Case report

Shiro Miura ‍ ‍,1 Takehiro Yamashita,1 Masaki Murata,2 Nicholas G Kounis ‍ ‍3
1

Department of Cardiology,
Hokkaido Ono MemorialHospital, Sapporo, Japan2
Department of SurgicalPathology, Hokkaido Ohno
Memorial Hospital, Sapporo,Japan
3
Department of Cardiology,
University of Patras School ofMedicine, Patras, Greece
Correspondence toDr Shiro Miura;​shirotan1027m@​yahoo.​co.​jp
Accepted 4 February 2021

SUMMARYA 69-­year-­old woman with a history of allergic reactions
to unknown metals who presented 1 year prior withacute coronary syndrome complicated by acute stent
thrombosis (ST) was admitted due to new-­onset chest
pain during mild exercise. She electively underwent
coronary angiography, revealing a newly developed
stenosis in the fourth branch of the posterior descending
artery, treated with an everolimus-­eluting stent. One
hour later, she reported of sudden chest tightness andnausea; ECG revealed significant ST-­segment elevationin the II, III and aVF leads. We suspected ST-­segment
elevation myocardial infarction resulting from an allergic
reaction (ie, Kounis syndrome type III) and managed
it properly by eliminating other potential causes. The
tentative diagnosis was confirmed by pathologicalexamination of aspirated materials. Kounis syndrome
type III may be a frequently undiagnosed clinical entity,emphasising the importance of pathological examinationof aspirated materials when implanting coronary stents
and history-­taking of allergies to stent metals.

BACKGROUND© BMJ Publishing Group
Limited 2021. Re-­use
permitted under CC BY-­NC. No
commercial re-­use. See rights
and permissions. Publishedby BMJ.
To cite: Miura S, Yamashita T,
Murata M, et al. BMJ Case
Rep 2021;14:e240704.
doi:10.1136/bcr-2020240704

The Kounis syndrome was first reported in 1991
as an acute coronary syndrome, including coronary spasm (type I), atheromatous plaque erosion
or rupture (type II) and stent thrombosis (ST) (typeIII), resulting from allergic or hypersensitivity reactions, or anaphylactic or anaphylactoid insults.1
In type III, all three components of drug-­eluting
stents (stent metals, polymers and eluted drugs)
could be responsible for inducing allergic reactions
and ST.2 To make an accurate diagnosis of Kounis
syndrome type III, an urgent aspiration of intrastent
thrombus, followed by histological examinationof aspirated material and staining for eosinophils(H&E) and mast cells (Giemsa) can be mandatory.3 Concerning this point, Kounis syndrome
type III may not be an uncommon disease but an
infrequently misdiagnosed entity, which, however,has clinical significance because of the wide rangeof triggers and possible fatal consequences, unlesspromptly recognised. Herein, we report a novel
case of repeated acute ST following a local allergic
reaction diagnosed that was managed properly in apatient with a history of metal allergy.

CASE PRESENTATION

A 69-­
year-­
old woman with a medical history ofhypertension was admitted to our heart centre
with symptoms of chest pain during exercise. Mildallergic reactions to unknown metals were reported
30 years prior but had not been investigatedfurther. Her medical history was noteworthy foracute coronary syndrome, 1 year before admission,
complicated by acute ST in the proximal left anterior descending artery (LAD). This occurred 1 hour(figure 1A) after the primary percutaneous coronary
intervention (PCI) with a 2.5×26 mm zotarolimus-­eluting stent (Resolute Onyx; Medtronic, Santa
Rosa, California, USA) under the guidance of intravascular ultrasound (IVUS).
After admission, she electively underwent coronary angiography (CAG) on hospital day 2 to determine the cause of her chest pain. CAG revealed noin-­stent restenosis in the proximal LAD (figure 1B)
and critical stenosis in the fourth branch of theposterior descending artery (figure 1C). To treat thestenosis, which was thought to be the culprit lesion
for her angina, a 2.25×38 mm everolimus-­elutingstent (XIENCE Sierra; Abbott Vascular, Santa Clara,California, USA) was implanted (figure 2A,B) thesame day. Aspirin (100 mg) and clopidogrel (75 mg)
were administered daily as maintenance treatment
7 days prior to implantation. An IVUS (AltaView;
Terumo Corporation, Tokyo, Japan) was performed
to optimise the stenting by probing that no stentcomplications such as under-­expansion, malposition
or stent fracture were observed (figure 2C,D). One
hour after the final angiogram, the patient reportedof sudden chest tightness and nausea. There was nogeneralised itching or cutaneous erythema, and hervital signs were as follows: blood pressure, 173/86
mm Hg; heart rate, 76 beats/min and oxygen saturation, 98%. An ECG revealed significant ST-­segment elevation in the II, III and aVF leads (figure 3).

