Thaler Johannes, Tripisciano Carla, Kraemmer Daniel, Hau Chi, Samadi Nazanin, Ruf Wolfram, Pabinger Ingrid, Knoebl Paul, Nieuwland Rienk, Ay Cihan
Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
Laboratory of Experimental Clinical Chemistry, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
Blood. 2024 Dec 19;144(25):2666-2677. doi: 10.1182/blood.2024025093.
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.
人类唾液中含有细胞外囊泡（EVs）。这些EVs会暴露组织因子（TF）和活化因子VII（FVIIa）的外源性凝血酶原酶复合物，并触发血液凝固。在此，我们表明，暴露外源性凝血酶原酶复合物的EVs也存在于重度A型血友病患者（即FVIII缺乏症患者）的唾液中。将这些唾液EVs添加到自体FVIII缺乏的血液中会导致FXa生成，从而弥补通过内源性凝血酶原酶（FVIIIa/FIXa）复合物生成FXa的不足。同样，在我们对未接受预防性FVIII替代治疗的重度A型血友病患者的回顾性分析中，口咽黏膜出血很少见且为自限性。相反，在重度FVII缺乏症患者（口咽出血很常见）的唾液中，功能性外源性凝血酶原酶复合物不存在，因为EVs缺乏FVII。重度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缺乏FVII。皮摩尔水平的重组FVIIa可以恢复FVII缺乏症患者唾液的凝血潜能。综上所述，我们的研究结果可能解释了A型血友病患者口咽出血较少以及重度FVII缺乏症患者出现此类出血的原因。
