulating evidence that there might be intrinsic bone defects in haemophilia A and that to some extent this is not corrected by coagulation factor prophylaxis. Liel et al. examined bone phenotypes in a murine model of haemophilia A (f8 knock-out mice) characterized by a lack of spontaneous bleeding [4]. In knock-out mice, the authors observed lower BMD and cortical bone mass and higher fracture rates than in wild-type littermates and suggested that factor VIII deficiency directly affects BMD independent of haemarthroses and reduced physical activity. Liel et al. postulate that this might be due to the recently demonstrated direct effects of thrombin on osteoblasts that could link factor VIII deficiency leading to reduced basal thrombin generation and bone homeostasis [4]. It has also been shown that reduced sex hormone levels are independent risk factors for low BMD in haemophilia [5], which links low BMD with the defects in sexual maturation described above. Similar Haemophilia (2015), 21, e70--e121
to the situation with delayed sexual maturation, bone loss is more severe in patients with inhibitor history [6]. At the same time, osteopenia is observed in both haemophilia A and B (although less studied in haemophilia B) as well as in patients on anticoagulation [7,8]. This suggests that the BMD phenotype is not specific for haemophilia A and suggests links between the coagulation cascade and bone formation and resorption. Other causes might be identical to those proposed above for delayed sexual maturation (inflammation and anaemia secondary to chronic bleeding, impact on genes in the vicinity of F8 or F9 loci). Several reports and recent metanalyses document increased prevalence of hypertension in haemophilia in different age populations including children. At the same time, there are conflicting reports and opinions on the frequency of other cardiovascular risk factors, atherosclerosis and cardiovascular morbidity in haemophilia and many authors suggest that there are protective effects of clotting factor deficiencies [9,10]. The mechanism for increased prevalence of elevated blood pressure in haemophilia is not clear though again the role for subclinical bleeding, especially renal microbleeds compromising kidney function and leading to renovascular hypertension is suggested. Still, this would imply progression of renovascular complications with increasing age of the patients due to accumulated renal damage, yet surprisingly hypertension is already seen in the young patients [9]. There is a lack of studies assessing hormonal regulation of blood pressure, including renin levels or abnormalities of renal vasculature that would be sufficient for testing this proposed ‘renal microbleeding’ mechanism. We have recently described a novel severe haemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 (BRCA1/BRCA2-containing complex, subunit 3) familial moyamoya gene. We provided the clinical description of the syndrome observed in a 10-year-old boy with severe haemophilia with inhibitor history and the surprising finding of an ischaemic stroke. The patient’s phenotype includes haemophilia A, severe narrowing of internal carotid arteries and their branches, and development of a collateral vascular network (i.e. moyamoya syndrome), mild facial dysmorphia, hypertension, osteopenia and duplication of the right renal artery [11]. Apart from our patient, literature and database searches yielded six likely individuals/families with this novel SHAM syndrome. The original SHAM patient and further cases are presented in Table 1. In five of seven cases/families, there is no neuroimaging data to confirm moyamoya angiopathy diagnosis but the recurrent clinical features, apart from haemophilia A, are developmental delay, dysmorphism and short stature. The prevalence of © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e85
Table 1. Clinical features of the patients with genetic defect at Xq28 affecting F8 and BRCC3 genes. Genetic characterization
Clinical phenotype
154 kbp Xq28 deletion including several F8 exons and BRCC3 Not available 270 kb Xq28 deletion including several F8 exons and BRCC3 Xq28 deletion including F8 and BRCC3 283 kb Xq28 deletion including several F8 exons and BRCC3 114 kbp Xq28 deletion including several F8 exons and BRCC3 439 kbp Xq28 deletion including F8 and BRCC3
Author
Haemophilia A, moyamoya angiopathy, mild facial dysmorphia, hypertension, osteopenia, duplication of a renal artery Haemophilia A, moyamoya angiopathy Haemophilia A, facial dysmorphia, dwarfism
Janczar et al. [11]
Haemophilia A, mental handicap, facial dysmorphia, short stature Haemophilia A, no further phenotypic characterization
Kenwrick et al.* Kim et al.*
Delayed speech and language development
ClinVar†
Global developmental delay, facial dysmorphia
ClinVar†
Matsuda et al.* Fujita et al.*
*Detailed bibliography is available in Janczar et al. [11]. † www.ncbi.nlm.nih.gov/clinvar.
