Histological changes in murine haemophilic synovitis: a quantitative grading system to assess blood‐induced synovitis

Abstract

Haemophilia is a congenital disorder that results in frequent bleeding into joints, in which a chronic and debilitating arthritis develops. The presence of blood evokes an inflammatory and proliferative synovial reaction. Although the molecular mechanisms and biochemical pathways which underlie this disorder are not known, significant advances have been made by studying a murine model of human haemophilic synovitis. In order to better understand and correlate the pathological, molecular and biochemical changes, it has become necessary to grade the histological changes observed. Despite a search of the literature and review of relevant publications, none of the currently utilized schemes were appropriate, and therefore a novel grading scheme was developed. After review of over 1000 histological sections, six characteristic changes were identified: (i) synovial hyperplasia; (ii) vascularity; (iii) discolouration by haemosiderin; (iv) the presence of blood (erythrocytes); (v) villus formation; and (vi) cartilage erosion. Synovial hyperplasia and vascularity were present in variable amounts and were quantitatively scored (0-3), while the other changes were qualitatively scored as absent or present (0 or 1). Application of the grading scheme was tested and a high interobserver correlation (greater than 80%) was found. The scheme was easy to learn even by novices, with no prior experience. The availability of the histological grading scheme for murine synovitis will allow for precise evaluation of the pathological changes following joint bleeding, and facilitate correlations with molecular and biochemical changes that lead to these changes.

Animal Models of Hemophilia

“…20; 180 The clinical, histopathologic, and radiologic changes initially described in hemophilia A mice by Valentino and colleagues are also seen in the hemophilia B mice. 180; 181 Importantly, these hemophilic changes are not seen in hemostatically normal mice.…”

“…Different parameters that are measured experimentally include: knee diameter, joint capsule bleeding score assessed by visual bleeding score, changes in body mass and histology using a grading scheme. 20; 21 Two different injury models were developed: one that induced a mechanical trauma to the joint and then required that the animals walk on a rotating rod apparatus and a second model induced hemarthrosis by puncture with a 30 gauge needle which was thought may mimic blood-induced arthropathy. 22 Using these models, recombinant hFVIII and human factor VIIa (hFVIIa) were evaluated for their ability to prevent acute joint bleeding in the hemophilia A mouse.…”

Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX

“…27 Three or more independent reviewers blinded to the experimental conditions examined the entire joint space and articular surfaces of 2 adjacent sagittal sections from each knee. Areas of greatest synovial thickening and vascularity were identified, and 3 nonoverlapping fields from these regions were scored at high magnification and total synovitis scores from each knee averaged.…”

Orthopedic disorders of the knee in hemophilia: A current concept review

“…Ex vivo studies with canine cartilage suggest that a 4-d duration of blood exposure produces loss of cartilage matrix [7] . Experimental studies have also demonstrated that after a major hemarthrosis the joint cavity is filled with a dense inflammatory infiltrate, and the tissues become brown-stained due to hemosiderin deposition following the breakdown of erythrocytes [8,9] . Vascular hyperplasia takes place resulting in tenous and friable vessels prone to bleed creating a viscous cycle of bleedingvascular hyperplasia-bleeding.…”