Osler-Weber-Rendu Disease (Hereditary Hemorrhagic Telangiectasia)

OWRD (ie, HHT) is the first identified human disease caused by defects in a TGF-β superfamily receptor.[14, 16] The clinical manifestations of OWRD are caused by the development of abnormal vasculature, including telangiectasias, AVMs, and aneurysms. Unaffected areas show normal vessel architecture on ultrastructural analysis.[17] Thus, researchers postulate that an initiating event combined with abnormal repair results in the lesions.[18]

Defects in the endothelial cell junctions, endothelial cell degeneration, and weakness of the perivascular connective tissue are thought to cause dilation of capillaries and postcapillary venules, which manifest as telangiectasias. Most commonly, telangiectasias involve the mucous membranes, as well as the skin, the conjunctiva, the retina, and the GI tract.

AVMs are abnormal tortuous vessels with both arterial and venous components. Larger AVMs can cause left-to-right shunting and, if sufficiently large, may contribute to high-output heart failure. Loss of the muscularis layer and disturbance of the elastic lamina of vessel walls may also give rise to aneurysms in multiple organ systems. AVMs are found in the lungs, brain, and liver.

Telangiectases and AVM bleeding tendency are attributed to localized vessel wall weakness, in part due to abnormal remodeling resulting from an imbalance in functions related to TGF-β.[11] Interactions with TGF-β signaling result in disorganized cytoskeletal structure and poor vascular tubule formation. The gene expression profiles of the vascular endothelial cells grown from HHT patients reveals dysregulation of genes involved with the following[19] :

• Angiogenesis
• Cytoskeletal integrity
• Cell migration
• Proliferation
• Nitric oxide synthesis

HHT has been classified into the following four types, though more may exist:

• HHT type 1
• HHT type 2
• HHT type 3
• HHT−juvenile polyposis overlap syndrome (JPHT)

The genes most commonly implicated in HHT are the endoglin gene (ENG; HHT type 1) and the ALK-1 gene (ALK1; HHT type 2); other genes are less frequently involved (see Etiology).[20] Endoglin and ALK-1 are type III and type I TGF-β receptors, and both are exclusively expressed on vascular endothelial cells.

The binding of TGF-β to the type II TGF-β receptor on endothelial cells, which is accelerated in the presence of endoglin, results in the phosphorylation of the type I TGF-β receptors ALK-5 and ALK-1. Endoglin and ALK-1 bind directly to bone morphogenetic protein (BMP)-9 and BMP-10 and mediate their defects in conjunction with the type II BMP receptor (BMPR II).[21, 22] Phosphorylated ALK-5 and ALK-1 activate the downstream proteins Smad2/3 and Smad1/5, respectively.[23]

The activated Smad proteins dissociate from the type I TGF-β receptor, bind to Smad4, and enter the nucleus to transmit TGF-β signals by regulating transcription from specific gene promoters involved in angiogenesis. Therefore, a balance between the two signaling pathways involving ALK-5 and ALK-1 is important in determining the properties of endothelial cells during angiogenesis.

Histopathologic studies reveal large, irregular, thinly walled blood vessels, but the pathogenesis has not been fully established. One theory states that systemic nevus vascular damage may not be equally expressed in all individuals with HHT. Individuals with blood group type O are affected more often, whereas males and females are affected equally. Coagulation abnormalities and increased fibrinolytic activity in the lesions may contribute to the tendency for bleeding.

OWRD (ie, HHT) is a disorder that is inherited in an autosomal dominant fashion,[24, 25] though 20% of patients are unaware of a positive family history, partly because the lesions may be minimal and because 10% of patients have no episodes of bleeding. The homozygous condition probably is fatal.

HHT is attributed to genetic mutations that involve signaling of TGF-β.[11] Defects in at least four genes are implicated in its development,[26]  as follows:

• Mutations of ENG (encoding endoglin) - These characterize HHT type 1 and involve chromosome 9, 9q33-34 ^[27]
• Mutations of ALK1 (encoding ALK-1), also called ACVRL1 (activin A receptor kinase type II-like 1) - These are implicated in HHT type 2 and involve chromosome 12, 12q13 ^[28]
• Mutations of chromosome 5 (5q31.1-32) - These are distinct from hereditary benign telangiectasia (HBT), a gene defect in RASA1 (chromosome 5q14) ^[12]
• Mutations of SMAD4/MADH4 (encoding Smad4) - These are described in JPHT, ^{[29, 30]} which is also autosomal dominant, involves chromosome 18, and combines clinical manifestations of HHT and juvenile polyposis

The first two (HHT types 1 and 2) account for approximately 85% of cases.

In addition, some families show no links to any of the known loci. One patient with HHT and pulmonary hypertension with no mutation in ENG, ACVRL1, or SMAD4 but was found to have a nonsense mutation in BMPR2.[31]

United States statistics

OWRD (ie, HHT) is rare in North America. The reported incidence is 1-2 cases per 100,000 population annually. The overall prevalence is estimated to be approximately 1-2 cases per 10,000 population. However, the prevalence may be underestimated because many cases may be asymptomatic.[32] In Vermont, the frequency has been estimated at 1 case per 16,500 population.[2] The disease has a clinical penetrance of 97%.

International statistics

The worldwide prevalence is 1 case per 5000-10,000 population In Europe and Japan, the frequency is estimated to be between 1 in 5000 to 8000 people.[4, 14, 33, 34] The prevalence of HHT in a Danish population increased from 13.8 cases per 100,000 population in 1974 to 15.6 cases per 100,000 population in 1995.[35]

The frequency may vary considerably between populations. The highest rates are seen in parts of the Dutch Antilles among the Afro-Caribbean population, with a prevalence of between 1 case per 200 persons and 1 per 1331 persons in the Curaçao and Bonaire regions.[36, 37] In the French department of Ain, the prevalence is 1 case per 2351 persons; in France overall, it is 1 per 8345.[6] Other examples include the Danish island of Funen (1 per 3500) and northern England (1 per 39,216).[38, 7]

Age-, sex-, and race-related demographics

HHT may occur in children, in whom a tendency to bleed may be the first symptom.[39] However, it is far more common during puberty or adulthood. The syndrome most often manifests by the second or third decade of life, though it may also be clinically silent. Pulmonary AVMs may be congenital and therefore may present within the first year of life. The risk of GI tract bleeding increases in patients older than 50 years.

HHT occurs with equal frequency and severity in males and females.[40] Although it most commonly occurs in whites, it has a wide geographic distribution and has been described in people of Asian, African, and Arabic descent.

