Author information
Pai K*, Raut D**, Samant PY***.
(* Assistant Professor, ** Third Year Resident, ***Additional Professor. Department of Obstetrics and Gynecology, Seth GS Medical College &KEM Hospital, Mumbai, India)
Abstract
Deep Vein Thrombosis (DVT) is caused by immobilization, trauma, surgery, malignancy or thrombophilia. In a very old female patient with endometrial hyperplasia, recent dilatation and curettage, lithotomy position, that could have been traumatic to leg vessels, lack of mobility, development of DVT and uncontrolled vaginal bleeding after warfarin created a catch twenty two situation. Otherwise safe; progesterone therapy also poses added risk of thromboembolism. Judicious use, with minimum dose of hormones and tailored treatment of DVT can help the patient.
Introduction
Endometrial hyperplasia is considered as a precursor to endometrial carcinoma, which is one of the commonest cancers of female genital tract. Kurman and colleagues in their sentinel study of classification of endometrial hyperplasia suggested that with proper monitoring, progestins administered orally is an acceptable option to hysterectomy.[1]
In cases of simple endometrial hyperplasia without atypia risk of endometrial cancer is less than 5% and in many cases, hyperplasia without atypia may regress spontaneously.[2]
The presence of DVT renders the patient at risk for medical management with progestins as well as that for surgical management with hysterectomy. We hereby report a case of endometrial hyperplasia complicated with DVT on anti-coagulants and the dilemmas we faced in her management.
Case Report
A 82 year old, post menopausal hypertensive lady presented with heavy vaginal bleeding for 8 days after anticoagulant therapy was started for deep vein thrombosis. She had an episode of vaginal bleeding 6 weeks before presentation. Ultrasonography (USG) showed endometrial thickness (ET) of 12 mm with features suggestive of hyperplasia. She underwent dilatation and curettage (D & C). Histopathological report was suggestive of endometrial hyperplasia without atypia. She had no history of using oral contraceptive pills or hormone replacement therapy. Twenty days after D & C, she developed pain and swelling of both the lower limbs, more on the left side. There was no history of fever, breathlessness or trauma to the lower limbs other than lithotomy position for D& C. Doppler USG of the lower limbs revealed DVT of the left external iliac vein and its tributaries. She was started on low molecular weight heparin (LMWH) 60 mg BD. After day 3, LMWH was stopped and she was started on warfarin 5 mg daily. The next day, she complained of vaginal bleeding needing 8-10 pads per day. All anticoagulants were stopped thereafter. Her PT-INR (prothrombin time, international normalized ratio) was 3.2. She was brought to the hospital at this stage. Her vital parameters were stable. There was mild pallor. Speculum examination could not be done due to pain caused by DVT. Her surgical notes mentioned normal cervical os. Her bimanual examination revealed a marginally bulky uterus with free non-tender fornices. She and her relatives were counseled about limited therapeutic options. She was started on tablet norethisterone 15 mg in divided doses and tablet tranexamic acid 500 mg three times (TDS) a day. Her bleeding stopped and tranexamic acid was omitted on day 2. INR dropped to 1.02 after 2 days. Surgery and hematology opinions were sought. Surgeons advised the use of compression stockings for swelling. Hematologists recommended starting anticoagulants after control of vaginal bleeding and daily review of INR. Patient was discharged on tablet norethisterone 5 mg TDS. Daily telephonic follow up was done. Norethisterone was tapered after 15 days and stopped after 6 weeks. The patient had only occasional spotting following stoppage of norethisterone. Rivaloxaban, factor Xa inhibitor was started after 6 weeks. Leg swelling completely disappeared over 6 weeks.
Discussion
The revised 2014 WHO classification categorizes endometrial hyperplasia into hyperplasia without atypia and atypical hyperplasia.[3] Although many gynecologists advise hysterectomy in atypical hyperplasia, younger patients who wish to preserve their fertility can be managed conservatively, and for older women who do not desire or cannot undergo hysterectomy due to high surgical or anesthetic risk.[4]
Progestogens given either orally or locally (levonorgestrel-releasing intrauterine system) are effective in achieving regression of endometrial hyperplasia without atypia. Medroxyprogesterone upto 20 mg/ day or norethisterone upto 15 mg/ day may be started.[2] Observation with follow up biopsies may also suffice. Our patient with her age and lack of atypia, was a suitable candidate for observation and surveillance.
