Kounis syndrome type III triggered by stents in patients with coronary artery disease: A review of clinical cases

Abstract

Kounis syndrome (KS) type III is a rare but life-threatening condition in which an acute allergic, anaphylactic, or anaphylactoid reaction precipitates acute coronary syndrome due to thrombosis or restenosis of a previously implanted coronary stent. The pathophysiological mechanism involves IgE-mediated or non-IgE-mediated mast cell activation, leading to coronary vasospasm, destabilization of atherosclerotic plaques, and intrastent thrombosis. Known triggers include various allergens such as medications (notably antibiotics and nonsteroidal anti-inflammatory drugs), metallic or polymeric stent components, and drugs eluted from the stent surface. A review of relevant clinical cases from PubMed and Scopus (1991-2025; 6 publications meeting the inclusion criteria, reporting 6 cases) showed a mean patient age of 66 ± 11 years, with a male predominance (4/6). Only 3 patients had a history of allergic disease. Clinical manifestations included chest pain (100%), cutaneous rash (2 cases), and ST-segment elevation on electrocardiogram (4 cases). Management included reperfusion therapy, corticosteroids, antihistamines, and dual antiplatelet therapy. Outcomes were generally favorable, although 1 patient died 3 years later due to KS-related complications. KS type III requires urgent recognition and simultaneous treatment of both the allergic reaction and coronary obstruction. In cases of unexplained stent thrombosis or restenosis, KS should be considered in the differential diagnosis.

Key Words: Kounis syndrome type III; Stent hypersensitivity; Allergic stent thrombosis; Coronary stent allergy; Acute coronary syndrome; Stent components; Eluted drugs

Core Tip: Kounis syndrome type III is a rare but life-threatening condition characterized by stent thrombosis or restenosis caused by allergic reactions to previously implanted coronary stent components, including metallic alloys, polymer coatings, and drugs eluted from the stent surface (e.g., sirolimus). A review of six clinical cases identified predominantly older male patients who uniformly presented with chest pain, while cutaneous rash was infrequent. Medications such as antibiotics and nonsteroidal anti-inflammatory drugs were identified triggers, underscoring the need for careful allergy assessment and prevention strategies.

INTRODUCTION

Nicholas G Kounis and G M Zavras first described Kounis syndrome (KS) in 1991, defining it as an acute coronary syndrome triggered by an allergic reaction. KS develops as a result of IgE-mediated or alternative activation of mast cells, leading to the release of mediators such as histamine, platelet-activating factor, proteases, and leukotrienes. These mediators induce a coronary artery spasm through stimulation of H1 receptors and angiotensin II, destabilize atherosclerotic plaques by activating matrix metalloproteinases, and promote thrombosis via platelet activation and thromboxane A2 release. The pathophysiology of KS integrates immune-inflammatory, vascular, and hemostatic mechanisms[1-3].

Currently, three major types of KS are recognized[1]. Type I develops in patients without atherosclerotic coronary artery disease or cardiovascular risk factors in which release of an allergic mediator induces a coronary spasm that may resolve without cardiac enzyme elevation or progress to myocardial infarction (MI). Type II occurs in patients with subclinical atherosclerosis; here, inflammatory mediators provoke a coronary spasm without enzyme elevation or destabilize atherosclerotic plaque, potentially causing MI. Type III is characterized by coronary thrombosis with eosinophil and mast cell infiltration within the thrombus. This category also includes patients with previously implanted stents who experience sudden cardiac death with histological evidence of eosinophil and mast cell accumulation in peri-stent tissue[4]. Some authors further subclassify type III into the subtypes IIIA (stent thrombosis) and IIIB (stent restenosis)[5]. A fourth type of KS has been proposed by Giovannini et al[6], Masuda et al[7], and Brancaccio et al[8] that develops in patients with prior coronary artery bypass grafting. Types I and II are the most frequently encountered, whereas type III is rare, comprising only 5.1%-8.9% of reported cases[9-11].