Overall, life expectancy appears to be shortened by OWRD (ie, HHT)[41] ; nevertheless, with appropriate screening and aggressive management, life expectancy for the majority of patients may approach that of the normal population. Mortality shows an early peak at age 50 years and a later peak at 60-79 years related to acute complications.[33]

The prognosis is highly dependent on the severity of the disease—in particular, on the degree of systemic involvement, especially pulmonary, hepatic, and CNS involvement. Only 10% of patients die of complications of HHT.

The prevalence of brain AVM in HHT1 patients is 1000-fold higher than the prevalence in the general population (10 in 100,000), and in HHT2 patients it is 100-fold higher.[16] Pulmonary and CNS arteriovenous aneurysms may appear later in life. Patients with pulmonary AVMs and telangiectasis of the GI tract are at risk for life-threatening hemorrhage of the lungs and GI tract. Other sites of bleeding may include sites in the kidney, spleen, bladder, liver, meninges, and brain.

Strokes may be either hemorrhagic or ischemic. Of patients who have pulmonary AVMs, 2% per year are estimated to have a stroke, and 1% per year are estimated to develop a brain abscess. Retinal arteriovenous aneurysms occur only rarely. Patients are also at risk for high-output cardiac failure, migraines and further sequelae.

Frequent nosebleeds and melena may result from telangiectasia in the nose and GI tract. Patients with the severe form of HHT have heavy bleeding and resultant iron-deficiency anemia. Recurrent epistaxis is observed in as many as 90% of patients. In half the patients, the epistaxis becomes more serious with age, and blood transfusions are required in 10-30% of patients.

Telangiectases of the skin and mucous membranes, epistaxis, and a positive family history make up the classic triad of Osler-Weber-Rendu disease (OWRD; ie, hereditary hemorrhagic telangiectasia [HHT]). Visceral and central nervous system (CNS) involvement may be asymptomatic but is important because of associated complications that may be preventable. The diagnosis is made on clinical grounds, in accordance with the Curaçao criteria (see DDx).[9]

The estimated frequency of manifestations in patients with HHT is as follows:

• Spontaneous, recurrent epistaxis - 90%
• Skin telangiectases - 75%
• Hepatic or pulmonary involvement (arteriovenous malformations [AVMs]) - 30%
• Gastrointestinal (GI) bleeding - 15% ^[32]
• CNS lesions ^[42]

It is recognized that the manifestations of HHT are not generally present at birth but develop with increasing age. Data suggest that by age 16 years, 71% of individuals will have developed some sign of HHT, and by age 40 years, more than 90% will have done so. However, these data mean that during their childbearing years, an apparently unaffected child of an HHT patient still has a 5-20% chance of actually carrying the HHT disease gene.[32]

A known progression in the onset of symptoms over time begins with epistaxis, continues with pulmonary AVMs, and then proceeds to cutaneous and mucous telangiectases.[32]

Epistaxis

Nosebleeds may occur as often as every day or as infrequently as once a month. Patients with epistaxis usually present before the second decade of life. Blood transfusions are required in 10-30% of patients, and as many as 50% of patients require surgical treatment.

At present, there is no universally accepted method of measuring epistaxis severity. Rebeiz developed a classification that stratified epistaxis as follows[43] :

• Mild - A few episodes per week without transfusion requirement
• Moderate - One or two episodes per day, with fewer than 10 transfusions required in the patient’s lifetime
• Severe - Daily episodes lasting longer than 30 minutes, with more than 10 transfusions required in the patient’s lifetime

More than 900 respondents from 21 countries are currently participating in a study intended to create an epistaxis severity score for use in patients with OWRD.[44]

Pulmonary symptoms

Pulmonary AVMs affect approximately 50% of patients with HHT.[45] and are particularly common in HHT1, with 85% of ENG mutation carriers demonstrating right-to-left shunts on contrast echocardiograms.[45, 46]

Pulmonary AVMs are present in 15-33% of patients with the disease. Dyspnea and exercise intolerance are often presenting symptoms of pulmonary AVMs; however, most patients with pulmonary AVMs have no significant respiratory symptoms.[47, 48] Pulmonary AVMs may cause enough right-to-left shunting to cause cyanosis, hypoxemia, and secondary polycythemia. Pulmonary AVMs also increase the incidence of infection as a result of septic emboli formation in the pulmonary vasculature.

Pulmonary hypertension is another vascular manifestation of HHT. Although much less common than pulmonary AVMs, it can result from systematic arteriovenous shunting in the liver that increases cardiac output, or it can be clinically and histologically indistinguishable from idiopathic pulmonary hypertension.[49]

Telangiectasia

Telangiectases often appear 1 year after the first episode of epistaxis. The mucous membranes are almost invariably involved. About 30% of affected individuals report telangiectases first appearing before age 20 years, and two thirds report first appearances before age 40 years.[50] Patients usually have a family history of telangiectasia and recurrent bleeding in other family members.

Neurologic symptoms

Migraine headaches occur in 13-50% of patients with OWRD. Although the reason is unclear, the headaches are more prevalent in patients with pulmonary AVMs. Other neurologic involvement occurs in 8-12% of patients with OWRD. A history of headache, seizures, and focal neurologic symptoms (eg, paraplegia or paralysis) may be presenting symptoms.

Stroke and brain abscess are more common in patients with OWRD than in the healthy population. This is because the normal filtering function of the pulmonary vasculature is lost in patients with pulmonary AVMs. These AVMs allow thrombotic and septic emboli to travel to the brain. Untreated patients have a 2% risk of stroke and a 1% risk of brain abscess per year.[51]

Spinal AVMs represent a rare manifestation that mainly affects children. Acute paraplegia due to spinal arteriovenous fistula has been described.[52, 53] Examining any child with a family history of HHT for spinal AVMs may be advisable for decreasing the risk of neurologic sequelae.

Gastrointestinal and hepatic symptoms

The risk of GI tract bleeding increases at approximately 50 years of age. Recurrent painless GI bleeding occurs in 10-40% of patients and generally occurs later in life than epistaxis does. Visceral AVMs may be evident.[54] Patients may report abdominal pain, which may be due to thrombosis of GI AVMs.

Liver involvement (often asymptomatic) is reported in as many as 40% of patients. Symptoms may include right-upper-quadrant pain, jaundice, symptoms of high-output cardiac failure, and bleeding from esophageal varices. The complication of cardiac failure is caused by a large left-to-right shunt that can occur between the hepatic arteries and veins. Occasionally, patients with HHT may present with atypical cirrhosis.

Other symptoms

Fatigue may be elicited on history and may be due to an iron deficiency anemia caused by recurrent blood loss.

Visual disturbances may be noted, possibly caused by intraocular hemorrhage. Patients may notice bloody tears, which are due to conjunctival telangiectases.

