tPA, uPA, and PAI-1 participate in the development of ICH, generation of d-dimers, and platelet counts post CHI. (A) Effect of endogenous tPA, uPA, and PAI-1 on ICH. CHI was induced in WT, tPA^−/−, uPA^−/−, and PAI-1^−/− mice, followed immediately by an IV injection of WT-tPA or WT-uPA either alone (5 mg/kg each) or together with tPA-S⁴⁸¹A (5 mg/kg). Two hours later, brain hemoglobin was determined as in Figure 3B. The mean ± SD of 3 experiments performed in 6 to 8 mice is shown. (B) Effect of endogenous tPA and uPA on fibrinolytic activity. Two hours post CHI, the fibrinolytic activity in CSF taken from WT, tPA^−/−, and uPA^−/− mice was measured as in Figure 3F. The mean ± SD of 3 experiments performed in 6 to 8 mice is shown. (C-D) Effect of endogenous tPA, uPA, and PAI-1 on d-dimers and thrombocytopenia. The experiment was performed as in panel A with the exception that some animals were given tPA-S⁴⁸¹A (1 mg/kg each), TA (10 mg/kg), or Ap (1 mg/kg) or TA plus Ap. Plasma d-dimers (DD) (C) and platelet counts (D) were measured as in Figures 4A and 4B, respectively. The mean ± SD of 3 experiments performed in 6 to 8 mice is shown. (E) tPA-S⁴⁸¹A inhibited expansion of ICH in mice treated with warfarin (WR). CHI was induced in WT, tPA^−/−, and uPA^−/− mice treated with WR to an INR of 2.5 ± 0.4 at the time of trauma. Saline or tPA-S⁴⁸¹A (1 mg/kg) was given immediately after CHI, and brain hemoglobin was measured 2 or 8 hours after the injury as in Figure 3B. (F) The prothrombotic effect of iron on delayed ICH. CHI was induced in WT mice given iron dextran (IR; 60 mg/kg) alone or together with deferoxamine (Def; 200 mg/kg). Brain hemoglobin was measured 2 to 24 hours postinjury. The mean ± 2 SD of 3 experiments performed in 7 to 9 mice is shown. INR, international normalized ratio.