BRCC3 defects or angiopathies in haemophilia A is not established, but in some patients with haemophilia A comorbidities could be exacerbated by the loss or dysregulation of BRCC3. There is a wide range of symptoms associated with BRCC3 loss with varied penetrance including moyamoya angiopathy, short stature, facial dysmorphism, hypogonadism, hypertension, heart diseases, cataract and premature hair greying [12]. There is a lack of mechanistic and clinical studies that could verify the biological grounds for systemic abnormalities in haemophilia. Further molecular studies may provide insights into the interaction between the coagulation cascade and bone or hormonal homeostasis or blood pressure regulation. Testing the hypothesis of microbleeding related persistent inflammation that is proposed for most discussed haemophilia comorbidities requires serial measurement of marker inflammatory cytokines or immune regulatory cell populations in a large population of patients and their correlation with the clini-
References 5 1 Donfield SM, Lynn HS, Lail AE, Hoots WK, Berntorp E, Gomperts ED. Delays in maturation among adolescents with hemophilia and a history of inhibitors. Blood 2007; 110: 3656–61. 2 Gouw SC, van den Berg HM, Oldenburg J et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: Systematic review and meta-analysis. Blood 2012; 119: 2922–34. 3 Barnes C, Wong P, Egan B et al. Reduced bone density among children with severe hemophilia. Pediatrics 2004; 114: e177–81. 4 Liel MS, Greenberg DL, Recht M, Vanek C, Klein RF, Taylor JA. Decreased bone density and bone strength in a mouse
© 2014 John Wiley & Sons Ltd
6
7
8
cal picture. We argue that in some patients the clinical phenotype might be impacted on by the genomic events leading to haemophilia but affecting, at least at the regulatory level, genes other than F8 and F9.
Acknowledgement The authors stated that they had no interests, which might be perceived as posing a conflict or bias.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
Author contributions S.J., O.W. and W.M. acquired and interpreted the data, drafted and revised the manuscript, M.K., M.S. and A.J.P interpreted data, drafted and revised the manuscript.
model of severe factor VIII deficiency. Br J Haematol 2012; 158: 140–3. Anagnostis P, Vakalopoulou S, Vyzantiadis TA et al. The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B. Haemophilia 2014; 20: 268–75. Gerstner G, Damiano ML, Tom A et al. Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia. Haemophilia 2009; 15: 559–65. Anagnostis P, Vakalopoulou S, Slavakis A et al. Reduced bone mineral density in patients with haemophilia A and B in Northern Greece. Thromb Haemost 2012; 107: 545–51. Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ III. Changes in bone density after exposure to oral antico-
9
10
11
12
agulants: A meta-analysis. Osteoporos Int 1999; 9: 441–8. Pocoski J, Ma A, Kessler CM, Boklage S, Humphries TJ. Cardiovascular comorbidities are increased in US patients with haemophilia A: A retrospective database analysis. Haemophilia 2014; 20: 472–8. Kamphuisen PW, Ten Cate H. Cardiovascular risk in patients with hemophilia. Blood 2014; 123: 1297–301. Janczar S, Fogtman A, Koblowska M et al. Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 genes. Blood 2014; 123: 4002–4. Miskinyte S, Butler MG, Herve D et al. Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am J Hum Genet 2011; 88: 718–28.
Haemophilia (2015), 21, e70--e121
caused by the chronic inflammatory eroding process due to chronic synovitis. Consistent with these articles that we had reviewed, severe articular cartilage destruction was confirmed by the histologic tests of the femoral head [1,4,6]. Additionally, chronic inflammation also excited at the surface and the inside of the subchondral bone and was eroding the subchondral bone, which was similar to the inflammatory bone loss in rheumatoid arthritis [7]. Although the diagnosis of osteonecrosis was wrong, but to this patient’s hip, the articular cartilage damage was so severe and only the THA can stop the hip pain and improve the joint function. So for hip haemophilic arthropathy patients, the cystic degeneration focus seen on the radiographic image may not be the result of osteonecrosis of the
References 1 Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8: 1895–902. 2 Kempton CL, Antun A, Antoniucci DM et al. Bone density in haemophilia: a single institutional cross-sectional study. Haemophilia 2014; 20: 121–8. 3 Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treat-
e83
femoral head but just a bone defect focus caused by inflammatory bone erosion. We sincerely recommend the orthopaedists to scrupulously analyse the imaging outcomes of haemophilic patient’s joint when it shows a cystic change.
