key: cord-0851708-f80qshoj
authors: Cornelissen, Anne; Kutyna, Matthew; Cheng, Qi; Sato, Yu; Kawakami, Rika; Sakamoto, Atsushi; Kawai, Kenji; Mori, Masayuki; Fernandez, Raquel; Guo, Liang; Pellegrini, Dario; Guagliumi, Giulio; Barakat, Mark; Virmani, Renu; Finn, Aloke
title: Effects of simulated COVID-19 cytokine storm on stent Thrombogenicity
date: 2021-04-08
journal: Cardiovasc Revasc Med
DOI: 10.1016/j.carrev.2021.03.023
sha: 97abf830e2f62c89ad1e29fffb996e142ada3cc5
doc_id: 851708
cord_uid: f80qshoj

BACKGROUND: Cytokine storm-related hypercoagulation may be important in the pathogenesis of stent thrombosis in patients with SARS-CoV-2. Whether stent polymers behave differently under such conditions has never been explored. METHODS: Fluorinated polymer-nanocoated and uncoated COBRA stents (CeloNova), BioLinx-polymer-coated Resolute Onyx stents (Medtronic), and Synergy stents (Boston Scientific), which are abluminally coated with a bioabsorbable polymer, were exposed to human blood from healthy donors which was supplemented with 400 pg/mL IL-6 and 100 pg/mL TNF-α, similar to what is seen in cytokine storm caused by SARS-CoV-2. Platelet adhesion and neutrophil activation, assessed by immunofluorescence, were compared under cytokine storm and control conditions (untreated blood) (n = 4 experimental runs). RESULTS: Platelet adhesion values, defined as %platelet-covered area x staining intensity, were significantly lower in coated and uncoated COBRA and in Resolute Onyx than in Synergy under control conditions (1.28 × 10(7) ± 0.43 × 10(7) vs. 2.92 × 10(7) ± 0.49 × 10(7) vs. 3.57 × 10(7) ± 0.73 × 10(7) vs. 9.94 × 10(7) ± 0.99 × 10(7); p ≤0.0001). In cytokine storm, platelet adhesion values remained low in coated COBRA-PzF (1.78 × 10(7) ± 0.38 × 10(7)) compared to all other devices (uncoated COBRA: 5.92 × 10(7) ± 0.96 × 10(7); Resolute Onyx: 7.27 × 10(7) ± 1.82 × 10(7); Synergy: 11.28 × 10(7) ± 1.08 × 10(7); p ≤0.0001). Although cytokine storm conditions significantly increased neutrophil activation in all stents, it was significantly less in coated and uncoated COBRA, and in Resolute Onyx than in Synergy. CONCLUSIONS: Blood-biomaterials interactions may determine the thrombogenic potential of stents. Under simulated cytokine storm conditions, fluoropolymer-coated stents showed the most favorable anti-thrombogenic and anti-inflammatory properties.

Cytokine storm-related hypercoagulation may be important in the pathogenesis of stent thrombosis in patients with SARS-CoV-2. Whether stent polymers behave differently under such conditions has never been explored.

Fluorinated polymer-nanocoated and uncoated COBRA stents (CeloNova), BioLinxpolymer-coated Resolute Onyx stents (Medtronic), and Synergy stents (Boston Scientific), which are abluminally coated with a bioabsorbable polymer, were exposed to human blood from healthy donors which was supplemented with 400pg/mL IL-6 and 100pg/mL TNF-, similar to what is seen in cytokine storm caused by SARS-CoV-2. Platelet adhesion and neutrophil activation, assessed by immunofluorescence, were compared under cytokine storm and control conditions (untreated blood) (n=4 experimental runs).

Platelet adhesion values, defined as %platelet-covered area x staining intensity, were significantly lower in coated and uncoated COBRA and in Resolute Onyx than in Synergy under control conditions (1.28x10 7 ± 0.43x10 7 vs. 2.92x10 7  0.49x10 7 vs. 3.57x10 7  0.73x10 7 vs. 9.94x10 7  0.99x10 7 ; p=<0.0001). In cytokine storm, platelet adhesion values remained low in coated COBRA-PzF (1.78x10 7  0.38x10 7 ) compared to all other devices (uncoated COBRA: 5.92x10 7  0.96x10 7 ; Resolute Onyx: 7.27x10 7  1.82x10 7 ; Synergy: 11.28x10 7  1.08x10 7 ; p=<0.0001). Although cytokine storm conditions significantly increased neutrophil activation in all stents, it was significantly less in coated and uncoated COBRA, and in Resolute Onyx than in Synergy.