KS is an underrecognized, complex, and likely underdiagnosed condition with limited data on optimal management strategies. KS may be triggered by any allergen, including food products[10,11], environmental exposures[12], or insect stings[13]. However, the most common causes are medications[14-16], particularly antibiotics and nonsteroidal anti-inflammatory drugs[16,17]. Coronary stents have also been implicated as potential triggers[18]. Hypersensitivity reactions to stents typically result from components such as polymer coatings or stainless steel alloys containing nickel, chromium, manganese, titanium, and molybdenum as well as from the eluted pharmacologic agents. Hypersensitivity to stainless steel is more frequently associated with in-stent restenosis rather than thrombosis[1,19].

Accurate diagnosis of KS type III may require urgent thrombus aspiration followed by histopathological examination of the aspirated material, including hematoxylin and eosin staining for eosinophils and Giemsa staining for mast cells[2]. Given these considerations, hypersensitivity reactions induced by coronary stents are of significant clinical interest. Accordingly, we conducted an analysis of reported cases of KS type III occurring after coronary stent implantation with a focus on identifying the role of stent components and eluted substances as potential triggers.

DATA PREPARATION

This study was conducted through a comprehensive literature review of English-language scientific sources indexed in PubMed and Scopus. The search was performed using the keyword “Kounis syndrome” and included publications from 1991 through May 2, 2025. Out of an initial 816 identified articles, 6 publications met the following inclusion criteria: Clinical case report or case series; stent component-related etiology of KS; patient age ≥ 18 years; and availability of the full text. Studies were excluded if the cause of KS was unspecified, it was a duplication, or if the diagnosis was not clearly indicated by the authors. Publications that did not meet criteria of scientific rigor were also excluded, including discussion materials (letters to the editor, commentaries, editorials), short formats (abstracts, clinical images, brief reports), and reviews lacking original data or opinion-based articles. Two reviewers independently screened titles and abstracts to assess potential eligibility. Subsequently, full-text versions of selected articles were reviewed to determine inclusion. Any disagreements were resolved by consensus.

CLINICAL CASE REPORTS

A total of six clinical cases were analyzed and are detailed below. The mean age of the patients was 66 ± 11 years, with a predominance of male patients (4 out of 6 cases). Patient characteristics and the specific features of MI presentation in these 6 cases are summarized in Table 1.

Table 1 Characteristics of patients described in the selected case reports and clinical features of myocardial infarction.

