Portal de Periódicos da CAPES

Long-Term Treatment of C1 Inhibitor Deficiency With ɛ-Aminocaproic Acid in Two Patients

1996; Elsevier BV; Volume: 71; Issue: 12 Linguagem: Inglês

10.4065/71.12.1175

1942-5546

Richard G. Van Dellen,

Pharmacological Effects and Toxicity Studies

Most patients who have hereditary angioedema receive treatment with androgens or impeded androgens. ɛ-Aminocaproic acid (EACA) is another treatment for C1 inhibitor deficiency. In two patients with angioedema and attacks of abdominal pain due to C1 inhibitor deficiency, long-term treatment with EACA (for more than 2 decades in one of them) was associated with a substantial decrease in the frequency and severity of episodes. One patient had definite hereditary angioedema, and the other had probable hereditary angioedema but the family history was negative for the disease. The EACA therapy caused no major side effects. Most patients who have hereditary angioedema receive treatment with androgens or impeded androgens. ɛ-Aminocaproic acid (EACA) is another treatment for C1 inhibitor deficiency. In two patients with angioedema and attacks of abdominal pain due to C1 inhibitor deficiency, long-term treatment with EACA (for more than 2 decades in one of them) was associated with a substantial decrease in the frequency and severity of episodes. One patient had definite hereditary angioedema, and the other had probable hereditary angioedema but the family history was negative for the disease. The EACA therapy caused no major side effects. Currently, the treatment of C1 inhibitor deficiency, particularly hereditary angioedema, focuses on the use of androgen therapy (stanozolol, danazol, and, in males, testosterone).1Sheffer AL Fearon DT Austen KF Clinical and biochemical effects of stanozolol therapy for hereditary angioedema.J Allergy Clin Immunol. 1981; 68: 181-187Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 2Sheffer AL Fearon DT Austen KF Hereditary angioedema: a decade of management with stanozolol.J Allergy Clin Immunol. 1987; 80: 855-860Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 3Hosea SW Santaella ML Brown EJ Berger M Katusha K Frank MM Long-term therapy of hereditary angioedema with danazol.Ann Intern Med. 1980; 93: 809-812Crossref PubMed Scopus (124) Google Scholar, 4Sheffer AL Fearon DT Austen KF Methyltestosterone therapy in hereditary angioedema.Ann Intern Med. 1977; 86: 306-308Crossref PubMed Scopus (48) Google Scholar In addition, ɛ-aminocaproic acid (EACA) has been efficacious in controlling attacks of angioedema due to C1 inhibitor deficiency.5Frank MM Sergent JS Kane MA Ailing DW Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study.N Engl J Med. 1972; 286: 808-812Crossref PubMed Scopus (232) Google Scholar This report describes two patients with C1 inhibitor deficiency whose symptoms were decreased in frequency and severity with the long-term use of EACA. EACA caused no side effects or toxicity. In 1974, a 26-year-old woman came to Mayo Clinic Rochester because of episodes of abdominal pain, vomiting, hives, and angioedema. The episodes of abdominal pain and vomiting had begun when she was 15 years old, had necessitated repeated hospitalizations, and were thought to be due to intermittent obstruction of the small bowel. In 1972, exploratory laparotomy was performed; the surgical report indicated that a kink of small bowel was found in a paraduodenal peritoneal pouch and was repaired, and a Meckel diverticulum was removed. Postoperatively, however, the episodes of abdominal pain continued. The patient estimated that she had been hospitalized 20 times for treatment of abdominal pain, including 8 times during the year before she came to the Mayo Clinic. Numerous medical records from elsewhere indicated that she was dehydrated and had obstruction of the small bowel. Two years before she was examined at the Mayo Clinic, episodic hives and angioedema developed; her abdominal attacks were often associated with hives and angioedema. Elimination diets were not beneficial, nor were antihistamines, including diphenhydramine, promethazine hydrochloride, and hydroxyzine. The patient had no family history of a similar problem. Her father had died at age 70 years of a stroke, and her mother had died at age 63 years of colon cancer. She had seven brothers, five sisters, and one child, none of whom had similar symptoms. Physical examination showed redness and swelling of the left big toe, which appeared to be an urticarial lesion. The serum level of C4 was less than 10.6 