Hematologists Should Take Primary Management Role in HHT

Hereditary hemorrhagic telangiectasia (HHT) affects roughly 1 in 5,000 people, making it the second most common inherited bleeding disorder after von Willebrand disease.¹ Due in part to the history of disease treatment, primary management has fallen to proceduralists and HHT has historically drawn relatively little research attention from hematologists. However, that is changing.

“HHT is twice as common as hemophilia, and it’s a big blind spot for the hematology community,” said Hanny Al-Samkari, MD, adult classical hematologist, associate professor of medicine at Harvard Medical School, and co-director of the HHT Center of Excellence at Massachusetts General Hospital in Boston. “It is a neglected bleeding disorder that has an order of magnitude less research funding than hemophilia.”

Underdiagnosis is a major concern in HHT. Dr. Al-Samkari noted that people are often diagnosed in their 30s, 40s, or later, though symptoms like epistaxis typically begin appearing during the teen years.

Adrienne M. Hammill, MD, PhD, a pediatric hematologist-oncologist and director of the HHT Center of Excellence at Cincinnati Children’s Hospital Medical Center, added, “We really need to reach out to hematologists so HHT is on their radar if somebody’s coming in with severe anemia for their nosebleeds or for their GI [gastrointestinal] bleeds.”

Early diagnosis and primary management by hematologists are key because, in addition to the common undertreatment of anemia that results from the condition, anti-fibrinolytics and anti-angiogenic therapies repurposed from other areas of hematology and oncology have become a cornerstone of therapy.

ASH Clinical News talked with Drs. Al-Samkari and Hammill about these and related issues in HHT, including disease pathophysiology, diagnosis, screening, and current and emerging treatments.

Background and Disease Characteristics

In 1896, French physician Henri Rendu first described a combination of hereditary epistaxis and telangiectasias distinct from hemophilia. Several case reports followed in the next decade, including ones by physicians Sir William Osler and Frederick Weber, leading to the eponymous name of the condition, Osler-Weber-Rendu disease.²

HHT is a condition of disordered angiogenesis that leads to malformed blood vessels. The autosomal dominant condition results from mutations in genes that mediate the transforming growth factor-β superfamily. This pathway plays a critical role in normal angiogenesis and the maintenance of proper structure and strength of blood vessels. Most patients have mutations in endoglin or activin receptor-like kinase 1 (ALK1), but roughly 20% have unidentified mutations.³

Dysregulation of the pathway results in increased expression of vascular endothelial growth factor (VEGF) and disordered vessel growth and connections. This leads to subsequent formation of telangiectasias on mucocutaneous surfaces and arterial venous formations (AVMs) in internal organs.

Fragile telangiectasias in the nose, found in more than 90% of patients, can lead to chronic and often severe nose bleeds that significantly impair patients’ activities. Without intervention, these and other disease characteristics tend to worsen over time as patients acquire additional telangiectasias and AVMs and their existing ones become structurally weaker.⁴

Telangiectasias also often develop in the stomach, small bowel, and colon, leading to chronic GI bleeding, with increased incidence with age. Both epistaxis and chronic GI bleeding may lead to iron deficiency anemia (IDA), though severe anemia is more likely to occur in the context of recurrent GI bleeds.

AVMs can occur in the lung, liver, or central nervous system, creating a variety of serious complications, including cerebral abscess, intracerebral hemorrhage, and paradoxical emboli leading to stroke. Liver AVMs manifest differently depending on the vessels involved but may cause portal hypertension, pulmonary hypertension, high-output heart failure, and liver necrosis with liver failure.¹

Diagnosis

Dr. Hammill pointed out that patients are sometimes followed for many years before someone, often a trainee, notices telangiectasias and considers the patient from a different diagnostic perspective. These small, bright red spots blanch with pressure and characteristically appear on the lips, oral cavity, fingers, or nose.

Under the Curaçao criteria, diagnosis of HHT is definite if at least three of four criteria are present: telangiectasias, recurrent spontaneous nosebleeds, family history in a first-degree relative, or visceral involvement (e.g., GI telangiectasia, hepatic AVM, cerebral AVM). Positive genetic testing of a known pathogenic HHT gene is also diagnostic.¹

Dr. Hammill noted that although these criteria are very specific, they are not very sensitive, especially in children, and added that genetic testing can rule out children who have a family history and known variant. However, this isn’t an option for patients whose family members have a yet-unidentified pathogenic gene.

