- Email: [email protected]
Therapeutic hypothermia, stent thrombosis and the Kounis mast cell activation-associated syndrome
International Journal of Cardiology 179 (2015) 504–506
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Therapeutic hypothermia, stent thrombosis and the Kounis mast cell activation-associated syndrome Nicholas G. Kounis a,⁎, George N. Kounis a, George D. Soufras b, Grigorios Tsigkas c, George Hahalis c a b c
Department of Medical Sciences, Southwesterrn Greece Highest Institute of Education and Technology, Patras, Achaia, Greece Department of Cardiology, “Saint Andrews” State General Hospital, Patras, Achaia, Greece Department of Cardiology, University of Patras Medical School, Patras, Achaia, Greece
a r t i c l e
i n f o
Article history: Received 27 October 2014 Accepted 4 November 2014 Available online 6 November 2014 Keywords: Cold-induced urticaria Hypothermia Kounis syndrome Mast cell degranulation Stent thrombosis
Cardiac arrest is a leading cause of mortality in Western countries and is mainly due to acute myocardial infarction. Coronary angiography and stent implantation, in order to detect and treat recent culprit coronary lesions, in patients with resuscitated cardiac arrest are of paramount importance. Since the brain is particularly sensitive to insufficient perfusion, death and disability secondary to anoxic brain damage remain a major problem following cardiac arrest. Hypothermia is associated with the improvement of neurological manifestations after cardiac arrest [1] despite that recent reports have shown that, in patients with severe bacterial meningitis, mild hypothermia did not improve outcome and may even be harmful [2]. However, it has been found that therapeutic hypothermia in post-cardiac arrest patients could increase survival to hospital discharge and improve neurological outcomes even in non-ventricular tachycardia/ventricular fibrillation patients [3]. Mild therapeutic hypothermia is defined as body temperature between 32 °C and 34 °C and appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest [4]. These temperatures are recommended by international guidelines especially when the initial rhythm, following cardiac arrest, is ventricular fibrillation. The American Heart Association and the European Resuscitation Council recommend considering therapeutic hypothermia for patients with spontaneous circulation after cardiac arrest [5]. Therapeutic ⁎ Corresponding author at: Queen Olgas Square, 7 Aratou Street, Patras 26221, Greece. E-mail address: [email protected] (N.G. Kounis).
http://dx.doi.org/10.1016/j.ijcard.2014.11.036 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
hypothermia reduces the cerebral metabolism of glucose and oxygen consumption possibly providing neurological protection [6]. Recently a high rate of stent thrombosis was reported questioning the safety of combining percutaneous coronary intervention and therapeutic hypothermia after cardiac arrest [7]. Reduced antiplatelet absorption, increased platelet activation, inefficient antiplatelet action, cardiac arrest prothrombotic status and slow down coronary flow seem to be possible causes of stent thrombosis associated with therapeutic hypothermia. Although stent thrombosis is regarded as a multifactorial phenomenon, hypersensitivity to stent scaffolds, eluted drugs, antiplatelet treatment and environmental exposures have been suggested as possible causes [8]. This is based on the histological examination of the obstructive thrombus which, in the majority of human and animal studies, has been found to be infiltrated by inflammatory cells including eosinophils and mast cells [9]. Therefore, searching for the exact nature of hypothermia and its possible association with stent thrombosis could help in the estimation, prediction, prevention and treatment of such a dangerous complication. Studies on the impact of therapeutic hypothermia on coronary flow [10], measured by thrombolysis in Myocardial Infarction frame count, have shown that an association exists between hypothermia and endothelial dysfunction. Such endothelial dysfunction is associated with thrombotic events [11]. Moreover, therapeutic hypothermia appears to slow down coronary flow [10]. In cardiac arrest patients treated with cooling [6], stenting for acute myocardial infarction was associated with a significantly higher incidence of confirmed acute or subacute stent thrombosis than in the control group: 10.9% vs 2.0% with reduction in survival rate, at 28 days, of only 50.1%. This study follows recent correspondence [12,13] according to which a disturbingly