Successful management of chronic gastrointestinal hemorrhage using bevacizumab in the setting of hereditary hemorrhagic telangiectasia

A 74-year-old gentleman was referred to our clinic because of a 6-month history of recurrent gastrointestinal bleeding. He had developed black stools prompting an endoscopic evaluation that revealed multiple AVMs. His chronic bleeding was so severe that he required regular blood transfusions, approximately one per week. His hemoglobin had dropped to 8.3 g dL−1. He was treated initially with amicar 500 mg every 6 hr without reduction in bleeding. He was later treated with cryoprecipitate transfusions with a regimen of 2 packs (10 U) three times a week with subsequent stability in hemoglobin at a level around 10 g dL−1. However, his hemoglobin subsequently decreased and he continued to require blood transfusions. Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu syndrome, is a genetic disorder that causes abnormal blood vessel formation, leading to chronic bleeding often requiring iron supplementation and blood transfusion 1. Telangiectasias occur in the skin and mucosal linings of the nose, while arteriovenous malformations (AVMs) occur in the liver, lungs, gastrointestinal tract, and brain. While most patients have asymptomatic lesions, a fifth of patients are affected by symptomatic digestive tract lesions that often lead to intermittent bleeding and iron deficiency anemia, and in rare cases lead to severe, refractory bleeding 2. The patient had an impressive family history of HHT (see Fig. 1). His disease was manifested by prolonged epistaxis as a child, with nosebleeds lasting over 30 min. In his teens he remembers feeling fatigued, reporting fainting episodes and occasions where he would fall asleep standing up. He also reported frequently falling asleep the moment he sat down, and this had gone on for most of his life. Other medical and surgical history included hyperlipidemia, hypothyroidism, and chronic kidney disease, a tonsillectomy at age 5 years, and anal fissure repair at age 30 years. Family pedigree demonstrating the variability in presentation of HHT within a single family. An asterisk (*) indicates those whose affectation status was confirmed by genetic testing. P denotes the proband individual evaluated in our clinic. Patients affected by HHT are numbered and the details of each individual's symptoms are presented in the discussion. Severity of symptoms ranged broadly and included recurrent prolonged epistaxis 1-8, chronic anemia requiring lifelong iron replacement 1, 2, stroke 9, 10, severe anemia requiring blood transfusions 7, 10, ocular arteriovenous malformations 3, pulmonary arteriovenous malformations 5, 11-13, and death during pregnancy 11. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The extensive family history of our patient reveals the variability in presentation and severity of this disease (see Fig. 1). While only the patient, his two sons, and two grandsons underwent genetic testing, with the patient and one son having the mutation, symptoms of several family members are classic features of HHT. From his childhood, the patient remembers his grandmother (individual 1) suffering from nosebleeds and always being on iron pills for anemia. His mother (individual 5) suffered from daily nosebleeds, and had an arteriovenous malformation on the side of her eye. Four family members died from HHT, including a maternal uncle (individual 3) and aunt (individual 4) who suffered strokes in their forties, a maternal cousin (individual 8) who died at age 21 while several months pregnant, and another maternal cousin (individual 7) who suffered daily nosebleeds and pulmonary arteriovenous malformations and died at age 50. Several other family members, including the patient's son (individual 14), had pulmonary arteriovenous malformations requiring surgical intervention. Many other family members suffered from recurrent epistaxis and fatigue (individuals 6, 9, 10, and 12) or chronic anemia requiring lifelong iron replacement (individual 3). This case highlights the life-threatening nature of HHT and the variable manifestations within a single family. Upon presenting to our clinic, the patient was noted to have telangiectasias on his lips and tongue. He appeared fatigued and reported very low energy levels. He was hospitalized and transfused, and his dose of amicar was increased. However, he continued to require blood transfusions over the following weeks, with hemoglobin and hematocrit dropping to 8.5 and 27.8 g dL−1, respectively, despite frequent transfusions. After 2 months, the patient was initiated on bevacizumab infusions at the standard dose used in solid tumors, 3.3 mg kg−1, every 2 weeks with a subsequent rise in his hemoglobin to 11–12 g dL−1 (see Fig. 2). His symptoms improved and he returned to clinic stating that he had regained energy he had not had for over a year, and was told by family members that he had his color back. Following 3 months of bevacizumab therapy with hemoglobin ranging between 12 and 13 g dL−1, his dosing interval was stretched to every 4 weeks, and he continued to do well without requiring transfusion. He reported occasional nosebleeds lasting 20 min, and telangiectasias on his lips and tongue remained, but his energy levels were significantly improved. Response to treatment with bevacizumab as measured by trend in hemoglobin over the months preceding and the year following initiation of therapy. Prior to the initiation of treatment, the patient had a heavy transfusion requirement, receiving both packed red blood cells and cryoprecipitate regularly. After bevacizumab was begun, the patient had a steady rise in hemoglobin, achieving a stable hemoglobin with no further requirement for transfusions. This stability persisted after increasing the interval between bevacizumab infusions. