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ANAESTHESIA, PAIN & INTENSIVE CARE www.apicareonline.com REVIEW ARTICLE

Hereditary hemorrhagic and the anesthesiologist

Sandeep Kumar Kar1, Tanmoy Ganguly2

ABSTRACT 1Assistant Professor; 2PDT Osler-Weber-Rendu disease (OWRD) or Hereditary Hemorrhagic Telangiectasia (HHT) is Department of Cardiac a rare autosomal dominant disorder that causes muco-cutanesous and visceral vascular Anesthesiology, Institute of dysplasia and results in increased tendency for . Patients with HHT presenting Postgraduate Medical Education with continuous bleeding pose a serious problem to the Anesthesiologist .Pre-existing & Research, Kolkata (India) due to recurrent bleeding is common and sudden decompensation may lead Correspondence: Dr Sandeep to failure. Uncontrolled bleeding may occur from skin lesions during patient Kumar Kar, Department of positioning and transport. Epistaxis may lead to aspiration of blood into trachea Cardiac Anesthesiology, causing pulmonary edema. Intravenous access may be difficult. Sudden change Institute of Postgraduate in may cause bleeding from arteriovenous malformations (AVMs) Medical Education & Research, anywhere in the body, most serious of which is from cerebral AVM. Gastric distension Kolkata (India); E-mail: may occur from ingested blood and may cause reflux and aspiration during induction. [email protected] Any instrumentation including laryngoscopy and intubation, nasogastric tube insertion, Received: 5 Mar 2017 urinary catheterization should be carried out with utmost caution as bleeding may Reviewed & Accepted: occur from undetected lesions. Management include , antifibrinolytics 16 Mar 2017 and surgical hemostasis. strategy should include and controlled hypotension. Key words: Telangiectasia, Hereditary Hemorrhagic; Osler-Rendu Disease; Osler-Weber- Rendu Syndrome; Congenital Abnormalities; Cardiovascular Abnormalities; Vascular Malformations; Arteriovenous Malformation

Citation: Kar SK, Ganguly T. Hereditary hemorrhagic telangiectasia and the anesthesiologist. Anaesth Pain & Intensive Care 2017;21(3):387-392

INTRODUCTION Osler-Weber-Rendu disease (OWRD) or Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autoso- mal dominant disorder that causes muco-cutanesous and visceral vascular dysplasia and results in in- creased tendency for bleeding1-4. Patients with HHT may present with variety of symptoms and manage- ment differs accordingly. Epistaxis is the most com- mon symptom of HHT and mucocutaneous telangi- ectasia is the most common sign5. INCIDENCE HHT is a rare systemic fibro vascular dysplasia6 with Figure 1: Endoscopic view of the angiofibroma incidence varying from 1 in 5,000 to 10,0007 to 1 to 2 in 1,00,0006. Sutton8 in 1864 first described this syn- giectasia in a 52 years old man. Osler10 in 1901 and drome in a man with a and Weber11 in 1907 further elaborated the association recurrent epistaxis. In 1896 Rendu9 first noted the between hemorrhagic lesions in skin and mucous association between hereditary epistaxis and telan- membranes and its familial inheritance. Although

ANAESTH, PAIN & INTENSIVE CARE; VOL 21(3) JUL-SEP 2017 387 hereditary hemorrhagic telangiectasia

the disease is popularly known as Osler-Weber-Ren- smooth muscle cells. As a result are du syndrome, the name ‘hereditary hemorrhagic tel- very sensitive to slight trauma and friction. HHT may angiectasia’ suggested by Hanes12 in 1909, recognizes present in children as bleeding but usual age of pre- the characteristics that define the disease. sentation in adulthood4. Male and females are equally 34 GENETICS OF HHT affected . Classic triad of presentation include tel- angiectasias of the skin and mucous membranes, HHT is manifested by mucocutaneous telangiecta- epistaxis, and a positive family history. Epistaxis may sias and arteriovenous malformations (AVMs) in dif- be present in upto 95% cases4,35 whereas skin lesions ferent parts of body. Lesions can affect the nasophar- account for 75-90% of presentations35,36. Skin telan- ynx, central nervous system (CNS), lung, , and giectasias rarely cause bleeding4. Gastrointestinal spleen, as well as the urinary tract, gastrointestinal telangiectasia may occur in 10-33% patients37 most (GI) tract, conjunctiva, trunk, arms, and fingers.2,13 commonly in the stomach and upper duodenum37. Impaired signaling of transforming growth factor- Significant bleeding from may ß/bone morphogenesis protein (TGF-β/BMP)14-17 as occur in 25% patients older than 60 years and may well as vascular endothelial growth factor (VEGF)18,19 increase with age38. Pulmonary involvement in the has been attributed as the primary cause of HHT. The form of arteriovenous malformations (AVMs) may be gene mutations found to be responsible are as follows present in 75% HHT1 and 44% HHT2 patients39. Pa- in Table 1. tients with pulmonary involvement are at high risk of DIAGNOSIS developing cerebral thrombotic and embolic events including stroke, brain abscess, or transient isch- The diagnosis of HHT is made clinically on the basis emic attacks due to right-to-left shunting14,37. Cere- of the Curaçao criteria3, established in June 1999 by bral AVMs may be present 15-20% HHT1 and 1-2% the Scientific Advisory Board of the HHT Founda- HHT2 patients39-43, and may present with , tion International, Inc. (Table 2), and recommended or intracranial haemorrhages4,44. Hepatic by HHT Foundation International - Guidelines AVMs may be present upto 74% cases45 but usually Working Group,33 or by identification of a causative asymptomatic4. mutation. MANAGEMENT Histopathology of HHT lesions show many layers of Management strategies for AVMs associated with smooth muscle cells without elastic fibers and very HHT may differ with location and presentation and frequently directly communicating with depicted in Table 3.