Blood-biomaterials interactions may determine the thrombogenic potential of stents. Under simulated cytokine storm conditions, fluoropolymer-coated stents showed the most favorable anti-thrombogenic and anti-inflammatory properties.

Graphic Abstract Severe COVID-19 infection is associated with overproduction of cytokines by macrophages, activated T-cells, and neutrophils. Especially IL-6 and TNF-α trigger hypercoagulation, potentially playing a role in the pathogenesis of MI. PCI in this situation holds an increased risk of ST. Under in vitro simulated cytokine storm conditions, stents with fluoropolymer coatings had less platelet adhesion and neutrophil activation than uncoated and BioLinx polymer-coated stents and compared with stents abluminally coated with bioabsorbable polymers. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in considerable morbidity and mortality throughout the world. 20%-30% of patients with this coronavirus disease 2019 (COVID-19) have evidence of cardiac injury defined as decline in ejection fraction or troponin I elevation, which is associated with an even higher mortality [1] . Severe SARS-CoV-2 infection is associated with overproduction of cytokines ("cytokine storm"). Notably interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-) surge during the illness and decline during recovery [2] . Both IL-6 and TNF-α have been implicated in promoting overexpression of tissue factor in platelets and macrophages [3, 4] , establishing a procoagulant shift in the hemostatic balance and promoting fibrin generation in severe inflammatory states.

Cytokine storm associated with SARS-CoV-2 causes hypercoagulation with excess risk of thrombotic events [5] . Patients presenting with ST-segment elevation myocardial infarction (STEMI) and concurrent COVID-19 infection had higher rates of multi-vessel thrombosis and stent thrombosis (ST) versus non-infected patients [6, 7] . Despite its clinical relevance, the performance of different stent biomaterials has never been explored in the setting of COVID-19 infection.

Here, we present cases from our stent database with and without COVID-19 infection who underwent stent implantation for STEMI and compare signs of inflammation and thrombosis in these stents. To evaluate which biomaterial has the least thrombogenicity and might be more beneficial for stent implantation during COVID-19, we simulated cytokine storm conditions in vitro and examined compared platelet and neutrophil adhesion to stents of different biomaterials.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

We searched the CVPath human coronary stent database for patients with and without confirmed COVID-19 infection who underwent stent implantation within 48 hours before death. Only stents of equal type were included.

For histological staining, stented arteries were processed as described previously [8] . Briefly, the stented artery segments were fixed in formalin, dehydrated in a graded series of ethanol, and embedded in methylmethacrylate polymer. Segments of 2-to 3mm thickness were sawed from each stent, and cross-sections of 4-to 6µm thickness were cut from each of the segments on a Leica RM2155 rotary microtome equipped with a tungsten carbide blade, mounted on slides, and stained with H&E and Movat pentachrome.

We tested the relative thromboresistance of stents coated with a fluorinated polymer (i.e. polyzene-F in COBRA-PzF (CeloNova, Carlsbad, CA)) versus the BioLinx polymer (i.e. C10, C19 and polyvinyl-pyrrolidinone polymers in Resolute Onyx (Medtronic, Minneapolis, MN)), and versus a bioabsorbable polymer (i.e. polylactic-co-glycolic acid in Synergy (Boston Scientific, Marlborough, MA)) ( Table 1) . Human blood was treated with TNF-α and IL-6 at levels consistent with what is seen in severe COVID-19 infections. Untreated blood served as control. The blood was circulated in a flow loop model, and stents were examined using confocal microscopy.