Acknowledgements This work was supported by the program for Zhejiang Leading Team of S&T Innovation and the program for Key Laboratory of Zhejiang Province.
Disclosures The authors stated that they had no interest which might be perceived as posing a conflict or bias.
ment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535–44. 4 Jansen NW, Roosendaal G, Lafeber FP. Understanding haemophilic arthropathy: an exploration of current open issues. Br J Haematol 2008; 143: 632–40. 5 Rodriguez-Merchan EC. Effects of hemophilia on articulations of children and adults. Clin Orthop Relat Res 1996; 328: 7–13.
6 Jansen NW, Roosendaal G, Wenting MJ et al. Very rapid clearance after a joint bleed in the canine knee cannot prevent adverse effects on cartilage and synovial tissue. Osteoarthritis Cartilage 2009; 17: 433–40. 7 Karmakar S, Kay J, Gravallese EM. Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention. Rheum Dis Clin North Am 2010; 36: 385– 404.
Are there systemic comorbidities in haemophilia unrelated to bleeding and transfusion-transmitted infections? S . J A N C Z A R , * O . W E G N E R , * M . K O S T R Z E W S K A , * M . S T O L A R S K A , * A . J . W . P A I G E † and W. MLYNARSKI* *Department of Paediatrics, Oncology, Hematology and Diabetology Medical University of Lodz, Poland; and †Department of Life Sciences University of Bedfordshire, UK
For decades, life expectancy and quality of life of patients with haemophilia were poor due to bloodborne infections and bleeding complications. Currently, prophylactic administration of coagulation factors has significantly reduced the frequency and severity of haemophilic arthropathies as well as the
Correspondence: Wojciech Mlynarski, Department of Paediatrics, Oncology, Haematology & Diabetology, Medical University of Lodz, Sporna 36/50, 91-738 Lodz, Poland. Tel.: +48426177750; fax: +48426177798; e-mail: [email protected] Accepted after revision 19 September 2014 DOI: 10.1111/hae.12560 © 2014 John Wiley & Sons Ltd
extent of patient immobility. The use of recombined clotting factors, modern pathogen inactivation and surveillance against viral infections has practically eradicated transfusion-related infections. Nevertheless, there continues to be a significant haemophilia comorbidity that may be explained by recurrent subclinical microbleeds and their consequences, an unreported biological role for factor VIII or IX outside the clotting cascade, or additional effects of the genomic events disrupting factor VIII (F8) and IX (F9) genes. Comorbidities are better described for haemophilia A because of higher prevalence of the disease. Many studies lack analysis restricted to haemophilia B patients making it difficult to establish if there are significant differences between comorbidities in these Haemophilia (2015), 21, e70--e121
e84
LETTERS TO THE EDITORS
two diseases. We discuss the evidence for systemic abnormalities in haemophilia that cannot be easily attributed to bleeding or transfusion- transmitted infections. These include delayed growth and sexual development, reduced bone mineral density and hypertension. An extensive study of 333 children and adolescents including 60 subjects with a history of inhibitors published by the Hemophilia Growth and Development Study Group demonstrated that adolescents with haemophilia A and B, and a history of inhibitors (but without HIV infection, 20 patients) displayed 9 or more months delay in skeletal maturation as compared to patients without inhibitors. Furthermore, the patients with inhibitors had features of delayed sexual maturation: older age at particular Tanner stages (pubertal progression from stage 0 to stage 5 ), lower maximal growth velocity and lower maximal testosterone levels. The significance of these results was preserved after controlling for HCV status. The authors speculated on the possible explanation for these observations and considered lack of stimulatory effects of physical activity, chronic upregulation of inflammatory cytokines, or anaemia due to persistent clinical and subclinical bleeding [1]. Considering the higher prevalence of gross genomic changes, such as large deletions or inversions, in patients with inhibitors [2], it can also be speculated that sexual maturation of patients with haemophilia might be partly due to disruption or defective regulation of other genes in the vicinity of F8 or F9 on chromosome X. There are several reports of reduced bone mineral density (BMD) in males with haemophilia A [3]. This is typically explained by relative immobility due to destruction of the joints, periods of symptomatic musculoskeletal bleeding, and lifestyle limitations. Nevertheless, there is accumulating evidence that there might be intrinsic bone defects in haemophilia A and that to some extent this is not corrected