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Our case highlights the successful use of bevacizumab in the treatment of lifethreatening hemorrhage caused by gastrointestinal AVMs caused by HHT, with persistent response in the setting of gradually widened intervals between infusions. While visible telangiectatic lesions persisted, the patients had a dramatic response to therapy, with reduced transfusion dependence and improved quality of life. Still to be determined are the precise mechanism of action of bevacizumab in relation to the abnormal blood vessel formation in HHT and the optimal duration of treatment to prevent recurrence of bleeding and anemia. The patient developed hypertension 5 months after initiation of bevacizumab and he was started on amlodipine with some improvement. After a brisk nosebleed necessitating a visit to the emergency room, an angiotensin receptor blocker was begun, with no further episodes of prolonged epistaxis. The interval between bevacizumab infusions was then further stretched to 8 weeks with stability in his hemoglobin, and eventually to every 12 weeks. His hemoglobin has continued to lie between 11 and 13 g day−1 over the 15 months of bevacizumab therapy without any need for transfusion. The patient reported greatly improved energy levels and overall wellbeing during the course of his treatment. While multiple reports have shown response to bevacizumab in patients with HHT in treating recurrent epistaxis 3-5, 9-11, 14, lung AVMs 3, 6-8, hepatic AVMs 2, 3, 8, 12, 13, 15, 16, and intestinal AVMs 3, 8, 17, only one case detailed response in the setting of lifethreatening gastrointestinal bleeding 2. The report describes an 85-year-old woman with small and large bowel angiodysplasias, as well as mucocutaneous lesions and recurrent epistaxis 2. After initial response to estroprogesterone, bleeding recurred and progressed through somatostatin analogues, thalidomide, and endoscopic argon plasma coagulation. She responded to bevacizumab 3 mg kg−1 infusions with decreased transfusion requirements, and received infusions every 3 weeks for 3 months. Upon stopping bevacizumab, she presented with hemorrhagic shock, and thereafter was continued on bevacizumab every 3 weeks for a year. From this experience and ours it is clear that bevacizumab must not be stopped abruptly, but the optimal duration and frequency need to be examined in prospective trials. An intriguing feature of our case is the persistence of telangiectasias on the patient's oropharynx and ears, despite clear improvement in transfusion requirement. This paradox raises questions about the mechanism of bevacizumab in treating HHT and regional differences in response. Eighty percent of HHT cases have functional insufficiency of Endoglin (HHT1) or ALK1 (HHT2). Concentrations of both VEGF and TGF-β are increased in the plasma of patients with HHT, and TGF-β stimulates the production of VEGF 6, 18. VEGF stimulation is necessary for brain AVM formation in mice subjected to focal Alk1 gene deletion 19. Bevacizumab is a monoclonal antibody that binds vascular endothelial growth factor (VEGF) with presumed decrease in VEGF concentration in patients with HHT. Bevacizumab reverses the brain AVM phenotype in mice by reducing vessel density and dysplasia 20. Increasing PDGF- β using thalidomide also reduces microhemorrhage and the number of abnormal blood vessels, and improves vascular integrity 21. While bevacizumab can increase the risk of perforation and bleeding in some patients with pulmonary AVMs, the use of transexamic acid together with bevacizumab diminishes hemorrhagic risk 7. While our patient showed a remarkable improvement in hemoglobin, both immediate and persistent, with no requirement for transfusions for more than a year after starting bevacizumab, our success was balanced by hypertension and recurrent epistaxis, well-known side effects of this therapy. Interestingly, epistaxis occurred 4 months after initiating bevacizumab, after not having had a severe nosebleed for decades. Worsening nosebleeds correlated with both increased blood pressure and increasing climate dryness. The paradoxical observation that bevacizumab can both reduce epistaxis in HHT in some patients and worsen epistaxis in others raises questions about the mechanism of its effect. We found that after adding losartan, an angiotensin type II receptor blocker, the patient's blood pressure improved, and his nosebleeds were dramatically reduced. Because angiotensin II receptor blockers are known to have effects on vascular remodeling 22, we hypothesize this mechanism may contribute to its efficacy in treating hypertension caused by bevacizumab. Disease severity has recently been reported to be associated with poorer self-reported quality of life in patients with HHT, including health-related and overall quality of life 23. Control of chronic bleeding with bevacizumab has the potential to greatly improve quality of life, as demonstrated in our patient. Future studies are required to determine the optimal frequency and duration of bevacizumab maintenance therapy in patients with HHT and its relationship with several health outcomes, including quality of life. All authors contributed to the writing of this manuscript. MS and VM wrote the first draft. TG prepared Figures. All authors approved of the final version of the article for publication.