Flow loops were assembled from silicone tubing (Cole-Palmer), connected via hose barb connectors (Cole-Parmer) (Figure 1 ). Coronary stents were deployed within the tubing based on the manufacturer's suggested nominal pressure to obtain a stent-to-tube ratio of 1.1:1.0. Coated and uncoated COBRA stents were compared with Resolute Onyx stents (n = 4 experimental runs) and with Synergy stents (n = 4 experimental runs). Each flow loop contained only one stent at a time, so one experimental run comparing 3 different types of stents (coated COBRA-PzF vs. uncoated COBRA vs. Resolute Onyx and coated COBRA-PzF vs. uncoated COBRA vs. Synergy) comprised 6 flow loops in a side-by-side experimental design (control vs. cytokine storm conditions, for each stent).

Ethical approval was obtained by the Institutional Review Board at CVPath Institute. Whole blood (60 mL) was collected by venipuncture from healthy volunteers, none of whom was on anti-platelet therapy or other regular prescription. Blood was mixed with sodium citrate to obtain a final concentration of 0.32%. To simulate cytokine storm conditions, blood was supplemented with 400pg/mL IL-6 (PeproTech) and 100pg/mL TNF-α (Sigma Aldrich). Cytokine concentrations were chosen in accordance with the highest blood levels of severe COVID-19 cases that have been published [9] [10] [11] , rounded up to the nearest 100. Each flow loop J o u r n a l P r e -p r o o f Journal Pre-proof was filled with whole blood and connected to a perfusion pump (ISMATEC). Blood was circulated at a flow rate of 35mL/min. for 60 min. at 37˚C, 5% CO 2 (Figure 1 ).

Stented tubing pieces were washed in PBS and immersion-fixed in Zamboni's fixative (American MasterTech Scientific, Inc.) for 20 minutes. Stents were bisected longitudinally and placed in 15% sucrose in PBS at 4˚C overnight.

One half of each stent was immunostained for adherent platelets using antibodies against CD42b (abcam) and CD61 (Immunotech). Staining against myeloperoxidase (MPO), which is released by activated neutrophils [12] , was performed in the other halves of each stent (Dako). The antibodies were visualized by secondary antibodies conjugated to an Alexa Fluor® 555 fluorophore (both Invitrogen). The nuclear counterstain was DAPI (Invitrogen).

After immunostaining, stents were mounted 'en face' on glass slides and coverslipped using aqueous mounting media. For platelet immunofluorescence, the entire surface of the stent was scanned (10x objective) (Zeiss, LSM 880, Zen Black software, 2.3 SP1). Representative high-power images were taken of 3 randomly selected struts from the proximal, mid, and distal part of each stent half using a 20x objective. Exported representative 20x JPG images were imported into Nikon NIS-Elements Advanced Research analysis software. To correct for possible photobleaching and other confocal error sources, image parameters were normalized by correcting the maximum pixel intensity value present to 255, and the average background value to 0. A stock noise reduction filter was applied uniformly across all images. A general analysis tool was created in NIS-Elements which applies a binary layer to the red channel, to pixels in the intensity range 40 to 255. The general analysis calculates the total pixel area with a red channel signal above 40 and calculates the sum of the intensities-per-pixel of every pixel covered by that binary. Total strut area was calculated, and the area fraction covered by platelets or neutrophils was calculated by dividing coverage area by total strut area. This area fraction was multiplied by the summed intensity to generate an intensity per coverage area metric (Coverage Area Fraction*Sum Red Channel Intensity), referred to as "Platelet Adhesion Value" and "MPO Quantification Value". Representative images with obvious and un-correctable imaging defects such as visible flaking, photobleaching, or out-of-plane Z axis artifacts were excluded from quantitation.

Data are expressed as means  SEM. The data were statistically analyzed using GraphPad Prism software (version 8.4.3). Shapiro-Wilk test was used to check normality. Overall group means were compared using one-way ANOVA, followed by Tukey's multiple comparisons test, and differences between cytokine storm and control conditions in each stent were compared using Student's t test. A value of p ≤ 0.05 was considered statistically significant.

