title: Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in endothelial cells.
abstract: Recurrent epistaxis is the most frequent clinical manifestation of hereditary haemorrhagic telangiectasia (HHT). Its treatment is difficult. Our objective was to assess the use of tranexamic acid (TA), an antifibrinolytic drug, for the treatment of epistaxis in HHT patients and to investigate in vitro the effects of TA over endoglin and ALK-1 expression and activity in endothelial cells. A prospective study was carried out on patients with epistaxis treated with oral TA in the HHT Unit of Sierrallana Hospital (Cantabria, Spain). Primary cultures of endothelial cells were treated with TA to measure the levels of endoglin and ALK-1 at the cell surface by flow cytometry. RNA levels were also measured by real-time PCR, and the transcriptional effects of TA on reporters for endoglin, ALK-1 and the endoglin/ALK-1 TGF-beta pathway were assessed. The results showed that the fourteen HHT patients treated orally with TA improved, and the frequency and severity of their epistaxis were decreased. No complications derived from the treatment were observed. Cultured endothelial cells incubated with TA exhibited increased levels of endoglin and ALK-1 at the protein and mRNA levels, enhanced TGF-beta signaling, and improved endothelial cell functions like tubulogenesis and migration. In summary, oral administration of TA proved beneficial for epistaxis treatment in selected patients with HHT. In addition to its already reported antifibrinolytic effects, TA stimulates the expression ofALK-1 and endoglin, as well as the activity of the ALK-1/endoglin pathway.
authors.affiliation: Centro de nvestigaciones Biologicas, CSIC, Ramiro de Maetzu, Madrid, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: Fernandez-L
authors.forename: Eva M
authors.initials: EM
authors.lastname: Garrido-Martin
authors.forename: Francisco
authors.initials: F
authors.lastname: Sanz-Rodriguez
authors.forename: Jose-Ramon
authors.initials: JR
authors.lastname: Ramirez
authors.forename: Carmelo
authors.initials: C
authors.lastname: Morales-Angulo
authors.forename: Roberto
authors.initials: R
authors.lastname: Zarrabeitia
authors.forename: Alfonso
authors.initials: A
authors.lastname: Perez-Molino
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabéu
authors.forename: Luisa-María
authors.initials: LM
authors.lastname: Botella
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000933:Antifibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000071063:Endoglin; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004844:Epistaxis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010958:Plasminogen / Q000037:antagonists & inhibitors; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D013030:Spain; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications*; D013997:Time Factors; D014148:Tranexamic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000933:Antifibrinolytic Agents; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014148:Tranexamic Acid; D010958:Plasminogen; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I