“We have to assume that these children have HHT until they’re old enough to be ruled out,” Dr. Hammill said. The optimal age to do so is under debate, as it’s been suggested that some patients may not meet criteria until their 30s.

Management and Monitoring

HHT is a multisystem bleeding disorder that requires input from multiple medical specialties, including hematology, pulmonology, cardiology, ENT (ear, nose, and throat), hepatology, neurology, and interventional radiology. Historically, many patients have been managed through ENT because procedures were the main treatments available.

However, Dr. Al-Samkari explained, “Given that the most common manifestations of this disease are bleeding and IDA, it is my strong belief that hematologists should now serve as the medical home for patients with HHT in much the same way that hematologists are the medical home for patients with hemophilia.”

For management considerations, clinicians can reference the 2020 international HHT guidelines, which provide detailed guidance on diagnosis and treatment.⁵ “Compared to the prior version of the guidelines, we are moving away from procedures toward using medicines first,” Dr. Al-Samkari said.

Ablative procedures for telangiectasias — laser treatment, radiofrequency ablation, or sclerotherapy — are sometimes still appropriate. For example, before stepping up to anti-angiogenic therapy for severe epistaxis, it may be helpful to get an ENT perspective on whether a patient has a single dominant lesion for which ablation might be helpful. However, according to Dr. Al-Samkari, the more invasive and extreme surgical approaches that were sometimes used in the past, such as septodermoplasty or nasal closure, are now rarely the right approach.

Dr. Al-Samkari pointed out that we now know that the trauma of ablative procedures may stimulate local VEGF release at the site of the trauma and the formation of new telangiectasias, resulting in worsened future bleeding and rendering a primary procedural approach inherently problematic. For GI bleeds, the current guidelines only recommend procedural intervention for a substantial active bleed and solely in those lesions visibly bleeding at the time of endoscopy.⁵

Management of anemia is a key part of hematologic management, and patients with HHT are often not adequately treated in terms of iron repletion. Per the guidelines, patients with HHT need to be monitored at least yearly for anemia, with most requiring more frequent testing.⁵ Most patients will ultimately need repeated intravenous (IV) iron infusions, with oral iron adequate in a minority of patients. The most severe patients — those in whom an acceptable hemoglobin is not possible even with frequent iron infusions — also require regular red blood cell transfusions.

“We manage their anemia to maintain a ferritin greater than 50 [mcg/L] and maintain their percent transferrin saturation at greater than 20,” Dr. Hammill said. “If they’re below that, they need more iron, even if their hemoglobin is normal. We need to keep these folks replete with good stores of iron because we know it’s just a matter of when they bleed again, not if.”

Drug and Monoclonal Antibody Therapeutics

To date, the U.S. Food and Drug Administration has not specifically approved any agents for use in HHT. However, hematologists have repurposed other agents used in hematology and oncology with some success. For example, the antifibrinolytics tranexamic acid and aminocaproic acid can be helpful for recurrent epistaxis or GI bleeding as firstline interventions (after basic measures such as nares humification).

However, Dr. Al-Samkari said these agents can require patients to take multiple pills more than once a day and cause significant side effects in some patients at the necessary doses. Moreover, as antifibrinolytics inhibit clot breakdown, they don’t manage the primary root cause in HHT: weak and fragile blood vessels.

Disease-modifying systemic anti-angiogenics are another option, particularly in patients who need their therapy stepped up. These include the anti-VEGF monoclonal antibody bevacizumab and the oral agents pazopanib, thalidomide, and pomalidomide. Dr. Al-Samkari pointed out that one can clinically see telangiectasias resolving over time as patients are treated with bevacizumab. Currently, it remains unknown which of these agents is the best approach because head-to-head trials have not been performed.

Dr. Hammill noted that when considering whether to start bevacizumab in a patient with severe anemia for GI bleeds, one might weigh the frequency of bevacizumab infusions versus the frequency of necessary iron infusions. It may also make sense to start some patients with an oral, less expensive anti-angiogenic agent instead of bevacizumab. However, at present, most of the oral agents are readily obtained only through clinical trials.

