Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Abstract

Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5,000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings. Blood Reviews _ HHT 2010_ Shovlin 3 Overview of HHTHHT, also known as Osler Weber Rendu syndrome [1][2][3] , is one of the most common disorders to be inherited as an autosomal dominant trait. Careful epidemiological studies reveal that it affects approximately 1 in 5,000 individuals, 4,5 with regional differences, 6 and isolated communities displaying higher prevalences due to founder effects. 7 8 HHT was first described as a familial disease characterised by severe recurrent nasal and gastrointestinal bleeding with associated anaemia, and visible dilated blood vessels (telangiectasia) on the lips and finger tips. The majority of HHT patients are also affected by larger arteriovenous malformations (AVMs) in the pulmonary, hepatic, cerebral, pancreatic, spinal and other circulations. 1,2,9 These features, presented in more detail within Table 1, are used as criteria to diagnose HHT. 2 The spectrum of disease within the HHT umbrella has extended beyond the telangiectatic/AVM HHT pathology delineated by the Curaçao criteria. 2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and poten...

The use of US health insurance data for surveillance of rare disorders: hereditary hemorrhagic telangiectasia

“…9,10 The signs of HHT may go unrecognized and untreated for decades or cause premature death. 11 A recent study from Italy involving 112 HHT patients who were index cases in their families reported that the mean age at which symptomatic disease manifested was 16.2 years, the mean age of referral for evaluation of those symptoms was 31.7 years, and the mean age of diagnosis of HHT was 45.9 years, for a mean delay of almost 30 years between onset of symptoms and diagnosis. 12 HHT is associated with significantly higher rates of premature mortality before 60 years of age.…”

Cardiopulmonary Exercise Testing Demonstrates Maintenance of Exercise Capacity in Patients With Hypoxemia and Pulmonary Arteriovenous Malformations

“…[14][15][16] In contrast, for PAVM patients, the absence of alveolar hypoxia/hypoxic pulmonary vasoconstriction, and PAVM-related structural alterations in the pulmonary vessels, mean that pulmonary vascular resistance at rest is low in severely hypoxemic patients. 3,6,7 The majority of PAVM patients have underlying hereditary hemorrhagic telangiectasia(HHT), 11,17,18 but overall, pulmonary hypertension is uncommon in PAVM/HHT patients. 12 When pulmonary hypertension does occur, 19,20 this results not from hypoxia, but from other pathophysiological processes, particularly pulmonary arterial hypertension, 12,[21][22][23][24] and pulmonary venous hypertension associated with hepatic AVMs and high outputs states.…”

BMP-9 balances endothelial cell fate

“…HHT patients present with recurrent nosebleeds and develop cutaneous and mucosal blood vessel dilatations. Some patients also develop life-threatening arteriovenous malformations (25). HHT can be caused by mutations in other ALK-1 pathway components, including the ALK-1 coreceptor endoglin that aids ligand binding, and Smad4, which partners with TGF-β-and BMP-activated Smads (25).…”

“…Some patients also develop life-threatening arteriovenous malformations (25). HHT can be caused by mutations in other ALK-1 pathway components, including the ALK-1 coreceptor endoglin that aids ligand binding, and Smad4, which partners with TGF-β-and BMP-activated Smads (25). Recently, causative BMP9 missense mutations have been implicated in an HHT-related syndrome (26).…”