high incidence of stent thrombosis is associated with therapeutic hypothermia. On the contrary, other recent reports have found that stent thrombosis associated with therapeutic hypothermia is almost identical to that of patients not treated with therapeutic hypothermia and that prothrombotic effects of therapeutic hypothermia are not clinically relevant in patients treated according to general recommendations. These recommendations include antithrombotic management with the third-generation P2Y12 inhibitors before primary percutaneous coronary interventions and intravenous aspirin with a crushed nasogastric administration of P2Y12 inhibitors [14]. However, these recommendations contradict findings published more recently [15] which showed that platelet inhibitory response to clopidogrel,
N.G. Kounis et al. / International Journal of Cardiology 179 (2015) 504–506
prasugrel and ticagrelor is significantly reduced by 82%, 32% and 30% respectively in patients treated with therapeutic hypothermia following cardiac arrest. This was attributed to reduced antiplatelet absorption, reduced clopidogrel conversion in the liver, inefficient antiplatelet action, cardiac arrest induced prothrombotic status and worsening of arterial stenoses from cholesterol crystallization. While all above agreed that new research and further prospective trials are needed to determine the cause and the incidence of stent thrombosis associated with therapeutic hypothermia, none of them has elaborated on the pathophysiology of stent thrombosis and the association of hypothermia with mast cell degranulation and platelet activation. Stent thrombosis is a multifactorial phenomenon caused by multiple causes but hypersensitivity to stent components has been established as one of its main causes [16]. Drug eluting stent components include the metal platform which contains nickel and other metals, the polymer coating and the impregnated antiproliferative drugs which constitute an antigenic complex that applies continuous, persistent, repetitive and chronic inflammatory irritation on the arterial intima lasting as long as the antigens stay present [17]. That is why some unexpected reports are appearing in the medical literature, according to which patients with implanted stents who accidentally developed a mast cell degranulation following hypersensitivity reaction elsewhere in the human body from various different causes are prone to develop, contemporarily intrastent thrombosis [18]. It seems likely that implanted stents attract like magnet mast cells in order to degranulate and release inflammatory mediators able to induce stent thrombosis. The specific antigenicity of polymers and metal anions can induce Kounis hypersensitivity-associated acute thrombotic syndrome by activating high and low affinity IgE receptors known as FCγRI, FCγRII, FCεRI and FCεRII receptors situated on both mast cell and platelet surface [19]. Kounis syndrome is the result of the action of inflammatory mediators released during direct or via IgE mediated mast cell degranulation. Type III variant of Kounis syndrome concerns patients with stent thrombosis in whom thrombus aspiration from the stented area shows infiltration by eosinophils and mast cells [20]. Based on the above, FDA has issued consumer information about stent implantation [21] which states clearly that there is contraindication for platinum-chrome and cobalt-chrome stent implantation in patients who have known hypersensitivity or contraindication to everolimus, zotarolimus and structurally-related compounds, cobalt, chromium, nickel, tungsten, acrylic, molybdenum and fluoropolymers or to phosphorylcholine polymer and its individual components. Mast cells degranulate and release many stored and newly synthesized inflammatory mediators. The degranulation takes mainly when antigenic complexes bridge nearby antibodies on FcγRI, FcγRII, FcεRI and FcεRII receptors. This takes place when the critical number of bridged IgE antibodies reaches the order of 2000 out of maximal number of some 500 000–1 000 000 in order to make 1000 bridges [22]. There are also other types of receptors that can markedly modulate mast cell activation. These include pathogen-recognizing Toll-like receptor family members, receptors for endogenous factors such as PGE2 via the EP3 receptor, adenosine via the A2b and A3 receptors, IL33 via the ST2 receptor and stem cell factor via KIT [23]. Mast cells are bone marrow generated cells and enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid for stem cell factor and have KIT receptors for the stem cell factor. They migrate into all the tissues, including the brain which does not suffer from allergic reactions because IgEs do not cross the blood–brain barrier and they differentiate and mature in all tissues. This procedure takes several days to weeks. Furthermore, mast cells are known to be activated, in susceptible patients, by food, infections, drugs and stress, physical stimuli such as exposure to cold or warm temperatures or vibration, a condition known as physically induced urticaria [24]. It is known that systematic exposure to cold can cause localized symptoms like a burning sensation dermatographism, erythema, pruritus, urticaria, and edema, but can