The areas involved dictate the signs that may be found on physical examination. Obvious physical findings of OWRD (ie, HHT) are limited to those in the skin and mucous membranes. However, physical findings may also be present in many other organs. Common sites of involvement include the following:

• Skin
• Nasal and oral mucosa
• CNS
• Respiratory system
• GI tract
• Liver
• Cardiovascular system
• Eyes

Skin

Skin lesions begin as dark red lines or as punctate, pulsating vascular papules the size of match heads. These may be found on the skin, oral mucosa, nasal mucosa, and conjunctiva.[40] More rarely, skin lesions are star-shaped and 1-3 mm in diameter; alternatively, they are nonpulsating telangiectases resembling spider angiomas. (See the images below.)

The lesions blanch partially with pressure. Fine telangiectases may be difficult to appreciate in patients with anemia. Lesions often are conspicuous in the nail beds.

Half of patients manifest cutaneous lesions by age 30 years, though lesions may arise during the teenage years.[6] The face, lips and mouth, nares, tongue, ears, hands, chest, and feet are most often affected, in descending order of frequency and in any combination. Lesions are multiple and may be of cosmetic concern, and the number of lesions may increase with age. Bleeding is rarely clinically significant.

Almost invariably, all of the mucous membranes are involved, including membranes throughout the GI, respiratory, and urinary tracts and those in the nasal septum, oral cavity, and nasopharynx.

Nose

Recurrent epistaxis is usually the presenting symptom in HHT. Recurrent epistaxis is present in 90% of patients with HHT and appears at a young age, manifesting in most patients by age 21 years.[55] Bleeding occurs spontaneously from telangiectases of the nasal mucosa.

Recurrent epistaxis results in fatigue and anemia. Iron supplementation and blood transfusion may be required. Bleeding symptoms are progressive with increasing age. The presence of pulmonary AVM does not predict a better or worse natural history for epistaxis.[56]

Lung

The majority of pulmonary AVMs occur as part of HHT,[45, 46] affecting approximately 50% of HHT patients. Pulmonary AVM, with right-to-left pulmonary shunting, is the major cause of transient ischemic attack, brain abscess, and ischemic stroke in HHT patients as a result of paradoxic embolization of bland or septic material into the cerebral vasculature. These symptoms may be either the first manifestation of pulmonary HHT involvement or the presenting symptoms of HHT itself.[6]

Small AVMs with shunting of less than 25% of pulmonary blood flow are asymptomatic in half of cases. These patients show no cyanosis but demonstrate dyspnea on exertion and easy fatigability. Larger AVMs, especially when multiple, may result in dyspnea, fatigue, cyanosis, clubbing, and polycythemia.[57] Such severe shunting, defined as more than 25% of pulmonary blood flow, is seen in 20% of cases.

A study published by Shovlin et al in 2014, which included 497 patients with computed tomography (CT)-proven pulmonary AVMs due to HHT, suggested that patients with compromised pulmonary capillary filtration due to pulmonary AVMs are at increased risk of ischemic stroke if they are iron-deficient and that mechanisms are likely to include enhanced aggregation of circulating platelets.[45]

Auscultation reveals a continuous thoracic bruit in half of patients with cyanosis. Cyanosis and clubbing are particularly associated with an increased risk of cerebral abscess and stroke. With pulmonary AVM, unlike hepatic AVM, increased cardiac output with high-output heart failure is unusual.

In one study, 36% of patients with a solitary pulmonary AVM had HHT.[58] With multiple lesions, the rate of HHT was 57%. Overall, as many as 60% of patients with pulmonary AVM have HHT. Conversely, a 20% incidence of pulmonary AVM can be expected in patients with HHT. ENG mutations of HHT type 1 are associated with a 30% incidence of pulmonary AVM, compared with 3% for HHT type 2 ALK1 mutations.[58]

In a French study of HHT patients with pulmonary AVMs, which included 79 women and 47 men, the AVM was diagnosed at a mean age of 43±17 years.[59] AVM was detected on screening in 29% of patients, incidentally detected by imaging in 15%, detected secondary to dyspnea in 22%, and detected secondary to CNS symptoms in 13%.

In this study, dyspnea on exertion was present in 56% of patients.[59] Thirteen cases of cerebral abscess were found, of which 54% were found concurrently with the diagnosis of HHT and the detection of pulmonary AVM. Eighty-three percent underwent treatment for their AVMs, 23% by surgical resection and 71% via embolization.

In an Italian study, diffuse pulmonary AVM was examined in 36 individuals out of a consecutive series of 821 AVM patients.[60] The study showed an 81% association with HHT (29 of 36 patients). Diffuse AVM was associated with female gender and bilaterality. This was a high-risk group, with nine deaths occurring in patients with bilateral involvement. Causes of death were as follows:

• Hemoptysis of bronchial artery origin (two patients)
• Duodenal ulcer with hemorrhage (one patient)
• Spontaneous liver necrosis (three patients)
• Cerebral hemorrhage (one patient)
• Cerebral abscess (one patient)
• Operative death during lung transplantation (one patient)

Despite shunt formation across the pulmonary tree from AVMs, HHT is also associated with pulmonary hypertension. Lung tissue of HHT patients with pulmonary hypertension appears histologically similar to that of patients with primary pulmonary hypertension. This manifestation of HHT is associated with ALK1 gene mutations.[61]

Central nervous system

CNS arteriovenous anastomoses and aneurysms may lead to paresthesia, stroke, brain abscess, or intracerebral hematoma with focal neurologic signs. Brain abscess and stroke account for much of the 10% mortality seen in HHT, underscoring the importance of this often initially silent entity.[62]

The estimated incidence of CNS involvement in HHT patients is 10-20%.[42] CNS manifestations stem from inherent CNS vascular lesions in one third of HHT patients, whereas most CNS complications are caused by paradoxic emboli from pulmonary AVMs.[63] Other CNS manifestations include the following[64] :

• Spinal AVMs
• Migraine (50% of patients)
• Seizure
• Paraparesis

Cerebral AVMs are associated with an annual hemorrhage rate of 1.4-2.0% per patient, a figure similar to that seen with non-HHT cerebral AVMs.[65] Patients with HHT-associated cerebral hemorrhage tend to have a good functional outcome.[66]

Spontaneous remission or regression of cerebral AVMs has been reported in three cases; this appears to be a rare phenomenon.[67, 68, 69]

Gastrointestinal tract

GI bleeding develops in 25-30% of patients with HHT.[70] Usually manifesting in the fifth or sixth decade, lesions can arise in any portion of the GI tract, though they most commonly involve the stomach and small bowel. Rectal examination may reveal frank blood. Nodular angiomas are visualized on endoscopy and are similar to cutaneous telangiectases in appearance.[38]

