Isolated Cortical Vein Thrombosis in a Young Woman on Transdermal Ethinyl Estradiol: Case Report and Literature Review

Abstract

Background/Objective

Cerebral venous thrombosis is an uncommon cause of stroke, often affecting young women and frequently associated with prothrombotic factors such as exogenous hormones. Estrogen therapy, used in contraception or hormone replacement, is a known risk factor for thrombosis. Although transdermal estrogen is thought to confer lower thrombotic risk than oral formulations, it is not risk-free. We report a case of isolated cortical vein thrombosis in a young woman on a transdermal estradiol patch.

Case Report

A 32-year-old woman on a low-dose transdermal estradiol patch for contraception presented with acute headache, hemiparesis, and Wernicke’s aphasia. Imaging revealed a left parietal infarction and thrombosis of a cortical vein in the left temporo-occipital region. The hypercoagulability work-up was unremarkable. She was treated with anticoagulation and supportive care, with gradual neurological improvement.

Discussion

This case highlights that even transdermal estrogen, often considered safer, can contribute to cerebral venous thrombosis. Oral estrogen therapy substantially increases venous thromboembolism risk (2- to 4-fold), whereas transdermal 17β-estradiol has a lower impact on coagulation. Collaboration between endocrinology and neurology is vital in managing hormone-related thrombosis.

Conclusion

Isolated cortical vein thrombosis is a rare stroke etiology that can be precipitated by estrogen therapy. Transdermal estradiol bypasses hepatic first-pass metabolism, yet it is not devoid of thrombosis risk. Clinicians should remain vigilant in prescribing and monitoring hormone therapies, balancing benefits with individualized risk assessment. This case highlights the importance of recognizing endocrine factors in unusual thrombotic events and tailoring hormone regimens to minimize vascular complications.

Highlights

• •Isolated cortical vein thrombosis is a rare but serious complication of estrogen therapy
• •Transdermal contraceptive patches may still induce thrombotic events despite bypassing hepatic metabolism
• •Ethinyl estradiol, even via the transdermal route, can retain procoagulant effects and raise venous thromboembolism risk
• •Magnetic resonance imaging/magnetic resonance venography is essential in diagnosing atypical stroke presentations in young women on hormonal therapy
• •Endocrinologists should evaluate thrombotic risk comprehensively when prescribing any estrogen formulation

Clinical Relevance

This case demonstrates that transdermal estrogen is not risk-free and may trigger cerebral thrombosis in otherwise low-risk patients. It highlights the need for individualized hormonal therapy, awareness of estrogen pharmacology, and vigilance in evaluating neurological symptoms in women using hormonal contraception.

Introduction

Cerebral venous thrombosis (CVT) is a rare form of stroke caused by clot formation in the dural sinuses or cortical veins. It accounts for approximately 0.5% to 3% of all strokes and predominantly affects younger individuals (mean age 40), with a marked female predominance. An uncommon subtype, isolated cortical vein thrombosis (ICVT), involves thrombosis confined to a cortical vein without major sinus involvement. ICVT comprises only 6% of CVT cases and less than 1% of all strokes but can lead to significant complications such as venous infarction, hemorrhagic conversion, and edema.¹ Given the demographic skew toward young women, hormonal factors have been strongly implicated in CVT risk. Pregnancy, postpartum state, and exogenous estrogen use are well-known prothrombotic conditions that increase CVT risk. Estrogen-containing contraceptives and hormone replacement therapy (HRT) have been associated with venous thromboembolism (VTE), including rare sites like cerebral veins.^2,3

Transdermal routes are considered safer from a thrombosis standpoint, and endocrine guidelines often recommend transdermal estrogen for women at elevated VTE risk.⁴ However, “safer” does not mean “risk-free.” There remains a potential for thrombosis even with transdermal hormone therapy. We present a clinical case of ICVT in a young woman on transdermal estradiol∗ therapy.

Case Report

A 32-year-old African American woman with a history of migraines without aura, alpha thalassemia trait, uterine fibroids with menorrhagia, and iron-deficiency anemia presented to the emergency department with the acute onset of headache, right arm weakness, and speech difficulty. She had been using a low-dose Transdermal Ethinyl Estradiol patch for contraception for the past 5 years, which was her only medication. Notably, she was a nonsmoker and had no personal or family history of thromboembolism.

