ASAIO Journal 2014

Review Article

Thrombus Formation Patterns in HeartMate II Continuous-Flow Left Ventricular Assist Devices: A Multifactorial Phenomenon Involving Kounis Syndrome? Nicholas G. Kounis,* George D. Soufras,* Periklis Davlouros,† Grigorios Tsigkas,† and George Hahalis†

Metallic devices are increasingly used in contemporary cardiological practice. They include coronary stents, artificial cardiac valves, bioprostheses for transcatheter aortic valve replacement, closure devices for patent foramen ovale and atrial septal defects, pacemakers, defibrillators, and left ventricular assist devices. Metals constitute the main components of these devices. Metal anions eluted from the components attached to circulating proteins can act as sensitizers able to induce hypersensitivity inflammation and thrombosis. Allergy to nickel occurs in up to one fourth of the population in several areas of the world and is the most frequent cause of allergic contact dermatitis. The HeartMate II device is made from titanium with ruby bearing. Titanium metal ions from HeartMate II are eluted through the action of blood, saline, proteins, and mechanical stress that can induce hypersensitivity and immune dysfunctions rendering titanium no longer biologically inert. An unexpected high rate of thrombosis with substantial morbidity and mortality has been observed with the use of this device, making the search of causality of thrombosis mandatory to predict and prevent this daunting complication. Although the cause of thrombosis seems to be multifactorial, careful history-taking regarding hypersensitivities, monitoring of inflammatory mediators, and lymphocyte transformation studies should be always performed in sensitive patients. ASAIO Journal 2014; 60:369–371.

in today’s clinical practice. Although they have proved to be life-saving devices, their use is associated, occasionally, with daunting and devastating thrombosis. All these devices have scaffold parts that contain metals. Stent struts are made from stainless steel, which contains nickel, chromium, titanium, manganese, and molybdenum.1 Devices for closure of patent foramen ovale and atrial septal defects have parts made from nitinol, which is nickel and titanium alloy.2 Cardiac pacemakers and defibrillators have generators, which are covered with titanium; conductor wires consisting of an alloy of nickel, cobalt, chromium, and molybdenum; and pacing electrodes, which are made of platinum alloyed with 10%–20% iridium.3 Artificial cardiac valves have parts made from an alloy of cobalt, chromium, nickel, and wolfram,4 although nickel-free artificial cardiac valves are also available today.5 Current left ventricular assist devices such as HeartMate II (HMII, Thoratec Corp., Pleasanton, CA) are made from titanium and ruby bearing.6 In the very interesting report published recently in ASAIO Journal,7 it was shown that elevated shear stress and recirculating blood flow patterns may increase device thrombogenicity and promote thrombus formation leading to device malfunction. In view of recent reports, which raise the incidence of thrombosis from 6% to more than 10%, with increased morbidity and mortality, we review the current developments concerning the metallic devices behavior as sensitizers able to induce blood clotting.

Key Words:  HeartMate II, hypersensitivity, Kounis syndrome, metallic cardiac devices

Thrombosis with HeartMate II Device

Medical devices for assisting cardiac function and clos-

Two studies published recently emphasized the need of conducting larger studies, excluding patients with obvious mechanical etiology, to investigate biological or management-related risk factors for device thrombosis. The first study conducted in three institutions found that pump thrombosis related to the use of the HeartMate II pump was 12.3% during 24 months of support and was associated with substantial morbidity and mortality.8 In this study, sectioned thrombus material, deposited near the inflow bearing, showed infiltration by lymphocytes, plasma cells, and eosinophils denoting hypersensitivity inflammation. Such thrombosis had been detected in blood-contacting surfaces of HeartMate II, in inflow cannula, in outflow conduit at pump replacement, at urgent transplantation, and at autopsy. A similar study found that device thrombosis of various etiologies developed in 19 of 177 patients (11%) with HeartMate II assist device implantation.9 Device thrombosis is a multifactorial phenomenon, its

ing patent cardiac defects, as well as stents, artificial cardiac valves, pacemakers, and defibrillators are increasingly used

