|Year : 2017 | Volume
| Issue : 3 | Page : 180-183
Recurrent pulmonary embolism associated with oral hormonal contraceptive use
Bhanukumar Muthaiah1, Vineetha Bharathan Menon2
1 Department of Internal Medicine, JSS Hospital and Medical College, JSS University, Mysore, Karnataka, India
2 Department of Clinical Pharmacy, JSS Hospital and Medical College, JSS University, Mysore, Karnataka, India
|Date of Web Publication||9-Aug-2017|
Department of Internal Medicine, JSS Hospital and Medical College, JSS University, Mysore - 570 004, Karnataka
Source of Support: None, Conflict of Interest: None
Pulmonary embolism (PE) is a dramatic and life-threatening complication of deep vein thrombosis, and thus, its prevention, diagnosis, and treatment are of special importance. One of the more common acquired risk factor of PE is the use of oral contraceptive (OCP) medications. We report a case of PE secondary to OCP use. A 30-year-old female patient presented with PE following OCP use. Diagnosis was confirmed with computed tomography angiography and treatment was started with thrombolytics. Although appropriate treatment was initiated and offending drug was withdrawn, patient succumbed to her illness. Thus, treatment with OCPs requires careful and thorough evaluation of patient history and regular follow-up, focusing on likely complications.
Keywords: Adverse event, ethinylestradiol, levonorgestrel, oral contraceptives, pulmonary embolism
|How to cite this article:|
Muthaiah B, Menon VB. Recurrent pulmonary embolism associated with oral hormonal contraceptive use. Int J Health Allied Sci 2017;6:180-3
|How to cite this URL:|
Muthaiah B, Menon VB. Recurrent pulmonary embolism associated with oral hormonal contraceptive use. Int J Health Allied Sci [serial online] 2017 [cited 2020 Sep 26];6:180-3. Available from: http://www.ijhas.in/text.asp?2017/6/3/180/212590
| Introduction|| |
Oral contraceptives (OCP) are used for their contraceptive as well as noncontraceptive effects ranging from reduction of menstrual bleeding and dysmenorrhea to treatment of premenstrual syndrome, menstrual migraines, acne, and hirsutism. Long-term use is known to reduce the risk of endometrial and ovarian cancer. Modern OCP are well tolerated and serious side effects are usually rare occurrences. Pulmonary embolism (PE) remains a rare but potentially serious complication of OCP use. It is a major health problem worldwide. It is associated with significant mortality rate, which is considerably >15% within the first 3 months after diagnosis. Other common risk factors for PE include immobility, old age, inherited clotting disorders, postoperative conditions, and history of smoking. Young women, who are healthy and active, without any genetic predisposition are considered to be at low risk to develop PE. Herein, we report an unusual case presentation where a young woman developed multiple PE likely due to OCP use.
| Case Report|| |
A 30-year-old female presented to the internal medicine unit of a tertiary care hospital with a 1 month history of cough occasionally associated with expectoration. There was no history of fever, wheezing, hemoptysis, trauma, or motor weakness. Her medical history was negative for any major disorders. However, she declared occasional exposure to cow dung and hay. On examination, patient was conscious oriented and dyspneic at rest. Respiratory system examination showed a few inspiratory crepitations in both infrascapular regions. Her blood pressure was 120/70 mm Hg; heart rate, 100 beats/min and regular; respiratory rate, 42 cycles/min; resting oxygen saturation, 90% breathing in ambient air; capillary blood glucose level, 88 mg/dL; and body mass index, 28.2 kg/m 2. Total leukocyte count was 12,590 cells/cumm (4000–11,000 cells/cumm), peripheral blood smear showed neutrophilic leukocytosis and erythrocyte sedimentation rate was 90 mm/h (0–20 mm/h), whereas other blood counts, serum electrolytes, and liver and renal function tests were within normal limits. Examination of sputum showed moderate number of inflammatory cells with Gram-positive cocci in pairs. Based on the clinical presentation and test results, provisional diagnosis of hypersensitive pneumonitis secondary to organic dust exposure with chronic cough and hypoxic respiratory failure was considered. She was started on empirical treatment with antibiotics, bronchodilators, steroids, and oxygen therapy.
