Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis.

Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE

Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]

Factor IX*/genetics ; Factor IX*/pharmacology ; Hemarthrosis*/drug therapy ; Hemarthrosis*/genetics ; Hemarthrosis*/metabolism ; Hemophilia B*/drug therapy ; Hemophilia B*/genetics ; Hemophilia B*/metabolism ; Joints*/injuries ; Joints*/metabolism ; Skin*/injuries ; Skin*/metabolism ; Wound Healing*/drug effects ; Wound Healing*/genetics; Animals ; Disease Models, Animal ; Mice ; Mice, Knockout

Wound healing requires interactions between coagulation, inflammation, angiogenesis, cellular migration, and proliferation. Healing in dermal wounds of hemophilia B mice is delayed when compared with hemostatically normal wild-type (WT) mice, with abnormal persistence of iron deposition, inflammation, and neovascularity. We observed healing following induced joint hemorrhage in WT and factor IX (FIX) knockout (FIX ^-/- ) mice, examining also parameters previously studied in an excisional skin wound model. Hemostatically normal mice tolerated this joint bleeding challenge, cleared blood from the joint, and healed with minimal pathology, even if additional autologous blood was injected intra-articularly at the time of wounding. Following hemarthrosis, joint wound healing in hemophilia B mice was impaired and demonstrated similar abnormal histologic features as previously described in hemophilic dermal wounds. Therefore, studies of pathophysiology and therapy of hemophilic joint bleeding performed in hemostatically normal animals are not likely to accurately reflect the healing defect of hemophilia. We additionally explored the hypothesis that the use of a FIX replacement protein with extended circulating FIX activity could improve synovial and osteochondral wound healing in hemophilic mice, when compared with treatment with unmodified recombinant FIX (rFIX) in the established joint bleeding model. Significantly improved synovial wound healing and preservation of normal osteochondral architecture are achieved by extending FIX activity after hemarthrosis using glycoPEGylated FIX when compared with an equivalent dose of rFIX. These results suggest that treating joint bleeding only until hemostasis is achieved may not result in optimal joint healing, which is improved by extending factor activity.

Comment in: Blood. 2017 Apr 13;129(15):2048-2049. (PMID: 28408422)

Haemophilia. 2012 Mar;18(2):222-8. (PMID: 21752160)
Haemophilia. 2015 Jan;21(1):109-15. (PMID: 25382849)
Arthritis Rheum. 2004 Jun;50(6):2024-31. (PMID: 15188380)
Blood. 1997 Nov 15;90(10):3962-6. (PMID: 9354664)
Blood. 2011 Aug 25;118(8):2333-41. (PMID: 21700771)
Haemophilia. 2014 Sep;20(5):716-22. (PMID: 24712867)
Blood. 2011 Sep 8;118(10):2695-701. (PMID: 21555744)
Blood. 2004 Sep 15;104(6):1733-9. (PMID: 15178576)
J Thromb Haemost. 2013 Feb;11(2):293-306. (PMID: 23231432)
J Thromb Haemost. 2013 May;11(5):881-93. (PMID: 23413986)
Haemophilia. 2009 Mar;15(2):559-65. (PMID: 19187193)
Blood. 2008 Dec 1;112(12):4532-41. (PMID: 18716130)
Br J Haematol. 2008 Dec;143(5):632-40. (PMID: 18950457)
Haemophilia. 2016 Jul;22(4):507-13. (PMID: 26936227)
J Orthop Res. 2014 Dec;32(12):1549-56. (PMID: 25224138)
Thromb Res. 2010 Apr;125 Suppl 1:S74-7. (PMID: 20170942)
Thromb Res. 2016 May;141:69-76. (PMID: 26970716)
J Exp Med. 1949 Aug 1;90(2):97-111. (PMID: 18136192)
N Engl J Med. 2007 Aug 9;357(6):535-44. (PMID: 17687129)
Haemophilia. 2013 Nov;19(6):908-12. (PMID: 23731369)
Thromb Haemost. 2013 Jul;110(1):173-83. (PMID: 23677440)
Haemophilia. 2013 Nov;19(6):926-32. (PMID: 23879625)
Bone. 2009 May;44(5):813-21. (PMID: 19442625)
Lab Invest. 1959 Nov-Dec;8:1269-77. (PMID: 13836046)
J Thromb Haemost. 2007 Aug;5(8):1577-83. (PMID: 17663728)
J Thromb Haemost. 2008 Jun;6(6):969-75. (PMID: 18363814)
Thromb Res. 2010 Feb;125(2):184-91. (PMID: 19804899)
Haemophilia. 2014 May;20 Suppl 4:4-10. (PMID: 24762268)
Blood. 2014 Dec 18;124(26):3880-6. (PMID: 25261199)
Br J Haematol. 2012 Jul;158(1):140-3. (PMID: 22469061)
Arthritis Res Ther. 2013 Oct 07;15(5):R148. (PMID: 24286243)
Hum Gene Ther. 2015 Feb;26(2):69-81. (PMID: 25419787)
J Rheumatol. 2003 Feb;30(2):339-44. (PMID: 12563692)
Wound Repair Regen. 2005 May-Jun;13(3):284-94. (PMID: 15953048)
Haemophilia. 2006 Nov;12(6):654-62. (PMID: 17083517)
Am J Pathol. 2011 Nov;179(5):2233-42. (PMID: 21907694)
Blood. 2015 Mar 26;125(13):2160-3. (PMID: 25645354)
Haemophilia. 2009 May;15(3):802-10. (PMID: 19444976)
Bone. 2003 Oct;33(4):733-43. (PMID: 14555279)
Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2445-53. (PMID: 16960106)
Blood. 2006 Nov 1;108(9):3053-60. (PMID: 16825491)
J Thromb Haemost. 2016 Jun;14(6):1216-25. (PMID: 27060449)
J Clin Invest. 1992 May;89(5):1469-77. (PMID: 1373740)
Thromb Haemost. 2001 Oct;86(4):1035-9. (PMID: 11686321)
Pediatrics. 2004 Aug;114(2):e177-81. (PMID: 15286254)
Am J Hematol. 2015 Nov;90(11):1027-35. (PMID: 26257191)
Haemophilia. 2012 Jul;18(4):607-12. (PMID: 22188657)
Br J Haematol. 2013 Feb;160(4):515-20. (PMID: 23278520)
Haemophilia. 2009 Jan;15(1):261-6. (PMID: 19149852)
Haemophilia. 2014 Jan;20(1):121-8. (PMID: 23902277)
Haemophilia. 2008 Jul;14 (4):804-9. (PMID: 18422608)
Int J Rheum Dis. 2009 Jul;12 (2):125-9. (PMID: 20374329)

9001-28-9 (Factor IX)

Date Created: 20170101 Date Completed: 20170428 Latest Revision: 20220408

20240829

PMC5391623

10.1182/blood-2016-08-734053

28039188