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Danazol Treatment for Paroxysmal Nocturnal Hemoglobinuria

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Danazol Treatment for Paroxysmal Nocturnal Hemoglobinuria Case Report Danazol Treatment for Paroxysmal Nocturnal Hemoglobinuria Masahiro MURAKAWA,Tsunefumi SHIBUYA, Mine HARADA, Takashi OKAMURA, Yoshinobu ASANO, Hideki OKAMURA and Yoshiyuki NlHO Danazol was administered to two patients with paroxysmal nocturnal hemoglobinuria (PNH)with a dramatic effect on the hematological findings. The patients, 31- and 41-year-old females, were initially diagnosed as having aplastic anemia, and were initially treated with anabolic steroid and immunosuppressive therapy, respectively. Sugar water and Hamtests turned positive at the start of danazol therapy in the former patient and after two months in the latter patient. This drug produced a dramatic improvement in the hemoglobin level and the platelet count and showedfew side effects in the patients. Apossible mechanismof action of danazol for PNHis briefly discussed. Key words: Hemolytic anemia, Aplastic anemia, Hematopoiesis, Therapy Danazol, a synthetic androgen with a reduced effective (10), the usefulness of this therapy has not virilizing effect, is administered for the treatment of been established. Recently, we experienced two cases endometriosis. Ahn et al (1) introduced this drug as of PNHin which danazol produced a dramatic an effective agent for the treatment of immune effect for the recovery from severe anemia. Danazol thrombocytopenic purpura (ITP), and it has also also had fewer side effects such as virilization and been reported to be useful in the treatment of skin complications than anabolic steroids and gave autoimmune hemolytic anemia (AIHA)even when encouraging results. Weherein report two cases of corticosteroids were ineffective (2). Furthermore, PNHsuccessfully treated with danazol. manyreports have described the effects of this agent CASE REPORT in patients with aplastic anemia (AA) (3), pure red cell aplasia (PRCA) (4) and myelodysplastic Case 1 (I.G.) syndrome (MDS) (5, 6). Paroxysmal nocturnal A 31-year-old Japanese womanwas admitted to hemoglobinuria (PNH) is a primary disorder of bone a local hospital on July 23, 1988, because of marrow hemopoietic cells characterized by an headache and transient left hemiparesis. At the age unusual susceptibility to the hemolytic action of of 27, dysfunctional genital bleeding had developed complement (7, 8). Pancytopenia and intravascular and she was diagnosed to have aplastic anemia (AA) hemolysis followed by hemoglobinuria and sub- on the basis of hematological and bone marrow sequent renal damage in the course are sometimes findings at a local hospital. Fluoxymesterone and difficult to control. Therapeutic trials of cortico- prednisolone (PSL) had produced some effects, but steroids and anabolic steroids for PNHhave not the patient had refused treatment with anabolic always been satisfactory (9). Although the ad- steroids and had been given blood transfusions ministration of danazol has been reported to be alone. From the First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka Received for publication August 14, 1989; Accepted for publication June 5, 1990 Reprint requests should be addressed to Tsunefumi Shibuya, MD,First Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan Jpn J Med Vol 29, No 4 (July, August 1990) 417 Murakawa et al At admission to a local hospital, Hb was 6.0 g/dl, on August 13, and she was discharged and followed RBC 1.63xlO12/l, Ht 19.7%, MCV 121 fl, MCH up in our outpatient clinic. In October 1988, the dose 36.8 pg, MCHC30.5% and PNH was diagnosed on of danazol was reduced to 200 mg/day because of the basis of positive sugar water and Hamtests. She amenorrhea and appearance of facial acne. The was transfused with 7 units of washed red blood cells hemoglobin level gradually increased from for two days, and then was referred to our depart- November 1988 (Fig. 1). On May 9, 1989, hemato- ment for further examination and for control of the logical findings were as follows; Hb 15.0 g/dl, RBC disease on August 8, 1988. At admission to our 4.51X1012/l, Ht 47.1%, MCV 104 fl, MCH 33.3 department, hematological findings just after pg, MCHC 31.8%, reticulocytes 1.9%, WBC transfusion were as follows (Table 1); Hb 7.7 g/dl, 2.7xlO9/l, and platelets 61x 109/L NCCof the RBC 2.21x1012/l, Ht 24.0%, MCV 109 fl, MCH bone marrow was 321 x 109/l with 36%erythroid 34.8 pg, MCHC32.1%, reticulocytes 2.3%, WBC series. In addition, the serum haptoglobin level 1.9x 109/l and platelets 38 x 109/l. Sugar water and