Subsequent chest X-ray showed bilateral ground-glass appearance with nodular opacities in the lower zone [Figure 1], which was suggestive of interstitial lung disease (ILD). Patient's condition worsened over the next few days following hospitalization, especially with regard to breathing. Resting oxygen saturation was maintained at 88% breathing in ambient air and 93% with oxygen therapy. The patient also had two episodes of hemoptysis. High-resolution computed tomography (CT) thorax was done which revealed multiple “tree in bud” and ground glass appearances in the left lower zone [Figure 2]. Based on the imaging, differential diagnosis of tuberculosis, sarcoidosis, and microvascular angiopathies was considered. Therefore, blood samples to test antinuclear antibodies, antineutrophil cytoplasmic antibodies and angiotensin converting enzyme and sputum samples to test for acid-fast bacilli and fungal elements were taken. A trial of antitubercular and antifungal drugs along with steroids was also considered.
|Figure 1: Bilateral ground glass appearance with nodular opacities in the lower zone|
Click here to view
|Figure 2: High-resolution computed tomography thorax cross-section suggestive of multiple “tree in bud” appearance (ground glass appearance) in the left lower zone|
Click here to view
Patient continued to be dyspneic and resting oxygen saturation dropped to 88% breathing with 4 L of oxygen therapy. In view of her worsening symptoms and fall in saturation for the second time during hospitalization, she was shifted to the Medical Intensive Care Unit and was managed with bilevel positive airway pressure. She was also started with intravenous furosemide 80 mg/day and methylprednisolone 1 g/day; however, there was no significant response to treatment. Blood gas analysis was found to be normal (pH: 7.43 [7.35–7.45], pCO2: 30.6 mmHg [35–45 mmHg], pO2: 180 mmHg [80–100 mmHg], HCO3: 20.0 mmol/L [22–28 mmol/L] and lactate: 1.4 mmol/L [0.5–1.6 mmol/L]). Electrocardiogram showed sinus tachycardia. Her resting echocardiogram showed severe pulmonary arterial hypertension of 74 mm Hg with normal left ventricular systolic function (ejection fraction-60%) and left ventricular diastolic dysfunction with the right ventricular dilatation and mild tricuspid regurgitation. Tricuspid annular plane systolic excursion was found to be normal. As per the literature since the pulmonary arterial hypertension >50 mm Hg is unlikely to occur in ILD, an alternate diagnosis other than ILD was considered. D-dimer was evaluated and was found to be negative. Bronchoscopy with lavage was advised. CT pulmonary angiography was also considered. However, as the patient's condition deteriorated, patient's relative did not agree for high-risk bronchoscopy, wanted to take second opinion and was thus referred to a higher medical center where CT pulmonary angiogram was done. CT pulmonary angiogram showed multifocal segmental acute to subacute pulmonary thromboembolism associated with bilateral pulmonary infarcts. Pelvic Doppler study of the pelvis veins and lower limb was also done and showed extensive thrombosis in the lower limb veins. Impression was made as acute on chronic thromboembolic pulmonary hypertension with multiple pulmonary infarcts with secondary infection of cavities of infarcts. When history was taken, she has been taking levonorgestrel/ethinyl estradiol 0.15/0.03 mg regularly since the past 2 years for her polymenorrhea, without any medical supervision. Therapeutic anticoagulation was started with low-molecular-weight heparin overlapping with oral anticoagulant, acenocoumarol 3 mg/day, for 3 days and later heparin was stopped and oral anticoagulant was continued. However, patient continued to have tachypnea and breathlessness at rest. Her blood pressure was 110/80 mm Hg; heart rate, 160 beats/min and regular; and resting oxygen saturation, 80% breathing in ambient air. Her blood gas analysis revealed respiratory alkalosis (pH: 7.51 [7.35–7.45], pCO2: 25.5 mmHg [35–45 mmHg], pO2: 70.7 mmHg [80–100 mmHg], HCO3: 20.3 mmol/L [22–28 mmol/L], and lactate: 1.9 mmol/L [0.5–1.6 mmol/L]). Patient was incubated and connected to mechanical ventilator in view of dropping saturation and respiratory failure. However, her condition worsened and saturation continued to drop down. In spite of all the measures to revive the patient, she succumbed to her illness.
