A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies.

ABSTRACT

Vascular anomalies represent a diverse group of disorders classified broadly as malformations or tumors and include the second most common hereditary bleeding disorder worldwide, hereditary hemorrhagic telangiectasia (HHT). Patients with HHT and other vascular anomalies suffer morbid consequences of these diseases, including bleeding, thrombosis, anemia, localized intravascular coagulation, tissue overgrowth, infections, and other complications. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis, and the treatments for vascular anomalies are rapidly evolving. Recent discoveries have elucidated the molecular basis of a number of common and uncommon vascular anomalies. HHT occurs due to mutations in the transforming growth factor beta (TGF-ß) pathway, resulting in vascular endothelial growth factor excess. Complex vascular anomalies including Klippel-Trénaunay syndrome (KTS) and arteriovenous malformation (AVM) may occur due to mutations in the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. The discovery of the pathophysiologic mechanisms driving these diseases has led to improved phenotype-genotype correlation and the opportunity to target molecular pathways with medical therapies. Therefore, targeted agents have quickly become a standard of care in the treatment of vascular disorders (particularly HHT). Herein, we provide a case-based approach to the use of antiangiogenic therapies including bevacizumab and pazopanib for the treatment of bleeding in HHT and the use of mammalian target of rapamycin (sirolimus), PIK3CA (alpelisib), and MEK (trametinib) inhibitors in the treatment of complex vascular anomalies.