Table 1: Types of HHT with genetic basis

HHT types Mutated genes Gene location HHT1 ENG20 Long arm of chromosome 921-23 HHT2 ALK1 (Activin receptor-like kinase 1), also Long arm of chromosome 12 called ACVRL124,25 hereditary benign telangiectasia (HBT), RASA1 26 chromosome 5q14 HHT3 HHT4 Chromosome 7p1427 HHT + Juvenile polyposis coli SMAD4/MADH428-30 18q21.2 HHT2 + primary pulmonary BMPRII31,32 2q33

Table 2: Curaçao criteria

Criterion Description Epistaxis Spontaneous and recurrent Telangiectasias Multiple, at characteristic sites: lips, oral cavity, fingers, nose Visceral lesions GI Telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs Family history A first degree relative with HHT according to these criteria “definite” if 3 or more criteria are present, “possible or suspected” if 2 criteria are present, and “unlikely” if 0 or 1 criterion is present.

388 ANAESTH, PAIN & INTENSIVE CARE; VOL 21(3) JUL-SEP 2017 review article

Table 3: Management strategy of HHT according to site of involvement

Location Lesions Indications of management Management Nose Telangiectasia, Recurrent epistaxis Sclerotherapy with sodium tetradecyl sulphate46, AVMs submucosal radiofrequency47, Bevacizumab48, Septal mucosal dermoplasty39,49, Embolization of external carotid branches50, Skin Telangiectasia Pain2, cosmesis4 Cauterization, hypertonic saline sclerotherapy, dye laser treatment51. Pulsed Nd:YAG laser52, Gastro AVMs, Angio- Chronic anemia, Diagnosis: Endoscopy, Angiography4 intestinal dysplasia4 Management: Bipolar electrocoagulation4, Laser4, tracts estrogen-progesterone therapy53, interferon α54 Lungs AVMs intolerance, cyanosis, Feeder vessel >3 mm: Transcatheter embolisation56, migraine , Smaller lesion: Follow up14 polycythemia and clubbing Antibiotic prophylaxis to prevent brain abscess CNS events14,40 During pregnancy55 Diffuse pulmonary Severe Lung transplantation4 AVM CNS Cerebral and Transcatheter embolization, resection, stereotactic spinal AVMs radiosurgery57,58 Life threatening portosystemic Liver transplant59-61 Liver AVMs, shunts Bevacizumab62

Patients with HHT presenting with continuous cause bleeding from AVMs anywhere in the body, bleeding pose a serious problem to the Anesthesiolo- most serious of which is from cerebral AVM. Gastric gist .Pre-existing anemia due to recurrent bleeding distension may occur from ingested blood and may is common and sudden decompensation may lead to cause reflux and aspiration during induction. Any . Uncontrolled bleeding may occur from instrumentation including laryngoscopy and intu- skin lesions during patient positioning and transport. bation, nasogastric tube insertion, urinary catheter- Epistaxis may lead to aspiration of blood into trachea ization should be carried out with utmost caution as causing pulmonary edema. Intravenous access may bleeding may occur from undetected lesions. be difficult. Sudden change in blood pressure may In hemodynamically stable patients, posted for elec- Box 1: Perioperative management problems in HHT tive surgery, preoperative optimization of the anemic patient status is corrected with oral or parenteral iron and if necessary erythropoiesis-stimulating agent63. Preop- Perioperative management risk and problems eratively angiogenesis inhibitors or therapy should be considered in selected patients to reduce perioperative bleeding. Careful history and physical 1. Patient may present with: examination may indicate any systemic involvement • Preexisting anemia and standard radiological imaging with angiogra- • AVMs elsewhere • Blood in stomach phy may be performed to search for hemangiomas • Aspiration in brain, lung, gastrointestinal tract, nose and para- 2. Surgery related: nasal sinuses. In unstable patient presenting with • Difficult exposure severe bleeding focus should be directed to simulta- • Difficult hemostasis neous and hemostasis. Blood transfu- • Prolonged surgery sion forms the mainstay of volume resuscitation in 3. Problems in anesthesia conduct: severely volume depleted patient. Epistaxis should • Positioning and transport be controlled with tight nasal packing immediately • Perioperative aspiration risk followed by cauterization of bleeding vessels and • Unstable hemodynamics • IV access Septodermoplasty if required. Since bleeding does • Instrumentation not result from a defect in coagulation cascade, but • Massive blood transfusion from the malformed vascular structures, platelet or

ANAESTH, PAIN & INTENSIVE CARE; VOL 21(3) JUL-SEP 2017 389 hereditary hemorrhagic telangiectasia plasma transfusions are of no use and reserved only may present with uncontrolled bleeding. Resuscita- to supplement the loss. Antifibrinolytics including tion along with hemostasis forms the cornerstone of 64,65 66 tranexamic acid and aminocaproic acid have treatment. As the bleeding occurs from malformed been used with success to control epistaxis. In addi- vessels, standard coagulation tests will reveal no tion to antifibrinolytic effects, tranexamic acid also abnormality. Management strategies include blood stimulates the expression of ALK-1 and endoglin, as well as the activity of the ALK-1/endoglin pathway67. transfusion, antifibrinolytics and surgical hemosta- Intraoperatively controlled hypotension should be sis. Anesthesia planning should include rapid se- achieved with nitroglycerine or inhaled anesthetics quence induction and controlled hypotension. or alpha 2 agonists to reduce bleeding. Conflict of interest: None declared by the authors CONCLUSION Authors’ Contribution: Patients with Osler-Weber-Rendu disease (OWRD) SKK: Concept and writing or Hereditary Hemorrhagic Telangiectasia (HHT) TG: Contributing author

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