mg/dL (normal, 14 to 51). The total serum complement was too low to measure. The C1 inhibitor value was less than 2.25 mg/dL (normal, 8 to 30). (Note: The ranges of normal values for C4 and C1 inhibitor have been modified more than once since 1974 because of changes in instrumentation and reagents and re-evaluation of the normal limits.) Treatment with EACA, 10 g daily in divided doses, was initiated. A letter from the patient's home physician 8 months later indicated that the treatment with EACA was successful. She had had no hives, angioedema, or further attacks of abdominal pain. The patient was next examined at the Mayo Clinic in November 1987 for dental extractions. She had continued to receive EACA, 10 g daily. She had had no recurrence of her abdominal pain and vomiting, although she reported rare attacks of mild angioedema with repetitive trauma. In 1981, she was given fresh frozen plasma before a wisdom tooth was extracted. In 1985, she was again given fresh frozen plasma for the extraction of more teeth and had a severe reaction, with swelling of the throat, difficulty breathing, and tightness in her chest that began minutes after the infusion. She was told that she had had cardiac arrest and was admitted to the intensive-care unit. At the Mayo Clinic in 1987, the patient's serum level of C4 was 8 mg/dL (normal, 12 to 72). Her serum level of C1 inhibitor was less than 5.8 mg/dL (normal, 8 to 24). Because the level of C1 inhibitor was low, no functional assay was done. The dental extractions were performed, and only EACA was given as prophylaxis. The dosage was increased to 15 g daily for the day before the extraction and for 2 days thereafter. Three teeth were extracted without difficulty, and she had no angioedema. The results of other laboratory tests were normal, including tests for creatine kinase and aspartate transaminase (serum glutamic-oxaloacetic transaminase). The patient continued to receive EACA, 10 g daily. Subsequent to this visit, the patient's Clq value was slightly increased at 17 mg/dL (normal, 7 to 15). In 1992, asthma (most likely, nonallergic asthma) developed and was controlled with bronchodilators, inhaled corti-costeroids, and occasional short courses of corticosteroids administered systemically. The patient's angioedema has remained well controlled with EACA. A 23-year-old man first came to Mayo Clinic Rochester in 1939 because of recurrent attacks of upper abdominal pain, vomiting, and intermittent angioedema that had occurred since he was 6 years old. The abdominal symptoms lasted for 3 to 4 days, and the episodes occurred every 6 to 8 weeks. He had had several episodes of swelling of the throat; with one episode, he was hospitalized and prepared for tracheostomy, although it was never needed. His mother, maternal grandfather, and two maternal aunts had similar symptoms. The cause of these episodes was unknown in 1939, but the diagnosis of abdominal migraine was considered. The patient next came to the Mayo Clinic in 1980 at age 64 years for a second opinion about carcinoma of the prostate found during a recent transurethral prostatic resection and for which he had been given radiation therapy. He was having difficulty urinating, and cystoscopic examination showed contracture of the bladder neck. With use of general anesthesia, surgical resection was accomplished, and no sequelae ensued. In 1981, the patient was first examined in the Division of Allergy at the Mayo Clinic, and the serum levels of C4 and C1 inhibitor were measured for the first time. The C4 value was less than 9 mg/dL (normal, 12 to 72). The C1 inhibitor value was 6.8 mg/dL (normal, 14.8 to 26.1). Because the C1 inhibitor level was low, a functional assay was not done. The patient reported that, 10 years previously, therapy with phenytoin (Dilantin) had been implemented, which seemed temporarily to alleviate his episodes. During the 6 months before the 1981 consultation, however, episodes of abdominal pain and vomiting had become more frequent, at times occurring every 1 to 2 weeks. Treatment with EACA (8 g daily) was begun; this treatment controlled his episodes of abdominal pain and angioedema. The patient has been examined annually since 1981. He continues to take EACA, 8 g daily, and has had no recurrence of angioedema or attacks of abdominal pain and vomiting. No side effects from the EACA have been detected. The serum levels of creatine kinase and aspartate transaminase have been normal, and no evidence of recurrence of his prostate cancer has been noted. In 