Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice
Abstract Background Hemophilic arthropathy is a debilitating morbidity of hemophilia caused by recurrent joint bleeds. We investigated if the joint bleed volume, before initiation of treatment, was linked to the subsequent degree of histopathological changes and the development of bone pathology in...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-06-01
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| Series: | Animal Models and Experimental Medicine |
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| Online Access: | https://doi.org/10.1002/ame2.12118 |
| _version_ | 1819091514209337344 |
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| author | Kåre Kryger Vøls Mads Kjelgaard‐Hansen Carsten Dan Ley Axel Kornerup Hansen Maj Petersen |
| author_facet | Kåre Kryger Vøls Mads Kjelgaard‐Hansen Carsten Dan Ley Axel Kornerup Hansen Maj Petersen |
| author_sort | Kåre Kryger Vøls |
| collection | DOAJ |
| description | Abstract Background Hemophilic arthropathy is a debilitating morbidity of hemophilia caused by recurrent joint bleeds. We investigated if the joint bleed volume, before initiation of treatment, was linked to the subsequent degree of histopathological changes and the development of bone pathology in a mouse model of hemophilic arthropathy. Methods FVIII knock‐out (F8‐KO) mice were dosed with a micro‐CT blood pool agent prior to induction of hemarthrosis. Eight hours after induction, the bleed volume was quantified with micro computed tomography (micro‐CT) and recombinant FVIII treatment initiated. On Day 8, inflammation in the knees was characterized by fluorescence molecular tomography. On Day 14, knee pathology was characterized by micro‐CT and histopathology. In a second study, contrast agent was injected into the knee of wild‐type (WT) mice, followed by histopathological evaluation on Day 14. Results The average joint bleed volume before treatment was 3.9 mm3. The inflammation‐related fluorescent intensities in the injured knees were significantly increased on Day 8. The injured knees had significantly increased synovitis scores, vessel counts, and areas of hemosiderin compared to un‐injured knees. However, no cartilage‐ or bone pathology was observed. The bleed volume before initiation of treatment correlated with the degree of synovitis and was associated with high fluorescent intensity on Day 8. In F8‐KO and WT mice, persistence of contrast agent in the joint elicited morphological changes. Conclusion When applying a delayed on‐demand treatment regimen to hemophilic mice subjected to an induced knee hemarthrosis, the degree of histopathological changes on Day 14 reflected the bleed volume prior to initiation of treatment. |
| first_indexed | 2024-12-21T22:40:56Z |
| format | Article |
| id | doaj.art-30ee7bef2d3d4d6da577be270b75ef8d |
| institution | Directory Open Access Journal |
| issn | 2576-2095 |
| language | English |
| last_indexed | 2024-12-21T22:40:56Z |
| publishDate | 2020-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Animal Models and Experimental Medicine |
| spelling | doaj.art-30ee7bef2d3d4d6da577be270b75ef8d2022-12-21T18:47:50ZengWileyAnimal Models and Experimental Medicine2576-20952020-06-013216016810.1002/ame2.12118Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic miceKåre Kryger Vøls0Mads Kjelgaard‐Hansen1Carsten Dan Ley2Axel Kornerup Hansen3Maj Petersen4Global Drug Discovery Novo Nordisk A/S Maaloev DenmarkVeterinary Clinical Sciences University of Copenhagen Frederiksberg DenmarkGlobal Drug Discovery Novo Nordisk A/S Maaloev DenmarkVeterinary and Animal Sciences University of Copenhagen Frederiksberg DenmarkGlobal Drug Discovery Novo Nordisk A/S Maaloev DenmarkAbstract Background Hemophilic arthropathy is a debilitating morbidity of hemophilia caused by recurrent joint bleeds. We investigated if the joint bleed volume, before initiation of treatment, was linked to the subsequent degree of histopathological changes and the development of bone pathology in a mouse model of hemophilic arthropathy. Methods FVIII knock‐out (F8‐KO) mice were dosed with a micro‐CT blood pool agent prior to induction of hemarthrosis. Eight hours after induction, the bleed volume was quantified with micro computed tomography (micro‐CT) and recombinant FVIII treatment initiated. On Day 8, inflammation in the knees was characterized by fluorescence molecular tomography. On Day 14, knee pathology was characterized by micro‐CT and histopathology. In a second study, contrast agent was injected into the knee of wild‐type (WT) mice, followed by histopathological evaluation on Day 14. Results The average joint bleed volume before treatment was 3.9 mm3. The inflammation‐related fluorescent intensities in the injured knees were significantly increased on Day 8. The injured knees had significantly increased synovitis scores, vessel counts, and areas of hemosiderin compared to un‐injured knees. However, no cartilage‐ or bone pathology was observed. The bleed volume before initiation of treatment correlated with the degree of synovitis and was associated with high fluorescent intensity on Day 8. In F8‐KO and WT mice, persistence of contrast agent in the joint elicited morphological changes. Conclusion When applying a delayed on‐demand treatment regimen to hemophilic mice subjected to an induced knee hemarthrosis, the degree of histopathological changes on Day 14 reflected the bleed volume prior to initiation of treatment.https://doi.org/10.1002/ame2.12118Animal modelsarthropathyhemarthrosishaemophilia Ain vivo imagingmicro‐CT |
| spellingShingle | Kåre Kryger Vøls Mads Kjelgaard‐Hansen Carsten Dan Ley Axel Kornerup Hansen Maj Petersen Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice Animal Models and Experimental Medicine Animal models arthropathy hemarthrosis haemophilia A in vivo imaging micro‐CT |
| title | Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice |
| title_full | Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice |
| title_fullStr | Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice |
| title_full_unstemmed | Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice |
| title_short | Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice |
| title_sort | initial joint bleed volume in a delayed on demand treatment setup correlates with subsequent synovial changes in hemophilic mice |
| topic | Animal models arthropathy hemarthrosis haemophilia A in vivo imaging micro‐CT |
| url | https://doi.org/10.1002/ame2.12118 |
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