Parameter	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Ref.	Miura et al[20], 2021	Almpanis et al[21], 2010	Boucher et al[22], 2022	Giraldo-Tugores et al[23], 2023	Hoshi et al[24], 2014	Fujisaki et al[25], 2020
Age (years)/sex	69/female	59/male	85/male	52/male	65/female	67/male
Allergy history	Allergic reactions to unidentified metals (30 years prior)	Bronchial asthma, nasal polyposis, hay fever, NSAID allergy	“Swelling” with penicillin	Childhood contact with vanadium-chromium auto tools (asymptomatic)	Not contributory	Not contributory
Case features	Recurrent stent thrombosis within 1 hour of implantation	NA	Multiple revascularizations (4 stents)	Recurrent in-stent restenosis; multiple revascularizations (7 stents)	Very late stent thrombosis	Very late stent thrombosis
Allergens	Nickel, cobalt	Nickel, chromium, polymer coating	Nickel, manganese, titanium, vanadium, zinc	Vanadium	Nickel, cobalt	Sirolimus
Allergic reaction in KS	None	None	Diffuse pruritic maculopapular rash with eosinophilia (day 74)	None	None	Recurrent generalized urticaria 14 years post-stenting
Stent type	Zotarolimus-eluting stent (Resolute Onyx); everolimus-eluting stent (XIENCE Sierra)	SES (CYPHER)	Zotarolimus-eluting stent (Resolute DP-DES)	Zotarolimus-eluting stent (Onyx)	SES (CYPHER)	SES
Time to thrombosis/restenosis	1 hour	2 hours	43 days	6 months	36 months	14 years
ECG findings	ST elevation in II, III, aVF	ST elevation in II, III, aVF	NSTEMI	NA	STEMI	ST elevation in V1-V5
CAG findings	Thrombosis in proximal LAD; subtotal thrombotic occlusion in 4th branch of PDA (TIMI 1-2)	RCA stent thrombosis	RCA stent thrombosis and aneurysm in proximal segment	Severe restenosis in LAD and later in LCx	Acute thrombotic stent occlusion; aneurysms at stent edges	LAD stent thrombosis; peri-stent contrast staining at 3 months
Complications	Recurrent stent thrombosis	Cardiogenic shock, ventricular flutter, atrial flutter, acute LV failure	RCA aneurysm	Neointimal changes, neoatherosclerosis	Coronary aneurysms at stent edges; stent malapposition; neoatherosclerosis	Coronary evaginations
Confirmation method	CAG, IVUS, OCT; patch test (nickel/cobalt); thrombus histology (eosinophils, no mast cells); CYP2C19 genotyping	CAG	CAG; skin tests (day 454): Metal sensitivity; blood eosinophilia (2500/μL, reference: 100-300/μL)	CAG; patch and lymphocyte transformation tests (vanadium); SEM of Onyx (vanadium 0.1%); OCT: Neointimal hyperplasia	CAG, OCT: Residual thrombus, malapposition, 8 mm aneurysm; IVUS; angioscopy; histology: Eosinophils and neutrophils (HE)	CAG; OCT: Evaginations
Histopathological confirmation	Yes	No	No	No	Yes	No
Diagnosis status	Confirmed	Suspected	Suspected	Suspected	Confirmed	Suspected
Treatment	IV hydrocortisone 125 mg, oxygen, saline; aspiration thrombectomy and balloon angioplasty; IABP; switch from clopidogrel to prasugrel	Coronary angioplasty, cardioversion (300 J), dopamine, dobutamine, fluids, diuretics, oxygen, amiodarone	Manual thrombectomy, balloon angioplasty; DAPT modified with addition of prednisolone 30 mg/day; fatal outcome	CABG × 2; stent-free strategy	Aspiration thrombectomy, balloon angioplasty	Thrombectomy, angioplasty, catheter thrombolysis (urokinase); lifelong DAPT; no steroids or antihistamines (patient declined)
Outcome	Favorable; discharged day 12; asymptomatic at 3 months	Favorable; discharged day 14; asymptomatic at 1 year	Death after 3 years	Favorable	Favorable	Favorable; discharged day 14; no recurrence at 1 year

NSAID: Nonsteroidal anti-inflammatory drugs; CAG: Coronary angiography; CABG: Coronary artery bypass grafting; OCT: Optical coherence tomography; IVUS: Intravascular ultrasound; STEMI: ST-elevation myocardial infarction; NSTEMI: Non–ST-elevation myocardial infarction; IABP: Intra-aortic balloon pump; DAPT: Dual antiplatelet therapy; CYP2C19: Cytochrome P450 family 2 subfamily C member 1; TIMI: Thrombolysis in myocardial infarction; ECG: Electrocardiogram; HE: Hematoxylin and eosin; IV: Intravenous; KS: Kounis syndrome; LAD: Left anterior descending; LCx: Left circumflex artery; LV: Left ventricle; NA: Not available; PDA: Posterior descending artery; RCA: Right coronary artery; SEM: Scanning electron microscopy; SES: Sirolimus-eluting stent.

Case report 1

In 2021, Miura et al[20] reported a case involving a 69-year-old female patient with a history of arterial hypertension and documented allergic reactions to metals (specific metals not identified in the clinical history). One year following initial stent implantation in the left anterior descending artery using a zotarolimus-eluting stent (Resolute Onyx; Medtronic, Dublin, Ireland) that was complicated by acute stent thrombosis within the first hour post-procedure, the patient presented with exertional chest pain.

Elective coronary angiography (CAG) revealed critical stenosis in the fourth branch of the posterior descending artery. The patient underwent implantation of an everolimus-eluting stent (XIENCE Sierra; Abbott Vascular, Santa Clara, CA, United States). Within 1 hour post-intervention she developed a second episode of acute stent thrombosis with ST-segment elevation in leads II, III, and aVF on electrocardiogram.

