Hereditary hemorrhagic telangiectasia (HHT, Osler Weber Rendu Syndrome) is an autosomal dominant vascular disease characterized by mucocutaneous telangiectasias, epistaxis, GI bleeding and iron deficiency. Arteriovenous malformations also frequently occur in pulmonary, hepatic and cerebral circulation. The disease prevalence has been estimated between 1:5000 and 1:8000, but much higher rates are seen in geographically isolated regions such as Curacao and Bonaire (1:1330). At least 5 genetic mutations have been implicated in the development of HHT but the two major gene targets are endoglin (chromosome 9) and activin receptor like kinase 1, ALK 1 (chromosome 12). Endothelial cells derived from HHT patients express one half the normal levels of these proteins. In addition, increased plasma levels of vascular endothelial growth factor(VEGF) and TGF-Beta-1 have been noted in HHT patients. Inhibition of VEGF would appear to be an appropriate target to arrest the aberrant vascular proliferation in this disease. Despite better understanding of the pathophysiology of this syndrome, treatment advances have been hampered by the variability in clinical presentation and a lack of controlled clinical trials. Recommendations are largely based on anecdotal experience and case reports.
We report a 77 year old patient with HHT (4/4 Curacao criteria) who developed a massive, prolonged transfusion requirement due to epistaxis and GI bleeding. Six units of packed red blood cells per week were required over a 4 year period to maintain a hemoglobin of 8 g/dl. He also required 400 mg of iron sucrose intravenously per week to maintain a ferritin level of 50ng/ml. Bone marrow biopsy demonstrated no evidence of a myelophthisic process or myelodysplastic syndrome. Erythropoietin levels were markedly elevated and coagulation studies were consistently normal. Bleeding persisted despite multiple endoscopies with extensive cauterization. He received sequential 3 month treatments with aminocaproic acid, sirolimus and thalidomide before receiving bevacizumab. Aminocaproic acid and sirolimus resulted in no change in the chronic 6 unit weekly transfusion requirement. Thalidomide transiently decreased the transfusion requirement to 4 units per week before being discontinued due to peripheral neuropathy. Bevacizumab at 5 mg/kg was administered every two weeks. By 4 weeks the transfusion requirement decreased to 1 unit per 2 weeks. By three months, he was transfusion independent and has remained so for three months.
HHT is a vascular disorder with evidence of disordered angiogenesis. The clinical presentation and severity of symptoms varies widely. 3 case reports have previously demonstrated amelioration of bleeding due to bevacizumab. Our case is significant for the severity and prolonged duration of the bleeding. Local measures, aminocaproic acid and sirolimus failed to have any effect on the rate of bleeding in this patient. Thalidomide had a modest benefit at the expense of development of peripheral neuropathy. Bevacizumab completely corrected the prolonged and extreme bleeding in this case and it effectiveness was evident after the first dose. Our experience suggests that angiogenesis inhibition may have a significant role in the management HHT. Further investigation into patient selection, optimum dosing and duration of treatment is needed.
Off Label Use: Bevacizumab is a monoclonal antibody to Vascular Endothelial Growth Factor. Our case describes its use to eliminate bleeding in a patient with Hereditary Hemorrhagic Telangiectasia.
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