From the *Department of Medical Science, Patras Highest Institute of Education and Technology, Patras, Achaia, Greece; and †Department of Cardiology, University of Patras Medical School, Patras, Achaia, Greece. Submitted for consideration February 2014; accepted for publication in revised form March 2014. Disclosure: The authors have no conflicts of interest to report. Correspondence: Nicholas G. Kounis, MD, PhD, FESC, FACC, 7 Aratou Street, Queen Olgas Square, Patras 26221, Greece. Email: [email protected]. Copyright © 2014 by the American Society for Artificial Internal Organs DOI: 10.1097/MAT.0000000000000081

369

370 KOUNIS et al. precise prevalence and etiology still remain uncertain, and differentiation of mechanical and nonmechanical causes is an essential step for individual diagnosis and treatment plans. In a patient with a HeartMate II assist device and near-normal native systolic function and an aortic valve opening with significant native heart ejection, the reduced systolic flow in the outflow and inflow cannulae and no forward flow through the device during diastole resulted in device thrombosis.10 The patient underwent successful device explant, and examination of the pump revealed thrombus on the rotor. It was proposed that abnormal flow through the device seen with recovery of left ventricular function may contribute to device thrombosis. Indeed, the rate of thrombosis seems unexpectedly high; therefore, the search of causality of thrombosis associated with this particular device is mandatory to predict and prevent this daunting complication. An important question that arises is whether titanium parts of this device can induce hypersensitivity inflammation and consequently thrombosis. It is known that metal anions eluted from nickel, cobalt, chromium, titanium, palladium, and gold are common allergic sensitizers. Allergy to nickel occurs in up to 24.6% of the population and is the most frequent cause of allergic contact dermatitis.11,12 It is also common that patients are sensitized to multiple metal anions. Concurrent sensitization, cross-reactivity, or both seem to be possible. It has been shown that sensitization to one metal anion increases the possibility of being sensitized to additional metals.13 Metals seem to “join forces” to sensitize individuals. Titanium Hypersensitivity and Kounis Hypersensitivity-Associated Thrombotic Syndrome Titanium metal ions from HeartMate II and salts from metal corrosion could be eluted through the action of blood, saline, proteins, and mechanical stress. They can act as haptens and become full allergens after reaction with proteins that can be present in the hosts’ antigen-presenting cells.14 Although titanium is considered as an excellent biocompatible metal with good corrosion behavior, hypersensitivity reactions to titanium have been already reported.15 Titanium alloy can induce hypersensitivity and immune dysfunctions rendering titanium no longer biologically inert.16 Elution of titanium ions is influenced by environmental pH and by crevice corrosion and can result in further implant corrosion and titanium allergy.17 The specific antigenicity of titanium ions, released by biocorrosion,18 can induce Kounis hypersensitivity-associated acute thrombotic syndrome by activating platelets via FCγRΙ, FCγRII, FCεRI, and FCεRII receptors.19 This Kounis syndrome is the concurrence of acute coronary events with conditions associated with mast cell activation, involving interrelated and interacting inflammatory cells, and includes anaphylactic or anaphylactoid and allergic or hypersensitivity insults. It is caused by preformed and newly synthesized inflammatory mediators released during the hypersensitivity process. Three variants of Kounis syndrome have been described so far: In type I variant arterial spasm, in normal or nearly normal arteries, associated with hypersensitivity reaction can progress to tissue damage and infarction. In type II variant culprit but quiescent preexisting atheromatous disease combined with hypersensitivity reaction can result in acute tissue damage and infarction. In type III variant, hypersensitivity to any implanted intracardiac and