1986, bilateral total knee arthroplasties were performed for severe degenerative arthritis of the knees. The treatment with EACA was discontinued 2 days before the operation. The patient was given danazol for several days preoperatively and for 5 days post-operatively, at which time treatment with EACA was resumed. Three days postoperatively, the patient had an attack of angioedema, with swelling of one hand and abdominal pain. When last examined in 1994, the patient was well and was still taking EACA, and no attacks of angioedema or abdominal pain had occurred. Other unrelated illnesses have developed in the patient, including severe recurrent paroxysmal atrial tachycardia (treated successfully with radio-frequency ablation), urinary incontinence, and bilateral leg pain, which was related to lumbar spinal stenosis with radiculopathies and loosening of one of the total knee arthroplasties. The patient's 83-year-old mother has also been examined at the Mayo Clinic and found to have low serum levels of C4 and C1 inhibitor. She has minimal symptoms and has never received treatment for hereditary angioedema. Through correspondence, information was obtained about the patient's sister, who has never had symptoms of angioedema; however, on two occasions, her serum level of C4 was determined to be low. Her serum level of C1 inhibitor was unknown. The two patients described in this report have received long-term treatment with EACA (for more than 2 decades in one of them) for severe symptoms from C1 inhibitor deficiency, and no evidence of side effects or toxicity has been noted. In the first patient (case 1), the treatment was initiated in 1974. Androgen therapy was not used in the second patient (case 2) because of prostate cancer, and EACA therapy was initiated in 1981. Long-term follow-up of both patients indicates a substantial decrease in the frequency and severity of their symptoms. Both patients had intestinal involvement—that is, frequent attacks of abdominal pain and vomiting—from their disease. The second patient has hereditary angioedema. Although the first patient has no family history of angioedema, the age at onset and the lack of a low serum level of Clq suggest that she may also have hereditary angioedema.6Cicardi M Bisiani G Cugno M Spath P Agostoni A Autoimmune C1 inhibitor deficiency: report of eight patients.Am J Med. 1993; 95: 169-175Abstract Full Text PDF PubMed Scopus (76) Google Scholar, 7Brasher GW C1q levels in hereditary angioedema.J Allergy Clin Immunol. 1977; 59: 263-265Abstract Full Text PDF PubMed Scopus (11) Google Scholar Her siblings and parents have not been tested. In one large series, 20% of affected kindreds had no affected relatives and were considered new mutants.8Agostoni A Cicardi M Hereditary and acquired C1 -inhibitor deficiency: biological and clinical characteristics in 235 patients.Medicine. 1992; 71: 206-215Crossref PubMed Scopus (561) Google Scholar The first patient had, by her description, what appeared to be hives or urticaria. Urticaria is unusual in hereditary angioedema. I have encountered one other patient with hereditary angioedema (who had a family history of the condition and typical complement abnormalities) who, by description and on examination, had urticarial lesions in association with the angioedema. Hereditary angioedema is an uncommon disease, and hives with or without angioedema is more common. Perhaps the presence of hives was coincidental; however, in one large series of patients with hereditary angioedema, mild urticarial eruptions did occur.8Agostoni A Cicardi M Hereditary and acquired C1 -inhibitor deficiency: biological and clinical characteristics in 235 patients.Medicine. 1992; 71: 206-215Crossref PubMed Scopus (561) Google Scholar EACA is used clinically as an antifibrinolytic agent in cases in which bleeding is due to fibrinolytic activity.9Nilsson IM Andersson L Bjorkman SE Epsilon-aminocaproic acid (E-ACA) as a therapeutic agent based on 5 years' clinical experience.Acta Med Scand Suppl. 1966; 448: 1-46PubMed Google Scholar This drug also inhibits the complement system.10Soter NA Austen KF Gigli I Inhibition by epsilon-aminocaproic acid of the activation of the first component of the complement system.J Immunol. 1975; 114: 928-932PubMed Google Scholar In 1966, EACA was given to a patient immediately after the onset of an attack of angioedema and was reported to be of benefit.9Nilsson IM Andersson L Bjorkman SE Epsilon-aminocaproic acid (E-ACA) as a therapeutic agent based on 5 years' clinical experience.Acta Med Scand Suppl. 