GI bleeding is the most common visceral manifestation of HHT; it presents later than epistaxis and has been shown to occur in both HHT1 and HHT2 families.[71] Massive transfusion requirements of more than 100 units of blood have been reported.[72] The presence and number of lesions detected in the stomach and duodenum on upper endoscopy correlate with the detection of lesions in the jejunum, though large (≥5 mm) upper-tract lesions do not necessarily suggest the presence of large jejunal lesions.[70]

Liver

Between 30% and 60% of patients with HHT have liver involvement.[73] Although many patients are asymptomatic,[74] the following manifestations have been described[75, 76] :

• High-output heart failure
• Hepatomegaly
• Portal hypertension
• Encephalopathy
• Right-upper-quadrant pain and jaundice
• Liver failure

The three most common clinical patterns are high-output cardiac failure, portal hypertension, and biliary disease. The biliary manifestations include biliary obstruction or sepsis in association with biliary strictures, dilatation, and bile cysts.[77]

Patients with clinically significant liver lesions most often present with hyperdynamic circulation (cardiac index, 4.6-6.8 L/min/m2).[78] This phenomenon may be observed without symptoms of heart failure and is due to shunting from hepatic artery to hepatic vein, from portal vein to hepatic vein, or both. Shunting from the hepatic artery to the portal vein causes arterialization of the portal system with nodular transformation of parenchyma without fibrous septa, a condition termed pseudocirrhosis.

Cardiovascular system

Vascular abnormalities deep in the digits have been detected in patients with HHT by using a handheld illuminator.[79]

Patients with anemia may be pale. As noted (see above), patients may have a hyperdynamic circulation if they have hepatic involvement and a large left-to-right shunt, and this hyperdynamic circulation may be exacerbated by anemia.

Eyes

Funduscopic examination may reveal retinal telangiectasias and hemorrhages. Bloody tears may be present because of conjunctival telangiectasias.

HHT in pregnancy

In pregnant women with HHT, pulmonary AVMs may cause life-threatening fetomaternal complications. Pulmonary hemorrhage can occur, compromising maternal and fetal health.

In a study of 262 pregnancies in 111 HHT patients, most pregnancies proceeded normally.[80] However, 13 patients had adverse events (not all of which were HHT-related): major pulmonary AVM bleed in 1%, maternal death in 1%, and stroke in 1.2%. In women experiencing a life-threatening event, prior knowledge of HHT or pulmonary AVM was associated with improved survival.

Most HHT experts recommend that pregnant women who have not had a recent evaluation for pulmonary AVMs be evaluated during pregnancy. Contrast echocardiography rules out evidence of pulmonary shunt and can be performed in the first trimester. If this study yields positive results, CT of the chest with abdominal shielding should be delayed until the second trimester.

Experience with a small series of seven women suggests that transcatheter embolization of pulmonary AVM can be accomplished safely by a skilled interventional radiologist after 16 weeks’ gestation.[81]

Complications that may occur in patients with OWRD (ie, HHT) include the following:

• Brain abscess
• Hemorrhagic or ischemic stroke
• High-output congestive heart failure
• Chronic GI bleeding and anemia
• Portal hypertension with esophageal varices
• Pulmonary hemorrhage
• Liver cirrhosis

Cerebral abscess due to impaired function of pulmonary vasculature is the most common neurologic manifestation of this condition. Ischemic strokes likely due to pulmonary AVMs are common, whereas hemorrhagic strokes due to cerebral AVMs are far less common. Of patients who have pulmonary AVMs, 2% per year are estimated to have a stroke, and 1% per year are estimated to develop a brain abscess.

The presence of large AVMs and blood loss may lead to high-output cardiac failure. This known complication of HHT has been linked with the onset of severe and recurrent epistaxis in a small sample of patients.[82]

Currently, no laboratory studies are widely available to confirm the diagnosis of Osler-Weber-Rendu disease (OWRD; ie, hereditary hemorrhagic telangiectasia [HHT]). However, certain laboratory tests may be helpful in identifying specific complications.

Because of the prevalence of arteriovenous malformations (AVMs) and associated sequelae, screening with multiple (presumably complementary) imaging modalities is increasingly employed. Some investigators advocate helical computed tomography (CT); others, chest radiography with pulse oximetry. Contrast echocardiography is noninvasive and sensitive[83] and identifies intracardiac shunts, whereas arterial blood gas evaluation and pulse oximetry do not. Magnetic resonance imaging (MRI) also appears highly effective.[84]

Some centers screen asymptomatic children with a family history of OWRD in an effort to reduce serious complications associated with AVMs.

At specific centers and laboratories, genetic tests are available for various mutations in the endoglin gene (ENG) found on chromosome 9 and the activin receptorlike kinase type I (ALK-1) gene (ALK1) found on chromosome 12. These tests should be ordered in coordination with a physician and genetic counselor.

Currently, prenatal diagnosis is rarely used in families affected by OWRD. These families are encouraged to have DNA diagnosis of affected individuals where available. If the specific mutation within the family is revealed, cord blood from neonates may be analyzed for the presence of the disease, and multiple screening modalities for AVMs may be used.

When a complete blood count (CBC) is done, hemoglobin may be decreased because of chronic bleeding and iron-deficiency anemia, or the patient may be polycythemic because of chronic hypoxemia from a right-to-left shunt. The platelet count may be normal or slightly increased. The white blood cell (WBC) count should be within the reference range unless an infectious complication (eg, a brain abscess) is present.

Coagulation profile findings may exclude a concurrent disorder or coagulopathy. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) values should be normal, unless severe liver involvement is present. A preliminary study also points to the usefulness of factor VIII antigen levels; elevated levels may influence thrombotic risk in OWRD.[85]

Urinalysis should be done to assess for hematuria.[86] Stool should be evaluated to look for the presence of blood. Liver function tests may reveal elevated enzyme levels.

Oximetry is performed with the patient standing and supine for 10 minutes in each position. An oxygen saturation level of less than 96% in either position is considered an indication for further testing. It is recommended that screening for pulmonary AVM using pulse oximetry in conjunction with chest radiography be performed once in childhood, once after puberty, before pregnancy, and at 10-year intervals thereafter.[87]

Arterial blood gas measurement can also be used as a screening test for pulmonary AVM. The quantification of a right-to-left shunt can be measured with the patient breathing 100% oxygen for at least 20 minutes. An arterial blood gas analysis is performed at the end of the study and shunt fraction is measured. This study can be performed in the pulmonary function laboratory.

If a right-to-left shunt is present, the arterial partial pressure of oxygen (PaO2) will be low. If such a shunt is suspected, PaO2 is measured while the patient is on 100% oxygen (so-called hyperoxic test). If PaO2 shows only a minor increase in this setting, the diagnosis of a right-to-left shunt is confirmed. If no shunt is present, PaO2 should increase to a much larger extent. Screening with a hyperoxic test has been shown to be 100% sensitive and 40% specific for the detection of pulmonary AVMs in OWRD patients suspected of having an AVM.