Causality was assessed using both Naranjo criteria and the World Health Organization probability scale, which revealed a “probable” causal relationship between the drug and the event. Severity of the reaction was evaluated using the Modified Hartwig and Siegel scale  and was categorized as severe (level 7 reaction) in its severity.
Consent was obtained from the patient on suitably designed informed consent form.
| Discussion|| |
OCP lead to increased incidence of thrombovascular diseases through their effect mediated on the hemostatic system by inducing multiple prothrombotic effects on proteins involved in coagulation. OCP increase the activity of coagulation factors II, VII, VIII, and X and fibrinogen and decrease levels of antithrombin and protein S., Moreover, OCP users also develop resistance to the anticoagulant action of activated protein C and decreased fibrinolytic potential. Platelet activity is also increased leading to accelerated aggregation. These changes create a state of hypercoagulability.
Thrombin formation occurs, however, when some local vascular wall damage exists or when other risk factors for thromboembolism coexist. Other risk factors for thrombosis include personal or family history of thrombosis and prothrombotic abnormalities such as V Leiden, prothrombin 20210A, and deficiencies of protein C, protein S, or antithrombin. Older age, overweight, cigarette smoking, surgical procedures, trauma, immobility, pregnancy, and peripartum are other common risk factors. Diseases of the carotid and coronary arteries, congestive heart failure, chronic obstructive pulmonary disease, acute infection, hypertension, hyperlipidemia, diabetes mellitus, and cancer are also associated with fatal outcome. Studies have identified that the coagulation effects of OCP depend on the dose of estrogen and type of progestogen used in the combination. Administration of pharmacological amounts of estrogen has been found to be associated with increase in production of clotting factors. In comparison to the most commonly used estrogen dose (30 mcg), OCP containing the lowest dose of estrogen, i.e., 20 mcg estrogen, have the least effect on the hemostatic factors, whereas those containing 50 mcg estrogen are found to be associated with the highest risk of thrombosis. Progestogen component of the OCP modifies the effect of estrogen on the hemostatic system. The third-generation progestogens have the maximum effect followed by the second- and first-generations, respectively. OCP confer an immediate effect. The risk of thrombosis is highest in the 1st year following administration which does not increase with longer duration and disappear when they are discontinued. Our patient was on 30 mcg of ethinylestradiol and 150 mcg of the second-generation progestogen, levonorgestrel, leading to hypercoagulability and PE. Other than the use of OCP, the identifiable risk factors for thrombus formation in our patient were overweight and presence of acute infection.
