Vascular remodeling underlies rebleeding in hemophilic arthropathy

Vikas Bhat, Merissa Olmer, Shweta Joshi, Donald L Durden, Thomas J. Cramer, Richard F.W. Barnes, Scott T. Ball, Tudor H. Hughes, Mauricio Silva, James V. Luck, Randy E. Moore, Laurent O. Mosnier, Annette von Drygalski

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.

Original languageEnglish (US)
Pages (from-to)1027-1035
Number of pages9
JournalAmerican Journal of Hematology
Volume90
Issue number11
DOIs
StatePublished - Nov 1 2015

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Joint Diseases
Blood Vessels
Joints
Hemophilia A
Hemorrhage
Smooth Muscle
Actins
Hemarthrosis
Elbow Joint
Doppler Ultrasonography
Blood Coagulation Factors
Ankle Joint
Knee Joint
Osteoarthritis
Vascular Endothelial Growth Factor A
Cartilage
Rheumatoid Arthritis
Perfusion
Vascular Remodeling

ASJC Scopus subject areas

  • Hematology

Cite this

Bhat, V., Olmer, M., Joshi, S., Durden, D. L., Cramer, T. J., Barnes, R. F. W., ... von Drygalski, A. (2015). Vascular remodeling underlies rebleeding in hemophilic arthropathy. American Journal of Hematology, 90(11), 1027-1035. https://doi.org/10.1002/ajh.24133

Vascular remodeling underlies rebleeding in hemophilic arthropathy. / Bhat, Vikas; Olmer, Merissa; Joshi, Shweta; Durden, Donald L; Cramer, Thomas J.; Barnes, Richard F.W.; Ball, Scott T.; Hughes, Tudor H.; Silva, Mauricio; Luck, James V.; Moore, Randy E.; Mosnier, Laurent O.; von Drygalski, Annette.

In: American Journal of Hematology, Vol. 90, No. 11, 01.11.2015, p. 1027-1035.

Research output: Contribution to journalArticle

Bhat, V, Olmer, M, Joshi, S, Durden, DL, Cramer, TJ, Barnes, RFW, Ball, ST, Hughes, TH, Silva, M, Luck, JV, Moore, RE, Mosnier, LO & von Drygalski, A 2015, 'Vascular remodeling underlies rebleeding in hemophilic arthropathy', American Journal of Hematology, vol. 90, no. 11, pp. 1027-1035. https://doi.org/10.1002/ajh.24133
Bhat, Vikas ; Olmer, Merissa ; Joshi, Shweta ; Durden, Donald L ; Cramer, Thomas J. ; Barnes, Richard F.W. ; Ball, Scott T. ; Hughes, Tudor H. ; Silva, Mauricio ; Luck, James V. ; Moore, Randy E. ; Mosnier, Laurent O. ; von Drygalski, Annette. / Vascular remodeling underlies rebleeding in hemophilic arthropathy. In: American Journal of Hematology. 2015 ; Vol. 90, No. 11. pp. 1027-1035.
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