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Semin Thromb Hemost 2015; 41(08): 832-837
DOI: 10.1055/s-0035-1564445
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Blood-Induced Arthropathy in Hemophilia: Mechanisms and Heterogeneity

Carl P. Blobel
1   Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York
2   Department of Medicine, Weill Cornell Medical College, New York, New York
3   Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York
4   Institute for Advanced Study, Technische Universität München, Garching, Germany
,
Coline Haxaire
1   Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York
,
George D. Kalliolias
1   Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York
2   Department of Medicine, Weill Cornell Medical College, New York, New York
,
Edward DiCarlo
5   Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, New York
,
Jane Salmon
2   Department of Medicine, Weill Cornell Medical College, New York, New York
6   Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York
,
Alok Srivastava
7   Department of Hematology, Christian Medical College, Vellore, Tamil Nadu, India
› Author Affiliations
Further Information

Publication History

Publication Date:
09 October 2015 (online)

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Abstract

Hemophilia A is an X-linked bleeding disorder that can be largely controlled by treatment with recombinant factor VIII. However, this treatment is only partially effective in preventing hemophilic arthropathy (HA), a debilitating degenerative joint disease that is caused by intra-articular bleeding events. The disease progression of HA has several distinct steps, beginning with hemophilic synovitis (HS), a hyperplasia of the synovial lining coupled with a neovascular response, followed by joint erosion with cartilage destruction and erosion of the underlying bone. The early stages of HA have certain features in common with arthritides such as rheumatoid arthritis (RA), whereas the later degenerative stages of HA have some similarities with osteoarthritis (OA). The main purpose of this review is to explore the similarities between HA with RA and OA and discuss how this information could potentially help understand the pathogenesis of HA and uncover new treatment opportunities.

Keywords

hemophilic arthropathy - rheumatoid arthritis - inflammation - osteoarthritis - cartilage degradation
 

