Disclaimer
The views expressed herein are those of the authors and do not necessarily reflect the views of the Department of Defense, the Defense Health Agency, the United States Army, or Carl R. Darnall Army Medical Center.
History of Present Illness
A 25-year-old female, otherwise healthy, presented to an emergency department with fevers for 10 days and the development of back pain over the past few days. Her outpatient clinic provider had empirically started antibiotics for a presumed UTI; however, the patient endorsed she had no dysuria or suprapubic pain, and added that she was familiar with UTI symptoms (and had not had any of these over the past 10 days).
The patient denied significant alcohol or other drug use. The patient also denied chronic medication use, endorsing the antibiotics recently prescribed for presumed UTI were the only medications she took.
Physical Exam
Vitals significant for fever to 102.2F, tachycardic to 141, normotensive at 118/79, respiratory rate 18, and 97% oxygen on room air. Physical exam was significant for a benign abdominal exam and very scant right-sided costovertebral angle tenderness.
Comprehension question: What next steps might you take in this case?
Work-up
Initial workup included: a urinalysis (contaminated with epithelial cells and not supporting of pyelonephritis as a cause of fevers for 10 days); complete blood count, remarkable for a mild leukocytosis of 11.9 (hemoglobin, hematocrit, and platelets were within normal limits); and a comprehensive metabolic panel with an AST 118U/L, ALT 260U/L, alkaline phosphatase 165U/L, and bilirubin and lipase within normal limits.
Comprehension question: What additional work-up (imaging or laboratory) does this information prompt?
Work-up, Continued
After verifying with the patient that she didn’t have an excessive alcohol use disorder past and had not had alcohol in the past 10 days, the clinical workup narrowed down to liver-specific infectious causes. The patient continued verifying minimal pain on deep palpation of right upper quadrant, therefore right upper quadrant ultrasound was not obtained in favor of more comprehensive CT abdomen and pelvis. Of note, if the patient had more significant right upper quadrant pain, right upper quadrant ultrasound would have been more appropriate in this young patient with abnormal liver function tests in order to better visualize the biliary tract, as CT abdomen pelvis does not visualize biliary pathology as well as right upper quadrant ultrasound, and sometimes misses cholecystitis/choledocholithiasis.
At the same time, as further imaging was being obtained, we broadened the laboratory evaluation to include further hepatotoxic infectious diseases: namely hepatitis and malaria panels. Both were negative. The CT scan, however, yielded the presumed cause of fever, tachycardia, and new back pain: portal vein thromboembolism.
Comprehension Question: What might have caused this?
Case Conclusion and Discussion
The leading causes of portal venous thrombosis are alcoholism and cirrhosis.1 Other causes include: local malignancy/hepatobiliary malignancy that compress the portal venous system, myeloproliferative neoplasms that increase coagulability, inherited thrombophilia such as factor V leiden, abdominal infections causing thrombophlebitis, estrogen containing OCPs, and antiphospholipid antibodies.2-7 Upon initial interview and secondary interview, this provider was not able to elucidate the likely cause of this unusual thromboembolism; the patient did not have cirrhosis, significant alcohol use, or evidence of myeloproliferative disorder. Therefore, with the understanding the ED physician had of the patient's history and associated lab results, the highest suspicion was for an unusual disorder like inherited thrombophilia or autoimmune disease. However, in reviewing the case after admission, the cause was likely much more common than these rarer (and more chronic) pathologies.
Further history taken by the admitting team revealed the patient was using the NuvaRing estrogen birth control. NuvaRing increases risk of venous thromboembolism events similar to other combined OCPs: 8.3–11.4 events per 10,000 woman-years.8 Although we in the medical field realize this is a risk for estrogen use (thinking of PERC and Wells risk tools), patients are often undereducated on the risks of estrogen therapy; and providers too often do not take the time to appropriately risk stratify patients for contraception use.9,10 With the combination of lack of comprehensive education regarding risks of contraception, and the fact that contraception in many cases is not treating a medical condition, many patients do not add birth control to their medication history during the initial emergency department interview. Therefore, these medications have to be teased out specifically in a separate question. As an example, as providers, we should ask not just “what medications are you taking” but also “what are you using for contraception/birth control” in order to obtain an accurate history and accurately risk stratify patients.
