Reduced thrombin generation in the study cases and response to rFVIIa and aPCC. (A) Pedigree of the study cases with traumatic bleeding indicated by the solid symbols and no abnormal bleeding by open symbols. Genotyped cases are indicated as +/V for the heterozygous THBDN p.Cys537Stop variant and +/+ for reference sequence. Plasma TM concentrations are indicated beneath each pedigree symbol. (B) A representative thrombin generation curve from case II.2 in recalcified plasma collected into 0.106 mM trisodium citrate, following activation with 1 pM tissue factor. The gray shading represents the limits of thrombin generation curves observed in 20 healthy controls. (C-D) Plasma ETP peak thrombin concentration from cases I.1 and II.1 (n = 10) with TM-AC and in plasma from 20 healthy controls in the absence or presence of recombinant C-terminal truncated human TM (sTM; 250-2500 ng/mL; high-TM model plasma). (E-F) ETP in plasma from cases I.1 and II.1 and in high-TM model plasma containing 500 ng/mL sTM and either 25 to 100 μg/mL rFVIIa or 0.25 to 0.75 U/mL aPCC. Statistical comparisons are between ETP values in the presence of the stated concentration of bypassing agent vs ETP in the corresponding sample with no added bypassing agent. The gray boxes indicate the range of ETP observed in 20 healthy control plasmas without addition of sTM. Data are means ± SEM; **P ≤ .01. NS, not significant.