Introduction:

• It is a autosomal dominant disorder characterised by mucocutaneous telangiectasias and visceral arteriovenous malformations
• Previously called Osler-Weber-Rendu syndrome
• Secondmost commoninherited bleedingdisorder

Epidemiology:

• 1 in 5,000-8,000 individuals

Etiology:

Pathogenesis:

Mutation in genes involved in TGF-Bsignaling

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Disrupted angiogenesis (Disorganized cytoskeleton and dysfunctional remodeling of the vascular endothelium)

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Vessels exhibit a loss of elasticity and remain chronically dilated

(AVMs can form in the brain, lungs, GI tract, spine, or liver)

Clinical features:

• Manifests usually in 2^nd decade of life
• Bleeding: Mild epistaxis to life-threatening intracranial bleeds
• Telangiectasias (Dilated blood vessels): Seen in skin and buccal/ nasal mucosa. Their number increases with age
• AVMs in various organs:
  • Lungs: Heart failure, venous thromboembolism
  • GI tract:Iron deficiency
  • Brain: Stroke, Migraine
  • Liver
  • Spine
• Polycythemia due to pulmonary AVNs
• Brain abscess: Due to entry of bacterial from pulmonary AVN into systemic circulation
• Positive family history

Complications:

• Internal hemorrhage
• Pulmonary AVMs can lead to strokes, massive hemoptysis, spontaneous hemothorax, transient ischemic attacks, and brain abscesses.
• Pulmonary and hepatic AVMs can lead to arteriovenous shunting which can result in high output cardiac failure and pulmonary hypertension
• Colorectal malignancies in HHT Associated with Juvenile Polyposis

Investigations:

• Genetic testing for detection of mutations
• CT thorax and abdomen and MRI brain: To identify AVMs.
• 2D echo: To identify presence of pulmonary hypertension
• Upper and lower GI scopies +/- capsule endoscopy if GI blood loss is suspected
• Annual complete blood count and ferritin

Criteria for diagnosis (Curaçao Criteria): 3 of the 4 criteria must be present

• Spontaneous, recurrent epistaxis
• Positive family history
• Cutaneous or mucosal telangiectasias
• Visceral lesions

Prognosis:

• Survival compared to general population is 3 years less.

Treatment:

• To avoid recurrent epistaxis:
  • Topical moisturizers and emollients
  • Nasal hygiene with humidifiers and nasal saline irrigations
  • Avoidance of triggers and blood thinners
• Treatment of epistaxis:
  • Topical decongestant spray
  • Manual pressure
  • Absorbable nasal packing
  • Chemical cauterization with silver nitrate
  • For refractory cases: surgical or endovascular interventions
• Following agents may be tried topically/ systemically
  • Estrogen agents (tamoxifen, raloxifene, and estriol ointment)
  • Tranexamic acid
  • Thalidomide
  • Beta-blockers (timolol or propranolol)
  • Vascular endothelial growth factor (VEGF) inhibitors(bevacizumab).
  • Inj. Bevacizumab5 mg/kg IV over 90min, at 14- to 21-day intervals. Total of 6 doses should be given. If bleeding gets controlled, maintenance treatment is used with an individualized schedule.
• Surgical interventions for epistaxis:
  • Electrosurgical plasma coagulation
  • Potassium titanyl phosphate laser photocoagulation
  • Sclerotherapy with sodium tetradecyl sulfate
  • Septodermoplasty
  • Young’s procedure: Closure of one or both nostrils using mucocutaneous flaps
• Anemia:
  • Oral/ IV iron supplementation
• GI Bleeding
  • Mild- moderate: Regular iron replacement
  • Severe:
    • Intravenous bevacizumab
    • Endoscopic argon plasma coagulation
• Pulmonary AVMs
  • Transcatheter embolization with embolic material such as metallic coils and Amplatzer vascular plugs
  • Lung transplantation
• Hepatic AVMs
  • Intravenous bevacizumab
  • Liver transplantation
  • Avoid hepatic artery embolization
• Cerebral AVMs (Treated if symptomatic or family history of hemorrhage)
  • Embolization
  • Microsurgery
  • Stereotactic radiation

Special situations:

• Pregnancy:
  • Avoid epidural anesthesia
  • If patient has cerebral AVMs or h/ohemorrhage: Deliver by cesarean section, as straining during vaginal delivery can cause hemorrhage.

Recent Advances:

Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia

In this randomized trial for recurrent bleeding due to small-intestinal angiodysplasia, thalidomide (100 mg or 50 mg) demonstrated efficacy compared to placebo. The effective response rates were 68.6%, 51.0%, and 16.0%, respectively, with thalidomide showing a significant reduction in bleeding episodes. Adverse events were more common in thalidomide groups, including constipation and somnolence.

https://doi.org/10.1056/NEJMoa2303706

MEK 1 inhibition and bleeding in hereditary haemorrhagic telangiectasia

This report discusses a case study of a patient with hereditary haemorrhagictelangiectasia (HHT) who experienced a reduction in nosebleeds and transfusion requirements after treatment with trametinib, a MEK inhibitor. The patient had been refractory to previous treatments, and the use of trametinib resulted in a notable improvement in symptoms. The study suggests a potential role for MEK inhibition in reducing morbidity associated with HHT-related bleeding and anaemia, although further research and clinical trials are needed to confirm these findings and establish optimal dosing regimens.

https://doi.org/10.1111/bjh.19167

Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia

In a randomized, placebo-controlled trial, pomalidomide was evaluated for treating hereditary hemorrhagic telangiectasia (HHT), focusing on reducing epistaxis severity. A total of 144 patients were enrolled, with 95 receiving pomalidomide and 49 receiving placebo. At 24 weeks, the pomalidomide group showed a significant reduction in the Epistaxis Severity Score by 0.94 points compared to placebo (P=0.004), along with a notable improvement in HHT-specific quality of life. The treatment was generally well-tolerated, with common adverse effects including neutropenia, constipation, and rash, indicating pomalidomide as a promising option for managing HHT symptoms.

https://doi.org/10.1056/NEJMoa2312749