Acute Haemarthrosis in the Haemophilia A Rat Generates a Local and Systemic Proinflammatory Response

Lövgren, K. M.; Christensen, Kristine Rothaus; Majewski, Wiktor; Skov, Søren; Wiinberg, Bo

doi:10.1160/th17-03-0149

Cited by 8 publications

(11 citation statements)

References 64 publications

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“…The inhibitor levels were significantly higher after a knee bleed. These data show that in rats FVIII replacement at the time of a joint bleed potentiates inhibitor development, and this is possibly due to the systemic inflammatory response induced by the bleed [72]. In human, similar such controlled studies are yet to be reported.…”

Section: Vaccination and Infectionmentioning

confidence: 65%

An update on the ‘danger theory’ in inhibitor development in hemophilia A

Schep

Boes

Schutgens

et al. 2019

Expert Review of Hematology

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Introduction: Nowadays, one of the most serious treatment complications in hemophilia A is the formation of neutralizing antibodies against coagulation factor VIII (FVIII). These so-called inhibitors develop in about 30% of all patients with severe hemophilia A. Once formed, inhibitors reduce FVIII efficacy in blood coagulation, which has a negative impact on patients' health and quality of life and significantly increases hemophilia A treatment costs. The pathophysiology of inhibitor development is a complex and multi-causal process, in which both genetic factors as well as environmental factors participate. So-called 'danger signals' are considered contributors to inhibitor formation, and can be triggered by surgery, joint bleeds or infections. A pro-inflammatory tissue micro-environment is thereby established, which is characterized by the upregulation of costimulatory molecules on antigen-presenting cells (APCs), that can facilitate the alloimmunization to FVIII and thereby inhibitor formation. Here, the authors will discuss evidence from (pre)clinical studies about this theory in hemophilia A. Areas covered: In this review, the current knowledge regarding the 'danger theory' with regard to inhibitor development in hemophilia A is summarized. Expert opinion: Danger signals might contribute to inhibitor development; however, the evidence is scarce and not conclusive. Future studies, like multinational registries, are warranted but challenging. ARTICLE HISTORY

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Section: Vaccination and Infectionmentioning

confidence: 65%

An update on the ‘danger theory’ in inhibitor development in hemophilia A

Schep

Boes

Schutgens

et al. 2019

Expert Review of Hematology

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“…In addition, previous studies have shown that in haemophilic rodent models, an induced joint bleed elicits a local and systemic angiogenic stimulus and upregulation of pro-inflammatory cytokines. 5,29,36 Thus, it cannot be ruled out that contralateral cartilage damage is induced by systemic modulators induced by the joint bleed. Moreover, neurogenic inflammation has been suggested as a cause of contralateral damage.…”

Section: Discussionmentioning

confidence: 99%

Proteoglycan synthesis rate as a novel method to measure blood‐induced cartilage degeneration in non‐haemophilic and haemophilic rats

et al. 2020

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Introduction:Haemophilic animal models are used to study blood-induced cartilage damage, but quantitative and sensitive outcome measures are needed. Aim:To develop a novel quantitative method for detecting early cartilage degeneration in a haemophilic rat model of blood-induced joint damage. Methods: The 35 Sulphate incorporation ( 35 SO 4 2− assay) was applied to tibial and patellar cartilage of wild-type rats to quantify baseline proteoglycan synthesis and to evaluate the effect of 4-day blood exposure in vitro. Next, haemarthrosis was induced in 39 FVIII-deficient rats and characterized by changes in knee joint diameter and development of bone pathology (using micro-CT). Four-and 16-day posthaemarthrosis proteoglycan synthesis rate (PSR) was assessed using the 35 SO 4 2− assay, with the contralateral knee as control.Results: In vitro, a decrease in PSR in tibial and patellar cartilage was demonstrated following blood exposure. In vivo, joint diameter and development of bone pathology confirmed successful induction of haemarthrosis. In the blood-exposed knee, tibial and patellar PSR was inhibited 4 and 16 days after induced haemarthrosis.Interestingly, at day 16 the proteoglycan synthesis in the contralateral knee was also inhibited to an extent correlating with that of the blood-exposed knee. Conclusion: For the first time, early changes in cartilage matrix synthesis upon blood exposure were quantified with the 35 SO 4 2− assay in a haemophilic rat model, establishing this assay as a novel method to study blood-induced cartilage damage. K E Y W O R D S arthropathies, cartilage, experimental animal models, haemarthrosis, haemophilia | e89 PULLES Et aL.

