Abstract
Kounis syndrome (KS) consists of an association between hypersensitivity reactions triggered by various environmental and pharmacological factors and acute coronary syndromes. Blood supply may be compromised by either vasospasm (type I), native plaque destabilization (type II) or stent thrombosis (type III). Although the prognosis is generally favorable, treatment should include aggressive anti-thrombotic and anti-allergic therapies. A case compatible with type III KS, manifested as a macular rash followed by two episodes of stent thrombosis after primary angioplasty (PCI) of the right coronary artery is presented, and complemented by a review on the topic.
1
Introduction
Kounis syndrome (KS) consists of an association between hypersensitivity reactions triggered by various environmental and pharmacological factors and acute coronary syndromes. The pathophysiology involves mast cell degranulation and the release of inflammatory mediators that could induce coronary vasospasm (type I), native plaque destabilization (type II) or stent thrombosis (type III) [ ]. Diagnosis relies essentially on the clinical identification of an allergic reaction preceding the cardiac manifestations. Allergy-related peripheral blood markers are difficult to identify because of their generally short half-life. Standard treatment strategies only directed to the ongoing acute coronary syndrome may be insufficient to adequately control the associated inflammatory response. As such, the case description reports a patient with an episode compatible with type III KS, manifested as a new-onset macular rash followed by two occurrences of stent thrombosis after primary angioplasty (PCI) of the right coronary artery (RCA). Solely optimizing antithrombotic therapy without anti-allergic medications was insufficient to prevent the second event.
2
Case description
A previously asymptomatic 57 year-old man with hypertension and dyslipidemia presented to the emergency department of our institution after 2 h of ongoing acute-onset chest pain. Previous medications included only candesartan and atorvastatin, and there was no history of allergies. On admission, his vital signs were normal but the initial electrocardiogram (EKG) revealed a 2 mm ST-segment elevation in leads DII, DIII and aVF ( Fig. 1 A ). Thereafter, 200 mg of aspirin and a 600 mg oral loading dose of clopidogrel were administered. The patient was immediately transferred to the catheterization laboratory and within 40 min of the first medical contact, primary PCI was performed through the right radial artery. The RCA was occluded with a substantial amount of thrombi before the bifurcation of the posterior descending and ventricular branches, and a significant obstructive lesion was identified in the proximal segment ( Fig. 1 B). All other arteries were free of any obstructions. Aspiration thrombectomy was performed and a total of 3 everolimus-eluting stents (Synergy®) were placed in the proximal segment and both the posterior descending and ventricular branches, with an angiographically successful outcome and resolution of the ST-segment deviation and chest pain ( Fig. 1 C and D). During the procedure, 5000 U of unfractionated heparin (UFH) and a total of 250 ml of a low-osmolar iodinated contrast medium were administered. In addition, both intracoronary and peripherally delivered abciximab were administered as two 5 mg loading doses, followed by a continuous infusion during the next 12 h, in the coronary intensive care unit (CICU).
On the next day, 19 h after the procedure and 1 h after receiving the 75 mg maintenance dose of clopidogrel and 100 mg of aspirin, the patient developed a macular, non-pruriginous rash, predominantly on the thorax and abdomen ( Fig. 2 ). Shortly afterwards he complained of a low intensity left-sided chest discomfort, and a new EKG revealed recurrence of the ST-segment elevation in the inferior wall and depression in the lateral and anterior leads ( Fig. 3 A ). An emergency coronary angiography was performed and demonstrated an occlusion of the middle segment of the RCA, once more with a considerable amount of thrombi ( Fig. 3 B). Although the occlusion initiated in a segment that had not been previously stented, proximal extension of a thrombotic process that began within the distal stents could not be excluded. Aspiration thrombectomy was then followed by placement of another everolimus-eluting stent in the middle segment of the RCA ( Fig. 3 C). Unfractionated heparin and intracoronary abciximab were once again administered and clopidogrel was replaced by prasugrel (60 mg periprocedural loading dose). Despite residual thrombi after the intervention, TIMI flow grade III was still achieved. The EKG no longer demonstrated an inferior wall ST-segment elevation and the patient returned to the CICU without symptoms ( Fig. 3 D).
Eighteen hours after the second intervention, the patient remained clinically stable and asymptomatic, although still with the same rash, as previously described. Nonetheless, continuous EKG monitoring revealed a reappearance of the ST-segment deviation in addition to a second degree atrioventricular block. A new 12 lead EKG confirmed a recurrence of the ST-segment elevation in the inferior leads ( Fig. 4 A ). An immediate coronary angiography was performed once again, which demonstrated proximal in-stent thrombosis occluding the RCA ( Fig. 4 B). Subsequently, two additional everolimus-eluting stents were placed with a successful angiographic outcome, though a residual ST-segment elevation remained in the inferior leads ( Fig. 4 C and D). A total of 6 everolimus-eluting stents were implanted throughout the 3 interventions, after which no other native segments were left to treat. Besides 5000 U of intravenous UFH, no further periprocedural antithrombotic treatment was added to the dual antiplatelet therapy. However, full dose subcutaneous enoxaparin (80 mg bid) was subsequently initiated in the CICU.
Blood samples for both the VerifyNow™ P2Y 12 and aspirin platelet reactivity tests were collected during the last procedure. The results for the P2Y 12 assay were not interpretable due to interference by recent abciximab administration. However, aspirin platelet inhibition was within the therapeutic range (377 ARU; therapeutic inhibition <549 ARU). Since a suspicion of type III Kounis syndrome was raised, 40 mg of oral prednisone and 180 mg of fexofenadine were prescribed after the third intervention. An elevated total IgE level (217 KU/L; reference value <114 KU/L) further supported the hypothesis of a hypersensitivity-mediated stent thrombosis, although no peripheral eosinophilia was identified and coronary thrombi were not recovered for analysis.
Prednisone and anti-histamines were maintained during three days, after which the rash subsided, no further dynamic EKG changes were identified and high-sensitivity troponin T levels progressively declined ( Fig. 5 ). Five days after the third procedure, full dose enoxaparin was also withdrawn. Thereafter, the patient had an uneventful recovery, with a pre-discharge echocardiogram revealing inferior wall akinesis, although with preserved global right and left ventricular function. He was prescribed bisoprolol, atorvastatin, aspirin and prasugrel.
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