Very late stent thrombosis associated with stent malapposition and uncovered struts after contrast-enhanced CT in a patient receiving long-term steroid therapy due to Kounis syndrome: a case report

Abstract

Background

Kounis syndrome (KS) is an acute coronary syndrome triggered by allergic or hypersensitivity reactions and is classified into three variants: coronary vasospasm, plaque rupture, and stent thrombosis. Type III KS involving stent thrombosis is extremely rare. The mechanisms linking allergic triggers with very late stent thrombosis (VLST) remain insufficiently characterized.

Case summary

We present a rare case of Type III KS triggered by contrast media in a 74-year-old man with a history of everolimus-eluting stent implantation ∼1 year and 10 months prior to presentation and chronic corticosteroid therapy for membranous nephropathy. Shortly after a contrast-enhanced computed tomography scan, the patient developed an ST-elevated myocardial infarction. Optical frequency-domain imaging revealed a heavy thrombus burden, malapposed stent struts, and uncovered struts. The drug-induced lymphocyte stimulation test was positive for iopamidol, confirming contrast-induced KS.

Discussion

This case highlights the potential interplay between mechanical vulnerability (malapposition and uncovered struts) and allergic responses in the pathogenesis of VLST. Chronic corticosteroid therapy may have delayed vascular healing, contributing to persistent uncovered struts. The combination of stent-related factors and systemic hypersensitivity likely promoted thrombus formation. Physicians should consider KS in the differential diagnosis of stent thrombosis even if it occurs long after percutaneous coronary intervention or if the patient is receiving long-term corticosteroid therapy.

Learning points.

• Type III Kounis syndrome should be considered in cases of stent thrombosis accompanied by signs of an allergic reaction.

• Long-term corticosteroid therapy may contribute to delayed endothelial healing, leading to persistent uncovered struts and heightened thrombotic risk.

• Mechanical factors, such as malapposition and uncovered struts, occurring with allergic inflammation, may be responsible for very late stent thrombosis.

Introduction

Kounis syndrome (KS), also known as allergic angina, is an acute coronary event triggered by allergic or hypersensitivity reactions. KS is classified into three clinical types: Type I involves coronary vasospasm in angiographically normal arteries, Type II is associated with acute coronary syndrome (ACS) triggered by plaque rupture in patients with existing atherosclerosis, and Type III is defined as stent thrombosis. According to previous literature, Type III represents only 5.1% of all KS cases, indicating its extreme rarity.^1,2 Despite its clinical importance, the underlying mechanisms of stent thrombosis in Type III KS have rarely been reported. We report a rare case of Type III KS presenting as very late stent thrombosis (VLST) in a patient on long-term corticosteroid therapy for membranous nephropathy, in whom contrast media administration appeared to trigger thrombotic occlusion associated with stent malapposition and uncovered struts.

Summary figure

Timeline

1 year and 11 months before admission	During hospitalization for steroid induction to treat membranous nephropathy, T-wave inversion in precordial leads was noted. Coronary angiography revealed right coronary artery (RCA) #3 chronic total occlusion (CTO) and left anterior descending artery (LAD) #6 90% stenosis. Bidirectional percutaneous coronary intervention (PCI) via the radial and right femoral arteries for RCA CTO was attempted but failed.
1 year and 10 months before admission	PCI was performed with an everolimus-eluting stent (2.5 × 48 mm) for LAD #6 90% stenosis. Post-procedural right groin cellulitis was treated conservatively with antibiotics. No pseudoaneurysm was detected on lower extremity ultrasound before discharge. Iopamidol was used as the contrast agent. Steroid therapy was initiated during this period.
2 months before admission	Patient began to experience right groin pain.
Day 0 (admission)	Admitted after contrast-enhanced computed tomography (CT) revealed a pseudoaneurysm of the right common femoral artery. Continuous intravenous (IV) nicardipine started.
Day 4	Maculopapular rash on the trunk developed. Suspecting drug eruption, nicardipine was switched to IV isosorbide dinitrate.
Day 7	Surgical repair of the femoral pseudoaneurysm performed.
Day 16	Follow-up of contrast-enhanced CT performed for post-surgical evaluation.
3 h after Day 16 CT scan	Patient developed chest pain. Electrocardiogram showed ST-segment elevation in V1–V4. Emergency coronary angiography revealed thrombus within the LAD artery stent. Very late stent thrombosis was diagnosed, and PCI was performed.
Post-PCI (coronary care unit stay)	Truncal erythema was noted. Treated with IV chlorpheniramine 5 mg and IV hydrocortisone 100 mg.
Day 27	Discharged without further complications.
1 year after discharge	No symptom recurrence during outpatient follow-up.

