Kounis Syndrome Is the Likely Culprit in Devastating Stent Thrombosis

Blich et al¹ reported for the first time as high as a 4.4% incidence of stent thrombosis in consecutive real-world, high-risk patients receiving a drug-eluting stent during a median follow-up period of 22 months, but they did not refer to the hypersensitivity inflammation occurring inside the stented coronary arteries.

However, we strongly believe that apart from procedural and technical factors, this high rate of stent thrombosis is mainly a manifestation of the Kounis hypersensitivity coronary syndrome² caused by an “antigenic complex” of nickel alloys, polymers, eluted drugs and possibly concomitant oral antiplatelet drugs. This antigenic complex applies persistent, repetitive and continuous allergen exposure and induces chronic allergic inflammation. So far, clinical reports and reported pathological findings in patients who have died from coronary stent thrombosis as well as animal studies and experiments point toward a hypersensitivity inflammation with infiltration of inflammatory cells including eosinophils, macrophages, T-cells and mast cells as follows:

Clinical Reports

1. In patients with stent implantations who developed intrastent thrombosis associated with generalized allergic reactions induced by environmental causes, stents, which attract like a magnet, constituted an area of possible intracoronary mast cell and platelet activation in the development of stent thrombosis.^3–7
2. In the RADAR project, 4 patients died from coronary thrombosis that extended into the stent. Blood examination from 3 certain cases showed peripheral eosinophilia and raised IgE titers over five times the normal level.⁸
3. Serum sickness-like reactions developed in 2 patients with Cypher stents on the 17th and 18th post-stenting days, respectively, including urticaria-like rash, myalgias and arthralgias. In the first patient, symptoms did not resolve after discontinuation of clopidogrel and substitution with ticlopidine. However, symptoms resolved with prednisone. In the second patient, symptoms resolved with prednisone and despite taking aspirin and clopidogrel, the patient continued to be symptom-free.⁹
4. In a patient with recurrent episodes of right upper-quadrant pain, anorexia, fever, thrills and jaundice, the stent was found, after surgery, to be completely occluded with biliary sludge. Pathologic examination of the material revealed infiltration of eosinophils and lymphocytes compatible with nickel allergic reaction.¹⁰

Thrombus Aspiration Studies

1. Studies evaluating other aspects have shown infiltration of the harvested thrombus from very late drug-eluting stent (DES) thrombosis by eosinophils associated with incomplete stent apposition.¹¹
2. Hematoxylin and eosin stained sections of extracted thrombus from DES have revealed a mixture of fibrin together with platelet aggregates infiltrated with inflammatory cells consisting of neutrophils and eosinophils. It was concluded that the inflammatory cells, particularly the eosinophils, represented an allergic hypersensitivity reaction induced by the stent polymer.¹²

Post-mortem Studies

1. The first report of localized coronary hypersensitivity vasculitis resulting in acute myocardial infarction secondary to late stent thrombosis at 18 months involved a Cypher coronary stent.¹³
2. According to the RADAR project, 3 additional patients who died of coronary thrombosis extending into stents were found at post-mortem examination to have eosinophilic infiltration of the thrombus.⁸
3. In another report concerning severe and diffuse coronary artery spasm in patients with DES, 5 of them experienced multivessel spasm. Of these 5 patients, 2 died. Histological examination in 1 patient revealed occasional inflammatory cells in the intima and adventitia and staining for mast cells showed few scattered mast cells.¹⁴

Physicians in general and interventional cardiologists in particular should be aware of the information sheets enclosed in the packaging of the new-generation stents which clearly recommend avoidance of such implantations in patients with known hypersensitivity to any of the stent components and associated drugs! Therefore, allergen-free stents should be developed and used in order to avoid this catastrophic stent complication.

Nicholas G. Kounis, MD, PhD, FESC, FACC^*, George C. Almpanis, MD, PhD^§, Grigorios G. Tsigkas, MD^£, Andreas Mazarakis, MD, PhD^*

^*Department of Medical Sciences, Patras Highest Institute of Education and Technology, Patras, Greece; ^§Department of Cardiology, Patras State General Hospital, Patras, Greece; ^£Department of Cardiology, University of Patras Medical School, Patras, Greece.