505
also induce hypersensitivity reactions in susceptible individuals [25]. Extensive cold contact (e.g. swimming in cold water) may lead to systemic reactions including shock [26]. Several cases of death due to anaphylaxis while swimming in cold water have been also reported [27]. Mast cells have the ability to degranulate in response to cold [28]. Following cold exposure, mast cell-derived mediators in the plasma raise [29] and can initiate the symptomatology associated with coldinduced urticaria. Despite the direct mast cell activation by physical exposures, a role for IgE mediated activation in the pathogenesis of cold urticaria has been proposed also. This is based on serum transfer studies [30] and successful treatment with the anti-IgE drug omalizumab [31]. Recently a case of cold induced urticaria was published that was associated with Kounis syndrome [32]. In this case the cold-induced urticaria was complicated by Kounis syndrome during swimming in sea water (swimmer's death) that survived but with severe and avoidable impairment of quality of life. Therefore environmental exposures such as cold and therapeutic procedures such as therapeutic hypothermia can induce mast cell degranulation leading to the development of type III Kounis syndrome that is associated with stent thrombosis. In response to the appeal of the above investigators [11–15] and until further studies characterizing the exact incidence and elucidating the exact cause of any stent thrombosis associated with therapeutic hypothermia are undertaken, we recommend, meticulous application of current recommendations as well as, for susceptible individuals, consideration of our suggestions concerning the specific mast cell degranulation etiology of hypothermia-induced stent thrombosis [33]. These suggestions incorporate careful history of adverse drug reactions and hypersensitivities in patients receiving stents, monitoring the levels of tryptase, histamine and arachidonic acid products immediately after stenting and considering the use of corticosteroids and mast-cell stabilizers because experiments have shown that these drugs have abrogated late thrombotic events [34]. Conflict of interest The authors declare there are no personal financial conflicts of interest relevant to this paper. Acknowledgments The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] K. Ibrahim, M. Christoph, S. Schmeinck, K. Schmieder, K. Steiding, L. Schoener, et al., High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest, Resuscitation 85 (2014) 649–656. [2] B. Mourvillier, F. Tubach, D. van de Beek, et al., Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful, JAMA 310 (2013) 2174–2183. [3] M. Ng, A.S. Wong, H.C. Chew, et al., Pilot prospective study of therapeutic hypothermia for treatment of post-cardiac arrest patients, Int. J. Cardiol. 173 (2014) 612–613. [4] S.A. Bernard, T.W. Gray, M.D. Buist, B.M. Jones, W. Silvester, G. Gutteridge, et al., Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia, N. Engl. J. Med. 346 (2002) 557–563. [5] J.M. Field, M.F. Hazinski, M.R. Sayre, L. Chameides, S.M. Schexnayder, R. Hemphill, et al., Part 1: executive summary: 2010 American heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, Circulation 122 (2010) S640–S656. [6] K.H. Polderman, Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: indications and evidence, Intensive Care Med. 30 (2004) 556–575. [7] J. Joffre, O. Varenne, W. Bougouin, J. Rosencher, J.P. Mira, A. Cariou, Stent thrombosis: an increased adverse event after angioplasty following resuscitated cardiac arrest, Resuscitation 85 (2014) 769–773. [8] N.G. Kounis, Kounis syndrome should be considered the culprit cause of the most feared stent thrombosis, J. Am. Coll. Cardiol. 58 (2011) 885. [9] N.G1. Kounis, S. Giannopoulos, G.G. Tsigkas, J. Goudevenos, Eosinophilic responses to stent implantation and the risk of Kounis hypersensitivity associated coronary syndrome, Int. J. Cardiol. 156 (2012) 125–132.
