Saliva of persons with hemophilia A triggers coagulation via extrinsic tenase complexes

• Published in: Blood 2024-12, Vol.144 (25), p.2666-2677
• Main Authors: Thaler, Johannes, Tripisciano, Carla, Kraemmer, Daniel, Hau, Chi, Samadi, Nazanin, Ruf, Wolfram, Pabinger, Ingrid, Knoebl, Paul, Nieuwland, Rienk, Ay, Cihan
• Format: Article
• Language: English
• Subjects: Adult; Blood Coagulation; Extracellular Vesicles - metabolism; Factor VIIa - metabolism; Female; Hemophilia A - metabolism; Humans; Male; Retrospective Studies; Saliva - metabolism; Thromboplastin - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2024025093

•Extrinsic tenase complexes are present in saliva of persons with hemophilia A and absent in saliva of persons with FVII deficiency.•Presence or absence of salivary extrinsic tenase complexes can explain differences in bleeding phenotypes. [Display omitted] 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. Human saliva contains extracellular vesicles (EVs) that expose extrinsic complexes of tissue factor and activated factor VII (FVIIa), triggering coagulation. Thaler et al demonstrate that these EVs are present in patients with severe hemophilia A and are capable of activating factor X. This may explain why patients with hemophilia do not generally have oropharyngeal mucosal bleeding while patients with FVII deficiency do.