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CASE REPORT Iron Deficiency Anemia Related to Hereditary Hemorrhagic Telangiectasia: Response to Treatment With Bevacizumab Jessica M. Fleagle, DO, Ravi K. Bobba, MD, Carl G. Kardinal, MD and Carl E. Freter, MD, PhD H organ systems such as the liver, lungs and brain. When on the skin, telangiectasias are generally more common on the face, chest and hands appearing bright red to purple and blanch with pressure. Mucosal telangiectasias exhibit similar characteristics. In the gastrointestinal tract, AVMs and telangiectasias can be difficult to see during endoscopy as the location may be distal to an esophagogastroduodenoscopy (EGD) or cephalad to a colonoscope. They also may be missed with capsule endoscopy. Bevacizumab was the first antiangiogenic agent approved for the treatment of nonsmall cell lung cancer, breast cancer and colorectal cancer.11 Bevacizumab has also been effective in treating retinal disorders, often used as repeated injections to control neovascularity.12,13 Furthermore, multiple treatments with bevacizumab by intranasal submucosal injection (100 mg) are effective in treating epistaxis in HHT patients; this has been shown to result in less emergency room visits, blood transfusions, iron infusions and potassium titanyl phosphate laser treatments.14 Although a previous case report described the use of bevacizumab in the primary treatment of mesothelioma and occult gastrointestinal bleeding secondary to HHT,15 the use of bevacizumab as a primary treatment for gastrointestinal bleeding alone in patients with HHT has not been reported. Herein, we describe our experience in the treatment of this rare disorder with iron deficiency anemia. From the Division of Hematology and Medical Oncology, Department of Internal Medicine, Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, Missouri. Submitted May 23, 2011; accepted in revised form November 17, 2011. Correspondence: Carl G. Kardinal, MD, Hematology and Medical Oncology, Ellis Fischel Cancer Center, University of Missouri-Columbia, 115 Business Loop 70 West, DC 116.71, Columbia, MO 65203 (E-mail: [email protected]). A 52-year-old woman presented to the University of Missouri Medical Center with HHT after failed responses to iron sucrose infusions every 2 months, frequent blood transfusions and hospitalizations for gastrointestinal bleeding and occasional hospitalizations for epistaxis. She failed cautery on multiple endoscopy procedures for at least 2 prominent gastric body vascular ectasias and 5 small vascular ectasias in the second/third portion of the duodenum. In the past, she also had a resection for a large pulmonary AVM. After presenting to our center, she was hospitalized for epistaxis once, gastrointestinal bleeding and epistaxis once and 2 separate hospitalizations for acute gastrointestinal bleeding alone. Two were life-threatening episodes of hemorrhage. She had also presented with bacteremia secondary to a port infection. The port had been placed for frequent transfusions and iron infusions. Her nadir for hemoglobin in our center was 6.4 g/dL (Figure 1). Despite the maximal treatment of her disease with iron infusions, she required repeated blood transfusions and cauterization of the ectasias, was doing very poorly and remained at risk for fatal hemorrhage or complications from her treatments (ie, the bacteremia secondary to the vascular access port). The patient was treated with bevacizumab at a dose of 5 mg/kg infusion every 2 weeks and was given 4 cycles.15 Before the initiation of bevacizumab, her iron studies revealed low serum iron of 22 g/dL and low ferritin of 6.9 ng/mL. She was also started on supplemental oral ferrous sulfate. Within 1 Abstract: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant condition associated with arteriovenous malformations (AVMs) or telangiectasias of the pulmonary, gastrointestinal or hepatic circulations. The authors present a case of a 52-year-old woman with a known diagnosis of HHT who presented for evaluation of anemia. She had an extensive history of iron sucrose infusions, frequent blood transfusions and hospitalizations for anemia related to gastrointestinal bleeding and epistaxis. The patient was treated with bevacizumab at a dose of 5 mg/kg infusion every 2 weeks for 4 cycles. In the next 4 months, her hemoglobin improved to 13.7g/dL and she did not require iron or packed red blood cell transfusions for the next 8 months. Abnormal angiogenesis primarily due to mutations in the transforming growth factor  receptor endoglin and the activin receptor-like kinases is a central contributor to the formation of AVMs in HHT. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor and therefore may be a useful treatment against AVM formation in patients with HHT. The authors do caution that therapy has to be individualized as there are no randomized trials regarding its usage in patients with HHT. Key Indexing Terms: Iron deficiency anemia; Hereditary hemorrhagic telangiectasia; Bevacizumab. [Am J Med Sci 2012;343(3):249–251.] ereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a rare, autosomal dominant condition occurring in 1 in 5000 to 8000 people.1– 4. The major presenting complaint in 90% of patients with HHT is epistaxis which when coupled with the varying degrees of penetrance of HHT may lead to misdiagnosis.3–5 The majority of patients actually are not aware that they have the disease. Other presenting symptoms include massive hemoptysis and epistaxis, anemia and iron deficiency, massive gastrointestinal bleeding or hemorrhagic stroke.6 HHT may also be associated