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A. Kritharis et al.
• telangiectasias at characteristic sites
• visceral arteriovenous malformations or telangiectasias • a first degree relative with HHT (inheritance is usually
autosomal dominant).
Patients are classified as follows:
3-4 criteria: definite HHT 2 criteria: probable HHT 0-1 criteria: HHT unlikely.
Genetic testing can be performed to inform family mem- bers, to increase patient awareness, and can guide more focused preventative screening and in cases of uncertainty. For patients with all 4 features present, the clinical sensitiv- ity of the 5 gene HHT panel (assessing for pathogenic muta- tions in ENG, ACVRL1, MADH4, RASA1, and BMP9) is approximately 87% or higher.19 Although there has recently been an increase in awareness of HHT, it has been estimat- ed that only 10% of all HHT patients are formally diag- nosed; this is because of minimal symptoms or the fact that caregivers are not familiar with the disease and its diagnos- tic criteria.56
Assessment and management
The prevention of future HHT complications is as impor- tant as treating the immediate active issues (e.g. bleeding) in caring for patients with HHT. Patients are often asympto- matic from undiagnosed AVMs that can lead to significant morbidity and mortality. Knowledge of a patient’s genetic mutation or family history may help confirm the urgency of certain screening tests over others. As outlined in Table 2, the following are relevant measures for identifying poten- tially significant AVMs: 1) brain magnetic resonance imag- ing (MRI)/magnetic resonance angiography (MRA); 2) transthoracic echocardiogram with bubble study, followed by computed tomography (CT) scan as appropriate; 3) colonoscopy/endoscopy/video capsule endoscopy; 4) abdominal doppler ultrasound of the liver, followed by CT scan or MRI as indicated; 5) full ENT evaluation (especially if the patient has epistaxis); and 6) skin evaluation. Hematologic evaluation must also include complete blood count, reticulocyte count, erythrocyte sedimentation rate, iron, total iron binding capacity and ferritin. Ferritin levels alone may not accurately reflect iron stores due to the increased inflammation seen in many HHT patients. Consideration should be given to assessment for inherited thrombophilias prior to using antifibrinolytics for treatment of bleeding associated with HHT.
Treatment options are patient-specific and are best grouped by local versus systemic measures in a stepwise approach. There are no standard medical therapies for HHT given the few randomized trials in this field. Management can include supportive care, lesion-specific therapy, and systemic treatment. Lesion-specific therapy may call for involvement from otolaryngology, interventional radiology and neurosurgery.
Management of epistaxis
The first step in epistaxis management should always be appropriate patient counseling and use of preventive measures within the home to prevent the nasal mucosa from becoming dry. These may include nasal humidifica- tion, use of over-the-counter saline sprays or ointments to keep the nasal mucosa moist, and avoidance of nasal trau- ma (i.e. from nose blowing and/or nose picking).20
When epistaxis occurs that does not cease within a short period of time at home, nasal packing and direct use of topical agents such as tranexamic acid-soaked gauze in an outpatient clinic or emergency room setting may help curtail bleeding but may also increase trauma to the nasal mucosa. Additional local measures that are commonly employed to control bleeding include laser treatments to the nasal mucosa and septodermoplasty.57 Historically, laser photocoagulation and other interventional proce- dures have been the cornerstone of therapy,58 although this may begin to shift with effective disease-modifying systemic therapeutics on the horizon, detailed later in this review. Nasal closure57 is an effective but extreme form of therapy that is rarely used.
Management of epistaxis with antifibrinolytic agents is another consideration when preventive measures and local or topical treatments fail. Hyperfibrinolysis con- tributes to the bleeding phenotype in HHT59,60 and antifib- rinolytics may work to inhibit fibrinolysis on the telang- iectatic wall. By preventing fibrin degradation from plas- min, these agents may act to slow bleeding. Epsilon- aminocaproic acid and tranexamic acid can be considered in the care of patients with moderate or severe epistaxis.61 In a randomized, double-blind, placebo-controlled, crossover study of 22 patients, tranexamic acid 1 g 3 times daily resulted in a 54% reduction in nosebleeds while on tranexamic acid as compared with the placebo treatment period, although there was no statistically sig- nificant improvement in hemoglobin concentration.62 Apart from its inhibition of plasmin, tranexamic acid may have some effect on the underlying disease process; it appears to increase endoglin and ALK1 levels on the endothelium, selectively stimulating the TGF-β path- way.63 Tranexamic acid may have a higher potency and longer half-life than aminocaproic acid in these patients.63 Dosing can be titrated upward if tolerable to tranexamic acid 650-1300 mg orally 3 times daily or aminocaproic acid 500-2000 mg orally every 4-8 hours.63 Other non-spe- cific hemostatic agents, such as desmopressin or factor replacement products, are not optimal management as HHT is not a disease of coagulation factor deficiency. Antifibrinolytics should be avoided in patients with hypercoagulable conditions and/or prior thrombotic events.
While the evidence for its use is limited, N-acetylcys- teine dosed 600 mg 3 times daily was modestly effective in reducing epistaxis in HHT patients in a pilot study, with the only statistically significant benefit seen in male patients and those with ENG mutations (HHT1).64
Management of GI bleeding
Evidence of GI bleeding or a sharp decline in hematocrit without epistaxis should involve a prompt GI evaluation and an upper and lower endoscopy and, if these do not provide clear results, consideration of video capsule endoscopy. Telangiectasias and AVMs may be visualized in the esophagus, stomach, small intestine and/or colon.65 If accessible, local endoscopic treatment should be attempted. Patients with recurrent bleeding, multiple AVMs, and small bowel AVMs may require additional pharmacological measures. As in the management of epis- taxis, antiangiogenic, antifibrinolytic agents and/or other hormonal agents may be considered. Octreotide therapy has also been proposed in reducing transfusion needs66 but is without much supporting data. Management of the ane-
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haematologica | 2018; 103(9)