Technetium-99m–tagged albumin microspheres have also been used for shunt detection in the brain and kidneys.[88]

Posteroanterior and lateral chest radiographs may reveal a mass of enlarged arteries and veins typical of pulmonary AVM. Commonly found in the posterior lung bases, these lesions may also be hidden by the diaphragm. Chest radiography may also show a peripheral noncalcified coin lesion attached by vascular strands to the hilum.[89]

Chest radiography followed by agitated saline solution transthoracic contrast echocardiography (TTCE) with grading has been recommended as the screening test of choice for pulmonary AVMs in patients with OWRD. Initial studies of this modality suggested that it might be more sensitive than CT; however, because long-term follow-up data are not yet available, all patients with even low-grade evidence of pulmonary pathology on TTCE require CT as a confirmatory study.[90]

Barium enema is useful if an ulcer or neoplasm is suspected.

Helical CT has been advocated as a screening method for pulmonary AVM. However, detractors believe that the radiation exposure is unnecessary and the cost is prohibitive. CT with contrast may be used to delineate AVMs of the lung or the brain. CT of the head is indicated in the workup of stroke and brain abscess and may reveal AVM. Abdominal CT may be useful for liver, kidney, and splenic lesions.

Contrast-enhanced MRI is appropriate as a screening modality for pulmonary AVM. Planning for embolic treatment is possible with three-dimensional (3D) reconstructed images.[84] MRI is also a useful screening modality for telangiectasias in the central nervpus system (CNS). When clinical suspicion is high, MRI or magnetic resonance angiography (MRA) may be useful in identifying CNS lesions not observed with CT.

One-step MRI may be useful for evaluating liver involvement in HHT, revealing vascular abnormalities, telangiectases, arteriovenous shunting, focal liver lesions, and ischemic cholangitis.[91]

Preoperative or preablative assessment of pulmonary AVM may warrant angiography for treatment planning. Mesenteric angiography may reveal a bleeding site or mesenteric AVM and facilitate surgical extirpation.[92] As with other causes of gastrointestinal (GI) bleeding, a hemorrhage rate of at least 1 mL/min is necessary for detection with angiography, though GI bleeding at rates as low as 0.5 mL/min may be detected with technetium-99m–labeled autologous RBC scanning. Cerebral angiography may be indicated in the preoperative workup of CNS lesions.

Doppler ultrasonography of the liver may be used for screening and first-line imaging in patients with OWRD who have hepatic AVM or other associated sequelae.

Contrast echocardiography has been shown to reveal pulmonary AVM when pulse oximetry examination or even pulmonary angiography findings were negative. Agitated saline, with its small air bubbles, creates visible contrast that can be observed in the left atrium on echocardiography. The presence of contrast in the left atrium indicates right-to-left shunt.

The ability to detect intracardiac shunts is an advantage that contrast echocardiography has over other shunt studies.[83] Higher-grade shunts (>20-30 microbubbles/frame) have higher positive predictive value.[93]

The sensitivity of molecular diagnosis is highest in probands with a clinically confirmed diagnosis of HHT.[25] However, a substantial fraction of probands do not carry an identifiable mutation in the coding exons of either of the two responsible genes, ENG and ALK1. Targeted family-specific mutation analysis for ENG exon deletions could lead to misdiagnosis of some affected family members with HHT, as was illustrated by the findings of a study in which two distinct ENG deletions were found in a single family.[94]

Upper and lower GI endoscopy may reveal telangiectases or AVMs. Colonoscopy reveals GI telangiectasias as small well-defined lesions surrounded by an anemic halo.

Push enteroscopy allows visualization of the proximal small bowel distal to the ligament of Treitz, though this or further intubation of the jejunum is technically demanding. Similarly, a skilled endoscopist can use a colonoscope placed proximal to the ileocecal valve to examine the distal ileum. The entire small bowel can be visualized with push enteroscopy; however, general anesthesia and intraperitoneal access (laparotomy or laparoscopy) are needed to manipulate and thread the small bowel over the endoscope inserted per os or per rectum.

Video capsule endoscopy is useful in the evaluation of occult GI bleeding of small-bowel origin.[95] Telangiectases from HHT can be visualized with this approach.[96] Using the capsule for diagnosis in a series of 18 patients, investigators noted small-bowel involvement in patients with known gastric telangiectases in 56% of patients.[97]

A study of 30 patients with HHT and overt gut bleeding or severe anemia found video capsule endoscopy to have a high diagnostic yield.[98] This approach enables precise mapping of accessible lesions that are amenable to endoscopic treatment; innumerable diffuse lesions require a medical approach. Video capsule endoscopy may be a first-line, noninvasive digestive tract examination in selected patients with HHT.

Spiral enteroscopy has been shown to be a safe method of accessing the small bowel in patients with HHT.[99]

Skin biopsy findings are often helpful in confirming the diagnosis of OWRD. Punch biopsy is usually adequate. Findings are localized in the dermal upper-horizontal plexus. The classic features are dilated capillaries and new vessel formation. In the dermis, the walls of dilated vessels may be thickened.

Telangiectases manifest as focal dilatation of the postcapillary venules. Early lesions maintain a portion of intervening capillary bed. Perivascular lymphocytic infiltrate is observed. Fully developed lesions lack an intervening capillary bed. Markedly dilated arterioles and venules connect directly in a tortuous network. The mature lesion also shows lymphocytic infiltrate, as well as multiple layers of thickened smooth-muscle cells around connecting venules.[100]

Orthodeoxia may be detected in patients with pulmonary AVM because of increased shunting of blood through lesions in inferior areas of the lung.[101]

Liver specimens from patients with significant liver involvement often reveal pseudocirrhosis attributable to shunting from the hepatic artery to the hepatic vein or shunting from the hepatic artery to the portal vein.

Medical therapy and surgical treatment in patients with Osler-Weber-Rendu disease (OWRD; ie, hereditary hemorrhagic telangiectasia [HHT]), are aimed at decreasing the amount of hemorrhage and minimizing the sequelae of arteriovenous malformations (AVMs), which may develop in multiple organ systems.[15]

Indications for intervention vary according to site of involvement and presentation. One third of cases of are mild, one third are moderate, and one third are severe. In mild cases of HHT, no treatment is necessary. In other cases, pharmacologic management may be effective. When nonpharmacologic treatment is called for, it can often be accomplished via catheter-based therapies that render surgical intervention (eg, thoracotomy or craniotomy) unnecessary.