We consulted our database for autopsy cases with and without COVID-19 who underwent stent implantation for STEMI within 48 hours before death and had patent stents at the time of death. Only stents of equal type and similar implantation duration were included. Our search yielded one 3.0 x 34 mm cobalt-chromium (CoCr) everolimus-eluting stent (EES) implanted for STEMI in a patient with severe COVID-19 infection and three CoCr-EES (3.0 x 23 mm, 3.0 x 28 mm, and 3.0 x 27 mm) that were implanted in patients without COVID-19. While we observed unusually high adhesion of inflammatory cells and platelets to the stent struts, but no ST, in the patient with confirmed COVID-19 infection (Figure 2a) , none of the patients without COVID-19 showed signs of platelet accumulation or severe inflammation around the stent struts (Figure 2b-c) . Although limited in number, these observations suggest COVID-19 infection may induce a pro-inflammatory and pro-thrombogenic environment. Prior reports suggested an increased risk of ST in COVID-19 patients presenting with STEMI [13] [14] [15] [16] [17] [18] [19] , suggesting COVID-19 may affect vascular responses to stenting.

In order to explore this hypothesis, we evaluated the thrombogenic and inflammatory potential of different types of stents during a simulated cytokine storm induced by COVID-19 using a novel in vitro flow loop. To simulate cytokine storm conditions, blood was supplemented with 400pg/mL IL-6 and 100pg/mL TNF-α. These concentrations were chosen in accordance with the highest blood levels seen in severe COVID-19 cases that have been published [9] [10] [11] . Each flow loop was filled with whole blood and connected to a perfusion pump (ISMATEC). Blood was circulated at a flow rate of 35mL/min. for 60 min. at 37˚C, 5% CO 2 (Figure 1) . We compared the relative thromboresistance of fluorinated polymer-coated stents (COBRA-PzF) versus BioLinx polymer-coated stents (Resolute Onyx) and versus an abluminally bioabsorbable polymer-coated stent (Synergy) ( Table 1) .

First, platelet adhesion was analyzed under control vs. cytokine storm conditions in each stent (Supplemental Table 1 ). While cytokine storm conditions did not enhance platelet adhesion in coated COBRA-PzF, we observed significantly greater platelet adhesion under cytokine storm conditions compared with control in uncoated COBRA stents, and a trend towards higher platelet adhesion under cytokine storm conditions in Resolute Onyx. Platelet adhesion in Synergy did not differ from control under cytokine storm conditions and was higher than for all other stent tested regardless of condition.

Next, we compared all four devices under control conditions and under cytokine storm conditions, respectively (Figure 3) . Under control conditions, platelet adhesion was significantly lower in coated COBRA-PzF, uncoated COBRA, and Resolute Onyx than in Synergy. No differences were seen between Resolute Onyx and coated and uncoated COBRA. Under cytokine storm conditions, platelet adhesion remained low in coated COBRA-PzF, with significantly lower platelet adhesion values than in all other stents tested. Platelet adhesion in cytokine storm was similar in uncoated COBRA and Resolute Onyx, andas opposed to control conditionsthere was no difference between Resolute Onyx and Synergy under cytokine storm conditions anymore. We also evaluated neutrophil activation under control and cytokine storm conditions by staining against MPO (Supplemental Table 2 ). Cytokine storm enhanced neutrophil activation in coated and uncoated COBRA stents, and in Resolute Onyx, albeit to a modest level (compared to its effect on Synergy). In Synergy, we observed tendencies towards enhanced neutrophil activation under cytokine storm conditions compared with control, but without statistical significance.

When directly comparing the devices, neutrophil activation was significantly higher in Synergy versus coated and uncoated COBRA stents, and versus Resolute Onyx, both under control and under cytokine storm conditions (Figure 4) . There was no difference between the coated and uncoated version of COBRA. Enhanced cell adhesion to Synergy as compared to coated and uncoated COBRA and Resolute Onyx stents was confirmed by SEM imaging ( Figure  5 ).

Discussion The purpose of this study was to assess acute thrombogenicity and inflammatory potential of different stent biomaterials under control and COVID-19-simulated cytokine storm conditions in an in vitro flow loop using human whole blood.

