**4. Conclusions**

The currently available pharmacological treatments for HHT are summarized according to their mechanism of action on Figure 3. The drugs here included may be used on an individual level; treatment for rare diseases should follow the premises of personalized medicine, relying on the reference doctor expertise. A first-line treatment to avoid or decrease epistaxis or GI bleeding is to reinforce the speed and stability of coagulation with antifibrinolytics, preferentially TA. The only contraindication may apply to patients with risk of thrombosis. Doses vary from 1.5 g/day up to 3 g/day in episodes of severe bleeding. In countries where TA is not commercially available, AC could be used instead.

For bleedings interfering with normal life, currently the best treatment option for women in fertile age are feminine hormones used for contraception. Women in peri- or post-menopausal age can benefit from the use of SERMs. Although SERMs are primarily used to prevent or treat osteoporosis, they have shown to be effective in HHT compensating partially, the haploinsufficiency present in HHT patients by increasing the protein levels of endoglin and ALK1. Raloxifene hydrochloride was designated as orphan drug by the EMA and by the FDA. Bazedoxifene acetate was also designated as orphan drug by the EMA but it is not commercialized in United States.

Among the list of drugs that increase the expression levels of endoglin and ACVRL1/ALK1, tacrolimus was demonstrated to activate the signaling of endoglin/ALK1 in ECs. It would be the treatment of choice for immunosuppression in transplanted patients. However, recent case reports have opened the possibility of using systemic tacrolimus at low, non-immunosuppressive doses, to treat HHT bleeding. Currently, around 25 patients are using tacrolimus as an "off-label" treatment and it will be very interesting to hear about the outcome of these patients. Other treatment includes NAC which increases the endoglin RNA and protein levels and can be used as an anti-inflammatory and antioxidant drug without any side effects.

BZ is used (off-label) for antiangiogenic strategy in HHT patients with severe bleeding or symptomatic liver AVMs, in order to reduce bleedings and excessive number of abnormal mucosa vessels. TKIs (pazopanib, nintenadib, sunitinib or buparlisib) and thalidomide have also been used or are planned to be used in clinical trials [22,83,101,102] (Table 3).

**Figure 3.** Therapeutic strategies of pharmacological treatments in HHT. (1) Antifibrinolytic strategy; prevents the conversion of plasminogen to plasmin, thus delaying the lysis of the fibrin clot, and therefore the bleeding. (2) Upregulation strategy. The drug works by increasing the expression of the *ENG* or *ALK1* genes, and thus resulting in increased amount of proteins, improving the BMP/TGF-β signaling and normalizing the formation of new vessels. (3) Antiangiogenesis strategy; makes disappear the excess of existing abnormal vasculature or normalizes it.

Another group of antiangiogenic drugs comprises the non-selective adrenergic β-blockers like propranolol and timolol. These drugs are preferentially used topically, as creams or gels. They reduce nose bleedings by decreasing and delaying the formation of telangiectases on the mucosa. Propranolol can also be used systemically, but special attention is indicated with regards to blood pressure and heart rate.

Lastly, as emerging treatments, the orphan drug designation of etamsylate for topical treatment of epistaxis opens a new perspective following the antiangiogenic strategy.

This review has delved into the various treatment strategies of HHT and the clinical trials that support these treatments. The repurposing strategy has led to the formal approval of several orphan drugs for HHT (Table 4).

**Author Contributions:** L.M.B. designed the project. L.M.B. wrote the manuscript with the contribution of V.A., A.M.C., E.G.-V., I.d.R.-P., and L.R.-P., V.A. and A.M.C. designed the figures. V.A., A.M.C., E.G.-V., I.d.R.-P., L.R.-P., proofread the text. C.B. revised the manuscript and provided funding. L.M.B. supervised the project and provided funding. All authors discussed the results and contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Ministry of Economy and Competitivity, gran<sup>t</sup> number SAF2017-83351-R to L.M.B.

**Acknowledgments:** In memoriam of José Sánchez Andújar, who passed away on 22 May 2020. He was a founder member and the first President of the Spanish Association of HHT patients.

**Conflicts of Interest:** The authors declare no conflict of interest.