by coagulation factor prophylaxis. Liel et al. examined bone phenotypes in a murine model of haemophilia A (f8 knock-out mice) characterized by a lack of spontaneous bleeding [4]. In knock-out mice, the authors observed lower BMD and cortical bone mass and higher fracture rates than in wild-type littermates and suggested that factor VIII deficiency directly affects BMD independent of haemarthroses and reduced physical activity. Liel et al. postulate that this might be due to the recently demonstrated direct effects of thrombin on osteoblasts that could link factor VIII deficiency leading to reduced basal thrombin generation and bone homeostasis [4]. It has also been shown that reduced sex hormone levels are independent risk factors for low BMD in haemophilia [5], which links low BMD with the defects in sexual maturation described above. Similar Haemophilia (2015), 21, e70--e121
to the situation with delayed sexual maturation, bone loss is more severe in patients with inhibitor history [6]. At the same time, osteopenia is observed in both haemophilia A and B (although less studied in haemophilia B) as well as in patients on anticoagulation [7,8]. This suggests that the BMD phenotype is not specific for haemophilia A and suggests links between the coagulation cascade and bone formation and resorption. Other causes might be identical to those proposed above for delayed sexual maturation (inflammation and anaemia secondary to chronic bleeding, impact on genes in the vicinity of F8 or F9 loci). Several reports and recent metanalyses document increased prevalence of hypertension in haemophilia in different age populations including children. At the same time, there are conflicting reports and opinions on the frequency of other cardiovascular risk factors, atherosclerosis and cardiovascular morbidity in haemophilia and many authors suggest that there are protective effects of clotting factor deficiencies [9,10]. The mechanism for increased prevalence of elevated blood pressure in haemophilia is not clear though again the role for subclinical bleeding, especially renal microbleeds compromising kidney function and leading to renovascular hypertension is suggested. Still, this would imply progression of renovascular complications with increasing age of the patients due to accumulated renal damage, yet surprisingly hypertension is already seen in the young patients [9]. There is a lack of studies assessing hormonal regulation of blood pressure, including renin levels or abnormalities of renal vasculature that would be sufficient for testing this proposed ‘renal microbleeding’ mechanism. We have recently described a novel severe haemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 (BRCA1/BRCA2-containing complex, subunit 3) familial moyamoya gene. We provided the clinical description of the syndrome observed in a 10-year-old boy with severe haemophilia with inhibitor history and the surprising finding of an ischaemic stroke. The patient’s phenotype includes haemophilia A, severe narrowing of internal carotid arteries and their branches, and development of a collateral vascular network (i.e. moyamoya syndrome), mild facial dysmorphia, hypertension, osteopenia and duplication of the right renal artery [11]. Apart from our patient, literature and database searches yielded six likely individuals/families with this novel SHAM syndrome. The original SHAM patient and further cases are presented in Table 1. In five of seven cases/families, there is no neuroimaging data to confirm moyamoya angiopathy diagnosis but the recurrent clinical features, apart from haemophilia A, are developmental delay, dysmorphism and short stature. The prevalence of © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e85
Table 1. Clinical features of the patients with genetic defect at Xq28 affecting F8 and BRCC3 genes. Genetic characterization
Clinical phenotype
154 kbp Xq28 deletion including several F8 exons and BRCC3 Not available 270 kb Xq28 deletion including several F8 exons and BRCC3 Xq28 deletion including F8 and BRCC3 283 kb Xq28 deletion including several F8 exons and BRCC3 114 kbp Xq28 deletion including several F8 exons and BRCC3 439 kbp Xq28 deletion including F8 and BRCC3
Author
Haemophilia A, moyamoya angiopathy, mild facial dysmorphia, hypertension, osteopenia, duplication of a renal artery Haemophilia A, moyamoya angiopathy Haemophilia A, facial dysmorphia, dwarfism
Janczar et al. [11]
Haemophilia A, mental handicap, facial dysmorphia, short stature Haemophilia A, no further phenotypic characterization
Kenwrick et al.* Kim et al.*
Delayed speech and language development
ClinVar†
Global developmental delay, facial dysmorphia
ClinVar†
Matsuda et al.* Fujita et al.*
*Detailed bibliography is available in Janczar et al. [11]. † www.ncbi.nlm.nih.gov/clinvar.