Baseline Characteristics

The patient has a body mass index of 20.3 kg/m² (height: 5'5", weight: 120 lbs). She had been on the transdermal estradiol patch continuously for 5 years, prescribed by her gynecologist. Before the onset of her symptoms, she had been preparing for work and denied any recent physical exertion, recent travel, viral illness, or prolonged immobility.

Examination

On arrival, her vital signs were temperature 98.6 °F, blood pressure 144/93 mmHg, heart rate 101 bpm (sinus rhythm on ECG with nonspecific T-wave inversions), respiratory rate 18/min, SpO₂ 99% on room air. She was alert but had profound expressive and receptive language deficits. Neurological exam showed right arm drift with 4/5 strength in the right upper extremity, mild right facial droop, and Wernicke’s aphasia characterized by fluent speech with impaired comprehension of spoken and written language. There were no meningeal signs. She did not look clinically dehydrated, and the rest of her physical examination was unremarkable. The initial NIH Stroke Scale score was 5 (notable for aphasia and mild hemiparesis).

Laboratory studies at presentation revealed normal complete blood count values (hemoglobin 13.2 g/dL, white blood cell count 7.4 × 10³/μL, platelet count 232 × 10³/μL) with mild microcytosis consistent with her known alpha thalassemia trait. Basic metabolic panel was unremarkable. HCG was negative. Coagulation studies showed normal prothrombin time (12.1 s), INR (1.0), and activated partial thromboplastin time (28 s). D-dimer was elevated at 1.2 μg/mL (normal <0.5 μg/mL).

Imaging

Noncontrast head computed tomography revealed a left parietal cortical hypodensity consistent with an acute infarct with no intracerebral hemorrhage (Fig. 1). Computed tomography angiography of the head and neck showed patent intracranial arteries with no large vessel occlusion. Magnetic resonance imaging of the brain confirmed an acute left temporoparietal infarction with cytotoxic edema (Fig. 2). Given the young age and atypical stroke location, a magnetic resonance venography was obtained, which demonstrated a filling defect in a cortical vein along the left posterior temporoparietal region, ICVT without dural sinus involvement (Fig. 3).

Fig. 1.

Noncontrast computed tomography (CT) of the head demonstrating a left parietal cortical hypodensity consistent with an acute infarct, with no evidence of intracerebral hemorrhage.

Fig. 2.

Magnetic resonance imaging (MRI) of the brain demonstrating an acute infarction in the left temporoparietal region, associated with cytotoxic edema.

Fig. 3.

Magnetic resonance (MR) venography showing a filling defect in a cortical vein along the left posterior temporoparietal region, consistent with isolated cortical vein thrombosis without involvement of the dural venous sinuses.

Hospital Course

The patient was promptly admitted to the intensive care unit for close monitoring. Standard stroke protocol measures were implemented. She received aspirin and high-intensity statin therapy for neuroprotective and pleiotropic benefits. Given the venous nature of her infarct, therapeutic anticoagulation was started with intravenous heparin (weight-based dosing). Importantly, her transdermal contraceptive patch was removed immediately.

Over the first 24 h in the intensive care unit, her neurological status improved modestly; her comprehension began to return, and NIH Stroke Scale improved to 2. After 24 h on IV heparin (and follow-up imaging showing no hemorrhagic transformation), she was transitioned to oral anticoagulation with apixaban 5 mg twice daily.

Extensive laboratory studies for hypercoagulable states (including factor V Leiden mutation, prothrombin gene mutation, antiphospholipid antibodies, protein C/S levels, antithrombin III, and homocysteine) were all within normal limits or negative. An endocrine evaluation of estrogen levels was not performed in the acute setting. Age-appropriate cervical cancer screening via pap smear (per USPSTF guidelines for women aged 21-65 years) was negative.⁵

The patient was discharged home on apixaban anticoagulation to complete a total of 3 months of therapy. Her estradiol patch was discontinued permanently. At discharge, she had minimal neurological deficits, and by her 3-month follow-up, she had recovered full language function and right arm strength.

Discussion

ICVT is a rare cerebrovascular event that can occur in young, otherwise healthy individuals, often unmasked by precipitating factors like estrogen therapy. This case demonstrates that transdermal estradiol, widely regarded as a safer alternative to oral estrogen, can still precipitate serious thrombotic complications.

