W. K. Hoots, Pathogenesis of hemophilic arthropathy, Semin Hematol, vol.43, pp.18-22, 2006.

A. D. Metjian, HTCN Study Investigators, Bleeding symptoms and laboratory correlation in patients with severe von Willebrand disease, Haemophilia, vol.15, pp.918-925, 2009.

A. G. Lau, Joint bleeding in factor VIII deficient mice causes an acute loss of trabecular bone and calcification of joint soft tissues which is prevented with aggressive factor replacement, Haemophilia, vol.20, pp.716-722, 2014.

G. Gerstner, Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia, Haemophilia, vol.15, pp.559-565, 2009.

M. Khawaji, Long-term prophylaxis in severe haemophilia seems to preserve bone mineral density, Haemophilia, vol.15, pp.261-266, 2009.

C. S. Kovacs and . Hemophilia, low bone mass, and osteopenia/osteoporosis, Transfus Apher Sci, vol.38, pp.33-40, 2008.

H. Mansouritorghabeh, Reduced bone density in individuals with severe hemophilia B, Int J Rheum Dis, vol.12, pp.125-129, 2009.

A. Lee, Premature changes in trabecular and cortical microarchitecture result in decreased bone strength in hemophilia, Blood, vol.125, pp.2160-2163, 2015.

M. Recht, The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption, Haemophilia, vol.19, pp.908-912, 2013.

A. Aronovich, A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure, Blood, vol.122, pp.2562-2571, 2013.

M. Baud'huin, RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases, Cell Mol Life Sci, vol.64, pp.2334-2350, 2007.

F. Deschaseaux, Mechanisms of bone repair and regeneration, Trends Mol Med, vol.15, pp.417-429, 2009.

S. Shahbazi, Characterization of the interaction between von Willebrand factor and osteoprotegerin, J Thromb Haemost, vol.5, pp.1956-1962, 2007.

A. C. Zannettino, Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor, J Cell Physiol, vol.204, pp.714-723, 2005.

M. Baud'huin, Factor VIII-von Willebrand factor complex inhibits osteoclastogenesis and controls cell survival, J Biol Chem, vol.284, pp.31704-31713, 2009.

L. A. Valentino, Histological changes in murine haemophilic synovitis: a quantitative grading system to assess blood-induced synovitis, Haemophilia, vol.12, pp.654-662, 2006.

J. Sun, Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating, Blood, vol.112, pp.4532-4541, 2008.

P. E. Monahan, Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial, Hum Gene Ther, vol.26, pp.69-81, 2015.

D. Heymann and A. V. Rousselle, Cytokine family and bone cells, Cytokine, vol.12, pp.1455-1468, 2000.

S. Kwan-tat, IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology, Cytokine Growth Factor Rev, vol.15, pp.49-60, 2004.

C. N. Pagel, Inhibition of osteoblast apoptosis by thrombin, Bone, vol.33, pp.733-743, 2003.

C. N. Pagel, Thrombin-stimulated growth factor and cytokine expression in osteoblasts is mediated by protease-activated receptor-1 and prostanoids, Bone, vol.44, pp.813-821, 2009.

C. E. Fiore, Altered osteoprotegerin/RANKL ratio and low bone mineral density in celiac patients on long-term treatment with gluten-free diet, Horm Metab Res, vol.38, pp.417-422, 2006.

A. R. Moschen, The RANKL/OPG system and bone mineral density in patients with chronic liver disease, J Hepatol, vol.43, pp.973-983, 2005.

S. Kaneshiro, IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro, J Bone Miner Metab, vol.32, pp.378-392, 2014.

S. Kotake, Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation, J Bone Miner Res, vol.11, pp.88-95, 1996.

N. A. Sims, Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways, J Clin Invest, vol.113, pp.379-389, 2004.

S. A. Paschou, Bone mineral density in men and children with haemophilia A and B: a systematic review and meta-analysis, Osteoporosis Int, vol.25, pp.2399-2407, 2014.