506
N.G. Kounis et al. / International Journal of Cardiology 179 (2015) 504–506
[10] A. Regueiro, X. Freixa, M. Heras, D. Penela, D. Fernández-Rodríguez, S. Brugaletta, et al., Impact of therapeutic hypothermia on coronary flow, Int. J. Cardiol. 172 (2014) 228–229. [11] S. Muxel, M. Fineschi, E.R. Hauser, T. Gori, Coronary slow flow or syndrome Y: dysfunction at rest, preserved reactivity of the peripheral endothelium, Int. J. Cardiol. 147 (2011) 151–153. [12] D. Penela, M. Magaldi, J. Fontanals, V. Martin, A. Regueiro, J.T. Ortiz, et al., Hypothermia in acute coronary syndrome: brain salvage versus stent thrombosis? J. Am. Coll. Cardiol. 61 (2013) 686–687. [13] C.R. Conti, Hypothermia: is it good for the brain and not for the arteries? J. Am. Coll. Cardiol. 61 (2013) 2113–2114. [14] S.O. Rosillo, E. Lopez-de-Sa, A.M. Iniesta, F. de Torres, S. del Prado, J.R. Rey, et al., Is therapeutic hypothermia a risk factor for stent thrombosis? J. Am. Coll. Cardiol. 63 (2014) 939–940. [15] N.G. Kounis, Eosinophils and Kounis hypersensitivity associated syndrome as contributors to very late coronary stent thrombosis, Int. J. Cardiol. 167 (2013) 594–595. [16] J.P. Chen, D. Hou, L. Pendyala, J.A. Goudevenos, N.G. Kounis, Drug-eluting stent thrombosis: the Kounis hypersensitivity-associated acute coronary syndrome revisited, JACC Cardiovasc. Interv. 2 (2009) 583–593. [17] N.G. Kounis, Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int. J. Cardiol. 110 (2006) 7–14. [18] N.G. Kounis, A. Mazarakis, G. Tsigkas, S. Giannopoulos, J. Goudevenos, Kounis syndrome: a new twist on an old disease, Future Cardiol. 7 (2011) 805–824. [19] N.G. Kounis, Coronary hypersensitivity disorder: the Kounis syndrome, Clin. Ther. 35 (2013) 563–571. [20] M. Biteker, A new classification of Kounis syndrome, Int. J. Cardiol. 145 (2010) 553. [21] Review of XIENCE V Everolimus Eluting Coronary Stent System and PROMUS Everolimus Eluting Coronary Stent System: P070015, Food and Drug Administration, Silver Spring, MD, 2008. (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/ pma/pma.cfm?num=p070015). [22] M. Wickman, When allergies complicate allergies, Allergy 60 (2005) 14–18.
[23] A.M. Gilfillan, C. Tkaczyk, Integrated signaling pathways for mast-cell activation, Nat. Rev. Immunol. 6 (2006) 218–230. [24] J.P. Dice, Physical urticaria, Immunol. Allergy Clin. N. Am. 24 (2004) 225–246. [25] Y. Cho, Y. Jang, Y.D. Yang, C.H. Lee, Y. Lee, U. Oh, TRPM8 mediates cold and menthol allergies associated with mast cell activation, Cell Calcium 48 (2010) 202–208. [26] A.A. Wanderer, K.E. Grandel, S.I. Wasserman, R.S. Farr, Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria, J. Allergy Clin. Immunol. 78 (1986) 417–423. [27] A.A. Alangari, F.J. Twarog, M.C. Shih, L.C. Schneider, Clinical features and anaphylaxis in children with cold urticaria, Pediatrics 113 (2004) e313–e317. [28] N. Medic, A. Desai, H. Komarow, et al., Examination of the role of TRPM8 in human mast cell activation and its relevance to the etiology of cold-induced urticaria, Cell Calcium 50 (2011) 473–480. [29] M. Abajian, A. Młynek, M. Maurer, Physical urticaria, Curr. Allergy Asthma Rep. 12 (2012) 281–287. [30] A.P. Kaplan, L. Gray, R.E. Shaff, Z. Horakova, M.A. Beaven, In vivo studies of mediator release in cold urticaria and chronic urticaria, J. Allergy Clin. Immunol. 55 (1975) 394–402. [31] J.A. Boyce, Successful treatment of cold-induced urticaria/anaphylaxis with anti-IgE, J. Allergy Clin. Immunol. 117 (2006) 1415–1418. [32] A. Mazarakis, K. Bardousis, A. Almpanis, I. Mazaraki, S. Markou, N.G. Kounis, Kounis syndrome following cold urticaria: the swimmer's death, Int. J. Cardiol. 176 (2014) e52–e53. [33] N.G. Kounis, G.N. Kounis, S.N. Kouni, G.D. Soufras, C. Niarchos, A. Mazarakis, Allergic reactions following implantation of drug-eluting stents: a manifestation of Kounis syndrome? J. Am. Coll. Cardiol. 48 (2006) 592–593. [34] A. Nemmar, P.H.M. Hoet, J. Vermylen, A.E. Epstein, G.N. Kay, Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters, Circulation 110 (2004) 1670–1677.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Therapeutic hypothermia, stent thrombosis and the Kounis mast cell activation-associated syndrome Nicholas G. Kounis a,⁎, George N. Kounis a, George D. Soufras b, Grigorios Tsigkas c, George Hahalis c a b c