recovered to 103 mg/dl. The remission has thereafter Hamtests were positive. Serum haptoglobin level been maintained for more than 12 months with a was less than 10 mg/dl. Bone marrow aspiration dose of only 100 mg/day of danazol. Liver func- showed a nucleated cell count (NCC) of 15 x 199/1 tion did not deteriorate during the course. with 26.0% erythroid series, and bone marrow Case 2 (S.T.) biopsy also showed highly hypoplastic marrow. A 41-year-old Japanese woman visited a Danazol, at a dose of 400 mg/day, was started physician on March 8, 1988, complaining of palpita- Table 1. Laboratory findings of patient 1 at admission. Peripheral Blood Blood Chemistry WBC 1 9x lO9/l T.bil. 0.7 mg/dl St. 3% LDH 526 IU/1 Seg. 51% BUN 9 mg/dl Mo. 4% Creat. 0.7 mg/dl Lym. 42% Iron 99 ^g/ml RBC 2.21 x lO12/l TIBC 253 /ug/m\ Hb 7.7 g/dl Ferritin 67.8 ng/ml Hct 24.0% Haptoglobin < 10 mg/dl Reticulocyte 2. 3 % Platelet 38 x l09/l Serology Sugar water test (+ ) CRP (-) Ham test (+) CH50 41 CH50-U C3 74 mg/dl Bone Marrow C4 31 mg/dl NCC 15 X 10V1 Coombs test (-) M/E ratio 0.68 Cold agglutinin test (-) Macro-Poly. 2.0% Macro-Orth. 1.2% Urine Examination Norm-Poly. 18.4% Occult blood (-) Norm-Orth. 4.4% Protein (-) Neu-Myelo. 3. 6% Urobilinogen (N) Neu-Meta. 2.0% Hemoglobin (-) Neu-Stab. 4.4% Casts (-) Neu-Seg. 7.6% Hemosiderin (-) Monocyte 1.2% Lymphocyte 55.2% Stool Examination Megakaryocyte (-) Occult blood (-) K aryotype 46XX Eggs (-) 418 Jpn J Med Vol 29, No 4 (July, August 1990) Danazol for PNH I.G. PNH m400mg s- Jul. Aug. Sep. Oct. Nov. Dec. Jan. Feb. Mar. '88 '89 Fig. 1. Clinical course of patient 1. Arrows show RBCtransfusions. tion. Severe pancytopenia was found and she was erythroid series. At this time, both sugar water and referred to our hospital immediately. Hamtests turned positive. Thereafter, the Hb level On admission, hematological findings revealed reached a plateau level of approximately 8 g/dl and marked pancytopenia (Table 2); Hb 4.1 g/dl, RBC the platelet count was then maintained at approxi- 1.05X 1012/l, Ht ll.2%, MCV 106 fl, MCH 39 pg, mately 50 X 109/l, as shown in Fig. 2. All symptoms MCHC 36.6%, reticulocytes 2.6%, WBC 2.6x due to pancytopenia were alleviated, although facial 109/l and platelets 22 x 109/l. Bone marrow aspira- acne and amenorrhea appeared after two months. tion showed a NCC of 43 x 109/l with 24% erythroid Liver function was not affected by the agent. series, and bone marrow biopsy also showed markedly decreased hemopoiesis. Neither sugar DISCUSSION water test nor Hamtest was positive at this time. Danazol is well knownto be effective in some She was diagnosed as having AAand two courses patients with chronic ITP who have failed to of pulse-therapy with methylprednisolone were ad- respond to prednisolone (PSL), immunosuppres- ministered without effect. On May 14, 1988, ad- sants and splenectomy (1 1-15). The mechanisms of ministration of cyclosporin A (Cy-A) at a dose of the effect of danazol for ITP have been explained 280 mg/day was started. The frequency of blood in terms of enhancement of thrombopoiesis (15), transfusions was decreased thereafter and the suppression of anti-platelet auto-antibody produc- leukocyte and platelet counts increased. tion (16, 17), and impairment of clearance of On September 6, 1988, Cy-A was stopped for immunoglobulin-bound platelets by macrophages economic reasons and danazol at a dose of 400 (18). mg/day was started. In two weeks, the hemoglobin A clinical trial of danazol for the treatment of level started to rise with a dramatic increase of autoimmune hemolytic anemia (AIHA) with an reticulocytes to more than 10.0% in the peripheral evaluable effect was reported by Ahn et al (2). In blood. On November 15, 1988, hematological that study, the reduction of the dose of cortico- findings were as follows; Hb 9.1 g/dl, RBC steroids became possible with concomitant ad- 2.39xlO12/l, Ht 29.0%, MCV 121 fl, MCH 38.1 ministration of danazol. It was speculated that pg, MCHC 31.4%, reticulocytes 9.6%, WBC danazol worked by blocking the binding of IgG and 3.1xl09/l, and platelets 58x l09/l. NCC of the C3 to erythrocytes. marrow increased up to 431 x lO9/l with 60.8% With respect to the effect of danazol for AAand Jpn J Med Vol 29, No 4 (July, August 1990) 419 Murakawa et al Table 2. Laboratory findings of patient 2 at admission. Peripheral Blood Blood Chemistry WBC 2.6x lO9/l T.bil. 1.4 mg/dl St. 1% D.bil. 0.2 mg/dl Seg. 56% LDH 593 IU/1 Mo. 2% BUN 20 mg/dl Lym. 41% Creat. 0.8 mg/dl RBC 1.05 x l012/l Iron 318 /ig/ml Hb 4.1 g/dl TIBC 345 ptg/m\ Hct 1 1.2% Haptoglobin <10 mg/dl Reticulocyte 2.
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