Ansari Shabbir A, Brake Marisa A, Pathak Nishtha, Flaumenhaft James T, Ludington Jacob G, Panwar Natasha, Turro Ernest, Schulman Sol
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
Blood. 2026 Feb 5;147(6):689-701. doi: 10.1182/blood.2025029571.
Tissue factor (TF), encoded by F3, binds factor VII (FVII)/activated factor VII (FVIIa) to initiate blood coagulation. Because standard clinical assays do not measure endogenous TF directly, the extent to which human F3 variants affect blood coagulation is unknown. We sought to determine the effect of the human TF missense variants with the highest allele frequency as well as additional rare variants occurring at sites predicted to perturb the initiation of blood coagulation. The variants with the highest allele frequency did not affect coagulation activation. By contrast, some rare human TF missense substitutions did profoundly affect TF-initiated plasma clotting time and the activation of FIX and FX by 2 distinct mechanisms: by precluding TF interaction with FVIIa, or by altering the TF exosite to prevent macromolecular but not amidolytic substrate cleavage. Individuals heterozygous for the rare p.Gly196Arg variant have reduced basal FVIIa-antithrombin complex and D-dimer levels but no major differences in TF or FVII levels. Gly196Arg supported impaired FVII autoactivation in vitro. These data demonstrate that rare missense variants in F3 can impair the activation of FVII, FIX, and FX, and suggest these variants impair the basal activation of blood coagulation in humans.
由F3编码的组织因子（TF）与因子VII（FVII）/活化因子VII（FVIIa）结合以启动血液凝固。由于标准临床检测方法不能直接测量内源性TF，人类F3变体对血液凝固的影响程度尚不清楚。我们试图确定具有最高等位基因频率的人类TF错义变体以及在预测会干扰凝血起始的位点出现的其他罕见变体的影响。具有最高等位基因频率的变体不影响凝血激活。相比之下，一些罕见的人类TF错义替换确实通过两种不同机制深刻影响了TF启动的血浆凝血时间以及FIX和FX的激活：通过阻止TF与FVIIa相互作用，或通过改变TF外位点以防止大分子而非酰胺分解底物的裂解。罕见的p.Gly196Arg变体杂合个体的基础FVIIa-抗凝血酶复合物和D-二聚体水平降低，但TF或FVII水平无重大差异。Gly196Arg在体外支持受损的FVII自激活。这些数据表明，F3中的罕见错义变体可损害FVII、FIX和FX的激活，并提示这些变体损害人类血液凝固的基础激活。