DIFFERENTIAL DIAGNOSIS

ST-­
segment elevation myocardial infarction/acutestent thrombosis resulting from►► Procedure related (stent under-­expansion,incomplete stent apposition and coronary
artery dissection).
►► Kounis syndrome (type III).
►► Heparin-­induced thrombocytopenia (HIT).
►► Clopidogrel resistance.
►► Plasma factors influencing the thrombophilic
propensity (protein C, protein S, antithrombin
III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, etc).

TREATMENTWe suspected ST-­
segment elevation myocardial
infarction resulting from an allergic reaction (ie,Kounis syndrome type III). Intravenous hydrocortisone (125 mg), oxygen and saline were immediately administered. Emergent CAG confirmed a

Miura S, et al. BMJ Case Rep 2021;14:e240704. doi:10.1136/bcr-2020-240704

1BMJ Case Rep: first published as 10.1136/bcr-2020-240704 on 1 March 2021. Downloaded from http://casereports.bmj.com/ on March 1, 2021 at Hokkaido Ohno Memorial Hospital.
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Uncommon but imperative cause of repeated acutestent thrombosis: Kounis syndrome type III

Case reportthrombotic semi-­occlusion of the stent site (figure 2E). Opticalfrequency domain imaging (OFDI) (LUNAWAVE, Terumo
Corporation, Tokyo, Japan) revealed a residual thrombus overlying the stent struts (figure 2F,G). Aspiration thrombectomy
and subsequent balloon angioplasty with a 3 mm non-­compliant
balloon were performed, which resulted in an improvementfrom thrombolysis in myocardial infarction (TIMI) flow grade
1–2 (figure 4A). The intra-­aortic balloon was left in place for 3days, during which time the TIMI flow grade in the right coronary artery was 3, as determined via CAG (figure 4B).

INVESTIGATIONS

After the bailout procedure, the peak troponin I and creatine
kinase-­MB levels were 27.8 pg/mL and 73.7 U/L, respectively.
The lowest platelet count after thrombectomy and angiography
was 180 x109/L (initial platelet count, 195 x109/L). The blood
eosinophil percentage was 0.5% at 5 hours after the onset. As wesuspected clopidogrel resistance, we replaced clopidogrel with

Figure 3 ECG during the stent thrombosis (ST) event showing ST-­
segment elevation in leads II, III and aVF and ST-­segment depression inleads V 1–3, I and aVL.
prasugrel (20 mg as the loading dose, followed by 3.75 mg as themaintenance dose) during the bailout PCI.
Pathological examination of the thrombotic aspirate(figure 5A) revealed platelet aggregates, fibrin and white cells,
including eosinophils and neutrophils (figure 5B); mast cells
were not detected (figure 5C). CYP2C19*2 and CYP2C19*3
genotyping via polymerase chain reaction-­restriction fragment
length polymorphism analysis revealed that the patient was anintermediate metaboliser (CYP2C19 *1/*3 genotype). The activities of protein C, protein S, antithrombin III, activated protein
C and α2-­antiplasmin were within normal limits according tohaematological tests. Antiphospholipid and anticardiolipin
antibodies were negative. The above-­mentioned findings werecompatible with acute ST due to an allergic reaction. A patch test
for metal allergies was strongly positive for nickel and cobalt,
which are the main components of the patient’s two implanted
coronary stents.