extracardiac device components can result in devastating thrombosis. Thrombosis, in general, is the result of platelet adhesion, activation, and aggregation.20 Platelet adhesion starts when shear forces induce extensions, known as tethers, in platelet membrane, which bind transiently to corroded metal in an “on and off and start and stop” fashion via interaction of the glucoprotein Ib receptor with Von Willebrand factor. Platelet tethering is followed by platelet rolling resulting from interaction between glucoprotein VI receptor and collagen. Platelet activation is taking place via stimulation of some known receptors in the platelet surface such as receptors for adenosine diphosphate, for thromboxane, for thrombin, for serotonin, for epinephrine, and some less known receptors such as receptors for platelet activating factor, for histamine for high affinity and low affinity IgE hypersensitivity receptors, which are known as FCγRΙ, FCγRII, FCεRI and FCεRII receptors. During their activation, platelets change shape from discoid to spiculated form and release granules that contain, proinflammatory, prothrombotic, adhesive, and aggregatory mediators. The third and final stage of thrombosis is platelet aggregation, which is the result of binding of glucoprotein IIb/IIIa receptor with fibrinogen and interaction with von Willebrand factor. Thrombin converts fibrinogen to fibrin, which serves as a stable lattice for the creation of thrombus. Therefore, receptors for hypersensitivity mediators participate in platelet activation, and these mediators are derived from degranulation of the so-called allergic unit of eosinophils and mast cells in the presence of specific IgE antibodies. This constitutes the pathophysiologic basis of type III variant of Kounis syndrome.21 Thrombosis associated with other cardiac devices seems to share a similar pathogenetic mechanism that has been reported with the use of coronary stents,22 closure devices for patent foramen ovale and atrial septal defects,23 artificial cardiac valves necessitating the development of nickel-free valves,5 pacemakers and defibrillators,24 and even with bioprostheses after transcatheter aortic valve replacement.25,26 Conclusions Sensitive patients who are going to receive such devices need careful history-taking regarding hypersensitivities, monitoring of inflammatory mediators, and lymphocyte transformation studies because titanium-specific T-lymphocytes demonstrate strong and specific antigenicity of titanium ions released by biocorrosion. Histological examination of thrombus and staining with henatoxylin-eosin and Giemsa for identification of eosinophils or mast cells should be always considered. Thereafter, the use of corticosteroids and mast-cell stabilizers might prove suitable preventive modality. References 1. Almpanis GC, Tsigkas GG, Koutsojannis C, Mazarakis A, Kounis GN, Kounis NG: Nickel allergy, Kounis syndrome and intracardiac metal devices. Int J Cardiol 145: 364–365, 2010. 2. Kounis NG, Kounis GN, Koutsojannis C, Tsigkas G, Almpanis G, Mazarakis A: Metal allergy, atrial septal occluder devices and the risk of Kounis syndrome. Ann Thorac Surg 90: 2087–2088, 2010. 3. Honari G, Ellis SG, Wilkoff BL, Aronica MA, Svensson LG, Taylor JS: Hypersensitivity reactions associated with endovascular devices. Contact Dermatitis 59: 7–22, 2008.



