Original Article
Brief Report
Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia with Aminocaproic Acid
N Engl J Med 1994; 330:1789-1790June 23, 1994
- Article
Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) is characterized by telangiectatic lesions of the nose, lips, and visceral organs including the liver, spleen, gastrointestinal tract, lungs, brain, and spinal cord1-5. It is inherited as an autosomal dominant trait. Its most common manifestations are recurrent epistaxis and gastrointestinal bleeding, which can be life threatening6. Nasal bleeding has been treated by dermatoplasty of the nasal septa, photocoagulation, and amniotic-membrane grafts6,7 and by the administration of estrogen and progesterone,8,9 but these treatments are often ineffective.
Aminocaproic acid is a potent inhibitor of the fibrinolytic system. In low doses it blocks the conversion of plasminogen to the powerful fibrinolytic enzyme plasmin10,11. Parenteral and oral aminocaproic acid therapy has proved effective in controlling bleeding in patients with refractory surgical bleeding12,13 and bleeding from the genitourinary tract,14,15 and topical aminocaproic acid is effective in patients with recurrent epistaxis16. We report the efficacy of small oral doses of aminocaproic acid in two patients with hereditary hemorrhagic telangiectasia who had recurrent epistaxis, gastrointestinal bleeding, and moderate anemia.
Case Reports
Patient 1
Patient 1 was a 61-year-old man of Mediterranean descent who had had recurrent epistaxis since childhood and was known to have hereditary hemorrhagic telangiectasia. The patient's siblings, two sisters and one brother, also had the disease. The patient had almost daily episodes of epistaxis lasting from 25 minutes to 3 hours and had had anemia throughout his life despite treatment with oral iron supplements. He had no proved episodes of gastrointestinal bleeding. Previous treatments included five nasal septoplasties, frequent nasal balloon tamponade, and sporadic blood transfusions.
Physical examination revealed multiple telangiectases of the palms, fingertips, and lips and a deformed nasal septum. The patient had a hemoglobin concentration of 8.8 g per deciliter (5.5 mmol per liter), hematocrit of 29 percent, white-cell count of 6100 per cubic millimeter, platelet count of 311,000 per cubic millimeter, serum iron concentration of 25 μg per deciliter (4.5 μmol per liter), total iron-binding capacity of 530 μg per deciliter (95 μmol per liter), and ferritin concentration of 10 μg per liter. Platelet function was normal, as were the plasma concentrations of coagulation factors.
The patient was treated with 1 g of aminocaproic acid twice daily and 325 mg of ferrous sulfate daily, both given orally. He had only one 10-minute episode of epistaxis during the first week of therapy and none thereafter. After one month his hemoglobin concentration was 13 g per deciliter (8 mmol per liter) (Figure 1Figure 1
Hemoglobin Concentrations during Aminocaproic Acid Therapy in Two Patients with Hereditary Hemorrhagic Telangiectasia.). At that time the dose of aminocaproic acid was reduced to 1 g daily. During the next seven months, the patient had two brief episodes of epistaxis, each lasting five to seven minutes, and his hemoglobin concentration remained normal. After 15 months of aminocaproic acid therapy at a daily dose of 1 g, the patient had a hemoglobin concentration of 11.3 g per deciliter (7.0 mmol per liter) and occasional episodes of epistaxis lasting 5 to 10 minutes. The dose of aminocaproic acid was increased to 1.5 g daily. Thereafter, the patient had only one brief (two to three minutes) episode of epistaxis every two to three weeks, and his hemoglobin concentration increased to 13.1 g per deciliter (8.1 mmol per liter). He had no side effects of therapy (nausea, cramps, diarrhea, hypotension, dizziness, sinusitis, skin rash, myopathy, fatigue, rhabdomyolysis, renal dysfunction, or thrombosis).Patient 2
Patient 2 was a 66-year-old woman of Mediterranean descent who presented with a diagnosis of hereditary hemorrhagic telangiectasia and a history of recurrent epistaxis, gastrointestinal bleeding, and anemia. Gastrointestinal endoscopy revealed telangiectatic lesions but no ulceration or polyps. She had three or four episodes of epistaxis per week, each lasting 20 to 30 minutes, despite having had multiple nasal septoplasties and septal dermatoplasty. She took iron supplements irregularly. A history of exertional chest pain was reported; cardiac catheterization revealed single-vessel coronary artery disease, which was treated with oral diltiazem and sublingual nitroglycerin as needed for pain. The patient's father, a paternal aunt, two daughters, one son, and one grandson had recurrent epistaxis.
Physical examination revealed multiple telangiectatic lesions on the palms of the hands, lips, and tongue. Studies of platelet function and clotting factors were normal. The patient had a hemoglobin concentration of 7.5 g per deciliter (4.6 mmol per liter), normal white-cell and platelet counts, a serum iron concentration of 5 μg per deciliter (0.9 μmol per liter), total iron-binding capacity of 480 μg per deciliter (86 μmol per liter), and a ferritin concentration of 30 μg per liter. A stool guaiac test was positive.
The patient was treated with 1.5 g of aminocaproic acid twice daily and 325 mg of ferrous sulfate daily, both given orally, and 3 units of packed red cells. Three days later her hemoglobin concentration was 11.1 g per deciliter (6.9 mmol per liter), and one month later it was 13 g per deciliter (8 mmol per liter) (Figure 1). She had no episodes of epistaxis after the start of therapy, and a stool guaiac test was negative. After two months of aminocaproic acid therapy, the daily dose was reduced to 2 g. During the next 13 months, the patient had no episodes of epistaxis, no gastrointestinal bleeding, and no side effects of therapy.
Discussion
The treatment of patients with hereditary hemorrhagic telangiectasia is difficult and frustrating. The pathogenesis of their bleeding diathesis is poorly understood. Possible explanations include mechanical fragility and rupture of telangiectatic vessel walls,17,18 impaired aggregation and adhesion of platelets,19-22 and abnormal synthesis of von Willebrand factor from defective endothelial cells23,24. An association of hereditary hemorrhagic telangiectasia with von Willebrand's disease or an inhibitor of factor VIII activity has been reported23-26. However, no abnormalities of platelet aggregation or factor VIII-von Willebrand factor complex were detected in a study of eight related patients with hereditary hemorrhagic telangiectasia27 or another study of seven unrelated patients,28 and we found no such abnormalities in our patients.
We found that aminocaproic acid therapy decreased the frequency of bleeding episodes in two unrelated patients with hereditary hemorrhagic telangiectasia. The effect was rapid and sustained and was not accompanied by side effects. We suggest that aminocaproic acid, by inhibiting fibrinolysis in the telangiectatic vessel wall, enabled fibrin deposits to seal bleeding sites effectively. This hypothesis is supported by studies29,30 demonstrating increased concentrations of plasminogen-activator activity in the telangiectatic vessel walls of patients with hereditary hemorrhagic telangiectasia.
Source Information
From the Division of Medical Oncology and Hematology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine (H.I.S., L.A.L.), and James A. Haley Veterans Hospital (H.I.S., G.A.M., L.A.L.) -- both in Tampa, Fla.
Address reprint requests to Dr. Saba at the Division of Medical Oncology and Hematology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612.
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Claire L. Shovlin. (2010) Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment. Blood Reviews 24:6, 203-219
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