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.

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

“…Antifibrinolytic agents, such as -aminocaproic or tranexamic acids, systemically administered have produced satisfactory results with an improvement in epistaxis and the associated anemia and with an increase in the transcriptional activity of ENG and ALK1 promoters (Fernandez et al, 2007;MoralesAngulo et al, 2007). However, contraindications appear in those patients prone to suffer thrombosis; hence, it is necessary to screen the HHT population for high levels of coagulant factors VIII and V and von Willebrand factor before Fig.…”

“…As a consequence of vascular alterations, telangiectases are very sensitive to slight traumata and even to the air when breathing, which gives rise to nose bleeds. Many different therapies have been assayed, but none of them with conclusive results, such as the antibrinolytic agents -aminocaproic or tranexamic acids (Fernandez et al, 2007;Morales-Angulo et al, 2007) or therapy based in hormones. Estrogens like raloxifene, a selective estrogen receptor modulator, at doses used for oral contraception may eliminate bleeding in women symptomatic for HHT, as we have published previously (Albiñ ana et al, 2010).…”

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…Therapeutic manipulation of coagulation and fibrinolytic pathways is often employed to try to limit blood loss in HHT 41,42,181,182 . These therapies have not yet been supported by data from randomized controlled trials.…”

“…High proportion without medical or ENT review 33,34 . New data: Surgery and embolization [35][36][37][38][39] ., medical treatments 31,[40][41][42][43][44][45] …”

Heterozygous deficiency of endoglin decreases insulin and hepatic triglyceride levels during high fat diet

“…Indeed, we cannot rule out the possibility that other factors important for insulin might be also affected in Eng +/2 mice. In this regard, a comparative gene expression analysis revealed that in endothelial cells from HHT1 patients, 20% of the deregulated genes (down or upregulated) respect to cells from healthy subjects were involved in general metabolism [22]. Among these genes it is worth mentioning the presence of several members of the solute carrier (SLC) protein family.…”