HEARTMATE II THROMBOSIS AND KOUNIS SYNDROME

4. Stepan LL, Levi DS, Carman GP: A thin film nitinol heart valve. J Biomech Eng 127: 915–918, 2005. 5. Lusini M, Barbato R, Spadaccio C, Chello M: Aortic valve replacement in a patient with severe nickel allergy. J Card Surg 26: 618–620, 2011. 6. Chiu WC, Girdhar G, Xenos M, et al: Thromboresistance comparison of the HeartMate II Ventricular Assist Device (VAD) with the Device Thrombogenicity Emulation (DTE)-Optimized HeartAssist 5 VAD. J Biomech Eng doi: 10.1115/1.4026254. [Epub ahead of print], 2013. 7. Chiu WC, Slepian MJ, Bluestein D: Thrombus formation patterns in the HeartMate II ventricular assist device: Clinical observations can be predicted by numerical simulations. ASAIO J 60: 237–240, 2014. 8. Starling RC, Moazami N, Silvestry SC, et al: Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 370: 33–40, 2014. 9. Uriel N, Han J, Morrison KA, et al: Device thrombosis in HeartMate II continuous-flow left ventricular assist devices: a multifactorial phenomenon. J Heart Lung Transplant 33: 51–59, 2014. 10. Sifain AR, Schwarz KQ, Hallinan W, Massey HT, Alexis JD. Ventricular assist device thrombosis following recovery of left ventricular function. ASAIO J 60: 243–245, 2014. 11. Oppel T, Schnuch A: The most frequent allergens in allergic contact dermatitis. Dtsch Med Wochenschr 131: 1584–1589, 2006. 12. Rui F, Bovenzi M, Prodi A, et al: Nickel, cobalt and chromate sensitization and occupation. Contact Dermatitis 62: 225–231, 2010. 13. Hegewald J, Uter W, Pfahlberg A, Geier J, Schnuch A; IVDK: A multifactorial analysis of concurrent patch-test reactions to nickel, cobalt, and chromate. Allergy 60: 372–378, 2005. 14. Ratner BD, Hoffman AS, Schoen FJ, Lemons JE. Biomaterials Science: An introduction to materials in medicine. San Diego, Elsevier Academic Press, 2004. 15. Vijayaraghavan V, Sabane AV, Tejas K: Hypersensitivity to titanium: A less explored area of research. J Indian Prosthodont Soc 12: 201–207, 2012.

371

16. Müller K, Valentine-Thon E: Hypersensitivity to titanium: Clinical and laboratory evidence. Neuro Endocrinol Lett 27 (suppl 1): 31–35, 2006. 17. Suito H, Iwawaki Y, Goto T, Tomotake Y, Ichikawa T: Oral factors affecting titanium elution and corrosion: An in vitro study using simulated body fluid. PLoS One 8: e66052, 2013. 18. Chan E, Cadosch D, Gautschi OP, Sprengel K, Filgueira L: Influence of metal ions on human lymphocytes and the generation of titanium-specific T-lymphocytes. J Appl Biomater Biomech 9: 137–143, 2011. 19. Kounis NG: Coronary hypersensitivity disorder: The Kounis syndrome. Clin Ther 35: 563–571, 2013. 20. Kounis NG, Giannopoulos S, Tsigkas GG, Goudevenos J: Eosinophilic responses to stent implantation and the risk of Kounis hypersensitivity associated coronary syndrome. Int J Cardiol 156: 125–132, 2012. 21. Kounis NG, Mazarakis A, Tsigkas G, Giannopoulos S, Goudevenos J: Kounis syndrome: A new twist on an old disease. Future Cardiol 7: 805–824, 2011. 22. Kounis NG, Hahalis G, Theoharides TC: Coronary stents, hypersensitivity reactions, and the Kounis syndrome. J Interv Cardiol 20: 314–323, 2007. 23. Kounis NG, Soufras GD, Mazarakis A: Late left atrial thrombosis of an Amplatzer patent foramen ovale occluder may be the result of Kounis hypersensitivity-associated syndrome. J Thorac Cardiovasc Surg 144: 276; author reply 276–276; author reply 277, 2012. 24. Rahbar AS, Azadani PN, Thatipelli S, Fleischmann KE, Nguyen N, Lee BK: Risk factors and prognosis for clot formation on cardiac device leads. Pacing Clin Electrophysiol 36: 1294–1300, 2013. 25. Cota L, Stabile E, Agrusta M, et al: Bioprostheses “thrombosis” after transcatheter aortic valve replacement. J Am Coll Cardiol 61: 789–791, 2013. 26. Pache G, Blanke P, Zeh W, Jander N: Cusp thrombosis after transcatheter aortic valve replacement detected by computed tomography and echocardiography. Eur Heart J 34: 3546, 2013.

Thrombus Formation Patterns in HeartMate II Continuous-Flow Left Ventricular Assist Devices: A Multifactorial Phenomenon Involving Kounis Syndrome?

Metallic devices are increasingly used in contemporary cardiological practice. They include coronary stents, artificial cardiac valves, bioprostheses ...
193KB Sizes 0 Downloads 3 Views