Effect of cytokine storm on coagulation and thrombogenicity Elevated cytokine levels have been found in patients with COVID-19-associated pneumonia [20] . Cytokine storm was simulated by the addition of IL-6 and TNF-α to human whole blood. To simulate a worst-case scenario, the dosages of 400pg/mL IL-6 and 100pg/mL TNF-α were chosen in accordance with the highest blood levels of these cytokines in patients with COVID-19 that have been published [9] [10] [11] . A study reporting data on 389 confirmed COVID-19 patients from Wuhan, China, reported IL-6 levels up to 160 pg/mL and TNFα levels up to 31 pg/mL even in patients with mild disease, while IL-6 rose to 300 pg/mL and TNFα went up to 41 pg/mL in patients with severe disease [10] . Likewise, IL-6 levels ranged between 68 and 333pg/mL in a single-center study reporting clinical features of the first 50 COVID-19 patients admitted to a German tertiary hospital [11] . Another study reported serum IL-6 levels up to nearly 2,000pg/mL in 54 patients with COVID-19 infection and macrophage activation syndrome or immune dysregulation, while TNFα levels ranged between 8 and 37pg/mL even in patients with only intermediate functional state of the immune system [9] .

SARS-CoV-2 infections are associated with coagulopathy ("COVID 19-associated coagulopathy", CAC), presenting with elevation of D-dimer and fibrin/fibrinogen-degradation products [21] . While the virus itself does not appear to intrinsically trigger coagulation, CAC is thought to derive from the profound inflammatory response [5] with excess production of proinflammatory cytokines contributing to the activation of coagulation [22] . Especially IL-6 and TNF-α are important mediators as they upregulate tissue factor on the cell surface [3, 4] , which initiates the extrinsic pathway of coagulation [23] . Furthermore, TNF-α suppresses endogenous anticoagulant pathways [4] . Hence, IL-6 and TNF-α establish a procoagulant shift in the hemostatic balance.

Patients with coronary artery disease (CAD) and those with cardiovascular risk factors are at increased risk for MI during infections [24] . Elevated troponin I levels have been found in 8%-28% of patients with COVID-19 [25, 26] . With surging numbers of COVID-19 patients, and given the high prevalence of CAD, reasonable numbers of patients with combined STEMI and COVID-19 can be expected. Primary PCI remains the gold standard of care for STEMI patients during the COVID-19 pandemic [27] . However, the procoagulant state of COVID-19 patients may trigger acute ST. While the event of ST in STEMI patients who have tested positive for COVID-19 has been described in a number of case reports [13] [14] [15] [16] [17] [18] [19] , only two larger multicenter studies have been published so far. The first multicenter study, published in July 2020, included 78 patients with STEMI and COVID-19. Stent thrombosis occurred in 4 out of 19 patients treated with primary PCI (21%) [28] . Another study compared in-hospital outcomes of 1010 consecutive STEMI patients with and without COVID-19 and reported a higher incidence of stent thrombosis in COVID-19 patients (3.3% vs. 0.8%; p=0.020) [6] .

Indeed, even though the case presented did not have a ST, we observed unusually high adhesion of inflammatory cells and platelets to the struts in a stent implanted for STEMI in a J o u r n a l P r e -p r o o f Journal Pre-proof patient with severe COVID-19 infection, while inflammation was practically absent around struts of the same type of stent in patients without COVID-19. We acknowledge the fact that findings in a single patient can only be hypothesis generating, however, in conjunction with the increased risk of ST in clinical studies, we assume the use of a stent that is less thrombotic and less likely causing inflammatory reactions might be beneficial in a situation of STEMI and simultaneous COVID-19 infection, but this needs to be confirmed in clinical trials.

Polymer coatings affect stent thrombogenicity, inflammation, and endothelialization Cytokine storm triggered platelet adhesion in uncoated COBRA stents, and in Biolinxcoated stents, while it was already high under control conditions in stents abluminally coated with bioabsorbable polymer. Furthermore, we observed enhanced neutrophil activation in all stents under cytokine storm conditions. These experiments confirmed our hypothesis that COVID-19-induced cytokine storm seems to affect the interaction of stents with blood. We saw more inflammation and platelet accumulation, consistent with our clinical case.