Estrogen and Thrombosis – Mechanistic Insights

Hepatic effects of estrogen are central to its thrombosis risk: Estrogen binds to estrogen receptor-α in hepatocytes, modulating gene transcription of numerous coagulation proteins. Oral estrogen (whether ethinyl estradiol in contraceptives or conjugated equine estrogen in HRT) greatly increases hepatic production of clotting factors II, VII, IX, X, and fibrinogen, while reducing levels of anticoagulant factors like protein S and perhaps protein C.^6,7 The net effect is a shift toward a procoagulant state. Additional risk factors like smoking, hypertension, or genetic thrombophilias further exacerbate estrogen-related hypercoagulability.⁸

Transdermal vs Oral Estrogen – An Endocrine Perspective

Transdermal 17β-estradiol at therapeutic doses has minimal impact on clotting factor levels, and clinical data support a substantially lower thrombotic risk with transdermal HRT.⁹ Furthermore, in women with inherent thrombophilic mutations or high body mass index, adding oral estrogen amplifies VTE risk synergistically, whereas adding transdermal estradiol did not confer additional risk in those high-risk subgroups.¹⁰ These findings have been influential in endocrinology: guidelines now emphasize selecting transdermal routes for estrogen therapy in women at elevated baseline risk of thrombosis, such as those with prior VTE or genetic predispositions. The Endocrine Society notes that transdermal hormone therapy may be safer from a coagulation standpoint, prompting a shift in practice patterns for managing menopausal symptoms and other indications in at-risk populations.^4,10

Why Then Did Our Patient Develop a CVT While on Transdermal Estrogen?

First, it is important to clarify that the patient’s “contraceptive patch” delivers ethinyl estradiol (a synthetic estrogen) plus a progestin, rather than pure 17β-estradiol. The transdermal contraceptive patch (norelgestromin/ethinyl estradiol) achieves systemic estrogen levels comparable to a moderate-dose oral contraceptive. Unlike transdermal estradiol used in HRT, the contraceptive patch still contains ethinyl estradiol, which is a potent estrogen derivative that can induce hepatic coagulation changes even without first-pass metabolism.¹¹ Some studies have suggested that the weekly patch might expose users to a higher cumulative estrogen dose than a daily pill, due to sustained delivery. The FDA has cautioned that contraceptive patch users may have an increased risk of VTE relative to oral contraceptive users, possibly related to the pharmacokinetics of transdermal ethinyl estradiol.¹² Thus, not all “transdermal estrogen” is equivalent – the type of estrogen and dose matter significantly. Bioidentical estradiol in lower doses (as in HRT) is less thrombogenic than synthetic ethinyl estradiol used for contraception. Our patient’s patch was delivering estrogen for contraception, so by necessity, it was a higher dose formulation aimed at suppressing ovulation.¹³

CVT and Estrogen

The association between oral contraceptives and CVT is well-documented. Up to 50% to 70% of young women with CVT have a history of oral contraceptive use or other estrogen exposure in some series.¹⁴ Table provides a comparative literature review of ICVT cases with emphasis on hormonal risk factors. CVT typically presents with headaches, focal deficits, seizures, or encephalopathy.¹ In this case, the patient's presentation with expressive aphasia was notable and corresponded to the rare location of her infarct. The absence of discussion regarding prior neuroimaging for the patient's chronic migraines limits causal inference, as CVT can present subclinically before acute decompensation. The literature shows that nearly 8.86% of patients with suspected primary headache have clinically significant abnormalities on imaging. However, the absence of prior neuroimaging appropriately reflects standard clinical practice, as routine brain imaging is not indicated in asymptomatic young women with typical migraine presentations without red flags such as sudden onset, focal deficits, or altered mental status. While subclinical CVT preceding this acute event cannot be entirely excluded, clinical suspicion for obtaining neuroimaging in an otherwise healthy 32-year-old woman with migraine without aura would have been exceptionally low and not justified by established guidelines.²⁴

Table.