Urgent CAG confirmed thrombotic occlusion of the stent that was managed with aspiration thrombectomy and balloon angioplasty. Intra-aortic balloon pump support was required for 72 hours. Diagnosis of KS type III was confirmed through histopathological identification of eosinophil infiltration in the aspirated thrombus (hematoxylin and eosin staining), strongly positive patch tests for nickel and cobalt (core stent components), and exclusion of alternative causes including stent malapposition/underexpansion (intravascular ultrasound)/optical frequency (domain imaging), thrombophilia (normal protein C/S, antiphospholipid antibodies), and heparin-induced thrombocytopenia (stable platelet count). Although mast cells were absent on Giemsa staining, this aligns with rapid thrombus aspiration post-event.

Genetic testing identified an intermediate metabolizer status for clopidogrel (CYP2C19 *1/*3 genotype), necessitating a switch to prasugrel. The patient was discharged on day 12 with favorable clinical outcomes observed at the 3-month follow-up.

Case report 2

In 2010, Almpanis et al[21] described a case of stent thrombosis interpreted as suspected KS in a 59-year-old male patient with an atopic history, including bronchial asthma, seasonal allergic rhinitis (pollinosis), and hypersensitivity to nonsteroidal anti-inflammatory drugs. During an episode of acute inferior and right ventricular MI and following successful thrombolysis, the patient underwent percutaneous coronary intervention with implantation of a sirolimus-eluting stent (CYPHER stent) in the right coronary artery. Notably, the following key confounders were excluded: The patient adhered to dual antiplatelet therapy; and initial angiography confirmed optimal stent deployment without malapposition or underexpansion.

However, within 2 hours post-procedure the patient developed acute stent thrombosis, which resulted in cardiogenic shock and life-threatening arrhythmias (specifically ventricular flutter). These complications necessitated emergency repeat revascularization, inotropic support (dopamine and dobutamine), and antiarrhythmic therapy with amiodarone. The patient’s clinical condition gradually improved, and by day 14 of hospitalization he was stabilized. At the 12-month follow-up, he remained asymptomatic and in stable condition.

It should be noted that the diagnosis of KS remained suspected due to the lack of histopathological analysis of thrombus (e.g., mast cell/eosinophil staining) or acute-phase allergy biomarkers (e.g., serum tryptase) despite the compelling temporal link to stent implantation and the patient’s high-risk atopic background.

Case report 3

In 2022, Boucher et al[22] reported the case of an 85-year-old male patient who presented with non-ST-segment elevation MI (STEMI) and underwent successful percutaneous coronary intervention with implantation of four nickel-containing drug-eluting stents (Resolute DP-DES; Medtronic). The patient was prescribed standard dual antiplatelet therapy consisting of aspirin and clopidogrel. However, 43 days after the implantation, the patient experienced a recurrent non-STEMI due to stent thrombosis and new coronary aneurysm formation in the right coronary artery. Management included thrombectomy and escalation of antiplatelet therapy to aspirin plus ticagrelor.

Seventy-four days after the initial stenting, the patient developed a generalized maculopapular rash accompanied by marked eosinophilia (2500/μL). A stepwise discontinuation of antiplatelet agents for > 6 weeks per drug excluded a drug-induced allergic etiology. Skin patch testing performed on day 454 revealed hypersensitivity to multiple metals used in the stents, including nickel, manganese, titanium, vanadium, and zinc.

A suspected diagnosis of allergic MI secondary to hypersensitivity to metallic stent components was established based on temporal association and metal sensitivity, although without histopathological confirmation of mast cell/eosinophil infiltration in thrombus or acute tryptase testing. The patient was deemed unsuitable for surgical stent removal and was therefore started on chronic immunosuppressive therapy with prednisolone (30 mg/day). Despite ongoing treatment both eosinophilia and cutaneous manifestations persisted for 3 years, requiring continuous steroids, ultimately culminating in the patient’s death. This represents a unique chronic KS variant with coronary aneurysm.

Case report 4

In 2023, Giraldo-Tugores et al[23] described a 52-year-old male patient with a history of multiple revascularization procedures, having received a total of seven coronary stents, including Onyx, Synergy (Boston Scientific, Marlborough, MA, United States), and Orsiro (Biotronik, Berlin, Germany). The patient experienced recurrent episodes of in-stent restenosis and was referred to an allergy department for evaluation due to atypical findings, namely neointimal hyperplasia detected by optical coherence tomography (OCT).

