TM and EPCR create an anticoagulant vascular domain in CCMs. Measurement of hemoglobin content of extravasated erythrocytes from hindbrains at P10. (A) Decreased cerebellar hemorrhages are observed in Pdcd10^ECKO;Thbd^ECKO/wt or Pdcd10^ECKO;Thbd^ECKO mice compared with Pdcd10^ECKO littermates. Pdcd10^fl/fl is a non-CCM lesion control (SEM, n = 5 or 8). (B) Blocking antibodies against TM (4.6 μg/g) and EPCR (2.6 μg/g) or immunoglobulin G (7.2 μg/g) control were injected retro-orbitally into Pdcd10^ECKO mice or control Pdcd10^fl/fl littermate controls at P7 (SEM, n = 3 or 13). (C) Schematic diagram of the formation of an anticoagulant domain in CCM lesion. Increased expression of KLF2 and KLF4 transcription factors lead to upregulation of brain endothelial TM. In addition, EPCR expression is upregulated in CCMs independently of KLF2 and KLF4. Increased levels of TM and EPCR create anticoagulant domains that predispose the CCM lesions to hemorrhages.