Department of Medical Sciences, Southwesterrn Greece Highest Institute of Education and Technology, Patras, Achaia, Greece Department of Cardiology, “Saint Andrews” State General Hospital, Patras, Achaia, Greece Department of Cardiology, University of Patras Medical School, Patras, Achaia, Greece
a r t i c l e
i n f o
Article history: Received 27 October 2014 Accepted 4 November 2014 Available online 6 November 2014 Keywords: Cold-induced urticaria Hypothermia Kounis syndrome Mast cell degranulation Stent thrombosis
Cardiac arrest is a leading cause of mortality in Western countries and is mainly due to acute myocardial infarction. Coronary angiography and stent implantation, in order to detect and treat recent culprit coronary lesions, in patients with resuscitated cardiac arrest are of paramount importance. Since the brain is particularly sensitive to insufficient perfusion, death and disability secondary to anoxic brain damage remain a major problem following cardiac arrest. Hypothermia is associated with the improvement of neurological manifestations after cardiac arrest [1] despite that recent reports have shown that, in patients with severe bacterial meningitis, mild hypothermia did not improve outcome and may even be harmful [2]. However, it has been found that therapeutic hypothermia in post-cardiac arrest patients could increase survival to hospital discharge and improve neurological outcomes even in non-ventricular tachycardia/ventricular fibrillation patients [3]. Mild therapeutic hypothermia is defined as body temperature between 32 °C and 34 °C and appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest [4]. These temperatures are recommended by international guidelines especially when the initial rhythm, following cardiac arrest, is ventricular fibrillation. The American Heart Association and the European Resuscitation Council recommend considering therapeutic hypothermia for patients with spontaneous circulation after cardiac arrest [5]. Therapeutic ⁎ Corresponding author at: Queen Olgas Square, 7 Aratou Street, Patras 26221, Greece. E-mail address: [email protected] (N.G. Kounis).
http://dx.doi.org/10.1016/j.ijcard.2014.11.036 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
hypothermia reduces the cerebral metabolism of glucose and oxygen consumption possibly providing neurological protection [6]. Recently a high rate of stent thrombosis was reported questioning the safety of combining percutaneous coronary intervention and therapeutic hypothermia after cardiac arrest [7]. Reduced antiplatelet absorption, increased platelet activation, inefficient antiplatelet action, cardiac arrest prothrombotic status and slow down coronary flow seem to be possible causes of stent thrombosis associated with therapeutic hypothermia. Although stent thrombosis is regarded as a multifactorial phenomenon, hypersensitivity to stent scaffolds, eluted drugs, antiplatelet treatment and environmental exposures have been suggested as possible causes [8]. This is based on the histological examination of the obstructive thrombus which, in the majority of human and animal studies, has been found to be infiltrated by inflammatory cells including eosinophils and mast cells [9]. Therefore, searching for the exact nature of hypothermia and its possible association with stent thrombosis could help in the estimation, prediction, prevention and treatment of such a dangerous complication. Studies on the impact of therapeutic hypothermia on coronary flow [10], measured by thrombolysis in Myocardial Infarction frame count, have shown that an association exists between hypothermia and endothelial dysfunction. Such endothelial dysfunction is associated with thrombotic events [11]. Moreover, therapeutic hypothermia appears to slow down coronary flow [10]. In cardiac arrest patients treated with cooling [6], stenting for acute myocardial infarction was associated with a significantly higher incidence of confirmed acute or subacute stent thrombosis than in the control group: 10.9% vs 2.0% with reduction in survival rate, at 28 days, of only 50.1%. This study follows recent correspondence [12,13] according to which a disturbingly high incidence of stent thrombosis is associated with therapeutic hypothermia. On the contrary, other recent reports have found that stent thrombosis associated with therapeutic hypothermia is almost identical to that of patients not treated with therapeutic hypothermia and that prothrombotic effects of therapeutic hypothermia are not clinically relevant in patients treated according to general recommendations. These recommendations include antithrombotic management with the third-generation P2Y12 inhibitors before primary percutaneous coronary interventions and intravenous aspirin with a crushed nasogastric administration of P2Y12 inhibitors [14]. However, these recommendations contradict findings published more recently [15] which showed that platelet inhibitory response to clopidogrel,
