Regulation of plasminogen activator inhibitor-1 promotes the immune response to factor VIII in murine hemophilia A.

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The development of inhibitory antibodies against factor VIII(FVIII) is the enormous impact on hemophilia A patients, who are treated with FVIII products. Plasminogen activator-plasmin system is associated with not only thrombolysis but also various reactions including inflammation. However, little is known about how fibrinolytic components coordinate immune response. Here we show that plasminogen activator inhibitor-1(PAI-1), a regulator of fibrinolytic system, is a key player in controlling immune response in a mouse model of hemophilia A. Genetic deletion of PAI-1 prevented FVIII deficient mice from development of inhibitor formation after repeated loading of FVIII. PAI-1 depletion was associated with decreased major histocompatibility complex class II expression by bone marrow F4/80 positive cells and reduced T cell proliferation. Transplantation of mouse bone marrow cells transduced with a short hairpin RNA sequence targeting PAI-1 as well as administration of synthetic PAI-1 inhibitor caused a significant reduction of anti-FVIII antibody titer in FVIII deficient mice. These results suggest that PAI-1 regulation before FVIII exposure may represent a novel therapeutic option for preventing the development of FVIII inhibitors in hemophilia A patients.