A Case of Thromboembolism After Injection of Gonadotropin-releasing Hormone Agonist.

Gonadotropin-releasing hormone agonist (GnRH-a) was one of the most used therapies in the treatment of endometriosis. But unfortunately, no literatures realized GnRH-a may be related to thrombosis until now. The case below was exactly about thromboembolism taking place after using GnRH-a because of estradiol (E2) peak short-time after injection.A 50-year-old woman presented to our institution with menorrhagia. Her medical history was notable for adenomyosis and dysmenorrhea for more than 10 years.In January 2014, the patient had blood transfusion because of anemia and progestogen (norethisterone) to control the menorrhagia. Two months later, after stopping norethisterone for 2 days, her vaginal bleeding increased. Subsequently, she was prescribed Marvelon for 3 months.On April 15, the patient went to our institution, the physical examination showed that her uterine was enlarged to 26-week size. She had curettage (dilation and curettage) followed by GnRH-a (leuprorelin acetate microspheres for injection, Shanghai Livzon Pharmaceutical Co., Ltd., China) 3.75 mg subcutaneous injection, and was advised to stop Marvelon. Vaginal bleeding recurred 3 days later, and she continued to take oral norethisterone 5 mg every 8 h. After 24 h, she felt unwell with decreased urine output. The blood test showed sodium 130 mmol/L, blood urea nitrogen 11.4 mmol/L, creatinine 436 μmol/L, C-reactive protein 303.6 mg/L, white blood cell count 27.6 × 109/L, hemoglobin 56 g/L, carbohydrate antigen 125 (CA125) 334 U/ml, alanine transaminase 103 U/L, aspartate aminotransferase 110 U/L, and D-Dimer 1.5 μg/ml. She was admitted to hospital subsequently.Upon admission, the patient was transfused with 4 units packed red blood cell. Further, blood test showed β2-glycoprotein 1 Immunoglobulin AGM (Ig AGM) antibody positive, anticardiolipin antibody (ACA) 35.5 RU/ml, and antinuclear antibodies negative. Upper abdominal and pelvic computerized tomography showed hematomata and bilateral pulmonary exudative process with bilateral pleural effusion. Ultrasound of bilateral kidney and renal artery: bilateral kidney diffuse lesions, sparse renal blood flow, and abnormal bilateral renal artery spectrum.We gradually reduced the dose of norethisterone. Her vaginal bleeding subsided. However, the renal function continued to deteriorate. As a result, the patient was transferred to nephrology department for hemodialysis. Her renal condition was improved after hemodialysis treatment. Nevertheless, her pulmonary ventilation and perfusion scanning [Figure ​[Figure1a1a and ​and1b]1b] showed a defect in lower lobe of the left lung, which did not match the pulmonary ventilation imaging, led to the diagnosis of “pulmonary embolism.” Her renal biopsy showed: 3/17 glomerular sclerosis, 7/17 coagulation necrosis, a portion of tubular epithelial necrosis, bare basement membrane formation, a large number of cellular pipe, particle of tube formation; a large number of lymph plasma cells and eosinophil granulocyte infiltration in interstitium, arteriolar wall thickening, and hyaline degeneration. The Seldinger technique of renal arteriography taken on May 8 showed that left renal artery–vascular distribution was sparse, and the right was in normal vascular distribution. Brain magnetic resonance imaging suggested that there was ischemia in the white matter region of right frontal lobe. ACA was retested and the value was 21.4 RU/ml, β2-glycoprotein 1 IgAGM antibody was positive. At this point, the patient was diagnosed as catastrophic antiphospholipid syndrome (CAPS) because of the onset of acute kidney injury with kidney embolism, pulmonary embolism, and cerebral infarction within 1 week. The patient received low molecular weight heparin and methylprednisolone (40 mg daily), amlodipine tablet 5 mg daily. Her physical condition was gradually improved. Five months later, she underwent hysterectomy + bilateral tubal resection + bilateral ovarian cystectomy.Figure 1(a and b) Pulmonary ventilation and perfusion scanning: defect in left lower lobe of lung, which did not match the pulmonary ventilation imaging.In this report, we observed a case of a woman with adenomyosis who developed pulmonary embolism and multiple organs failure shortly after the injection of GnRH-a. GnRH-a was a synthetic derivative of GnRH. In the initial stage, it could promote secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by binding to GnRH receptor competing with GnRH. When continuously administered, pituitary was desensitized, releasing of GnRH would be suppressed. Therefore, there was a short E2 peak in early stage. Some research data showed that within 12 h after injection, the concentration of serum FSH increased by 5 times, LH increased by 10 times, and E2 increased by 4 times. Estrogen could lead to increase of synthesis of several coagulation factors including fibrinogen, factor II, VII, and X, and at the same time, thrombin inhibitors such as synthetic and activities of antithrombin III, protein C, and protein S were reduced, which made the blood easier to coagulate, more prone to cause thrombosis. Hence, we speculated that the patient was in high coagulation state during the long history of adenomyosis, thrombosis took place because of triggering of E2 peak after injection of GnRH-a.It was notable that the patient had multiple risk factors which led to hyper-coagulation state, the details were as follows: