(See also Overview of Vascular Bleeding Disorders Overview of Vascular Bleeding Disorders Bleeding may result from abnormalities in Platelets Coagulation factors Blood vessels Vascular bleeding disorders result from defects in blood vessels, typically causing petechiae, purpura,... read more .)
More than 80% of patients have mutations in one of the following genes (1 General reference Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women. (See also Overview of Vascular Bleeding... read more 
):
Endoglin (ENG) gene, which encodes a receptor for transforming growth factor beta-1 (TGF-β1) and transforming growth factor beta-3
ACVRL1 gene, which encodes the activin receptor-like kinase (ALK1)
MADH4 gene, which encodes SMAD4, a protein active in the TGF beta signalling pathway
General reference
1. Kritharis A, Al-Samkari H, Kuter D: Hereditary hemorrhagic telangiectasia: Diagnosis and management from the hematologist’s perspective. Haematologica 103:1433–1443, 2018. doi: 10.3324/haematol.2018.193003
Symptoms and Signs
The most characteristic lesions of hereditary hemorrhagic telangiectasia are small red-to-violet telangiectatic lesions on the face, lips, oral and nasal mucosa, and tips of the fingers and toes. Similar lesions may be present throughout the mucosa of the gastrointestinal (GI) tract, resulting in recurrent GI bleeding. Patients may experience recurrent, profuse nosebleeds. Some patients have pulmonary arteriovenous malformations (AVMs). These AVMs may cause significant right-to-left shunts, which can result in dyspnea, fatigue, cyanosis, or erythrocytosis. However, the first sign of the presence of AVMs may be a brain abscess, transient ischemic attack Transient Ischemic Attack (TIA) A transient ischemic attack (TIA) is focal brain ischemia that causes sudden, transient neurologic deficits and is not accompanied by permanent brain infarction (eg, negative results on diffusion-weighted... read more , or stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more 
as a result of infected or noninfected emboli. Cerebral or spinal AVMs occur in some families and may cause subarachnoid hemorrhage Subarachnoid Hemorrhage (SAH) Subarachnoid hemorrhage is sudden bleeding into the subarachnoid space. The most common cause of spontaneous bleeding is a ruptured aneurysm. Symptoms include sudden, severe headache, usually... read more 
, seizures Seizure Disorders A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered... read more , or paraplegia. Hepatic AVMs may lead to liver failure Acute Liver Failure Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more and high output heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular failure causes shortness of breath and fatigue, and right ventricular failure causes peripheral and abdominal fluid... read more 
. Chronic iron deficiency anemia Iron Deficiency Anemia Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more 
is commonly present.
This photo shows a close-up of the face of a patient with multiple telangiectasias secondary to hereditary hemorrhagic telangiectasia.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is an autosomal dominant disorder that manifests with widespread cutaneous, mucosal, and visceral telangiectases and arteriovenous malformations. Papular, punctate, and linear telangiectases occur predominantly on the tongue, lips, digit tips, perioral region, and trunk.
By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
Diagnosis
Clinical evaluation
Sometimes endoscopy or angiography
Sometimes genetic testing
Diagnosis of hereditary hemorrhagic telangiectasia is based on the finding of characteristic arteriovenous malformations on the face, mouth, nose, digits, and/or internal organs in the context of epistaxis and family history. The Curaçao criteria include the following:
Spontaneous recurrent epistaxis
Multiple telangiectasias in typical locations
Documented visceral arteriovenous malformations (eg, in the lung, liver, brain, and spine)
First-degree family member with hereditary hemorrhagic telangiectasia
Hereditary hemorrhagic telangiectasia is definite if 3 of these criteria are met and possible if 2 are met (1, 2 Diagnosis references Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women. (See also Overview of Vascular Bleeding... read more ).
Endoscopy or angiography is sometimes needed. Laboratory findings are usually normal except for iron deficiency anemia Iron Deficiency Anemia Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more in many patients.
Testing for the ENG, ACVRL1, and MADH4 mutations may be helpful in some patients with atypical features or for screening asymptomatic family members.