Individual skin lesions may be obliterated with cauterization, hypertonic saline sclerotherapy, or dye laser treatment.[102]

In severe cases of HHT, recurrent epistaxis refractory to ablative treatment is treated surgically with nasal septum skin transplants by using skin taken from the lower trunk. Severe cases of HHT may respond to estrogen therapy.[103]

Control of intermittent gastrointestinal (GI) bleeding may be achieved medically. However, brisk hemorrhage may call for endoscopic treatment or surgical resection.

Pulmonary hemorrhage may be treated surgically by using silicone balloon tamponade or other means. Embolization (embolotherapy) or surgical resection is indicated for pulmonary AVM if it is localized and accessible, with the goal of limiting the risks of embolic central nervous system (CNS) complications, hemodynamic sequelae, or hemorrhage.

Hemodynamically significant shunt from hepatic AVM may be treatable with embolization to stabilize heart failure or encephalopathy. Extensive or symptomatic liver disease may warrant evaluation for liver transplantation.

Currently available therapies, including microsurgery, embolization, and radiosurgery, are invasive and associated with considerable adverse effects. No specific medical therapy is available for brain AVM patients.[16] For selected CNS lesions, neurosurgical resection may be indicated. Embolotherapy and radiotherapy may be alternative options, depending on lesion morphology.

Antibiotic prophylaxis should be considered before surgical or dental procedures in all patients with known pulmonary AVMs or positive contrast echocardiography findings (agitated saline solution transthoracic contrast echocardiography [TTCE] grade 1 or higher).

Studies recommend that women with HHT who conceive should be considered to have high-risk pregnancies because of rare major complications and improved survival outcome following prior recognition.[80]

In most patients, no special diet is required. Iron can be depleted if the patient experiences chronic blood loss. Folate requirements can be high if the bone marrow is chronically activated. Most patients can continue normal activities.

Prospective trials aimed at determining ideal management of HHT have been limited by the small and varied population and by the multiorgan nature of the disease. A coordinated team approach is recommended. Preclinical work targeting endoglin (also known as CD105) has shown promising results in cancer-related research.[104] Such studies may complement concurrent HHT-specific research in developing new therapies.[105]

In September 2020, the Second International Hereditary Hemorrhagic Telangiectasia (HHT) Guidelines, aimed at developing evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications, were published.[106]  (See Guidelines.)

Epistaxis is often recurrent, necessitating multiple treatments. Moderate and mild epistaxis can be treated medically or with endoscopic ablation; severe epistaxis calls for surgical treatment.

Nonoperative treatment of epistaxis may include the following:

• Iron supplementation
• Humidification
• Packing
• Transfusion
• Estrogen therapy
• Aminocaproic acid
• Electrocautery and argon beam ablation
• Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser ablation ^[107]
• Thalidomide

In more severe cases, iron replacement may be indicated because of blood loss. Humidification of the ambient air helps decrease the amount of mucosal bleeding. Hormone therapy, including antiestrogen therapy with tamoxifen, for the treatment of epistaxis due to HHT has produced good responses, though its use remains controversial.[108] Antifibrinolytics (eg, aminocaproic acid) may be used to enhance hemostasis when fibrinolysis contributes to bleeding.[109]

Although estrogen-related hormones and antifibrinolytic agents are commonly used to manage bleeding, some studies suggest that this probably increases the risk of thrombotic events in OWRD patients with pulmonary AVMs. Accordingly, patients should undergo screening for the presence of pulmonary AVMs before treatment is started.

Pulsed dye laser treatment may be used to photocoagulate telangiectasias in the nasal mucosa. As many as three subsequent treatments may be necessary before any change in bleeding frequency or severity is observed.

A small prospective randomized trial (26 patients) from Germany of topical estrogen (0.5 mg of 0.1% estriol ointment twice daily) after argon beam coagulation in HHT patients with recurrent epistaxis suggested improved outcome over argon beam coagulation with application of ointment.[58]

Although only a few cases have been reported, the published literature is concordant regarding the potential benefit of thalidomide in reducing the frequency and intensity of epistaxis in HHT patients, improving their hemoglobin levels and therefore reducing the need for transfusions.[4]

Lebrin et al in 2010 observed in six of seven patients that treatment with thalidmide 100 mg/day resulted in lowering the frequency of epistaxis within 1 month and that none of the four transfusion-dependent patients needed further transfusion during thalidomide therapy.[4] Thalidomide reduced the severity and frequency of epistaxis in the majority of a small group of patients with HHT, which suggests that it may hold promise as a therapeutic option.[110]

Future research should be directed toward identifying the minimum dose of thalidomide effective in long-term control of bleeding symptoms in HHT patients without inducing thrombotic adverse events.[4] It appears to be a potential candidate for the treatment of severe HHT-associated epistaxis unresponsive to conventional therapies.[4]

Septal dermoplasty can reduce the severity of epistaxis by 75%. This procedure involves replacing the nasal mucosa with autologous skin grafts. Telangiectasias may also develop on the autologous skin grafts, however. Septal dermoplasty decreases the need for, but does not obviate, repeated laser ablation.[111] Septectomy combined with septal dermoplasty may also be a viable option for patients with severe transfusion-dependent epistaxis.[112]

Endovascular embolization for treatment of severe acute epistaxis is another treatment modality that may be considered.[113] Patients who undergo endovascular embolization often require repeat embolization and surgical procedures.

N-acetylcysteine has been studied as an option for management of recurrent epistaxis in patients with HHT.[114] Multiple case reports have illustrated the use of bevacizumab in the treatment of HHT,[115, 105] and the efficacy of this agent for the management of epistaxis in HHT is being studied. Two case reports have documented the regression of OWRD lesions with the use of interferon alfa in patients who were treated for other indications.[116, 117]

Nonoperative treatment of GI bleeding may include the following:

• Estrogen-progesterone therapy
• Transfusion
• Aminocaproic acid
• Endoscopic photoablation or electrocautery
• Bevacizumab

Aminocaproic acid blocks the conversion of plasminogen to plasmin and thus acts as a powerful inhibitor of fibrinolysis. Although coagulation is thought to be normal in HHT, some investigators believe that the cause of the bleeding tendency is multifactorial. Increased plasminogen-activator activity has been demonstrated in the telangiectatic vessel walls of some patients with HHT.

A distinction is made between the malformations of HHT and lesions of angiodysplasia, both of which tend to manifest with age. The lesions of HHT are most often diffuse, and extensive surgical resection is generally not indicated for episodic bleeding, though it may be indicated for massive hemorrhage.

A treatment regimen involving intranasal administration of diluted bevacizumab has been shown to be clinically effective in patients with HHT1 and severe GI bleeding.[118]

Life-threatening GI bleeding can often be effectively treated by means of segmental bowel resection.