Allergy testing revealed pronounced hypersensitivity to vanadium, confirmed by a strongly positive patch test (+++) and a positive lymphocyte transformation test (stimulation index ≥ 3). Notably, vanadium was not listed as a component in the Onyx stent; however, subsequent laboratory analysis identified trace vanadium content (0.1%) in the stent alloy. The patient was diagnosed with suspected KS type IIIB, hypothesized as allergy-mediated in-stent restenosis despite no acute thrombosis or biomarker evidence (e.g., tryptase). The clinical course was complicated by recurrent restenosis, ultimately necessitating two coronary artery bypass grafting surgeries. The therapeutic strategy involved surgical revascularization and strict avoidance of stents containing vanadium, although the causal role of vanadium hypersensitivity remained unproven given the minimal concentration and absence of controlled challenge tests.

Case report 5

Hoshi et al[24] reported in 2014 a histopathologically confirmed case of KS in a 65-year-old female who developed very late stent thrombosis 36 months after sirolimus-eluting stent implantation in the left anterior descending artery. The event resulted in STEMI. Acute management included aspiration thrombectomy and balloon angioplasty, restoring thrombolysis in MI flow grade 3 (complete perfusion).

One month later follow-up angiography revealed coronary aneurysms at both proximal and distal stent edges. Multimodal imaging, including OCT, intravascular ultrasound, and coronary angioscopy, demonstrated residual thrombus with histologically confirmed eosinophil/neutrophil infiltration, severe positive vessel remodeling (8.0 mm diameter), stent malapposition, and neointimal hyperplasia exhibiting high-risk yellow neoatherosclerosis.

The diagnosis of KS was validated by eosinophilic infiltrates, confirming hypersensitivity as the pathogenic mechanism for both thrombosis and aneurysm formation with alternative triggers (e.g., infection, autoimmune disorders) excluded. This represents the first documented association of KS with coronary aneurysm development following drug-eluting stent thrombosis.

Case report 6

In 2020, Fujisaki et al[25] described a suspected case of KS type III in a 67-year-old male patient with coronary artery disease and two sirolimus-eluting stents implanted in the left anterior descending artery in 2003. Fourteen years after stent placement, the patient developed generalized urticaria, which resolved spontaneously within 24 hours without pharmacologic intervention. Three days later, the rash recurred and was followed by acute chest pain.

Echocardiogram demonstrated ST-segment elevation in leads V1-V5. CAG revealed stent thrombosis. Despite initial management with thrombectomy and balloon angioplasty, thrombosis recurred, necessitating catheter-directed thrombolysis. At the 3-month follow-up, OCT demonstrated coronary evaginations (vessel wall outpouchings) at the stented segment, which had previously been obscured by a thrombus. The diagnosis remained suspected due to lack of histopathological confirmation (e.g., eosinophil/mast cell staining in thrombus) and acute-phase allergy biomarkers (tryptase), although the temporal association between urticaria and thrombosis supported KS pathophysiology. Alternative causes were systematically excluded. Malapposition/underexpansion was ruled out by OCT showing well-apposed struts. Neoatherosclerosis was absent on imaging. Hypercoagulability was deemed unlikely with normal coagulation studies. Finally, systemic inflammation/infection was excluded clinically and by laboratory testing. This was the longest documented latency (14 years) for KS post-implantation.

DIAGNOSTIC AND TREATMENT ASPECTS

Among the three types of KS, type III is distinguished by its particular diagnostic and therapeutic complexity, primarily due to its pathophysiology involving coronary thrombosis or in-stent restenosis. The diagnosis and management of KS type III are especially challenging in cases of hypersensitivity to stent components or the drugs eluted from the stent. Analysis of 6 clinical cases highlighted key features of this variant of KS. In 5 of the 6 cases, the cause was attributed to metals and/or polymeric materials while in 1 case sirolimus (the drug eluted from the stent) was the suspected allergen.