N.G. Kounis et al. / International Journal of Cardiology 179 (2015) 504–506
prasugrel and ticagrelor is significantly reduced by 82%, 32% and 30% respectively in patients treated with therapeutic hypothermia following cardiac arrest. This was attributed to reduced antiplatelet absorption, reduced clopidogrel conversion in the liver, inefficient antiplatelet action, cardiac arrest induced prothrombotic status and worsening of arterial stenoses from cholesterol crystallization. While all above agreed that new research and further prospective trials are needed to determine the cause and the incidence of stent thrombosis associated with therapeutic hypothermia, none of them has elaborated on the pathophysiology of stent thrombosis and the association of hypothermia with mast cell degranulation and platelet activation. Stent thrombosis is a multifactorial phenomenon caused by multiple causes but hypersensitivity to stent components has been established as one of its main causes [16]. Drug eluting stent components include the metal platform which contains nickel and other metals, the polymer coating and the impregnated antiproliferative drugs which constitute an antigenic complex that applies continuous, persistent, repetitive and chronic inflammatory irritation on the arterial intima lasting as long as the antigens stay present [17]. That is why some unexpected reports are appearing in the medical literature, according to which patients with implanted stents who accidentally developed a mast cell degranulation following hypersensitivity reaction elsewhere in the human body from various different causes are prone to develop, contemporarily intrastent thrombosis [18]. It seems likely that implanted stents attract like magnet mast cells in order to degranulate and release inflammatory mediators able to induce stent thrombosis. The specific antigenicity of polymers and metal anions can induce Kounis hypersensitivity-associated acute thrombotic syndrome by activating high and low affinity IgE receptors known as FCγRI, FCγRII, FCεRI and FCεRII receptors situated on both mast cell and platelet surface [19]. Kounis syndrome is the result of the action of inflammatory mediators released during direct or via IgE mediated mast cell degranulation. Type III variant of Kounis syndrome concerns patients with stent thrombosis in whom thrombus aspiration from the stented area shows infiltration by eosinophils and mast cells [20]. Based on the above, FDA has issued consumer information about stent implantation [21] which states clearly that there is contraindication for platinum-chrome and cobalt-chrome stent implantation in patients who have known hypersensitivity or contraindication to everolimus, zotarolimus and structurally-related compounds, cobalt, chromium, nickel, tungsten, acrylic, molybdenum and fluoropolymers or to phosphorylcholine polymer and its individual components. Mast cells degranulate and release many stored and newly synthesized inflammatory mediators. The degranulation takes mainly when antigenic complexes bridge nearby antibodies on FcγRI, FcγRII, FcεRI and FcεRII receptors. This takes place when the critical number of bridged IgE antibodies reaches the order of 2000 out of maximal number of some 500 000–1 000 000 in order to make 1000 bridges [22]. There are also other types of receptors that can markedly modulate mast cell activation. These include pathogen-recognizing Toll-like receptor family members, receptors for endogenous factors such as PGE2 via the EP3 receptor, adenosine via the A2b and A3 receptors, IL33 via the ST2 receptor and stem cell factor via KIT [23]. Mast cells are bone marrow generated cells and enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid for stem cell factor and have KIT receptors for the stem cell factor. They migrate into all the tissues, including the brain which does not suffer from allergic reactions because IgEs do not cross the blood–brain barrier and they differentiate and mature in all tissues. This procedure takes several days to weeks. Furthermore, mast cells are known to be activated, in susceptible patients, by food, infections, drugs and stress, physical stimuli such as exposure to cold or warm temperatures or vibration, a condition known as physically induced urticaria [24]. It is known that systematic exposure to cold can cause localized symptoms like a burning sensation dermatographism, erythema, pruritus, urticaria, and edema, but can