For additional information, see Lower GI Bleeding and Upper GI Bleeding.

Localized lesions can be effectively addressed by means of surgical resection. Diffuse multiple AVMs smaller than 1.5 cm can be observed. As with non-HHT AVMs, an enlarging or symptomatic lesion should be resected. Small solitary lesions in a patient with HHT should be considered for resection because of the tendency to enlarge over time.

Embolization has been shown to be effective in closing shunts and should be weighed with surgery as an option for addressing pulmonary AVM.[59] It is a safe procedure that prevents brain abscess and ischemic stroke if complete occlusion of all pulmonary AVMs is achieved.[119] Embolization is currently recommended for every pulmonary AVM with a feeding artery of 3 mm or more.[47]

Special considerations must be applied in the management of pulmonary AVM in women planning pregnancy; progression of pulmonary shunt and fatal rupture have been described.[120]

For additional information, see Arteriovenous Malformations and Pulmonary Arteriovenous Fistulae.

Embolization of the hepatic artery is a potential option for selected patients with liver involvement, as is liver transplantation.[121, 122]

Liver transplantation may be considered in patients with symptomatic hepatic HHT who present with life-threatening conditions such as hepatobiliary sepsis and severe cardiopulmonary changes.[122] In a study involving 40 patients followed up for a median of 70 months, patient and graft actuarial survival was 82.5% at 10 years. Indications for transplantation included cardiac failure (n = 14), biliary necrosis with hepatic failure (n = 12), severe portal hypertension (n = 5), or a combination of two or more of these conditions (n = 9).

In a brief report of two HHT patients who underwent liver transplantation for cardiac failure, the patients had normal cardiac function 2 and 3 years after transplantation.[123] Hepatic embolization in patients with extensive liver involvement has been discouraged because of the potential complications of liver parenchymal or biliary necrosis with ensuing sepsis.[122]

Mitchell et al reported a case in which the use of bevacizumab reversed the need for liver transplantation in an HHT patient with heart failure from hepatic vascular malformations.[124]

Consultation with multiple specialists can be useful in the diagnosis and treatment of OWRD (ie, HHT). Optimal management of AVMs may require a multidisciplinary approach. Similarly, management of syndromes resulting from severe hepatic disease (eg, encephalopathy, portal hypertension, and heart failure) may require cooperation between many disciplines. Certain specialists may have to be consulted only when particular complications arise.

Consultations to be considered, depending on the severity and manifestations of HHT, include the following:

• Dermatologist
• Pulmonologist
• Hematologist
• Cardiologist
• Gastroenterologist
• Neurologist
• Neurosurgeon
• Interventional radiologist
• Transplant surgeon

Long-term, systematic follow-up is indicated. Known lesions may recur or progress and new manifestations of the syndrome may develop over time. Patients should be monitored for symptoms and signs of blood loss and anemia with yearly stool guaiac testing and complete blood count (CBC) with differential.

Patients should be screened for pulmonary, hepatic, and CNS AVMs at the time of diagnosis and at the onset of any suggestive symptoms and signs. Children who have a parent with HHT carry a 50% chance of harboring the same genetic mutation. Accordingly, pulmonary AVM screening and long-term follow-up are advocated for these children, beginning in childhood.[125]

In September 2020, the Second International Hereditary Hemorrhagic Telangiectasia (HHT) Guidelines, aimed at developing evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications, were published.[106] The guidelines included the following recommendations.

Management of epistaxis

To reduce HHT-related epistaxis, use moisturizing topical therapies that humidify the nasal mucosa.

Consider oral tranexamic acid (TXA) for epistaxis that does not respond to moisturizing topical therapies.

Consider ablative therapies (eg, laser treatment, radiofrequency ablation [RFA], electrosurgery, and sclerotherapy) for nasal telangiectasias that have not responded to moisturizing topical therapies.

Consider systemic antiangiogenic agents for epistaxis that has not responded to moisturizing topical therapies, ablative therapies, or TXA.

Consider septodermoplasty for epistaxis that has not responded sufficiently to moisturizing topical therapies, ablative therapies, or TXA.

Consider nasal closure for epistaxis that has not responded sufficiently to moisturizing topical therapies, ablative therapies, or TXA.

Management of gastrointestinal bleeding

Esophagogastroduodenoscopy (EGD) is recommended as the first-line diagnostic test for suspected HHT-related bleeding. Patients who meet colorectal cancer screening criteria and patients with SMAD4-HHT (genetically proven or suspected) should also undergo colonoscopy.

Consider capsule endoscopy for suspected HHT-related bleeding when EGD does not reveal significant HHT-related telangiectasia.

Grade the severity of HHT-related gastrointestinal (GI) bleeding according to the following proposed framework: mild (hemoglobin [Hb] goals [reflective of age, gender, symptoms, and comorbidities] met with oral iron replacement); moderate (Hb goals met with intravenous [IV] iron treatment); or severe (Hb goals not met despite adequate iron replacement, or blood transfusions needed).

Use endoscopic argon plasma coagulation only sparingly during endoscopy.

Consider treating mild HHT-related GI bleeding with oral antifibrinolytics.

Consider treating moderate-to-severe HHT-related GI bleeding with IV bevacizumab or other systemic antiangiogenic therapy.

Anemia and anticoagulation

Test for iron deficiency and anemia in all adult HHT patients, regardless of symptoms, and in all pediatric HHT patients with recurrent bleeding and/or symptoms of anemia.

Provide iron replacement for treatment of iron deficiency and anemia as follows: initial therapy with oral iron; IV iron replacement for patients in whom oral iron is not effective, not absorbed, or not tolerated or who are presenting with severe anemia.

Provide red blood cell (RBC) transfusions in the following settings: hemodynamic instability/shock; comorbidities requiring a higher Hb target; need to increase Hb acutely (eg, before surgery or during pregnancy); and inability to maintain adequate Hb despite frequent iron infusions.

Consider evaluation for additional causes of anemia in the setting of an inadequate response to iron replacement.

Provide HHT patients with anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when there is an indication, with individualized bleeding risks taken into consideration; bleeding in HHT is not an absolute contraindication for these therapies.

Where possible, avoid the use of dual antiplatelet therapy (DAPT) and/or a combination of antiplatelet therapy and anticoagulation.

Liver vascular malformations

Offer screening for liver vascular malformations (VMs) to adults with definite or suspected HHT.

Perform diagnostic testing for liver VMs in HHT patients with symptoms and/or signs suggestive of complicated liver VMs, using Doppler ultrasonography (US), multiphase contrast computed tomography (CT), or contrast abdominal magnetic resonance imaging (MRI).