Case presentation

A 74-year-old man was referred to our hospital due to right groin pain. His medical history included hypertension, dyslipidaemia, and a lacunar infarction at age 71. He had no known drug allergies or relevant family history. His regular medications included acetylsalicylic acid (100 mg) for chronic coronary syndrome and prednisolone (5 mg) daily for membranous nephropathy. Contrast-enhanced CT revealed a pseudoaneurysm in the right common femoral artery, and the patient was admitted for surgical repair (Figure 1).

Figure 1.

Contrast-enhanced computed tomography reveals a pseudoaneurysm in the right common femoral artery.

On admission, his blood pressure was 151/83 mmHg, and continuous intravenous (IV) nicardipine was administered. On hospital Day 4, the patient developed a maculopapular trunk rash. Suspecting a nicardipine-induced eruption, antihypertensive therapy was changed to IV isosorbide dinitrate, and oral loratadine was administered. The rash promptly resolved. Surgical repair was completed without complications on Day 7. Loratadine was discontinued on Day 10.

On Day 16, ∼3 h after the follow-up contrast CT, the patient experienced acute chest pain. The patient remained alert and stable (BP 127/67 mmHg, HR 60 bpm, RR 24, SpO₂ 95%). No wheezes were heard. Laboratory tests showed elevated troponin I (278.9 pg/mL; reference <34.2) with a normal eosinophil count and CK. Electrocardiography showed ST-segment elevation in V1–V4 (Figure 2); echocardiography revealed severe anterior wall hypokinesis. Anterior ST-elevation myocardial infarction was suspected, and emergent coronary angiography was performed.

Figure 2.

A 12-lead electrocardiogram showing ST-segment elevation and hyperacute T waves in leads V1–4.

Angiography revealed a thrombus within the previously implanted stent in the left anterior descending artery. Right coronary artery segment #3 was chronically occluded with Rentrop grade 2 collateral flow from the septal branches (Figure 3; Movie  S1). Optical frequency-domain imaging (OFDI) revealed a substantial white thrombus burden in the proximal stent segment, ∼400 µm malapposition in proximal stent areas, and incomplete strut endothelialization (Figure 4; Movie  S2). The thrombus aspiration was unsuccessful. Balloon angioplasty with a compliant balloon (3.0 × 20 mm) and post-dilatation with a non-compliant balloon (3.5 × 8 mm) restored TIMI III flow. Soon after percutaneous coronary intervention (PCI), the patient developed a recurrent truncal rash (Figure 5), and KS was suspected. The patient was treated with IV chlorpheniramine (5 mg) and hydrocortisone (100 mg), with gradual symptom resolution. Eosinophilia appeared the next day, but the serum IgE level remained normal. Drug-induced lymphocyte stimulation test (DLST) was positive for iopamidol (a contrast agent) and negative for nicardipine. Based on the clinical features and test results, contrast-induced KS was diagnosed. The patient remained stable on loratadine and was discharged on Day 27 without further complications.

Figure 3.

(A, B) In-stent thrombus (yellow arrows indicate the culprit lesion). (C) Chronic total occlusion (CTO) of the right coronary artery, previously documented.

Figure 4.

(A) Red dotted lines (B–E) corresponding to the cross-sectional optical frequency-domain imaging locations. (B) Substantial white thrombus and ∼400 µm stent malapposition are observed (yellow arrows indicate sites of malapposition). (C, D, E) Uncovered struts and white thrombus are identified (blue arrows indicate uncovered struts).

Figure 5.

Erythema observed on the trunk and extremities.

Discussion

KS is defined as the occurrence of ACS triggered by the release of inflammatory mediators such as histamine and leukotrienes from activated mast cells, which promotes platelet aggregation during an allergic reaction.^3,4 It has been classified into three types (I, II, and III), of which Type III, involving stent thrombosis, is rare and primarily described only in case reports.^2,5

In this case, acetylsalicylic acid was not discontinued before the procedure, and antiplatelet withdrawal was excluded as a causal factor. The last exposure to unfractionated heparin was during PCI, ∼1 year and 10 months earlier, and no thrombocytopenia or other findings suggestive of heparin-induced thrombocytopenia were observed. OFDI revealed a white thrombus at the culprit site without evidence of neointimal formation, making a metal allergy less likely. Considering the concurrent appearance of truncal erythema, peripheral eosinophilia, and positive DLST results for the contrast agent, a diagnosis of contrast-induced KS was established.