  • References

  • 1 Simpson ML, Valentino LA. Management of joint bleeding in hemophilia. Expert Rev Hematol 2012; 5 (4) 459-468
    CrossrefPubMedSearch in Google Scholar
  • 2 Stephensen D, Rodriguez-Merchan EC. Orthopaedic co-morbidities in the elderly haemophilia population: a review. Haemophilia 2013; 19 (2) 166-173
    CrossrefPubMedSearch in Google Scholar
  • 3 Rodriguez-Merchan EC. Prevention of the musculoskeletal complications of hemophilia. Adv Prev Med 2012; ; doi: 10.1155/2012/201271
    PubMedSearch in Google Scholar
  • 4 Aznar JA, Marco A, Jiménez-Yuste V , et al; Spanish Haemophilia Epidemiological Study Working Group. Is on-demand treatment effective in patients with severe haemophilia?. Haemophilia 2012; 18 (5) 738-742
    CrossrefPubMedSearch in Google Scholar
  • 5 Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult patients with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life. Eur J Haematol 2012; 88 (4) 329-335
    CrossrefPubMedSearch in Google Scholar
  • 6 Manco-Johnson MJ, Abshire TC, Shapiro AD , et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357 (6) 535-544
    CrossrefPubMedSearch in Google Scholar
  • 7 Jayandharan GR, Srivastava A. The phenotypic heterogeneity of severe hemophilia. Semin Thromb Hemost 2008; 34 (1) 128-141
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Valentino LA, Hakobyan N, Enockson C , et al. Exploring the biological basis of haemophilic joint disease: experimental studies. Haemophilia 2012; 18 (3) 310-318
    CrossrefPubMedSearch in Google Scholar
  • 9 Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8 (9) 1895-1902
    CrossrefPubMedSearch in Google Scholar
  • 10 Sen D, Chapla A, Walter N, Daniel V, Srivastava A, Jayandharan GR. Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia. J Thromb Haemost 2013; 11 (2) 293-306
    CrossrefPubMedSearch in Google Scholar
  • 11 Forsyth AL, Rivard GE, Valentino LA , et al. Consequences of intra-articular bleeding in haemophilia: science to clinical practice and beyond. Haemophilia 2012; 18 (Suppl. 04) 112-119
    PubMedSearch in Google Scholar
  • 12 Haxaire C, Blobel CP. With blood in the joint - what happens next? Could activation of a pro-inflammatory signalling axis leading to iRhom2/TNFα-convertase-dependent release of TNFα contribute to haemophilic arthropathy. Haemophilia 2014; 20 (Suppl. 04) 11-14
    CrossrefPubMedSearch in Google Scholar
  • 13 Nieuwenhuizen L, Roosendaal G, Mastbergen SC , et al. Antiplasmin, but not amiloride, prevents synovitis and cartilage damage following hemarthrosis in hemophilic mice. J Thromb Haemost 2014; 12 (2) 237-245
    CrossrefPubMedSearch in Google Scholar
  • 14 Melchiorre D, Morfini M, Linari S, Zignego AL, Innocenti M, Matucci Cerinic M. Anti-TNF-α therapy prevents the recurrence of joint bleeding in haemophilia and arthritis. Rheumatology (Oxford) 2014; 53 (3) 576-578
    CrossrefPubMedSearch in Google Scholar
  • 15 Narkbunnam N, Sun J, Hu G , et al. IL-6 receptor antagonist as adjunctive therapy with clotting factor replacement to protect against bleeding-induced arthropathy in hemophilia. J Thromb Haemost 2013; 11 (5) 881-893
    CrossrefPubMedSearch in Google Scholar
  • 16 van Meegeren ME, Roosendaal G, Coeleveld K, Nieuwenhuizen L, Mastbergen SC, Lafeber FP. A single intra-articular injection with IL-4 plus IL-10 ameliorates blood-induced cartilage degeneration in haemophilic mice. Br J Haematol 2013; 160 (4) 515-520
    CrossrefPubMedSearch in Google Scholar
  • 17 Astermark J, Dolan G, Hilberg T , et al. Managing haemophilia for life: 4th Haemophilia Global Summit. Haemophilia 2014; 20 (Suppl. 05) 1-20
    PubMedSearch in Google Scholar
  • 18 Cross S, Vaidya S, Fotiadis N. Hemophilic arthropathy: a review of imaging and staging. Semin Ultrasound CT MR 2013; 34 (6) 516-524
    CrossrefPubMedSearch in Google Scholar
  • 19 Sierra Aisa C, Lucía Cuesta JF, Rubio Martínez A , et al. Comparison of ultrasound and magnetic resonance imaging for diagnosis and follow-up of joint lesions in patients with haemophilia. Haemophilia 2014; 20 (1) e51-e57
    CrossrefPubMedSearch in Google Scholar