Clinically significant venous thromboembolism following gynecological surgery is rare. It is commonly associated with malignancy, prolonged anesthesia and surgery or hypercoagulable factors. The incidence of DVT in gynecologic surgery varies according to the risk factors present in the patient. Venous thromboembolism is less common, diagnosed clinically at the rate of 1% to events laboratory diagnosis up to 12%. Pulmonary embolism accounts for 3% of all deaths after gynecologic surgery.[5] The risk of pulmonary embolism is very high in a patient who already has a history of venous thromboembolism or has a thrombophilia. Our patient was one such 82 year old woman with deep vein thrombosis of the external iliac vein and its tributaries, was on anti-coagulants and was in the surgical and anesthesia high risk category. The dilemma for the treating consultant is the choice of suitable progesterone for conservative management of hyperplasia in the settings of DVT with patients on anticoagulants. Kuhnz et al suggest that the metabolic conversion of norethisterone to ethinyl estradiol, makes it risky for the patient with pre-existing DVT.[6]
An increased incidence of venous thromboembolism (VTE) was reported in women taking high-dose oral progestogens for therapeutic indications [7,8]. No particular progestogen was named but the authors warned against prescription of 'therapeutic' doses in women at increased risk of VTE. They suggested that either the progestogen increased the risk of VTE or women requiring therapeutic doses of progestins may have an inherent increased VTE risk. A safe progesterone in the correct dose for treatment of endometrial hyperplasia has still remained undetermined.[9] Mansour suggested 10 mg of medroxyprogesterone as a suitable option to norethisterone as the latter is supposed to be metabolized to ethinyl estradiol and poses VTE risk.[10] Our patient had very heavy bleeding and she needed urgent control. She was also eligible for progesterone but only for a brief period (during management of bleeding with anticoagulants). She could be managed with observation only after the crisis was over. We resorted to tapering the dose of norethisterone and omitted the same at 6 weeks. A careful follow up was diligently maintained.
Conclusion
Progestins have to be given for endometrial hyperplasia, even with DVT. Definitive management of hyperplasia is tailored to patient’s needs based on presence or absence of atypia, age, fertility issues and surgical fitness. A multidisciplinary approach involving surgeons, and hematologists and diligent follow up is a must.
References
- Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: A long-term study of “untreated” hyperplasia in 170 patients. Cancer. 1985;56(2):403-412.
- Management of Endometrial Hyperplasia; Green Top Guidelines No.67; RCOG/BSGE Joint Guideline; February 2016.
- Zaino R, Carinelli S G, Ellenson L H. Tumors of the uterine corpus: epithelial Tumours and Precursors; In Kurman RJ, Carcangiu ML, Herrington CS, Young RH, editors. WHO Classification of Tumours of Female Reproductive Organs. 4th ed. Lyon: IARC 2014;pp 125-6.
- Clark TJ, Neelakantan D, Gupta JK. The management of endometrial hyperplasia: an evaluation of current practice. Eur J Obstet Gynecol Reprod Biol. 2006;125(2):259-64.
- Clarke-Pearson DL, Geller EJ. Complications of hysterectomy. Obstet Gynecol. 2013;121(3):654-73.
- Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K. In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women. Contraception. 1997;56(6):379-85.
- Poulter NR, Chang CL, Farley TM, Meirik O. Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications. Lancet. 1999;354(9190):1610.
- Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet. 1999;354(9190):1610-1.
- Stanczyk FZ. Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev Endocr Metab Disord. 2002;3(3):211–224.
- Mansour D. Safer Prescribing of Therapeutic Norethisterone for Women at Risk of Venous Thromboembolism; J Fam Plann Reprod Health Care. 2012;38 (3):148-149.
Pai K, Raut D, Samant PY. Anticoagulant Induced Vaginal Bleeding in Case of Deep Vein Thrombosis- A Therapeutic dilemma. JPGO 2016. Volume 3 No. 10. Available from: http://www.jpgo.org/2016/10/anticoagulant-induced-vaginal-bleeding.html