Comparative Analysis of Isolated Cortical Vein Thrombosis Cases

Study/author (year)	Age/sex	Primary risk factors	Clinical presentation	Thrombosis location	Key imaging findings	Treatment approach	Clinical outcome	Study type
Current manuscript	32/F	Transdermal estradiol (5 y), iron deficiency anemia	Acute onset of headache, right arm weakness, and speech difficulty	Cortical vein along the left posterior temporoparietal region	T2/FLAIR hyperintensity	Therapeutic anticoagulation, patch discontinuation	Full neurological recovery	Case report
Hirata et al (2024)15	35/F	Transdermal estradiol patch (0.72 mg/2 d), recent surgery	Recurrent focal seizures, sensory aphasia	Right parietal cortical vein	T2/FLAIR hyperintensity, cord sign, hemorrhagic transformation	Edoxaban 60 mg daily × 3 mo	Complete clinical recovery at 3 mo	Case report
Sá et al (2025)16	26/F	Combined oral contraceptive (3 y use)	Progressive headaches, visual field defects	Left transverse sinus, sigmoid sinus, internal jugular vein	MRI/CT venography confirmed thrombosis	Therapeutic anticoagulation, contraceptive cessation	Full neurological recovery	Case report
Aldraihem et al (2024)17	37/M	Topical OCP application (accidental male exposure)	Sudden severe right-sided headache	Right internal jugular, sigmoid, transverse, straight sinuses	CT venogram confirmed extensive CVT	Therapeutic anticoagulation, OCP discontinuation	Clinical improvement (follow-up limited)	Case report
Ferro et al (2014)18 - Case A	21/F	Combined oral contraceptive use	Headache, focal seizures, right arm weakness	Isolated cortical vein (location NOS)	Cord sign on MRI	Therapeutic anticoagulation	Complete recovery	Systematic review case
Ferro et al (2014)18 - Case B	54/F	Hypercoagulable state, intracranial hypotension	Progressive left limb weakness, focal seizures	Isolated cortical vein with parenchymal involvement	Parenchymal hemorrhagic infarction	Therapeutic anticoagulation	Complete recovery	Systematic review case
Ferro et al (2014)18 - Case C	26/F	Combined hormonal contraceptive	Refractory headaches, no response to analgesics	Left transverse and sigmoid sinuses	MRI/MRV confirmed sinus thrombosis	Anticoagulation, contraceptive modification	Full resolution of symptoms	Systematic review case
Bales et al (2015)19	34 ± 12 y (5F, 2M)	Hypercoagulable states (4/7), intracranial hypotension (3/7)	Headaches (4/7), seizures (3/7), focal deficits (3/7)	Various cortical veins (5 ICVT, 2 mixed)	SWI most sensitive (100%), parenchymal involvement (5/7)	Therapeutic anticoagulation (5/7 cases)	Complete resolution (5/5 treated cases)	Case series
Gopalakrishnan et al (2018)20	20/F	Combined oral contraceptive, warfarin resistance	Bifrontotemporal headache, progressive weakness	Left frontal cortical vein (progressive)	Venous infarct with vasogenic edema, cord sign	LMWH (due to warfarin inefficacy despite therapeutic INR)	Significant improvement with LMWH	Case report with follow-up
Kupfer & Rubin (2006)21 - IBD Case 1	23/F	Ulcerative colitis, previous DVT, OCP use	Headache, nausea, vomiting, neck stiffness	Transverse and sigmoid sinuses	MRV confirmed occlusion	Heparin → warfarin transition	Complete recovery	Case report
Kupfer & Rubin (2006)21 - IBD Case 2	16/M	Crohn's disease, anticardiolipin antibodies positive	Lethargy, severe anemia symptoms, headaches	Superior sagittal sinus, bilateral transverse sinuses	MRI showed thrombosis with partial recanalization	Heparin → warfarin transition	Excellent recovery	Case report
Adam et al (2025)22	35/F	Postpartum day 13, severe anemia (Hb 4.2 g/dL)	Right-sided weakness, seizures, altered consciousness	Superior sagittal sinus	Hemorrhagic venous infarction	ICU management, therapeutic anticoagulation	Substantial clinical improvement	Case report
Wang et al (2017)23 - Cohort Study	43 cases (mixed ages)	Pregnancy/postpartum (43 cases), various thrombophilia	Headache (74%), seizures (35%), focal deficits (43%)	Superior sagittal (67%), transverse (64%), cortical (12%)	Variable presentations, recanalization in 77%	Anticoagulation (various agents)	Recovery rate 77.14%, mortality 4.65%	Retrospective cohort

Abbreviations: CT = computed tomography; DVT = deep vein thrombosis; ICU = intensive care unit; ICVT = isolated cortical vein thrombosis; LMWH = low-molecular-weight heparin; MRI = magnetic resonance imaging; MRV = magnetic resonance venography; OCP = oral contraceptive pill; SWI = susceptibility-weighted imaging; T2/FLAIR = T2-weighted/fluid-attenuated inversion recovery (MRI sequences).