505
also induce hypersensitivity reactions in susceptible individuals [25]. Extensive cold contact (e.g. swimming in cold water) may lead to systemic reactions including shock [26]. Several cases of death due to anaphylaxis while swimming in cold water have been also reported [27]. Mast cells have the ability to degranulate in response to cold [28]. Following cold exposure, mast cell-derived mediators in the plasma raise [29] and can initiate the symptomatology associated with coldinduced urticaria. Despite the direct mast cell activation by physical exposures, a role for IgE mediated activation in the pathogenesis of cold urticaria has been proposed also. This is based on serum transfer studies [30] and successful treatment with the anti-IgE drug omalizumab [31]. Recently a case of cold induced urticaria was published that was associated with Kounis syndrome [32]. In this case the cold-induced urticaria was complicated by Kounis syndrome during swimming in sea water (swimmer's death) that survived but with severe and avoidable impairment of quality of life. Therefore environmental exposures such as cold and therapeutic procedures such as therapeutic hypothermia can induce mast cell degranulation leading to the development of type III Kounis syndrome that is associated with stent thrombosis. In response to the appeal of the above investigators [11–15] and until further studies characterizing the exact incidence and elucidating the exact cause of any stent thrombosis associated with therapeutic hypothermia are undertaken, we recommend, meticulous application of current recommendations as well as, for susceptible individuals, consideration of our suggestions concerning the specific mast cell degranulation etiology of hypothermia-induced stent thrombosis [33]. These suggestions incorporate careful history of adverse drug reactions and hypersensitivities in patients receiving stents, monitoring the levels of tryptase, histamine and arachidonic acid products immediately after stenting and considering the use of corticosteroids and mast-cell stabilizers because experiments have shown that these drugs have abrogated late thrombotic events [34]. Conflict of interest The authors declare there are no personal financial conflicts of interest relevant to this paper. Acknowledgments The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] K. Ibrahim, M. Christoph, S. Schmeinck, K. Schmieder, K. Steiding, L. Schoener, et al., High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest, Resuscitation 85 (2014) 649–656. [2] B. Mourvillier, F. Tubach, D. van de Beek, et al., Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful, JAMA 310 (2013) 2174–2183. [3] M. Ng, A.S. Wong, H.C. Chew, et al., Pilot prospective study of therapeutic hypothermia for treatment of post-cardiac arrest patients, Int. J. Cardiol. 173 (2014) 612–613. [4] S.A. Bernard, T.W. Gray, M.D. Buist, B.M. Jones, W. Silvester, G. Gutteridge, et al., Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia, N. Engl. J. Med. 346 (2002) 557–563. [5] J.M. Field, M.F. Hazinski, M.R. Sayre, L. Chameides, S.M. Schexnayder, R. Hemphill, et al., Part 1: executive summary: 2010 American heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, Circulation 122 (2010) S640–S656. [6] K.H. Polderman, Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: indications and evidence, Intensive Care Med. 30 (2004) 556–575. [7] J. Joffre, O. Varenne, W. Bougouin, J. Rosencher, J.P. Mira, A. Cariou, Stent thrombosis: an increased adverse event after angioplasty following resuscitated cardiac arrest, Resuscitation 85 (2014) 769–773. [8] N.G. Kounis, Kounis syndrome should be considered the culprit cause of the most feared stent thrombosis, J. Am. Coll. Cardiol. 58 (2011) 885. [9] N.G1. Kounis, S. Giannopoulos, G.G. Tsigkas, J. Goudevenos, Eosinophilic responses to stent implantation and the risk of Kounis hypersensitivity associated coronary syndrome, Int. J. Cardiol. 156 (2012) 125–132.