Screening
If a family history of pulmonary, hepatic, or cerebral arteriovenous malformations exists, screening at puberty and at the end of adolescence with pulmonary CT, hepatic CT, and cerebral MRI is recommended.
Diagnosis references
1. Shovlin CL, Guttmacher AE, Buscarini E, et al: Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91(1):66–67, 2000. doi: 10.1002/(sici)1096-8628(20000306)91:1<66::aid-ajmg12>3.0.co;2-p
2. Faughnan ME, Mager JJ, Hetts SW, et al: Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med 173(12):989–1001, 2020. doi: 10.7326/M20-1443
Treatment
Sometimes laser ablation, surgical resection, or embolization of symptomatic arteriovenous malformations
Supplemental iron therapy
Possibly blood transfusions
Sometimes antifibrinolytic drugs (eg, aminocaproic acid, tranexamic acid)
Sometimes angiogenesis inhibitors (eg, bevacizumab, pomalidomide, thalidomide)
Treatment for most patients is supportive, but accessible telangiectasias (eg, in the nose or gastrointestinal tract via endoscopy) may be treated with laser ablation. Arteriovenous malformations in the lungs can be treated by surgical resection or coil embolization.
Repeated blood transfusions Blood Products Whole blood can provide improved oxygen-carrying capacity, volume expansion, and replacement of clotting factors and was previously recommended for rapid massive blood loss. However, because... read more may be needed; therefore, immunization with hepatitis B vaccine Hepatitis B (HepB) Vaccine The hepatitis B vaccine is 80 to 100% effective in preventing infection or clinical hepatitis B in people who complete the vaccine series. For more information, see Hepatitis B Advisory Committee... read more is important.
Many patients require continuous iron therapy to replace iron lost in repeated mucosal bleeding (see treatment of Iron Deficiency Anemia Treatment Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more ). Many patients also require parenteral iron, and sometimes recombinant erythropoietin is necessary.
Treatment with drugs that inhibit fibrinolysis, such as aminocaproic acid or tranexamic acid, may be beneficial.
Treatment with drugs that inhibit angiogenesis such as bevacizumab, pomalidomide, thalidomide, or pazopanib can reduce the number and density of abnormal vessel growth (1 Treatment references Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women. (See also Overview of Vascular Bleeding... read more ). In addition, bevacizumab has recently been shown to reduce the incidence of nasal and gastrointestinal bleeding (2–4 Treatment references Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women. (See also Overview of Vascular Bleeding... read more ).
To avoid paradoxical embolization of particulate matter to the brain through pulmonary arteriovenous malformations, all IV fluids need to given through a filter.
Treatment references
1. Al-Samkari H: Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood 137 (7): 888–895, 2021.
2. Al-Samkari H, Kasthuri RS, Parambil JG, et al: An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica 106(8):2161–2169, 2021. doi: 10.3324/haematol.2020.261859
3. Al-Samkari H, Kritharis A, Rodriguez-Lopez JM, Kuter D: Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia. J Intern Med 285(2):223–231, 2019. doi: 10.1111/joim.12832
4. Faughnan ME, Mager JJ, Hetts SW, et al: Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med 173(12):989–1001, 2020. doi: 10.7326/M20-1443
Key Points
Nasal and gastrointestinal telangiectasias may cause significant external hemorrhage in patients with hereditary hemorrhagic telangiectasia.
Vascular malformations in the central nervous system, lungs, and liver may bleed; hepatic and pulmonary malformations may cause significant shunting.
Accessible mucosal telangiectasias and arteriovenous malformations may be treated with laser ablation; coil embolization or surgical resection may be needed for pulmonary vascular malformations.
Antifibrinolytic drugs and angiogenesis inhibitors may reduce the incidence of bleeding.
Many patients require parenteral iron supplements because of chronic blood loss.
All IV solutions should be given through a filter to avoid paradoxical embolization of particulate matter to the brain through pulmonary arteriovenous malformations.