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“…In fact, iron-laden synovial tissue produces various inflammatory cytokines promoting the proliferation of fibroblast-like synoviocytes, which are considered key players of joint inflammation and destruction through the aggressive invasion of the extracellular matrix and production of proinflammatory mediators and cartilage-degrading enzymes [3,4,8,9]. Studies on animal models have recently helped to shed some light on the underlying pathobiology driving hemarthrosis toward HA [14,15]. A rapid in vivo proinflammatory response characterized by both local and systemic innate inflammatory mediators has been demonstrated following acute hemarthrosis in hemophilic rats [14].…”

Section: Introductionmentioning

confidence: 99%

“…Studies on animal models have recently helped to shed some light on the underlying pathobiology driving hemarthrosis toward HA [14,15]. A rapid in vivo proinflammatory response characterized by both local and systemic innate inflammatory mediators has been demonstrated following acute hemarthrosis in hemophilic rats [14]. In particular, gene expression analysis revealed increased synovial fluid levels of multiple proinflammatory mediators, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, while plasma analysis demonstrated significantly increased systemic levels of IL-6 [14].…”

Section: Introductionmentioning

confidence: 99%

“…A rapid in vivo proinflammatory response characterized by both local and systemic innate inflammatory mediators has been demonstrated following acute hemarthrosis in hemophilic rats [14]. In particular, gene expression analysis revealed increased synovial fluid levels of multiple proinflammatory mediators, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, while plasma analysis demonstrated significantly increased systemic levels of IL-6 [14]. Another recent study focusing on the detailed mapping of the early HA pathogenesis through a time-course study of induced hemarthrosis in hemophilic rats revealed proliferative synovitis dominated by neutrophil and macrophage infiltration that develops within hours after hemarthrosis [15].…”

Section: Introductionmentioning

confidence: 99%

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TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A

Manetti

Linari

Romano

et al. 2019

JCM

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Hemophilic arthropathy (HA) typically begins with proliferative synovitis that shares some similarities with inflammatory arthritides, in which the proinflammatory cytokine tumor necrosis factor (TNF)-α has a crucial pathogenetic role. Inappropriate release of TNF-α was shown to contribute to arthropathy development following intra-articular bleeding in hemophilic mice. Here, we were interested in determining whether systemic levels of TNF-α and synovial tissue expression of the TNF-α/TNF receptor (TNF-R) system could be increased and related to joint damage in hemophilia A patients with severe HA. Serum levels of TNF-α measured by quantitative enzyme-linked immunosorbent assay (ELISA) were significantly increased in HA patients (n = 67) compared to healthy controls (n = 20). In HA patients, elevated TNF-α levels were significantly associated with the number of hemarthroses, the grade of synovial hypertrophy, and both the clinical World Federation of Hemophilia score and ultrasound score. The expression of TNF-α, TNF-R1, and TNF-R2 was strongly increased in HA synovium (n = 10) compared to the non-inflamed osteoarthritis control synovium (n = 8), as assessed by both immunohistochemistry and Western blotting. Increased protein levels of TNF-α, TNF-R1, and TNF-R2 were retained in vitro by HA fibroblast-like synoviocytes (n = 6) with respect to osteoarthritis control fibroblast-like synoviocytes (n = 6). Stimulation with TNF-α resulted in a significant increase in HA fibroblast-like synoviocyte proliferation quantified by the water-soluble tetrazolium (WST)-1 assay, while it had no relevant effect on osteoarthritis fibroblast-like synoviocytes. Quantification of active/cleaved caspase-3 by ELISA demonstrated that TNF-α did not induce apoptosis either in HA or in osteoarthritis fibroblast-like synoviocytes. The TNF-α/TNF-R system may represent a crucial mediator of proliferative synovitis and, therefore, a new attractive target for the prevention and treatment of joint damage in HA patients. Our findings provide the groundwork for further clinical investigation of anti-TNF-α therapeutic feasibility in hemophiliacs.

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Acute Haemarthrosis in the Haemophilia A Rat Generates a Local and Systemic Proinflammatory Response

Cited by 8 publications

References 64 publications

An update on the ‘danger theory’ in inhibitor development in hemophilia A

An update on the ‘danger theory’ in inhibitor development in hemophilia A

Proteoglycan synthesis rate as a novel method to measure blood‐induced cartilage degeneration in non‐haemophilic and haemophilic rats

TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A

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