PhD Defense: Novel diagnostics and therapeutics in hereditary hemorrhagic telangiectasia

Despite the increase in awareness and knowledge, hereditary hemorrhagic telangiectasia (HHT) remains a disease in which long diagnostic delay resulting in severe but preventable morbidity is not uncommon. Even after a correct diagnosis, the existing treatment options are not always suffice to decrease the disease burden enough and to treat the recurrent epistaxis and gastro-intestinal blood loss. In this thesis we have tried to address both challenges in HHT care. We have investigated the clinical characteristics and evaluated novel diagnostics to increase the knowledge of HHT and develop tools to aid in a correct diagnosis. The use of capillary microscopy has proven to be an useful diagnostic tool for a correct HHT diagnosis in certain cases. A novel quantification method of transthoracic contrast echocardiography for the detection of treatable pulmonary arteriovenous malformations (PAVMs) using a change in gray density following contrast injection has led to a substantial decrease in needed thoracic CT scans and thus avoidance of harmful Rontgen radiation. The clinical and radiographical features of patients with PAVMs without identifiable cause were largely like HHT associated PAVMs. Systematic screening and treatment if needed, in a HHT center according to a standardized protocol has resulted in the normalization of the life-expectancy of HHT patients compared to the life-expectancy of their relatives. In the search for affordable and well tolerated drugs to treat HHT related bleeding and subsequent anemia, we repurposed three existing drugs: octreotide, itraconazole and tacrolimus. These three novel treatment options in HHT have shown promising results by decreasing blood loss and required number of blood transfusions. These drugs should be considered as viable treatment options for severe HHT related bleeding.