A. Iorio, Bone mineral density in haemophilia patients. A meta-analysis

, Thromb Haemost, vol.103, pp.596-603, 2010.

C. Barnes, Reduced bone density among children with severe hemophilia, Pediatrics, vol.114, pp.177-181, 2004.

H. Mansouritorghabeh, Are individuals with severe haemophilia A prone to reduced bone density?, Rheumatol Int, vol.28, pp.1079-1083, 2008.

H. Mansouritorghabeh, Reduced bone density in individuals with combined factor V and VIII deficiency, Haemophilia, vol.13, pp.340-343, 2007.

M. S. Liel, Decreased bone density and bone strength in a mouse model of severe factor VIII deficiency, Br J Haematol, vol.158, pp.140-143, 2012.

R. K. Andrews, Molecular mechanisms of platelet adhesion and activation, Int J Biochem Cell Biol, vol.29, pp.91-105, 1997.

H. J. Weiss, Stabilization of factor VIII in plasma by the von Willebrand factor. Studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand's disease, J Clin Invest, vol.60, pp.390-404, 1977.

K. S. Sakariassen, Human blood platelet adhesion to artery subendothelium is mediated by factor VIII-Von Willebrand factor bound to the subendothelium, Nature, vol.279, pp.636-638, 1979.

M. Lak, Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease, Br J Haematol, vol.111, pp.1236-1239, 2000.

G. Castaman, Factor VIII:C increases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease, Br J Haematol, vol.89, pp.147-151, 1995.

, The Diagnosis, Evaluation, and Management of von Willebrand Disease, pp.8-5832, 2007.

N. Nakbunnnam, IL-6 receptor antagonist as adjunctive therapy with clotting factor replacement to protect against bleeding-induced arthropathy in hemophilia, J Thromb Haemost, vol.11, pp.881-893, 2013.

H. A. Mann, Heterotropic bone formation as a complication of elective joint replacement in haemophilic patients -a case report and literature review, Haemophilia, vol.12, pp.672-675, 2006.

S. J. Gallacher, Association of severe haemophilia A with osteoporosis: a densitometric and biochemical study, Q J Med, vol.87, pp.181-186, 1994.

J. A. Kanis, The diagnosis of osteoporosis, J Bone Miner Res, vol.9, pp.1137-1141, 1994.

A. Srivastava, Guidelines for the management of hemophilia, Haemophilia, vol.19, pp.1-47, 2013.

J. Hanley, Guidelines for the management of acute joint bleeds and chronic synovitis in haemophilia: A United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) guideline, Haemophilia, vol.23, pp.511-520, 2017.

E. Armstrong, In collaboration with the national patient member organizations in the Nordic countries, Nordic Hemophilia Guidelines, 2015.

C. L. Kempton, Bone health in persons with haemophilia, Haemophilia, vol.21, pp.568-577, 2015.

, Australian Hemophilia Centre Directors' Organisation. Guidelines for the management of hemophilia in Australia, 2016.

S. Ranta, Hypercalciuria in children with haemophilia suggests primary skeletal pathology, Br J Haematol, vol.153, pp.364-371, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00621305

L. Bi, Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A, Nat Genet, vol.10, pp.119-121, 1995.

H. F. Lin, A coagulation factor IX-deficient mouse model for human hemophilia B, Blood, vol.90, pp.3962-3966, 1997.

C. Denis, A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis, Proc Natl Acad Sci, vol.95, pp.9524-9529, 1998.

, day three and peaked at day seven. C: cortical bone; P: periosteum; M: skeletal muscle. Original magnification: X200. n=5-8 per group

, µCT measurements were compared using t-test comparison between WT and KO of each line. FVIII WT n=16, KO n=14; FIX WT n=14, KO n=14; VWF WT n=10, KO n=17. DXA measurements BMD and BMC were compared using 2-way ANOVA with multiple comparisons