Human saliva contains extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes of tissue factor (TF) and activated factor VII (FVIIa), and trigger blood coagulation. Here, we show that EVs exposing extrinsic tenase complexes are also present in saliva of persons with severe hemophilia A, that is, persons with FVIII deficiency. Addition of these salivary EVs to autologous FVIII-deficient blood results in FXa generation, thereby compensating for the lack of FXa generation via intrinsic tenase (FVIIIa/FIXa) complexes. Consistently, in our retrospective analysis of persons with severe hemophilia A who do not receive prophylactic FVIII substitution, oropharyngeal mucosal bleedings are infrequent and self-limited. Conversely, in saliva of persons with severe FVII deficiency, in whom oropharyngeal bleedings are prevalent, functional extrinsic tenase complexes are absent, because EVs lack FVII. Saliva of persons with severe FVII deficiency is unable to restore blood coagulation, which is because of the absence of FVII in both their saliva and blood. Picomolar levels of recombinant FVIIa can restore the coagulant potential of saliva of persons with FVII deficiency. Taken together, our findings may explain the paucity of oropharyngeal bleedings in persons with hemophilia A as well as the occurrence of such bleedings in persons with severe FVII deficiency.

中文翻译：

---

血友病 A 患者的唾液通过外源性 tenase 复合物触发凝血


人类唾液含有细胞外囊泡 （EV）。这些 EV 暴露组织因子 （TF） 和活化因子 VII （FVIIa） 的外源性 tenase 复合物，并触发血液凝固。在这里，我们表明暴露外源性 tenase 复合物的 EV 也存在于严重血友病 A 患者（即 FVIII 缺乏症患者）的唾液中。将这些唾液 EV 添加到自体 FVIII 缺陷型血液中会导致 FXa 生成，从而通过内源性 tenase（FVIIIa/FIXa）复合物补偿 FXa 生成的缺失。一致地，在我们对未接受预防性 FVIII 替代治疗的严重血友病 A 患者的回顾性分析中，口咽粘膜出血很少见且具有自限性。相反，在口咽出血普遍的严重 FVII 缺乏症患者的唾液中，不存在功能性外源性 tenase 复合物，因为 EV 缺乏 FVII。严重 FVII 缺乏症患者的唾液无法恢复血液凝固，这是因为他们的唾液和血液中都不存在 FVII。重组 FVIIa 的 Picomolar 水平可以恢复 FVII 缺陷患者唾液的凝血潜力。综上所述，我们的研究结果可以解释血友病 A 患者口咽出血的缺乏以及严重 FVII 缺乏症患者发生此类出血的原因。