506
N.G. Kounis et al. / International Journal of Cardiology 179 (2015) 504–506
[10] A. Regueiro, X. Freixa, M. Heras, D. Penela, D. Fernández-Rodríguez, S. Brugaletta, et al., Impact of therapeutic hypothermia on coronary flow, Int. J. Cardiol. 172 (2014) 228–229. [11] S. Muxel, M. Fineschi, E.R. Hauser, T. Gori, Coronary slow flow or syndrome Y: dysfunction at rest, preserved reactivity of the peripheral endothelium, Int. J. Cardiol. 147 (2011) 151–153. [12] D. Penela, M. Magaldi, J. Fontanals, V. Martin, A. Regueiro, J.T. Ortiz, et al., Hypothermia in acute coronary syndrome: brain salvage versus stent thrombosis? J. Am. Coll. Cardiol. 61 (2013) 686–687. [13] C.R. Conti, Hypothermia: is it good for the brain and not for the arteries? J. Am. Coll. Cardiol. 61 (2013) 2113–2114. [14] S.O. Rosillo, E. Lopez-de-Sa, A.M. Iniesta, F. de Torres, S. del Prado, J.R. Rey, et al., Is therapeutic hypothermia a risk factor for stent thrombosis? J. Am. Coll. Cardiol. 63 (2014) 939–940. [15] N.G. Kounis, Eosinophils and Kounis hypersensitivity associated syndrome as contributors to very late coronary stent thrombosis, Int. J. Cardiol. 167 (2013) 594–595. [16] J.P. Chen, D. Hou, L. Pendyala, J.A. Goudevenos, N.G. Kounis, Drug-eluting stent thrombosis: the Kounis hypersensitivity-associated acute coronary syndrome revisited, JACC Cardiovasc. Interv. 2 (2009) 583–593. [17] N.G. Kounis, Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int. J. Cardiol. 110 (2006) 7–14. [18] N.G. Kounis, A. Mazarakis, G. Tsigkas, S. Giannopoulos, J. Goudevenos, Kounis syndrome: a new twist on an old disease, Future Cardiol. 7 (2011) 805–824. [19] N.G. Kounis, Coronary hypersensitivity disorder: the Kounis syndrome, Clin. Ther. 35 (2013) 563–571. [20] M. Biteker, A new classification of Kounis syndrome, Int. J. Cardiol. 145 (2010) 553. [21] Review of XIENCE V Everolimus Eluting Coronary Stent System and PROMUS Everolimus Eluting Coronary Stent System: P070015, Food and Drug Administration, Silver Spring, MD, 2008. (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/ pma/pma.cfm?num=p070015). [22] M. Wickman, When allergies complicate allergies, Allergy 60 (2005) 14–18.
[23] A.M. Gilfillan, C. Tkaczyk, Integrated signaling pathways for mast-cell activation, Nat. Rev. Immunol. 6 (2006) 218–230. [24] J.P. Dice, Physical urticaria, Immunol. Allergy Clin. N. Am. 24 (2004) 225–246. [25] Y. Cho, Y. Jang, Y.D. Yang, C.H. Lee, Y. Lee, U. Oh, TRPM8 mediates cold and menthol allergies associated with mast cell activation, Cell Calcium 48 (2010) 202–208. [26] A.A. Wanderer, K.E. Grandel, S.I. Wasserman, R.S. Farr, Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria, J. Allergy Clin. Immunol. 78 (1986) 417–423. [27] A.A. Alangari, F.J. Twarog, M.C. Shih, L.C. Schneider, Clinical features and anaphylaxis in children with cold urticaria, Pediatrics 113 (2004) e313–e317. [28] N. Medic, A. Desai, H. Komarow, et al., Examination of the role of TRPM8 in human mast cell activation and its relevance to the etiology of cold-induced urticaria, Cell Calcium 50 (2011) 473–480. [29] M. Abajian, A. Młynek, M. Maurer, Physical urticaria, Curr. Allergy Asthma Rep. 12 (2012) 281–287. [30] A.P. Kaplan, L. Gray, R.E. Shaff, Z. Horakova, M.A. Beaven, In vivo studies of mediator release in cold urticaria and chronic urticaria, J. Allergy Clin. Immunol. 55 (1975) 394–402. [31] J.A. Boyce, Successful treatment of cold-induced urticaria/anaphylaxis with anti-IgE, J. Allergy Clin. Immunol. 117 (2006) 1415–1418. [32] A. Mazarakis, K. Bardousis, A. Almpanis, I. Mazaraki, S. Markou, N.G. Kounis, Kounis syndrome following cold urticaria: the swimmer's death, Int. J. Cardiol. 176 (2014) e52–e53. [33] N.G. Kounis, G.N. Kounis, S.N. Kouni, G.D. Soufras, C. Niarchos, A. Mazarakis, Allergic reactions following implantation of drug-eluting stents: a manifestation of Kounis syndrome? J. Am. Coll. Cardiol. 48 (2006) 592–593. [34] A. Nemmar, P.H.M. Hoet, J. Vermylen, A.E. Epstein, G.N. Kay, Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters, Circulation 110 (2004) 1670–1677.