  • 20 Martinoli C, Della Casa Alberighi O, Di Minno G , et al. Development and definition of a simplified scanning procedure and scoring method for Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US). Thromb Haemost 2013; 109 (6) 1170-1179
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Melchiorre D, Linari S, Innocenti M , et al. Ultrasound detects joint damage and bleeding in haemophilic arthropathy: a proposal of a score. Haemophilia 2011; 17 (1) 112-117
    CrossrefPubMedSearch in Google Scholar
  • 22 Doria AS. State-of-the-art imaging techniques for the evaluation of haemophilic arthropathy: present and future. Haemophilia 2010; 16 (Suppl. 05) 107-114
    PubMedSearch in Google Scholar
  • 23 Lundin B, Manco-Johnson ML, Ignas DM , et al; International Prophylaxis Study Group. An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group. Haemophilia 2012; 18 (6) 962-970
    CrossrefPubMedSearch in Google Scholar
  • 24 Doria AS, Keshava SN, Mohanta A , et al. Diagnostic accuracy of ultrasound for assessment of hemophilic arthropathy: MRI correlation. AJR Am J Roentgenol 2015; 204 (3) W336-47
    PubMedSearch in Google Scholar
  • 25 Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 2013; 9 (1) 24-33
    PubMedSearch in Google Scholar
  • 26 Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2010; 233 (1) 233-255
    CrossrefPubMedSearch in Google Scholar
  • 27 Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423 (6937) 356-361
    CrossrefPubMedSearch in Google Scholar
  • 28 Strand V, Kimberly R, Isaacs JD. Biologic therapies in rheumatology: lessons learned, future directions. Nat Rev Drug Discov 2007; 6 (1) 75-92
    CrossrefPubMedSearch in Google Scholar
  • 29 Feldmann M, Maini SR. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol Rev 2008; 223: 7-19
    CrossrefPubMedSearch in Google Scholar
  • 30 Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 2009; 5 (10) 578-582
    CrossrefPubMedSearch in Google Scholar
  • 31 Øvlisen K, Kristensen AT, Jensen AL, Tranholm M. IL-1 beta, IL-6, KC and MCP-1 are elevated in synovial fluid from haemophilic mice with experimentally induced haemarthrosis. Haemophilia 2009; 15 (3) 802-810
    CrossrefPubMedSearch in Google Scholar
  • 32 Jansen NW, Roosendaal G, Hooiveld MJ , et al. Interleukin-10 protects against blood-induced joint damage. Br J Haematol 2008; 142 (6) 953-961
    CrossrefPubMedSearch in Google Scholar
  • 33 van Meegeren ME, Roosendaal G, van Veghel K, Mastbergen SC, Lafeber FP. A short time window to profit from protection of blood-induced cartilage damage by IL-4 plus IL-10. Rheumatology (Oxford) 2013; 52 (9) 1563-1571
    CrossrefPubMedSearch in Google Scholar
  • 34 Rodriguez-Merchan EC. Musculoskeletal complications of hemophilia. HSS J 2010; 6 (1) 37-42
    CrossrefPubMedSearch in Google Scholar
  • 35 Lambert T, Auerswald G, Benson G , et al. Joint disease, the hallmark of haemophilia: what issues and challenges remain despite the development of effective therapies?. Thromb Res 2014; 133 (6) 967-971
    CrossrefPubMedSearch in Google Scholar
  • 36 Rodriguez-Merchan EC, De la Corte-Rodriguez H, Jimenez-Yuste V. Radiosynovectomy in haemophilia: long-term results of 500 procedures performed in a 38-year period. Thromb Res 2014; 134 (5) 985-990
    CrossrefPubMedSearch in Google Scholar
  • 37 Thomas S, Gabriel MB, Assi PE , et al; Brazilian Hemophilia Centers. Radioactive synovectomy with Yttrium90 citrate in haemophilic synovitis: Brazilian experience. Haemophilia 2011; 17 (1) e211-e216
    CrossrefPubMedSearch in Google Scholar
  • 38 Hakobyan N, Enockson C, Cole AA, Sumner DR, Valentino LA. Experimental haemophilic arthropathy in a mouse model of a massive haemarthrosis: gross, radiological and histological changes. Haemophilia 2008; 14 (4) 804-809
    CrossrefPubMedSearch in Google Scholar
  • 39 Valentino LA, Hakobyan N. Histological changes in murine haemophilic synovitis: a quantitative grading system to assess blood-induced synovitis. Haemophilia 2006; 12 (6) 654-662
    CrossrefPubMedSearch in Google Scholar
  • 40 Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med 2006; 354 (8) 841-848
    CrossrefPubMedSearch in Google Scholar