OUTCOME AND FOLLOW-UP

The patient’s clinical course was uneventful afterward, and she
was discharged on hospital day 12 and had no symptoms at the3-­month follow-­up visit.

DISCUSSION

Type III Kounis syndrome is defined as ST with eosinophils andmast cells in the aspirated thrombus.2 The lack of mast cells in
our patient’s thrombotic material may have been due to the very
short period between symptom onset and aspiration. In mostpreviously reported cases with mast cells observed in implanted
stent sites, histological analyses were performed several hours
after the event or even during the autopsy.4 All components ofdrug-­eluting coronary stents can potentially cause allergic reactions and Kounis syndrome type III along with possibly concomitant oral antiplatelet drugs and environmental exposures.2 Ourpatient had a positive allergic patch test response to nickel andFigure 2 Elective percutaneous coronary intervention andintracoronary imaging findings. (A) A drug-­eluting stent (2.25×38 mm)
was deployed in the distal right coronary artery; the kissing balloon
technique was not employed. (B) Stent placement provided excellent
results in the final angiogram. The red arrows denote the areas shownin panels C and D, respectively. (C, D) Intravascular ultrasound imaging
confirmed optimal stent expansion in the distal right coronary artery (C,stent proximal; D, stent distal). (E) One hour after the final angiogram,angiographic appearance of multiple thrombi in the stent (yellowarrowheads) is noted. The red arrows denote the areas shown inpanels F and G, respectively. (F, G) Optical frequency domain imaging
confirming the presence of the thrombus mainly in the proximal (F) anddistal (G) regions of the implanted stent.
2Figure 4 Final angiogram after thrombus aspiration and balloon
angioplasty (A). Absence of the thrombus in the distal right coronary
artery following a 3-­day use of the intra-­aortic balloon pump (B).
Miura S, et al. BMJ Case Rep 2021;14:e240704. doi:10.1136/bcr-2020-240704

BMJ Case Rep: first published as 10.1136/bcr-2020-240704 on 1 March 2021. Downloaded from http://casereports.bmj.com/ on March 1, 2021 at Hokkaido Ohno Memorial Hospital.
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Figure 1 Coronary artery angiography. (A) Acute stent thrombosisof the left anterior descending coronary artery (LAD) following
implantation of a stent (red arrow) 1 year prior. (B) Left coronary artery
angiography without signs of restenosis (red arrow heads) in theproximal LAD where the acute stent thrombosis had developed 1 yearprior. (C) Tight stenotic lesions (yellow arrowheads) in the distal rightcoronary artery (RCA) are noted.

Case reportcobalt, which are the two main components of two different
stents (everolimus-­eluting and zotarolimus-­eluting stents) thatwere implanted separately. Hence, hypersensitivity to these
metals likely accounted for her apparent repeated acute ST.5
Notably, her clinical course included focal hypersensitivity to thecoronary stent that resulted in acute ST immediately following
stent implantation. Less commonly, she did not demonstrate
typical systemic allergic reactions, such as skin itching, pruritus,dyspnoea, and hypotension.6
The mechanisms underlying ST are multifactorial. Before
concluding acute ST resulting from allergic reactions after the
implantation of drug-­eluting stents, we should explore otherpotential mechanisms, such as patient-­related, procedural andpostprocedural factors (including type and duration of antiplatelet therapy) as discussed previously.4 In our case, proceduralfactors, such as stent under-­expansion, incomplete apposition
and fracture, were unlikely to cause acute ST because the procedure was carefully performed via IVUS guidance and we alsosafely confirmed that these stent-­related causes were much lesslikely via OFDI during the bailout PCI. HIT was a differential
diagnosis if the patient administered heparin presented withthrombocytopenia or thrombosis. While the platelet count inthis patient was within the normal limit and the relative change
in platelets was not definitive to diagnose HIT, although the HITPatient’s perspective
I am greatly engaged and interested in this clinical research ofthis especially unusual but important medical problem that I
was suffering from. This novel report could hopefully contributenot only to improve my health condition in the future but also
to deepen the understanding of the Kounis syndrome, leading to
the further development of specific treatments for this clinicalentity.