1966; 448: 1-46PubMed Google Scholar Other reports have described successful control of angioedema in C1 inhibitor deficiency with EACA or its analogue tranexamic acid.5Frank MM Sergent JS Kane MA Ailing DW Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study.N Engl J Med. 1972; 286: 808-812Crossref PubMed Scopus (232) Google Scholar, 11Sheffer AL Austen KF Rosen FS Tranexamic acid therapy in hereditary angioneurotic edema.N Engl J Med. 1972; 287: 452-454Crossref PubMed Scopus (199) Google Scholar EACA has been used pro-phylactically for dental work in patients with hereditary angioedema.12Pence HL Evans R Guernsey LH Gerhard RC Prophylactic use of epsilon aminocaproic acid for oral surgery in a patient with hereditary angioneurotic edema.J Allergy Clin Immunol. 1974; 53: 298-302Abstract Full Text PDF PubMed Scopus (25) Google Scholar Currently, emphasis is on the use of androgens in treating C1 inhibitor deficiency.1Sheffer AL Fearon DT Austen KF Clinical and biochemical effects of stanozolol therapy for hereditary angioedema.J Allergy Clin Immunol. 1981; 68: 181-187Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 2Sheffer AL Fearon DT Austen KF Hereditary angioedema: a decade of management with stanozolol.J Allergy Clin Immunol. 1987; 80: 855-860Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 3Hosea SW Santaella ML Brown EJ Berger M Katusha K Frank MM Long-term therapy of hereditary angioedema with danazol.Ann Intern Med. 1980; 93: 809-812Crossref PubMed Scopus (124) Google Scholar, 4Sheffer AL Fearon DT Austen KF Methyltestosterone therapy in hereditary angioedema.Ann Intern Med. 1977; 86: 306-308Crossref PubMed Scopus (48) Google Scholar EACA could be considered an alternative treatment in cases in which androgens are contraindicated or produce unacceptable side effects. A double-blind study showed that EACA (16 g daily) adequately controlled symptoms due to hereditary angioedema in four of five patients.5Frank MM Sergent JS Kane MA Ailing DW Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study.N Engl J Med. 1972; 286: 808-812Crossref PubMed Scopus (232) Google Scholar During the double-blind part of the study, the fifth patient had two attacks of angioedema while taking EACA and four attacks while receiving placebo. The symptoms of this patient were controlled in the open trial with EACA after the double-blind study. In this open trial of EACA, the disease was controlled with 7 to 10 g of EACA taken daily in divided doses; however, profound weakness, with increased levels of creatine kinase and aldolase, developed in one of the study patients and necessitated discontinuation of the treatment.5Frank MM Sergent JS Kane MA Ailing DW Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study.N Engl J Med. 1972; 286: 808-812Crossref PubMed Scopus (232) Google Scholar The symptoms of the two patients described herein have been controlled with 8 and 10 g daily of EACA. Muscle necrosis is a side effect of EACA therapy,5Frank MM Sergent JS Kane MA Ailing DW Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study.N Engl J Med. 1972; 286: 808-812Crossref PubMed Scopus (232) Google Scholar, 13Kane MJ Silverman LR Rand JH Paciucci PA Holland JF Myonecrosis as a complication of the use of epsilon amino-caproic acid: a case report and review of the literature.Am J Med. 1988; 85: 861-863Abstract Full Text PDF PubMed Scopus (25) Google Scholar but it generally occurs with use of higher doses (24 g or more daily).13Kane MJ Silverman LR Rand JH Paciucci PA Holland JF Myonecrosis as a complication of the use of epsilon amino-caproic acid: a case report and review of the literature.Am J Med. 1988; 85: 861-863Abstract Full Text PDF PubMed Scopus (25) Google Scholar Thus, muscle enzyme levels should be monitored in patients receiving EACA. Postural hypotension has also been reported to occur with use of higher doses of EACA. Other reported side effects include weakness, fatigue, and prolonged menstrual flow.5Frank MM Sergent JS Kane MA Ailing DW Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study.N Engl J Med. 1972; 286: 808-812Crossref PubMed Scopus (232) Google Scholar Neither of the two patients in the current report had evidence of side effects or toxicity due to the EACA therapy during prolonged follow-up. No evidence of muscle damage was noted. The serum level of creatine kinase was regularly monitored and remained normal in both patients. Neither patient had evidence of fhrombotic episodes. Androgen therapy effectively controls the symptoms of hereditary angioedema, and sufficiently large doses increase the serum levels of C1 inhibitor and C4.1Sheffer AL Fearon DT Austen KF Clinical and biochemical effects of stanozolol therapy for hereditary angioedema.J Allergy Clin Immunol. 