• GI bleeding
• Liver disease

• Humans
• Arteriovenous Malformations/complications
• Arteriovenous Malformations/diagnosis
• Bevacizumab/therapeutic use
• Esophageal and Gastric Varices/etiology
• Gastrointestinal Hemorrhage/etiology
• Hepatic Artery/abnormalities
• Hepatic Veins/abnormalities
• Hypertension, Portal/etiology
• Hypertension, Portal/complications
• Liver/blood supply
• Liver/pathology
• Liver Failure/etiology
• Telangiectasia, Hereditary Hemorrhagic/diagnosis

• Epistaxis
• HTT
• Monoclonal antibodies
• Osler-Weber-Rendu syndrome
• VEGF

研究一个遗传性出血性毛细血管扩张症（HHT）家系的ENG、ACVRL1、SMAD4基因突变情况，探讨其分子发病机制。

对1例HHT患者进行临床诊断和家系调查。采集先证者及其长子外周血标本，应用芯片捕获高通量测序法进行ENG、ACVRL1、SMAD4基因分析，对检出的突变以Sanger测序法进行验证。

71名家系成员中有9名被临床诊断为HHT，均以反复鼻腔出血为主要表现。基因分析结果显示，先证者及其长子ENG基因9号外显子存在框移突变c.1502-1503insGG（p.Gly501GlyfsX18），未检出ACVRL1、SMAD4基因突变。

ENG基因框移突变c.1502-1503insGG（p.Gly501GlyfsX18）是这个HHT家系致病的遗传学基础。

• Frameshift mutation
• Gene, ENG
• Pedigree
• Telangiectasia, hereditary hemorrhagic

• Dysplasias
• Hereditary hemorrhagic telangiectasia
• Mucocutaneous lesions
• Osler-Weber-Rendu syndrome

Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events and deaths) of HHT patients treated by intravenous bevacizumab in France.

Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network.

Forty-six patients (median age: 68 years) were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks) was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect’s duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients.

Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed.

• Adult
• Aged
• Aged, 80 and over
• Bevacizumab/administration & dosage
• Bevacizumab/therapeutic use
• Female
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Retrospective Studies
• Telangiectasia, Hereditary Hemorrhagic/drug therapy

• bevacizumab
• brain edema
• brain metastasis

• Adult
• Aged
• Angiogenesis Inhibitors/therapeutic use
• Bevacizumab/therapeutic use
• Brain Edema/diagnosis
• Brain Edema/drug therapy
• Brain Edema/etiology
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/pathology
• Brain Neoplasms/secondary
• Female
• Humans
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Retrospective Studies
• Treatment Outcome
• Young Adult

Hereditary hemorrhagic telangiectasia is an inherited autosomal dominant disease presenting with recurrent bleeding episodes and iron deficiency anemia due to vascular malformations. Hereditary hemorrhagic telangiectasia is associated with an increased risk of stroke, gastrointestinal bleeding and pulmonary hypertension and life expectancy is significantly reduced. Excess vascular endothelial growth factor (VEGF) plays a key role in the pathophysiology of the disease.

Here we report about a male patient with hereditary hemorrhagic telangiectasia presenting with pulmonary and central nervous system involvement experiencing repetitive nosebleeds, necessitating frequent local cauterization and transfusion of more than 100 units of packed red blood cells. After initiation of temporary therapy with the anti-VEGF antibody bevacizumab at a dosage of 1 mg/kg body weight every 2 weeks, the nose bleeding episodes and the epistaxis severity score significantly decreased and long-lasting transfusion independence was achieved. Reinitiation of low-dose bevacizumab after relapse again proved effective without any documented therapy-related adverse events. In comparison to other reported anti-VEGF antibody protocols in hereditary hemorrhagic telangiectasia, our treatment approach proved to be cost-efficient.

Intermittent low-dose therapy with bevacizumab represents an effective and cost-efficient treatment option for transfusion-dependent patients with hereditary hemorrhagic telangiectasia.

• Anemia
• Bevacizumab
• Nosebleeds
• Telangiectasia
• Transfusion
• VEGF

• Angiodysplasias
• Bevacizumab
• Gastrointestinal bleeding
• Hereditary hemorrhagic telangiectasia
• Rendu-Osler-Weber disease
• Telangiectasias

• Ear, nose and throat/otolaryngology
• Respiratory system

Intravenous bevacizumab decreased mucosal bleeding in some patients with hereditary hemorrhagic telangiectasia (HHT). We treated a 47-year-old male who had HHT, severe epistaxis, and gastrointestinal bleeding, alcoholic cirrhosis, and portal hypertension with intravenous bevacizumab 2.5 mg/kg every 2 weeks. We tabulated these measures weekly during weeks 1–33 (no bevacizumab); 34–57 (bevacizumab); and 58–97 (no bevacizumab): hemoglobin (Hb) levels; platelet counts; units of transfused packed erythrocytes (PRBC units); and quantities of iron infused as iron dextran to support erythropoiesis. We performed univariate and multivariable analyses. We sequenced his ENG and ACVRL1 genes. Epistaxis and melena decreased markedly during bevacizumab treatment. He reported no adverse effects due to bevacizumab. Mean weekly Hb levels were significantly higher and mean weekly PRBC units and quantities of intravenous iron were significantly lower during bevacizumab treatment. We performed a multiple regression on weekly Hb levels using these independent variables: bevacizumab treatment (dichotomous); weekly platelet counts; weekly PRBC units; and weekly quantities of intravenous iron. There was 1 positive association: (bevacizumab treatment; p = 0.0046) and 1 negative association (PRBC units; p = 0.0004). This patient had the novel ENG mutation E137K (exon 4; c.409G→A). Intravenous bevacizumab treatment 2.5 mg/kg every 2 weeks for 24 weeks was well-tolerated by a patient with HHT due to ENG E137K and was associated with higher weekly Hb levels and fewer weekly PRBC units.

• Bevacizumab
• ENG E137K
• Hereditary hemorrhagic telangiectasia
• Iron dextran
• Transfusion
• Vascular endothelial growth factor

We report a case of severe, refractory gastrointestinal (GI) bleeding in a patient with hereditary hemorrhagic telangiectasia (HHT) whose massive transfusion dependence was lifted shortly after treatment with bevacizumab, an anti-vascular endothelial growth factor. The patient’s bleeding had been refractory to repeated endoscopic interventions, tranexamic acid, and tamoxifen. However, following treatment with bevacizumab at 5 mg/kg every other week, nearly 300 units of packed red blood cell transfusions were avoided in one year’s time. Despite its relatively high cost, bevacizumab may have a more active role in the management of severe GI bleeding in HHT if such remarkable response can be consistently demonstrated.

• Bevacizumab
• Vascular endothelial growth factor
• Hereditary hemorrhagic telangiectasia
• Bleeding
• Osler-Weber-Rendu syndrome

• Colorectal
• Hereditary cancer
• Inherited polyposis syndromes
• Intestine
• Stomach

• Angiogenesis Inhibitors/adverse effects
• Angiogenesis Inhibitors/therapeutic use
• Bevacizumab/adverse effects
• Bevacizumab/therapeutic use
• Bile Duct Diseases/drug therapy
• Bile Duct Diseases/etiology
• Budd-Chiari Syndrome/chemically induced
• Female
• Heart Atria
• Heart Diseases/chemically induced
• Humans
• Middle Aged
• Pulmonary Embolism/chemically induced
• Telangiectasia, Hereditary Hemorrhagic/complications
• Thrombosis/chemically induced

• VEGF
• anemia
• bevacizumab
• epistaxis
• hemorrhage
• hereditary hemorrhagic telangiectasia