Proposed mechanism of vascular bed–specific bleeding in aHA vs congenital HA. The congenital HA mouse is characterized by excessive tail and joint bleeding. In contrast, the aHA mouse featured a divergent bleeding phenotype existing of excessive tail bleeding but mild joint bleeding. Therefore, the divergent bleeding was vascular bed specific, encompassing different fibrinolytic mechanisms. (A) Endogenous TAFI did not control tail bleeding in either aHA or congenital HA mice, because tail bleeding in aHA was not exacerbated by TAFI gene deficiency. In contrast, antifibrinolytic treatment with exogenous TAFI⁵³  or TXA was able to restore hemostasis after tail resection, suggesting that tPA-driven hyperfibrinolysis contributed to hemophilic tail bleeding. (B) In the joints, the extent of bleeding diverged between aHA (minimal bleeding) vs congenital HA (excessive bleeding), and this difference in bleeding severity was due to the extent of TAFI activation. Residual thrombin formation in aHA provided adequate TAFI activation for bleed protection, but the defective TAFI activation in congenital HA was not associated with bleed protection and instead contributed to severe bleeding. Hemophilic joint bleeding was primarily mediated by uPA and largely unresponsive to treatment with TXA, in contrast to hemophilic tail bleeding. (C-D) Primary mechanisms responsible for achieving hemostasis (coagulation vs antifibrinolysis by TAFIa) for each type of bleeding (tail vs joint) depending on the level of FVIII (or the inverse anti-FVIII antibody level). (C) No differences were observed in the extent of tail bleeding between congenital HA (FVIII^−/−) and aHA WT mice (even when treated at a low dose of anti-FVIII antibody). (D) In contrast, joint bleeding in aHA WT mice was minimal but became severe upon elimination of TAFI. Moreover, aHA TAFI^−/− mice and congenital HA mice bled to the same extent after joint injury. Therefore, the hemostasis gap between aHA and congenital HA in the joint was due to adequate vs defective activation of TAFI, respectively. This indicated that residual thrombin generation in aHA was insufficient to induce functional coagulation to arrest bleeding but proficient to activate TAFI and achieve hemostasis in the joints. This study points to an important modifying role for TAFI in joint bleeding in hemophilia.