Learning points►► Kounis syndrome is an acute coronary syndrome caused by anallergic reaction to various drugs or substances.

►► Kounis syndrome type III may be a frequently undiagnosed

clinical entity when implanting coronary stents.

►► Kounis syndrome type III warrants careful consideration,emphasising the importance of pathological examination ofaspirated materials and history-­taking of previous allergic
reactions to stent metals.

Miura S, et al. BMJ Case Rep 2021;14:e240704. doi:10.1136/bcr-2020-240704

Contributors SM was involved in the case selection, the main manuscript writing
and the collection of references. TY revised the manuscript critically for important
intellectual content and gave the final approval for the version published. MM
conducted pathological examinations. NGK supervised the case presentation andreviewed the entire manuscript.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,and license their derivative works on different terms, provided the original work
is properly cited and the use is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/.
ORCID iDs
Shiro Miura http://​orcid.​org/​0000-​0002-​9634-​5980
Nicholas G Kounis http://​orcid.​org/​0000-​0002-​9751-​6710

REFERENCES

1 Kounis NG, Zavras GM. Histamine-­Induced coronary artery spasm: the concept ofallergic angina. Br J Clin Pract 1991;45:121–8.
2 Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis andtherapeutic management. Clin Chem Lab Med 2016;54:1545–59.
3 Kounis NG. Coronary hypersensitivity disorder: the Kounis syndrome. Clin Ther
2013;35:563–71.
4 Chen JP, Hou D, Pendyala L, et al. Drug-­Eluting stent thrombosis: the Kounis
hypersensitivity-­associated acute coronary syndrome revisited. JACC Cardiovasc Interv
2009;2:583–93.
5 Kirtane AJ, Stone GW. How to minimize stent thrombosis. Circulation
2011;124:1283–7.
6 Adachi H, Ihara M, Nojima Y, et al. Kounis syndrome caused by anaphylaxis without
skin manifestations after cefazolin administration. J Allergy Clin Immunol Pract
2019;7:317–9.
7 Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response toclopidogrel. N Engl J Med 2009;360:354–62.
8 Jinnai T, Horiuchi H, Makiyama T, et al. Impact of CYP2C19 polymorphisms on
the antiplatelet effect of clopidogrel in an actual clinical setting in Japan. Circ J
2009;73:1498–503.

3BMJ Case Rep: first published as 10.1136/bcr-2020-240704 on 1 March 2021. Downloaded from http://casereports.bmj.com/ on March 1, 2021 at Hokkaido Ohno Memorial Hospital.
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Figure 5 (A) Thrombotic material is aspirated from the right coronaryartery. (B) The aspirate consists of platelet aggregates, fibrin and whitecells, including eosinophils (yellow arrows) and neutrophils (bluearrows). H&E. (C) Mast cells are not present in the aspirate—Giemsastain.

test showed a weakly positive reaction. Similarly, plasma factors
influencing the thrombophilic propensity, such as protein C,protein S, antithrombin III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, were all within
the normal range. Clopidogrel resistance is associated withsubacute ST.7 We immediately switched 75 mg of clopidogrel to3.75 mg of prasugrel, a third generation thienopyridine agent
with greater platelet inhibition, and later, the patient disclosed
not carrying CYP2C19 loss of-­function alleles, which are seen
more frequently in Japanese population.8 Overall, the above-­mentioned findings were compatible with acute repeated ST due
to an allergic reaction.
To the best of our knowledge, this is the first report of repetitive acute ST induced by an allergic reaction, highlighting
eosinophilic infiltration in the aspirated thrombus on pathological examination. Using intradermal skin tests, we identified nickel and cobalt as the causes of the allergic reaction andconsequent Kounis syndrome. Herein, this novel case conveys
a significant message that Kounis syndrome type III should beconsidered when implanting coronary stents. Rather than beinga rare disease, Kounis syndrome type III is a frequently undiagnosed clinical entity. Hence, we emphasise the importance ofthe pathological examination of aspirated materials and history-­taking of previous allergic reactions to stent metals in cases ofidiopathic ST.

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