Three of the six patients had a documented history of atopy, and one had prior contact with a relevant allergen but was asymptomatic at the time. In 4 out of the 6 cases, the patients exhibited no classical signs of allergy during the acute KS episode. Instead, the allergic reaction manifested as acute stent thrombosis, in-stent restenosis, coronary artery aneurysms, or evaginations. In 50% of patients (3/6), KS type III manifested as coronary aneurysms/evaginations (cases 3, 5, and 6), confirming the role of allergic inflammation in vascular wall remodeling. Aneurysms in KS type III arose from degradation of the extracellular matrix by mediators released from mast cells (histamine, tryptase) and eosinophils (major basic protein, matrix metalloproteinases). This led to loss of vascular wall integrity and dilation (positive remodeling) as observed in cases 3 and 5. These events led to life-threatening complications. Cutaneous symptoms such as rash were observed in only 2 patients.

There are no standardized diagnostic tests for confirming KS[26]. In addition to clinical presentation, electrocardiographic findings, and myocardial injury biomarkers, clinicians should consider measuring histamine, tryptase, and total IgE levels. However, due to the very short half-life of histamine, it must be assessed within 10 minutes of symptom onset. Tryptase levels by contrast typically peak around 30 minutes post-reaction and decline by 120 minutes[27].

The diagnosis of KS type III in the analyzed cases required a comprehensive and multimodal approach, including histological examination of aspirated thrombi (with detection of eosinophilic infiltration), allergy testing (patch testing, lymphocyte transformation test), and advanced imaging techniques such as OCT and CAG. Only 2/6 cases (33%) had histopathological confirmation; the remainder relied on clinical suspicion.

One potential strategy for preventing KS type III triggered by stent materials could involve preprocedural allergen testing to stent components. However, identifying appropriate target populations for such screening remains a significant challenge at present.

Treatment of KS type III remains complex. In the reviewed cases reperfusion therapies, antiplatelet agents, and corticosteroids were employed. Nevertheless, even after successful acute-phase management, some patients experienced delayed complications, such as persistent eosinophilia or recurrent stent thrombosis. In 5 of the 6 reported cases, clinical outcomes were favorable while 1 patient died as a consequence of KS.

Case 4 was particularly noteworthy, emphasizing the importance of meticulous medical history taking. The clinical presentation and diagnostic findings (positive patch test for vanadium and ostensibly absent in the stent) necessitated exhaustive investigation to confirm the presence and clinical relevance of vanadium in the stent. Ultimately, trace vanadium content was confirmed. This case underscored the critical need for transparent and comprehensive labeling of stents and other medical devices, akin to food product labeling, to ensure that all potential material components are clearly disclosed. According to the authors, such practices could mitigate risk and improve outcomes and quality of life for affected patients[23].

For optimization of future diagnosis of KS type III, it is necessary to include point-of-care tryptase and histamine tests as well as absolute eosinophil count in the standard workup for stent thrombosis. When using imaging methods during percutaneous coronary intervention for stent thrombosis, it is necessary to detect and analyze hypersensitivity markers (evaginations, aneurysms).

Limitations

The primary limitations of this analysis included the small number of available cases, the retrospective nature of the data, reliance on the quality and completeness of original case reports, and limited generalizability of findings. Furthermore, diagnosing KS type III poses substantial challenges that likely contribute to both misdiagnosis and underreporting. This diagnostic complexity stems from atypical clinical presentations in which allergic reactions manifest solely as coronary complications without classic allergic symptoms, combined with infrequent measurement of allergy biomarkers (e.g., tryptase, histamine) during acute coronary events and frequent inability to perform histopathological analysis of thrombi for eosinophil/mast cell infiltration. Consequently, some KS type III cases are erroneously attributed to technical factors or patient non-adherence, introducing selection bias in published literature in which only definitive cases meet reporting thresholds. This diagnostic gap inherently distorts prevalence estimates and may underestimate the true clinical burden of KS type III. Some included cases relied on temporal associations without definitive allergic confirmation, reflecting real-world diagnostic constraints.

CONCLUSION

KS type III warrants heightened clinical attention in patients with implanted coronary stents, particularly those with a history of allergic conditions. Key strategies for improving prognosis include preprocedural hypersensitivity testing for stent components and considering KS in the differential diagnosis of unexplained stent thrombosis or restenosis. Management of such patients should be individualized and must address both the acute coronary syndrome and the underlying allergic response.