This highlights an important clinical consideration: the emergence of new neurological deficits or severe headaches in women receiving estrogen therapy should prompt thorough evaluation for thrombotic complications. Magnetic resonance imaging/magnetic resonance venography remains the diagnostic modality of choice and was instrumental in confirming the CVT in this case.²⁵

Addressing the Question of Idiopathic ICVT

The literature recognizes that a significant portion of CVT cases (around 12.5%) are still classified as idiopathic despite thorough evaluation.¹ Specifically, in ICVT, diagnostic challenges are even greater, with some cases possibly going unnoticed due to imaging limitations and diverse clinical signs.²⁶ What makes this case particularly instructive is that the transdermal route, often considered protective against thrombosis compared to oral estrogen, was still associated with this rare thrombotic event.

While our retrospective attribution of the patient's ICVT to estrogen exposure is based primarily on the exclusion of other causes rather than direct biochemical evidence of estrogen-induced hypercoagulability, several factors strengthen this association: estrogen's established VTE risk (54.3% of female CVT cases involve contraceptives),²⁷ strong biological plausibility through prothrombotic mechanisms, and compelling temporal relationship with 5-year exposure preceding the event. Nevertheless, thrombosis typically results from multiple interacting factors rather than a single cause.⁴

However, several limitations should be acknowledged. Most notably, estradiol concentration measurements were not performed during the acute presentation, which would have strengthened the causal relationship between the transdermal patch and thrombosis. Estrogen levels vary substantially between individuals using transdermal patches due to differences in skin absorption and metabolic clearance, and measuring levels during thrombotic events could have confirmed systemic exposure and strengthened the causal argument.²⁸ While the temporal association is compelling, quantifying the patient's systemic estrogen exposure would have provided important pharmacokinetic data. Iron deficiency anemia should be recognized as an independent CVT risk factor (adjusted OR 1.10-2.22) rather than merely a coexisting condition. The mechanism involves reactive thrombocytosis, increased factor VIII levels, and altered blood rheology. This modifiable risk factor may have been the primary thrombotic trigger, particularly given the patient's long-term stable estrogen use.²⁹ This patient's 5-year continuous estrogen use places her outside the peak VTE risk period, which occurs in the first 6-12 months of hormone initiation. The risk decreases from 2-4 fold in year one to 1.5-2-fold after 12 months of continuous use. This temporal discordance significantly weakens the argument for estrogen as the primary causative factor and suggests other triggers should be prioritized.⁷

Rather than attributing causation to estrogen alone, this case illustrates a multifactorial thrombotic risk where iron deficiency anemia, combined with long-term estrogen exposure, created a synergistic prothrombotic state. VTE typically results from the interaction of multiple risk factors following Virchow's triad. Comprehensive risk factor assessment and correction of modifiable factors (particularly iron deficiency) may be more clinically relevant than hormone discontinuation alone.³⁰

Outcomes and Follow-Up

Most patients with CVT, if diagnosed early and treated with anticoagulation, have favorable outcomes; up to 80% to 85% achieve functional independence.¹ The patient recovered well, but her case will impact future endocrine management. She must permanently avoid estrogen-containing therapies to prevent recurrence, which complicates contraception and symptom management for menstruation or menopause. If HRT is needed later, nonestrogen or ultra-low-dose transdermal estradiol with close monitoring may be considered. She received anticoagulation for at least 3–6 months, and follow-up ruled out thrombophilia, confirming estrogen as the likely cause.

Conclusion

This case suggests a possible link between transdermal estradiol use and ICVT, but does not prove causation, highlighting the need for further research into the underlying mechanisms. Regular follow-up and patient education about thrombotic symptoms are essential parts of HRT.

Disclosure

The authors have no conflicts of interest to disclose.