Provide intensive first-line management only for patients with complicated and/or symptomatic liver VMs, and tailored such management to the type of liver VM complication(s).

It is recommended that HHT patients with high-output cardiac failure and pulmonary hypertension be comanaged by the HHT Center of Excellence and an HHT cardiologist or a pulmonary hypertension specialty clinic.

Estimate the prognosis of liver VMs using available predictors so as to identify patients in need of closer monitoring.

Consider IV bevacizumab for patients with symptomatic high-output cardiac failure due to liver VMs who have not responded sufficiently to first-line management.

Refer patients with symptomatic complications of liver VMs (eg, refractory high-output cardiac failure, biliary ischemia, or complicated portal hypertension) for consideration of liver transplantation.

Pediatric care

Offer diagnostic genetic testing for asymptomatic children of a parent with HHT.

Screen for pulmonary arteriovenous malformations (AVMs) in asymptomatic children with HHT or at risk for HHT at the time of presentation/diagnosis.

Treat large pulmonary AVMs and pulmonary AVMs associated with reduced oxygen saturation in children.

Repeat pulmonary AVM screening in asymptomatic children with or at risk for HHT, typically at 5-year intervals.

Screen for brain VMs in asymptomatic children with HHT or at risk for HHT at presentation/diagnosis.

Treat brain VMs with high-risk features.

Pregnancy and delivery

Discuss preconception and prenatal diagnostic options, including preimplantation genetic diagnosis, with HHT-affected individuals.

Perform testing with unenhanced MRI in pregnant women with symptoms suggestive of brain VMs.

For pregnant women with HHT without recent screening and/or treatment for pulmonary AVM:

• Asymptomatic – Perform initial pulmonary AVM screening with either agitated saline transthoracic contrast echocardiography (TTCE) or low-dose noncontrast chest CT, depending on local expertise; chest CT, if performed, should be done early in the second trimester
• Symptoms suggestive of pulmonary AVM – Perform diagnostic testing with low-dose noncontrast chest CT; this may be done at any gestational age, as clinically indicated

Treatment of pulmonary AVMs should start in the second trimester unless otherwise indicated.

It is recommended that pregnant women with HHT be managed at a tertiary care center by a multidisciplinary team if they have untreated pulmonary AVMs and/or brain VMs or have not been recently screened for pulmonary AVMs.

Do not withhold an epidural because of a diagnosis of HHT; screening for spinal VMs is not required.

Allow women with known non-high-risk brain VMs to labor and proceed with vaginal delivery; an assisted second stage may be required on a case-by-case basis.

Mild forms of Osler-Weber-Rendu disease (OWRD), also referred to as hereditary hemorrhagic telangiectasia (HHT), do not require treatment. When treatment is indicated, agents to be considered include iron salts, estrogen-based formulations, antifibrinolytics, and immunomodulators.

Class Summary

Iron replacement therapy provides symptomatic relief in patients with anemia.

Ferrous sulfate (Feosol, Fer-In-Sol, Fer-Iron, Iron Supplement Children's)

This is the mainstay of treatment for patients with iron deficiency anemia. It should be continued for about 2 months after correction of the anemia and its etiologic cause in order to replenish body stores of iron. Ferrous sulfate is the most common and cheapest form of iron used. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain a smaller dose of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.

Iron dextran (Dexferrum, INFeD)

Iron dextran is used to treat microcytic, hypochromic anemia resulting from iron deficiency. It replenishes depleted iron stores in the bone marrow, where it is incorporated into hemoglobin. Parenteral use of iron-carbohydrate complexes has caused anaphylactic reactions, and its use should be restricted to patients with an established diagnosis of iron deficiency anemia whose anemia is not corrected with oral therapy. The required dose can be calculated (3.5 mg iron/g of hemoglobin) or obtained from tables in the Physician's Desk Reference (PDR). For intravenous use, INFeD may be diluted in 0.9% sterile saline. Do not add it to solutions containing medications or parenteral nutrition solutions. A test dose of 0.5 mL (in children, 0.25 mL) should be administered before therapy is started. This agent is available as 50 mg iron/mL (as dextran).

Iron sucrose (Venofer)

Iron sucrose is used to treat iron deficiency in patients in whom absorption of iron from the gastrointestinal (GI) tract is insufficient. The incidence of anaphylaxis is lower with iron sucrose than with other parenteral iron products.

Ferric gluconate (Ferrlecit)

Ferric gluconate replaces the iron found in hemoglobin, myoglobin, and specific enzyme systems, allowing transportation of oxygen via hemoglobin.

Class Summary

Oral contraceptives may be used to reduce bleeding. Topical preparations may be used to help strengthen the mucosa and decrease the susceptibility of the mucosa to external trauma. Before use, screening tests for pulmonary arteriovenous malformations (AVMs) should be performed because of the risk of complications involving thromboembolism.

Estrogen therapy may also be beneficial in some women with HHT and may be used to decrease the amount of bleeding. Oral contraceptives have been shown to be more effective than estrogen alone in mucosal bleeding.

Norethindrone acetate and ethinyl estradiol (Junel 1.5/30, Microgestin 1.5/30, Loestrin 21 1.5/30)

Norethindrone acetate−ethinyl estradiol is used to decrease mucosal bleeding. It probably works by strengthening mucosal tissues and thereby making them more resistant to trauma.

Estradiol (Estrace, Climara, Femring, Elestrin, Alora, Minivelle, Vivelle-Dot)

Estradiol increases synthesis of DNA, RNA, and many proteins in target tissues. Norethindrone acetate−ethinyl estradiol is an option.

Class Summary

Antifibrinolytic agents are used to enhance hemostasis when fibrinolysis contributes to bleeding. In view of the risk of thromboembolic events, screening for pulmonary AVMs should be performed before these agents are used.

Aminocaproic acid (Amicar)

Aminocaproic acid inhibits fibrinolysis through inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. It is used to prevent or treat mucosal bleeding caused by bleeding disorders or trauma.

Tranexamic acid (Cyklokapron)

Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by inhibiting plasminogen activators.

Class Summary

Case reports have documented regression of OWRD lesions with the use of interferon alfa in patients who were treated for other indications.

Interferon alfa-2a (Pegasys)

Interferon alfa-2a is a protein product manufactured by recombinant DNA technology. The mechanism of its antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Peginterferon alfa-2b (PEG-Intron)

PEG-IFN consists of interferon alfa-2b attached to a single 12-kd polyethylene glycol (PEG) chain. It is excreted by the kidneys. PEG-IFN has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon, which permits more convenient once-weekly dosing and significantly improves quality of life for patients.

Class Summary

These agents may inhibit microvascular growth, which, in turn, may retard the growth of all tissues, including metastatic neoplastic growth.

Bevacizumab (Avastin)