BRCC3 defects or angiopathies in haemophilia A is not established, but in some patients with haemophilia A comorbidities could be exacerbated by the loss or dysregulation of BRCC3. There is a wide range of symptoms associated with BRCC3 loss with varied penetrance including moyamoya angiopathy, short stature, facial dysmorphism, hypogonadism, hypertension, heart diseases, cataract and premature hair greying [12]. There is a lack of mechanistic and clinical studies that could verify the biological grounds for systemic abnormalities in haemophilia. Further molecular studies may provide insights into the interaction between the coagulation cascade and bone or hormonal homeostasis or blood pressure regulation. Testing the hypothesis of microbleeding related persistent inflammation that is proposed for most discussed haemophilia comorbidities requires serial measurement of marker inflammatory cytokines or immune regulatory cell populations in a large population of patients and their correlation with the clini-
References 5 1 Donfield SM, Lynn HS, Lail AE, Hoots WK, Berntorp E, Gomperts ED. Delays in maturation among adolescents with hemophilia and a history of inhibitors. Blood 2007; 110: 3656–61. 2 Gouw SC, van den Berg HM, Oldenburg J et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: Systematic review and meta-analysis. Blood 2012; 119: 2922–34. 3 Barnes C, Wong P, Egan B et al. Reduced bone density among children with severe hemophilia. Pediatrics 2004; 114: e177–81. 4 Liel MS, Greenberg DL, Recht M, Vanek C, Klein RF, Taylor JA. Decreased bone density and bone strength in a mouse
© 2014 John Wiley & Sons Ltd
6
7
8
cal picture. We argue that in some patients the clinical phenotype might be impacted on by the genomic events leading to haemophilia but affecting, at least at the regulatory level, genes other than F8 and F9.
Acknowledgement The authors stated that they had no interests, which might be perceived as posing a conflict or bias.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
Author contributions S.J., O.W. and W.M. acquired and interpreted the data, drafted and revised the manuscript, M.K., M.S. and A.J.P interpreted data, drafted and revised the manuscript.
model of severe factor VIII deficiency. Br J Haematol 2012; 158: 140–3. Anagnostis P, Vakalopoulou S, Vyzantiadis TA et al. The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B. Haemophilia 2014; 20: 268–75. Gerstner G, Damiano ML, Tom A et al. Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia. Haemophilia 2009; 15: 559–65. Anagnostis P, Vakalopoulou S, Slavakis A et al. Reduced bone mineral density in patients with haemophilia A and B in Northern Greece. Thromb Haemost 2012; 107: 545–51. Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ III. Changes in bone density after exposure to oral antico-
9
10
11
12
agulants: A meta-analysis. Osteoporos Int 1999; 9: 441–8. Pocoski J, Ma A, Kessler CM, Boklage S, Humphries TJ. Cardiovascular comorbidities are increased in US patients with haemophilia A: A retrospective database analysis. Haemophilia 2014; 20: 472–8. Kamphuisen PW, Ten Cate H. Cardiovascular risk in patients with hemophilia. Blood 2014; 123: 1297–301. Janczar S, Fogtman A, Koblowska M et al. Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 genes. Blood 2014; 123: 4002–4. Miskinyte S, Butler MG, Herve D et al. Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am J Hum Genet 2011; 88: 718–28.
Haemophilia (2015), 21, e70--e121
