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Am J Hematol. 2015 Nov;90(11):1027-35. doi: 10.1002/ajh.24133. Epub 2015 Oct 8.

Vascular remodeling underlies rebleeding in hemophilic arthropathy.

Author information

1
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.
2
Department of Medicine, University of California San Diego, San Diego, California.
3
Department of Pediatrics, University of California San Diego, California.
4
Department of Orthopaedic Surgery, University of California San Diego, San Diego, California.
5
Department of Radiology, University of California San Diego, San Diego, California.
6
Orthopedic Institute for Children University of California Los Angeles, Los Angeles, California.
7
General Musculoskeletal Imaging Inc, Cincinnati, Ohio.

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.

PMID:
26257191
PMCID:
PMC4618067
DOI:
10.1002/ajh.24133
[Indexed for MEDLINE]
Free PMC Article

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