Ongoing clinical trials may open new treatment options and give more information on which current off-label approaches might work best for which patients. The first U.S. prospective study of bevacizumab for bleeding in HHT is ongoing, as is a phase II/III trial of the VEGF receptor tyrosine kinase inhibitor pazopanib and a phase II trial of the immunomodulatory agent pomalidomide. Vaderis is also developing an AKT1 inhibitor for HHT; if approved, it will become the first targeted therapy developed specifically for the condition.

Managing Anticoagulation Risks

Hematologists can also play a role in managing anticoagulation in patients with HHT. Although HHT is a bleeding disorder, it also carries an elevated thrombotic risk. Dr. Al-Samkari said this may partly result from low iron stores and elevated levels of factor VIII that are seen in the disease, as well as potentially from abnormalities in the vasculature itself.

Patients can receive prophylactic or therapeutic treatment with anticoagulation or antiplatelet therapy if medically indicated for other issues. However, Dr. Hammill noted that according to the recent guidelines, clinicians should avoid dual anticoagulation where possible.⁵

Screening and Visceral Disease Management

Notably, patients with HHT who receive systematic screening and follow-up treatment, such as those recommended in the guidelines, may have a similar life expectancy compared to unaffected persons.⁶

Current guidelines recommend that children and adults be screened for brain vascular malformations via MRI at initial time of diagnosis.⁵ Depending on the time of diagnosis, children may benefit from one or two additional screens, Dr. Hammill said. Such lesions are typically asymptomatic but run the risk of hemorrhagic stroke. High-risk lesions require collaboration with neurology, neurosurgery, and neuroradiology to determine whether potential embolization, resection, or focal radiation might be needed.

Screening for lung AVMs is also important. Such AVMs can be asymptomatic, chronic with symptoms such as shortness of breath, or manifest as acute presentations, including paradoxical embolization leading to stroke. Interventional radiologists can use a coil embolization technique to treat based on size and clinical context.

Dr. Hammill shared that bubble echo is accepted as the initial screen for such lesions in adults, as noted in the guidelines.⁵ This is also typically the approach used in the U.S. for children, she noted, and it is much more dependable than using chest X-ray plus pulse oximetry, an approach sometimes employed in Europe.

The best approach to liver lesions is an evolving topic in HHT. Assessing and treating liver lesions is challenging, partly because the liver circulation and resulting liver disease is so varied and complex. Although the majority of patients with HHT have some sort of liver circulation abnormality, only a minority have significant liver problems. Currently, it remains difficult to predict who will show liver disease that might require transplantation or who might benefit from anti-angiogenic therapies.

“At a minimum, you’re doing extra labs and an exam focused on the liver, and ideally you’re doing some more advanced imaging, but it’s not clear how frequently that needs to be done,” said Dr. Hammill. “It’s very uncommon for people to run into trouble with their liver AVMs before the age of 30, so doing a good set of imaging around then would be reasonable.”

Such complications may be best managed at one of the HHT Centers for Excellence; current guidelines recommend patients be evaluated at such a center at least once. Here, center directors and associated experts can help guide initial evaluation and more complex treatment decisions. Local hematologists, though, play a critical role in everyday management, including properly repleting with IV iron if needed and prescribing antifibrinolytics.

“Not every patient is near [an HHT Center of Excellence],” Dr. Hammill said. “So that’s where we need to reach out to all the hematologists across the country so they’ll potentially consider HHT in their initial differential and partner with the Centers of Excellence to follow the most recent guidelines.”

References

1. Hammill AM, Wusik K, Kasthuri RS. Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management. Hematology Am Soc Hematol Educ Program. 2021;2021(1):469-477.
2. Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med. 1995;333(14):918-924.
3. Kritharis A, Al-Samkari H, Kuter DJ. Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist’s perspective. Haematologica. 2018;103(9):1433-1443.
4. Al-Samkari H. Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood. 2021;137(7):888-895.
5. Faughnan ME, Mager JJ, Hetts SW, et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2021;174(7):1035-1036.
6. de Gussem EM, Kroon S, Hosman AE, et al. Hereditary hemorrhagic telangiectasia (HHT) and survival: the importance of systematic screening and treatment in HHT Centers of Excellence. J Clin Med. 2020;9(11):3581.