Fluoropolymers are known to have anti-thrombotic properties. Based on a CoCr alloy, COBRA-PzF has a nano-thin coating of poly-bis(trifluoroethoxy)phosphazene (Polyzene-F or PzF) which has been shown to preferentially adsorb albumin instead of coagulation-stimulating proteins [29] . Less platelet adhesion was observed in COBRA-PzF as compared to conventional drug-eluting stents (DES) in a pig shunt study [30] , and clinical studies reported low incidences of ST and spontaneous MI [31] [32] [33] [34] . On the other hand, hydrophilic polymer surfaces, such as BioLinx in Resolute Onyx, have been suggested to have superior biocompatibility compared with hydrophobic polymer coatings, mostly because they do not induce monocyte adhesion [35] . Consisting of an outer shell of CoCr and a platinum-iridium inner core, Resolute Onyx showed particularly low rates of ST [36] . Bioabsorbable polymers are often cited as an alternative to biostable polymers for DES coatings. Synergy is an EES on a platinum-chromium (PtCr)-based platform with abluminal bioabsorbable polymer coating which demonstrated accelerated vascular healing and minimal inflammation in animal studies [37] and excellent outcomes in randomized trials [38] .

When comparing these devices in our study, coated COBRA-PzF showed the most favorable anti-thrombogenic and anti-inflammatory properties, both under control and under cytokine storm conditions, whereas platelet adherence and neutrophil activation were highest in Synergy. While cytokine storm conditions enhanced platelet adhesion in uncoated COBRA and in Resolute Onyx, we did not observe significant differences between control and cytokine storm conditions in coated COBRA-PzF and in Synergy. Platelet adherence in Synergy, however, was already high under control conditions, and cytokine storm might not have had the ability to further increase it. In contrast, platelet adhesion was overall low in coated COBRA-PzF, suggesting that the anti-thrombogenic properties can be attributed to its PzF-nanocoating.

The question why even the uncoated COBRA stent had less platelet and neutrophil adhesion than the bare luminal surface of Synergy may be related to differential stent platforms. COBRA stents have thinner struts than Synergy (71µm vs. 79µm plus the 4µm-abluminal polymer coating), which is an important determinant of thrombogenicity [39] . Furthermore, the metal alloy is different in COBRA and Synergy. While COBRA is manufactured from a CoCr alloy, PtCr is used in Synergy. Recent data from 7,045 patients suggested that Synergy was associated with a higher risk of acute ST when compared with a CoCr-based EES (1.2% vs.

J o u r n a l P r e -p r o o f 0.3%, p=0.032) [40] . Of note, 14 of 15 acute ST events among those treated with Synergy, occurred in high-risk patients.

Our study has several limitations. First, this is a pure benchwork study, and we did not confirm our findings in animals. Second, although cytokine storm is considered the major determinant for thrombogenicity in SARS-CoV-2 infections, we did not perform the experiments with blood from COVID-19-infected patients. Thus, we might have missed the potential impact of other blood components potentially playing a role in CAC. In addition, although IL-6 and TNF-α are believed to be the most important players in COVID-19 induced cytokine storm [41, 42] , we excluded other cytokines which may have additional effects on stent thrombogenicity. Third, we compared platelet and neutrophil adhesion in a select set of stents only, all of which, however, were specifically designed to reduce inflammation and to enhance vascular healing after PCI [35, 43, 44] . Fourth, stents were implanted in non-endothelialized silicone tubes, missing the important pro-or anticoagulant impact of endothelial cells. Considering these important limitations, the findings of our study can only be hypothesis generating, and not practice changing.

Furthermore, the histopathology comparison between stents in COVID-19-infected and non-COVID-19-infected patients did not allow for representative statistical evaluation because of the small sample size given the limited availability of stent samples obtained from autopsy of COVID-19 cases. Nevertheless, to the best of our knowledge, histopathology data from patients with acute stent implantation during COVID-19 infection have never been published before, and our findings emphasize the clinical relevance of evaluating thromboresistance of stents in a situation of cytokine storm.

Nanocoated COBRA-PzF showed the most favorable anti-thrombogenic and antiinflammatory properties, both under control and under cytokine storm conditions, whereas platelet adherence and neutrophil activation were highest in Synergy. We assume the antithrombogenic properties can be attributed to the unique Polyzene-F nanocoating, preventing platelet adhesion even in an in vitro simulated cytokine storm. 

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