1981; 68: 181-187Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 2Sheffer AL Fearon DT Austen KF Hereditary angioedema: a decade of management with stanozolol.J Allergy Clin Immunol. 1987; 80: 855-860Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 3Hosea SW Santaella ML Brown EJ Berger M Katusha K Frank MM Long-term therapy of hereditary angioedema with danazol.Ann Intern Med. 1980; 93: 809-812Crossref PubMed Scopus (124) Google Scholar, 4Sheffer AL Fearon DT Austen KF Methyltestosterone therapy in hereditary angioedema.Ann Intern Med. 1977; 86: 306-308Crossref PubMed Scopus (48) Google Scholar Nevertheless, androgen therapy is less effective in treating acquired deficiency of C1 inhibitor,6Cicardi M Bisiani G Cugno M Spath P Agostoni A Autoimmune C1 inhibitor deficiency: report of eight patients.Am J Med. 1993; 95: 169-175Abstract Full Text PDF PubMed Scopus (76) Google Scholar and the dose needed to increase the levels of C4 and C1 inhibitor has been substantially larger in patients with acquired disease,14Sheffer AL Austen KF Rosen FS Fearon DT Acquired deficiency of the inhibitor of the first component of complement: report of five additional cases with commentary on the syndrome.J Allergy Clin Immunol. 1985; 75: 640-646Abstract Full Text PDF PubMed Scopus (61) Google Scholar in which the decrease in the C1 inhibitor is due to an increased catabolic rate of the inhibitor.15Melamed J Alper CA Cicardi M Rosen FS The metabolism of C1 inhibitor and C1q in patients with acquired C1-inhibitor deficiency.J Allergy Clin Immunol. 1986; 77: 322-326Abstract Full Text PDF PubMed Scopus (54) Google Scholar In some patients, treating the acquired disease has been difficult. For example, Alsenz and associates16Alsenz J Bork K Loos M Autoantibody-mediated acquired deficiency of C1 inhibitor.N Engl J Med. 1987; 316: 1360-1366Crossref PubMed Scopus (157) Google Scholar described two patients who had no response to purified C1 inhibitor concentrate, danazol, or EACA; however, only 3 g of EACA was administered daily, and a larger dose is needed. Cicardi and colleagues6Cicardi M Bisiani G Cugno M Spath P Agostoni A Autoimmune C1 inhibitor deficiency: report of eight patients.Am J Med. 1993; 95: 169-175Abstract Full Text PDF PubMed Scopus (76) Google Scholar reported that EACA was effective in treating acquired C1 inhibitor deficiency in six of seven patients. Concern about fhrombotic episodes exists with the use of EACA, but this complication seems to be uncommon. Because of this potential problem in the second patient in the current report, EACA treatment was discontinued before a major surgical procedure was performed. A course of an impeded androgen (stanozolol) was administered pre-operatively. EACA treatment should be stopped before a major surgical procedure is performed. Several regimens have been recommended for prophylaxis preoperatively, including stanozolol, 4 mg four times daily for 5 days preoperatively2Sheffer AL Fearon DT Austen KF Hereditary angioedema: a decade of management with stanozolol.J Allergy Clin Immunol. 1987; 80: 855-860Abstract Full Text PDF PubMed Scopus (66) Google Scholar or 6 mg daily for 6 days preoperatively and for 3 days postoperatively.8Agostoni A Cicardi M Hereditary and acquired C1 -inhibitor deficiency: biological and clinical characteristics in 235 patients.Medicine. 1992; 71: 206-215Crossref PubMed Scopus (561) Google Scholar A major drawback to EACA treatment is its cost. EACA is dispensed in 500-mg tablets, and the current cost for 1,000 tablets is approximately $1,677. EACA treatment is an alternative to androgen therapy for patients with either acquired or hereditary C1 inhibitor deficiency. In these two patients, EACA was safe and resulted in a notable decrease in the frequency and severity of their attacks of angioedema. EACA should be considered in male patients with C1 inhibitor deficiency who have prostate cancer or other prostate problems that might be aggravated by androgens. In addition, EACA should be considered in women with C1 inhibitor deficiency who have unacceptable side effects from currently available impeded androgens, such as stanozolol and danazol. Furthermore, EACA is a therapeutic option for patients with acquired C1 inhibitor deficiency.