Acute hemarthrosis in the hemophilia A rat generates a local and systemic pro-inflammatory response

Replacement therapy with coagulation factor VIII (FVIII) products concurrent with bleeds (on-demand) in hemophilia A (HA) patients, seems to increase the risk for developing anti-drug antibodies (i.e. inhibitors). A danger signal environment characterized by tissue damage and inflammation at the site of a bleed is thought to contribute to the anti-FVIII response. The nature of this inflammatory reaction is however not fully known. The purpose of this study was to characterize the inflammatory response, locally and systemically, during the first 24h following a knee joint bleed in the HA rat. HA rats received either a needle induced knee joint bleed (n=83) or a sham procedure (n=41). Blood samples were collected at selected time-points from 0-24h post injury/sham. Synovial fluid as well as intra-articular knee tissue and popliteal lymph nodes were collected at 24h. Cytokine and chemokine concentrations and mRNA gene expression on tissue samples were measured. Gene expression analysis revealed a rapid inflammatory response in the injured knees, accompanied by significantly increased levels of specific gene products in the synovial fluid; IL-1, TNF, KC/GRO, IL-6, Eotaxin, MCP-1, MCP-3, MIP-1, MIP-2, RANTES, A2M and AGP. Plasma analysis demonstrated significantly increased systemic levels of KC/GRO, IL-6 and AGP in the blood of injured rats, already few hours following the injury. In conclusion, a rapid pro-inflammatory response, both locally and systemically, characteristic of innate immunity, was demonstrated following an induced knee joint bleed in the HA rat. Results reveal a more comprehensive inflammatory picture than previously shown, with resemblance to human hemophilic arthropathy.

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