Elsevier

Blood Reviews

Volume 24, Issue 6, November 2010, Pages 203-219
Blood Reviews

REVIEW
Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

https://doi.org/10.1016/j.blre.2010.07.001Get rights and content

Abstract

Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5000 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attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded.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.

Section snippets

Overview of HHT

HHT, 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 5000 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,

Histopathology

As in other telangiectatic states,89 the smallest HHT cutaneous telangiectatic lesion appears to be a focal dilatation of the post capillary venule in the upper horizontal plexus.90 Computer reconstruction of serial 1–2 mm sections suggest that the dilated post capillary venules enlarge, connect with dilated arterioles with loss of the intervening capillary bed, and form arteriovenous communications,90 associated with a lymphocytic perivascular cell infiltrate.90 Microscopic telangiectasia are

Management overview

Several helpful articles have been published in recent years guiding management practice. International HHT Guidelines published on line more than 12 months ago 32 were based on systematic assessments of the HHT publications up to October 2006. The 33 recommendations, representing the product of a fairly strenuous review process involving multiple experts, are a very helpful starting point for the field, and are presented in a separate column within Table 1.

The 2006–9 HHT evidence base

Clinical diagnosis

The mainstay of diagnosis remain the Curaçao Criteria, international consensus diagnostic criteria developed between 1997 and 1999 2 (Table 1), and recently validated.72 An individual has a diagnosis of “definite HHT” if three criteria are present; “suspected HHT” if two are present, and “unlikely HHT” if only one is present. A crucial issue for families and medical practitioners, is that no child of a patient with HHT can be informed they do not have HHT, unless they have been shown not to

AVMs

Details of the treatment of each type of AVM are beyond the scope of this text: the interested reader is referred to the references in Table 1, and recent treatment texts for general aspects of HHT [3], [32] and AVMs in cerebral,[68], [209], [210], [211] pulmonary,[57], [58], [59], [60], [61], [66], [105] hepatic[73], [74], [75], [76] and spinal[67], [68], [74], [75], [76] circulations.

Management of iron deficiency anaemia

In this chronic condition, it is essential to reserve treatments carrying higher risk, for patients with the

Perspective

For families with HHT, the recent advances in scientific and medical understanding of their condition are encouraging after the decades of limited advances. There are genuine hopes for improved and targeted treatment modalities, and emerging evidence that existing strategies are already offering affected individuals a better medical outlook than their grandparents.

Yet there are others for whom the deluge of new and frightening information holds concerns. As one attendee of the 2009 UK HHT

Conflict of interest statement

No conflicts of interest to declare.

Acknowledgments

The author thanks Dr. James Jackson, Dr. Alan Guttmacher and Dr. Fatima Govani for reviewing the manuscript; Katharine Thompson for bibliographical software assistance; and Professor John West for his framework of pulmonary circulatory concepts. She acknowledges support from the NIHR Biomedical Research Centre Funding Scheme, the British Heart Foundation, and British HHT families.

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