Plasma cells targeting endogenous factor VIII (FVIII) mainly arise in the spleen of mice with hemophilia A, according to a new study published in Thrombosis Research.

After the intravenous administration of recombinant FVIII plus lipopolysaccharide in FVIII knockout mice, the study’s authors observed a marked increase in anti-FVIII antibody induction, along with increasing FVIII-specific plasma cells, particularly in the spleen.

The same treatment in splenectomized or congenitally asplenic FVIII knockout mice led to a decrease in inhibitor titers of approximately 80%, with 76% less anti-FVIII immunoglobulin (Ig) G and 78% less anti-IgM, compared with mice with an intact spleen.

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“These results indicated that the absence of the spleen strongly reduced the augmented anti-FVIII immune response, even in mice injected with recombinant FVIII plus lipopolysaccharide. Thus, the spleen is not only responsible for the initial inhibitor response as previously shown, but also for enhancing inhibitor production,” the study’s authors said.

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The results of the study also suggest that the spleen may provide a microenvironment prone to the maintenance of FVIII-specific plasma cells, as anti-FVIII IgG was detected in the serum of immune-deficient mice engrafted with splenocytes, but not bone marrow, from FVIII knockout mice with inhibitor.

Moreover, the authors observed FVIII-specific plasma cells in the spleen but not in the bone marrow of the engrafted animals.

Additionally, splenectomized immune-deficient mice engrafted with splenocytes from FVIII knockout mice with inhibitor showed reduced inhibitor levels in the serum compared with sham-operated, immune-deficient mice.

Because human and mouse spleens exhibit important anatomical differences, future studies addressing the role of the spleen during high-titer inhibitor formation in humans with hemophilia would be necessary.


Oda A, Furukawa S, Kitabatake M, et al. The spleen is the major site for the development and expansion of inhibitor producing-cells in hemophilia A mice upon FVIII infusion developing high-titer inhibitor. Thromb Res. Published online March 17, 2023. doi:10.1016/j.thromres.2023.03.003