Majority of the clot has their origin in the deep veins of the pelvis or legs where they remain asymptomatic. These lower limb clots then flow into the inferior vena cava and then into the right ventricle before obstructing the pulmonary arterial circulation. Saddle PE occurs due to a large clot in the pulmonary artery at its bifurcation, whereas a small clot in the peripheral pulmonary artery can result in pulmonary infarction. Depending on the degree and extent of occlusion, various pathophysiological changes occur. Large embolism can obstruct the right ventricular outflow tract leading to dramatic increase in the pulmonary vascular resistance and acute right heart failure with no time left for physiological compensation. Pulmonary arterial occlusion can also lead to ventilation-perfusion mismatch, resulting in increased dead space, and decreased gas exchange units. Alveolar hyperventilation occurs due to stimulation of receptors. Consequent bronchoconstriction occurs with PE results in increased airway resistance. Pulmonary compliance is decreased due to lung edema, loss of surfactant, and lung hemorrhage. The prominent symptoms of PE include dyspnea, chest pain, anxiety, and cough. Similar symptoms were observed in our patient. Initially in the patient, an infection was considered as the primary pathology, as evidenced by multiple tree-in-bud and ground-glass appearances. Nevertheless, with imaging, the diagnosis was made as acute on chronic thromboembolic pulmonary hypertension with multiple pulmonary infarcts with secondary infection of cavities of infarcts. The clue to alternative diagnosis other than ILD was high pulmonary arterial hypertension >50 mm Hg. The severe hypertension and recurrent deterioration in the patient's general condition during hospital stay were a result of recurrent, small, and multiple embolism causing occlusive vascular disease.
The main treatment for PE in clinically stable patients is with anticoagulants which prevent the clot from getting larger and also reduces the risk of further clots from developing. In severe cases as seen in clinically unstable patients with PE, guidelines recommend the use of thrombolytic treatment. Less commonly surgery may be required in life-threatening cases., There patients with high-risk PE have a high mortality rate when anticoagulant treatment is given alone. In this setting, the hemodynamic effects of thrombolytic therapy outweigh its bleeding risk, and the only contraindication to its use is active uncontrollable bleeding. Studies have shown that thrombolysis in these patients is associated with a reduction in mortality and recurrent PE.
| Conclusion|| |
This case report highlights the importance of taking personal and family history of thrombosis or clotting disorders in patients while prescribing with OCP. Counseling about the side effects as well as evaluation of risk factors is also mandatory before prescribing the drug. Regular follow-up should be done to identify any drug-induced cardiovascular and cerebrovascular events. Patients should be constantly monitored for signs and symptoms of thrombosis.
The authors would like to thank the Principal, JSS College of Pharmacy and JSS University, Mysore for the support and encouragement.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Reid R; Society of Obstetricians and Gynaecologists of Canada. SOGC clinical practice guideline. No 252, December 2010. Oral contraceptives and the risk of venous thromboembolism: An update. J Obstet Gynaecol Can 2010;32:1192-204.
Prasad BN. Pulmonary thromboembolism: Indian scenario. In: Muruganathan A, editor. Medicine Update. New Delhi, India: Jaypee Brothers Medical Publishers Pvt., Ltd.; 2013. p. 493-502.
Rand K, Sherman CB. An unusual case of pulmonary embolism in a young healthy female competitive rower. R I Med J 2014;97:57-9.
Olsson S, Parthasarathi G. Adverse drug reactions and pharmacovigilance. In: Parthasarathi G, Nyfort-Hansen K, Nahata MC, editors. A Textbook of Clinical Pharmacy Practice: Essential Concepts and Skills. 2nd
ed. Hyderabad: Universities Press Pvt., Ltd.; 2012. p. 104-22.
Norris LA, Bonnar J. Haemostatic changes and the oral contraceptive pill. Baillieres Clin Obstet Gynaecol 1997;11:545-64.
Witczak A, Prystupa A, Mosiewicz J. Pulmonary embolism associated with oral contraceptive use – Case report. J Preclin Clin Res 2014;8:120-2.
Speroff L. A clinician's response to the oral contraceptive thrombosis controversy. Hum Reprod Update 1999;5:654-63.
Rosing J, Curvers J, Tans G. Oral contraceptives, thrombosis and haemostasis. Eur J Obstet Gynecol Reprod Biol 2001;95:193-7.
Meyer G, Vieillard-Baron A, Planquette B. Recent advances in the management of pulmonary embolism: Focus on the critically ill patients. Ann Intensive Care 2016;6:19.
[Figure 1], [Figure 2]