According to the 2023 ESC guidelines for the management of ACSs, new-generation drug-eluting stents are associated with lower rates of target lesion revascularization and stent thrombosis than bare-metal stents.⁶ However, stent thrombosis remains a rare but potentially fatal complication, even with contemporary drug-eluting stents, underscoring the importance of understanding its underlying mechanisms.

The aetiology of stent thrombosis is typically multifactorial and involves patient-, stent-, and procedure-related factors.⁷ From a device perspective, several mechanisms have been implicated, including stent underexpansion, malapposition, edge dissection, neoatherosclerosis, stent fracture, negative remodelling, new plaque rupture, and uncovered struts.⁸ In our case, OFDI demonstrated ∼400 μm of malapposition at the site of thrombus formation and additional uncovered struts at a different location, suggesting a mechanical substrate for thrombosis.

Intravascular ultrasonography (IVUS)-guided PCI has been associated with a lower risk of stent thrombosis compared with angiography-guided PCI, highlighting the importance of intravascular imaging.⁹ In our case, IVUS-guided PCI was performed at the index procedure, and the distal reference lumen diameter was measured at 2.5 mm, leading to the selection of a drug-eluting stent of the same size. Post-dilatation was subsequently carried out using non-compliant balloons measuring 2.75 mm in the segment distal to the diagonal branch and 4.0 mm in the proximal segment. Final IVUS demonstrated adequate stent expansion, indicating that the post-dilatation balloon sizing during the index PCI was appropriate.

The use of systemic corticosteroids as a patient-related factor might be associated with the presence of uncovered stent struts. A previous study demonstrated that the median proportion of uncovered struts in everolimus-eluting stents (EES) was 6.9% at 3 months and decreased to 1.3% at 12 months, indicating that most struts were covered relatively early after implantation.¹⁰ To our knowledge, no previous study has specifically investigated the effect of corticosteroids on EES. However, previous reports involving bare-metal stents have shown that patients receiving corticosteroids may exhibit reduced neointimal formation, and delayed endothelialization has been documented in association with steroid use.^11,12 In this case, uncovered stent struts were identified at a site without malapposition even 1 year and 10 months after PCI, suggesting the possibility that prolonged corticosteroid therapy may have contributed to delayed vascular healing. Therefore, we speculate that, in a patient with predisposing mechanical vulnerabilities to stent thrombosis, the superimposed allergic reaction led to enhanced platelet activation, ultimately culminating in KS.

Contrast-induced Type III KS has been documented in a few case reports.^13–17 Most reported cases occurred within the acute or subacute phase after stent implantation, where Type I hypersensitivity responses are believed to activate the coagulation cascade, triggering thrombus formation on the uncovered struts. In contrast, this case involved VLST, a presentation not previously reported in association with contrast-induced KS. It is plausible that the uncovered struts served as a nidus for thrombosis in the context of systemic allergic inflammation.

Treatment of Type III KS requires not only standard ACS management but also the suppression of allergic reactions. H1 and H2 blockers, corticosteroids, and intramuscular adrenaline have been used depending on clinical severity.^2,4 In this case, the patient remained haemodynamically stable and did not require epinephrine. Following plain balloon angioplasty, IV dimetindene and hydrocortisone were administered, and no recurrence of allergic symptoms or haemodynamic instability occurred during follow-up. After 1 year post-discharge, the patient remains symptom-free during outpatient follow-up. It should be noted, however, that low-dose oral prednisolone (5 mg/day) may be insufficient as a prophylaxis against KS. Future contrast-enhanced studies should consider premedication with high-dose corticosteroids and alternative contrast agents.

In conclusion, we report a rare case of KS triggered by contrast media in a patient receiving long-term corticosteroids who presented with VLST with malapposition and uncovered struts. We propose that the combination of mechanical vulnerability and an allergic cascade, particularly platelet hyper-reactivity mediated by inflammatory signals, contributed synergistically to the pathogenesis of stent thrombosis in this case.

Lead author biography

Dr. Yuichiro Tomida was born in Shizuoka, Japan, in 1994 and received his MD from Hamamatsu University School of Medicine in 2019. He completed 2 years of general residency training before working as a cardiology resident at Hamamatsu University Hospital (2021), Seirei Mikatahara General Hospital (2022-2024), and Kikugawa General Hospital (2024–present). His clinical and research interests include interventional cardiology and coronary imaging.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Author contributions

Yuichiro Tomida (Conceptualization, Investigation, Visualization, Writing—original draft), Yoshitaka Kawaguchi (Writing—review & editing, Supervision [supporting]), Keisuke Miyajima (Investigation [supporting]), Yasushi Wakabayashi (Supervision [supporting]), and Yuichiro Maekawa (Supervision [supporting])