with other diseases such as juvenile polyposis syndrome and primary pulmonary hypertension.7 Available evidence demonstrates that patients with HHT exhibit arteriovenous malformations (AVMs) or telangiectasias of the pulmonary (15%–30%), gastrointestinal (⬃30%) or hepatic (⬃30%) circulations although no study has determined the prevalence of AVMs in multiple vasculatures of patients with HHT.8,9 The Curacao criteria for diagnosing HHT were developed in 1999.10 A helpful review of current screening recommendations has recently been published.6 Telangiectasias and AVMs occur on mucocutaneous surfaces (ie, nose, gastrointestinal tract and skin) or in large CASE REPORTS The American Journal of the Medical Sciences • Volume 343, Number 3, March 2012 249 Fleagle et al FIGURE 1. Hemoglobin graph showing the initiation of bevacizumab and the trend in the hemoglobin. month of the infusions, her hemoglobin reached 11 g/dL, the highest on record including outside hospital records even with no transfusion. She was hospitalized for methicillin-resistant staphylococcal aureus sepsis and was treated with vancomycin. Her hemoglobin trended down during that time to 9.4 g/dL but did not require any transfusions. In the next 8 months, she had not presented to an emergency room or was hospitalized for bleeding and did not require iron infusions or transfusions. The hemoglobin was 13.7 g/dL at 4 months and 11.7 g/dL at 8 months from the initiation of the bevacizumab infusions. Repeat esophagogastroduodenoscopy was considered but withheld due to clinical improvement. DISCUSSION Abnormal angiogenesis primarily due to mutations in the transforming growth factor  (TGF-) receptors endoglin and the activin receptor-like kinases (ALKs) is a central contributor to the formation of AVMs in HHT.3,4,16 TGF- is an upstream regulator of the well-described angiogenic mediator vascular endothelial growth factor (VEGF), and circulating concentrations of both TGF- and VEGF are significantly elevated in patients with HHT.17,18 The degree of VEGF elevation correlates with the severity of bleeding from any site.19 Bevacizumab is a monoclonal antibody against VEGF and therefore may be a useful treatment against AVM formation in patients with HHT.3,4 The differential stimulation of ALK-1 and ALK-5 is thought to regulate different phases of angiogenesis, activating the angiogenic process, subsequently increasing the production of VEGF. VEGF stimulates the proliferation of vascular endothelial cells and increases vascular permeability and thus is a central mediator in early angiogenesis.18 As the initial phase is characterized by VEGF-dependent formation and the sprouting of vessels consisting of endothelial cells, the microenvironmental concentrations of VEGF seem to determine the normal or aberrant angiogenesis induction.20 250 From a trial done with HHT and epistaxis in local injections of bevacizumab, a case report of bevacizumab reversing need of transplantation in HHT and a case report of reduced gastrointestinal bleeding with the treatment of mesothelioma in a patient with HHT, it was shown that patients who received bevacizumab had a significant reduction in bleeding.14,15,21 The current patient was treated with bevacizumab at a dose of 5 mg/kg infusion every 2 weeks, similar to a previous report.15 Within 1 month of the infusions, her hemoglobin reached 11 g/dL, the highest on record including outside hospital records even without transfusion. In the next 6 months, she did not present to an emergency room or require hospitalization for bleeding and did not require iron infusions or transfusions other than for sepsis. In a reported case with bevacizumab infusion and local injection in the nose, there was no change in the visualization of the AVMs.14,22 Flieger et al15 had used bevacizumab in a patient with recurrent bleeding from HHT and progression in a patient with mesothelioma. For patients with epistaxis, submucosal nasal injections with bevacizumab resulted in an effect lasting 7.3 months on the average.14 In addition to saving recurrent life-threatening hemorrhage in this patient, bevacizumab has improved some additional parameters: lifestyle, hospital costs and decreased exposure to health care-associated pathogens and potential complications related to procedures such as conscious sedation and repeated cauterizations and blood products.23 As with all treatments, there are side effects and complications. There have been some common side effects noted in association with bevacizumab treatment in the oncology literature including hypertension, proteinuria, hypophosphatemia, thrombocytopenia, gastrointestinal perforation, cardiac dysfunction, bleeding and thrombosis; all of which tend to be mild to moderate and manageable.11 When used for patients older than 65 years with renal cell cancer, the risk of arterial thrombotic events increased from 2% to 18%.11 Our patient Volume 343, Number 3, March 2012 Treatment of Iron-Deficient Anemia With Bevacizumab has had worsening hypertension requiring more frequent monitoring of her blood pressure and titration of her antihypertensive medications. In conclusion, bevacizumab may be a useful alternative in patients with HHT with uncontrolled gastrointestinal bleeding, but this should be individualized as there are no randomized trials regarding its usage in patients with HHT. 11. Boehm S, Rothermundt C, Hess D, et al. 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Iron deficiency anemia related to hereditary hemorrhagic telangiectasia: response to treatment with bevacizumab. J Clin Oncol 2011;29(suppl):abstract e13521. 251