  • 41 Fosang AJ, Beier F. Emerging Frontiers in cartilage and chondrocyte biology. Best Pract Res Clin Rheumatol 2011; 25 (6) 751-766
    CrossrefPubMedSearch in Google Scholar
  • 42 Chu CR, Millis MB, Olson SA. Osteoarthritis: From Palliation to Prevention: AOA Critical Issues. J Bone Joint Surg Am 2014; 96 (15) e130
    CrossrefPubMedSearch in Google Scholar
  • 43 Kiapour AM, Murray MM. Basic science of anterior cruciate ligament injury and repair. Bone Joint Res 2014; 3 (2) 20-31
    CrossrefPubMedSearch in Google Scholar
  • 44 Olson SA, Horne P, Furman B , et al. The role of cytokines in posttraumatic arthritis. J Am Acad Orthop Surg 2014; 22 (1) 29-37
    CrossrefPubMedSearch in Google Scholar
  • 45 Glasson SS. In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr Drug Targets 2007; 8 (2) 367-376
    CrossrefPubMedSearch in Google Scholar
  • 46 Glasson SS, Askew R, Sheppard B , et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 2005; 434 (7033) 644-648
    CrossrefPubMedSearch in Google Scholar
  • 47 Glasson SS, Blanchet TJ, Morris EA. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 2007; 15 (9) 1061-1069
    CrossrefPubMedSearch in Google Scholar
  • 48 Ma HL, Blanchet TJ, Peluso D, Hopkins B, Morris EA, Glasson SS. Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthritis Cartilage 2007; 15 (6) 695-700
    CrossrefPubMedSearch in Google Scholar
  • 49 Little CB, Barai A, Burkhardt D , et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 2009; 60 (12) 3723-3733
    CrossrefPubMedSearch in Google Scholar
  • 50 Stanton H, Rogerson FM, East CJ , et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 2005; 434 (7033) 648-652
    CrossrefPubMedSearch in Google Scholar
  • 51 Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta 2012; 1824 (1) 133-145
    CrossrefPubMedSearch in Google Scholar
  • 52 Miller RE, Lu Y, Tortorella MD, Malfait AM. Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets. Curr Rheumatol Rep 2013; 15 (8) 350
    CrossrefPubMedSearch in Google Scholar
  • 53 Bayliss MT, Hutton S, Hayward J, Maciewicz RA. Distribution of aggrecanase (ADAMts 4/5) cleavage products in normal and osteoarthritic human articular cartilage: the influence of age, topography and zone of tissue. Osteoarthritis Cartilage 2001; 9 (6) 553-560
    CrossrefPubMedSearch in Google Scholar
  • 54 Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis—insights from studies of aggrecan and collagen proteolysis?. Curr Drug Targets 2010; 11 (5) 561-575
    CrossrefPubMedSearch in Google Scholar
  • 55 Fosang AJ, Little CB. Drug insight: aggrecanases as therapeutic targets for osteoarthritis. Nat Clin Pract Rheumatol 2008; 4 (8) 420-427
    PubMedSearch in Google Scholar
  • 56 Lafeber FP, van Spil WE. Osteoarthritis year 2013 in review: biomarkers; reflecting before moving forward, one step at a time. Osteoarthritis Cartilage 2013; 21 (10) 1452-1464
    CrossrefPubMedSearch in Google Scholar
  • 57 Conaghan PG, Kloppenburg M, Schett G, Bijlsma JW ; EULAR osteoarthritis ad hoc committee. Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee. Ann Rheum Dis 2014; 73 (8) 1442-1445
    CrossrefPubMedSearch in Google Scholar
  • 58 Hunter DJ, Nevitt M, Losina E, Kraus V. Biomarkers for osteoarthritis: current position and steps towards further validation. Best Pract Res Clin Rheumatol 2014; 28 (1) 61-71
    CrossrefPubMedSearch in Google Scholar
  • 59 Lotz M, Martel-Pelletier J, Christiansen C , et al. Value of biomarkers in osteoarthritis: current status and perspectives. Ann Rheum Dis 2013; 72 (11) 1756-1763
    CrossrefPubMedSearch in Google Scholar
  • 60 Jansen NW, Roosendaal G, Lundin B , et al. The combination of the biomarkers urinary C-terminal telopeptide of type II collagen, serum cartilage oligomeric matrix protein, and serum chondroitin sulfate 846 reflects cartilage damage in hemophilic arthropathy. Arthritis Rheum 2009; 60 (1) 290-298
    CrossrefPubMedSearch in Google Scholar
  • 61 van Vulpen LF, van Meegeren ME, Roosendaal G , et al. Biochemical markers of joint tissue damage increase shortly after a joint bleed; an explorative human and canine in vivo study. Osteoarthritis Cartilage 2015; 23 (1) 63-69
    CrossrefPubMedSearch in Google Scholar