This question of hormonal risk factors is increasingly important in the epidemiologic context U.S. clinicians face with the obesity epidemic. Obesity increases the risk of VTE associated with estrogen contraceptive use.11-13 Therefore, it is highly likely that most U.S. practicing emergency physicians will encounter estrogen-containing contraceptive-associated venous thromboembolism due to the comorbid obesity epidemic. As this unusual case demonstrates, clinicians need to widen the diagnostic suspicion for venous thromboembolism from lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) clinical signs and symptoms to fever and vague abdominal symptoms as well. Therefore, comprehensive history of contraception use is important in all patients, not just when applying DVT and PE algorithms. Additionally, thinking back to surgical rotations and the causes of post-operative fevers, remember fever can be associated with blood clot alone and should remain high on the differential of fever of unknown etiology.
Key Take-Aways
- Always ask separately about contraception. Patients often don’t consider it medicine; however, it does have side effects and risks, particularly in the current U.S. population.
- Think venous thromboembolism in cases of fever of unknown etiology, and not just with associated shortness of breath or leg swelling.
- Do not anchor on previous diagnostics: if the providers had simply broadened antibiotics for a UTI with presumptive pyelonephritis (fever, back pain) then the patient’s portal vein thromboembolism would have been missed.
References
- Kaplan DE, Ripoll C, Thiele M, et al. AASLD Practice Guidance on Risk Stratification and Management of Portal Hypertension and Varices in Cirrhosis. Hepatology (Baltimore, Md.). 2024;79(5):1180-1211.
- Modolell I, Guarner L, Malagelada JR. Vagaries of Clinical Presentation of Pancreatic and Biliary Tract Cancer. Annals of Oncology: Official Journal of the European Society for Medical Oncology. 1999;10 Suppl 4:82-4.
- Rumi E, Cazzola M. Diagnosis, Risk Stratification, and Response Evaluation in Classical Myeloproliferative Neoplasms. Blood. 2017;129(6):680-692.
- Seligsohn U, Lubetsky A. Genetic Susceptibility to Venous Thrombosis. N Eng J Med. 2001;344(16):1222-31.
- Mederos MA, Reber HA, Girgis MD. Acute Pancreatitis: A Review. JAMA. 2021;325(4):382-390.
- Schreuder A, Mokadem I, Smeets NJL, et al. Associations of Periconceptional Oral Contraceptive Use with Pregnancy Complications and Adverse Birth Outcomes. Intl J Epidem. 2023;52(5):1388-1399.
- Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Eng J Med. 2018;378(21):2010-2021.
- NuvaRing. Food and Drug Administration. Updated date: 2025-03-21.
- Ibrahim MJ, Khalife LE, Ghanem YD, Baz GS, Cherfane MM. Gap in Knowledge of Health Benefits and Risks of Combined Oral Contraceptives among Lebanese Women. BMC Public Health. 2024;24(1):60.
- Teal S, Edelman A. Contraception Selection, Effectiveness, and Adverse Effects: A Review. JAMA. 2021;326(24):2507-2518.
- Suchon P, Al Frouh F, Henneuse A, et al. Risk Factors for Venous Thromboembolism in Women under Combined Oral Contraceptive. The PILl Genetic RIsk Monitoring (PILGRIM) Study. Thromb Haemost. 2016;115(1):135-42.
- Higginbotham S. Contraceptive Considerations in Obese Women: Release Date 1 September 2009, SFP Guideline 20091. Contraception. 2009;80(6):583-90.
- Teal S, Edelman A. Contraception Selection, Effectiveness, and Adverse Effects: A Review. JAMA. 2021;326(24):2507-2518.