Administration of MAPC1591 that selectively blocks anticoagulant activity and not signaling function of APC prevents joint bleed–induced hemophilic synovitis, inflammation, and neoangiogenesis. FVIII−/− mice were administered with control IgG, MPC1609, or MAPC1591 (1 mg/kg, ip). Twenty-four hours later, joint bleeding was induced with a needle puncture. Two weeks after the injury, mice were euthanized; knee joints were excised and fixed, and joint tissue sections were processed for histopathological analysis by staining with H&E (A). Two thin black arrows pointing to each other indicate the width of the synovial lining; the yellow arrowhead points out red blood cells, and the thick black arrows point out synovial villi. (B) The joint tissue pathology was quantified by scoring H&E-stained sections on a 0 to 6 scale for synovial hyperplasia (0, normal, <4 cell layers thick; 1, four to five layers thick; 2, six to seven layers thick; 3, more than seven layers thick; the presence of RBC [0, absent; 1, present], villus formation [0, absent; 1, present], and discoloration by hemosiderin [0, absent; 1, present]). (C) Immunostaining of joint tissue sections with macrophage marker F4/80. Arrows point out macrophages. (D) Macrophage infiltration was quantified on a 0 to 4 scale (0, absence of macrophages; 1, scattered macrophages; 2, line of macrophages; 3, a cluster of macrophages; 4, sheets of macrophages). (E) Immunostaining of tissue sections with CD31 antibody to identify neoangiogenesis. Arrows point out blood vessels. (F) The number of blood vessels counted per field. Top panel images were captured at ×4 magnification. The squared area was imaged at ×40 magnification (bottom panel). The images shown are representative, and the data in bar graphs are mean ± SEM (n = 7 to 8 mice per group). **P < .01; ***P < .001; ****P < .0001. Note: Data shown for no treatment control group (no tr.) in this figure, and other figures were from our earlier publication.8 They were shown to illustrate that control IgG treatment had no significant effect on joint bleed–induced pathology in FVIII−/− mice.