Vascular Bleeding Disorders

Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Disease)

Hereditary hemorrhagic telangiectasia (HHT) is a systemic autosomal dominant (AD) vascular disease that is characterized by mucocutaneous telangiectasias and multiple arteriovenous malformations (AVMs). It is the most common inherited vascular bleeding disorder with an estimated incidence of 1 in 5000–10,000 people and affects all ages, races, and sexes equally.

There are three identified pathologic gene variants that cause HHT, which are thought to play a role in regulating angiogenesis. The most common mutation (HHT type 1), is of the ENG gene on chromosome 9q for the glycoprotein endoglin. HHT type 2 is due to variants in ACVRL1 on chromosome 12 encoding activin receptorlike kinase 1. Roughly, 1% of cases are due to mutation in the MADH4 gene ( SMAD4 ), resulting in a combined syndrome of HHT and juvenile polyposis.

HHT has a wide variety of clinical manifestations. Telangiectasias (dilated blood vessels with thin fragile walls and defective endothelial cell junctions, leading to rupture and bleeding) are present at birth, but enlarge and become visible in childhood. Bleeding occurs spontaneously or after minor trauma and may be prolonged due to defective vessel contraction. Slow progressive bleeding from epistaxis (the most common manifestation) or lesions in the gastrointestinal (GI) tract can lead to iron deficiency anemia. Up to half of patients have multiple AVMs in the lungs, causing decreased oxygenation and/or hemorrhage. Telangiectasis in the liver and central nervous system can increase mortality. In addition to hemorrhagic complications, some patients may suffer from pulmonary hypertension or thromboembolic events.

Diagnosis is primarily clinical; however, molecular genetic testing is available. Platelet counts and coagulation studies are normal. Management is primarily symptomatic, although recurrent GI or pulmonary bleeding may require surgical intervention and/or interventional radiology interventions. In some instances, antifibrinolytic therapy may be beneficial.