"Very" Very Late Stent Thrombosis: A Detailed Look at Two Cases.

Although percutaneous coronary intervention (PCI) has radically transformed the scope of treating coronary artery disease with stenting, stent thrombosis (STh) remains a feared complication. Very late STh, a rare complication after PCI, refers to STh occurring greater than one year after post-stent implantation. An even rarer phenomenon, "very" very late stent thrombosis (VVLST), is described in the literature as STh occurring more than five years post-stent implantation. To our knowledge, there are only 10 case reports and one case series describing VVLST. We discuss two additional complex clinical cases of VVLST presenting as ST-elevation myocardial infarction. We highlight epidemiology, pathophysiology, presentation, diagnostic methods, treatment approach, associated complications, and the need for more extensive future work to minimize the risk of VVLST.

Neoatherosclerosis: A Distinctive Pathological Mechanism of Stent Failure.

With the development of drug-eluting stents, intimal re-endothelialisation is significantly inhibited by antiproliferative drugs, and stent restenosis transforms from smooth muscle cell proliferation to neoatherosclerosis (NA). As a result of the development of intravascular imaging technology, the incidence and characteristics of NA can be explored in vivo, with some progress made in illustrating the mechanisms of NA. Experimental studies have shed light on the molecular characteristics of NA. More critically, sufficient evidence proves NA as a significant cause of late stent failure. Treatments for NA are still being explored. In this review, we summarise the histopathological characteristics of different types of stent NA, explore the potential relationship of NA with native atherosclerosis and discuss the clinical significance of NA in late stent failure and the promising present and future prevention and treatment strategies.

Type III Kounis Syndrome Caused by Iodine Contrast Media After Improvement of Allergic Symptoms.

Kounis syndrome is an acute coronary syndrome (ACS) caused by an allergic reaction that almost always occurs immediately and simultaneously with allergic symptoms. We present a case of Kounis syndrome type III that developed after complete resolution of contrast-induced anaphylaxis in a 60-year-old man with a coronary stent placed in the proximal left anterior descending (LAD) artery branch for ischemic heart disease. Contrast-enhanced computed tomography revealed anaphylactic shock. Symptoms quickly improved with intramuscular adrenaline injection; however, chest pain appeared after approximately 30 min. ECG revealed ST-wave elevation in the precordial leads. Coronary angiography revealed acute stent thrombosis with total occlusion of the proximal LAD, and percutaneous coronary angioplasty was performed. We diagnosed Kounis syndrome based on the allergic symptoms and ACS. Because some cases of Kounis syndrome develop after anaphylactic symptoms have resolved, it is advisable to follow-up patients with allergic symptoms and pay attention to chest symptoms and ECG changes, especially when they have a history of noted or treated coronary artery disease.

Very Late Stent Thrombosis Complicating Immune Thrombocytopenia: Insights From Optical Coherence Tomography and Thrombopathology.

Immune thrombocytopenia (ITP) carries bleeding and thrombotic risks; however, thromboses associated with ITP have not been histologically examined. This report presents optical coherence tomography images of the culprit lesion and histology of coronary aspirates in very late stent thrombosis complicating severe ITP, providing evidence of platelet-rich thrombus formation. (Level of Difficulty: Advanced.).

An elderly case with late carotid stent thrombosis: possible role of antiphospholipid antibodies.

The case study speculates that the antiphospholipid antibodies acquired during the follow-up period of carotid artery stenting may cause late stent thrombosis that is resistant to direct oral anticoagulants. A 73-year-old man was hospitalized with complaints of weakness in the right lower extremity. The patient had undergone carotid artery stenting for symptomatic stenosis of the left internal carotid artery 6 years prior and had received antiplatelet therapy with clopidogrel 75 mg/day. As the patient had developed atrial fibrillation without stent stenosis at the age of 70 years, anticoagulation therapy with rivaroxaban15 mg/day was initiated while discontinuing clopidogrel. On admission, diffusion weighted imaging (DWI) revealed acute brain infarcts in the territory of the left middle cerebral artery. Contrast-enhanced computed tomography and cerebral angiography exposed severe stenosis in the left carotid artery accompanied by a filling defect caused by a floating thrombus. Laboratory examination revealed the presence of three types of antiphospholipid antibodies, with marked prolongation of activated partial thromboplastin time (APTT). Replacement of rivaroxaban with warfarin eliminated the thrombus without recurrent stroke. In conclusion, late stent thrombosis may be associated with antiphospholipid antibodies acquired during the follow-up period of carotid artery stenting.

Genetic Backgrounds Associated With Stent Thrombosis: A Pilot Study From a Percutaneous Coronary Intervention Registry.

Background: Stent thrombosis (ST) is a rare, yet devastating, complication following percutaneous coronary intervention (PCI), with poorly understood pathophysiologic characteristics and genetic backgrounds. Objectives: The authors performed a genome-wide association study to identify the common genetic loci associated with early stent thrombosis (EST) and late/very late ST (LST/VLST) in a contemporary Japanese multicenter PCI registry. Methods: Among 8,642 PCI patients included in the registry, 42 who experienced stent thrombosis [EST (n = 15) and LST/VLST (n = 27)] were included (mean age, 67.6 ± 10.8 years; and 88.1% men). We conducted a genome-wide association study using the BioBank Japan patient population as the control (control #1: acute coronary syndrome [n = 29,542] and control #2: effort angina [n = 8,900]) to identify significant single nucleotide polymorphisms (SNPs) and evaluate the performance of polygenic risk scores (PRSs) for predicting these conditions. Results: We compared patients with EST with controls #1 and #2 and identified SNPs (rs565401593 and rs561634568) in NSD1, and patients with LST/VLST with controls #1 and #2 and identified SNPs (rs532623294 and rs199546342) in GRIN2A. PRS for LST/VLST showed high predictive performance (area under the curve 0.83 [95% CI: 0.76-0.89] and 0.83 [95% CI: 0.77-0.89]), whereas PRS for EST showed modest predictive performance (area under the curve 0.71 [95% CI: 0.58-0.85] and 0.72 [95% CI: 0.58-0.85]). Conclusions: We identified different genetic predispositions between EST and LST/VLST and demonstrated that the incorporation of PRS may aid in risk prediction of this highly fatal event.

Very Late Stent Thrombosis Due to Neoatherosclerosis After Implantation of an Ultra-Thin Strut Stent.

A 69-year-old man developed very late stent thrombosis (VLST) 3 years after Orsiro stent implantation in the proximal left anterior descending coronary artery. Intravascular imaging evaluations before and after the onset of VLST allowed us to document neoatherosclerosis as the etiology of VLST.

Inhibition of mitochondrial complex I leading to NAD+/NADH imbalance in type 2 diabetic patients who developed late stent thrombosis: Evidence from an integrative analysis of platelet bioenergetics and metabolomics.

Type 2 diabetes mellitus (T2DM) is a strong indicator of late stent thrombosis (LST). Platelet bioenergetic dysfunction, although critical to the pathogenesis of diabetic macrovascular complications, remains uncharacterized in T2DM patients who developed LST. Here, we explored the mechanistic link between the alterations in platelet bioenergetics and LST in the setting of T2DM. Platelet bioenergetics, metabolomics, and their interactomes were analyzed in a nested case-control study including 15 T2DM patients who developed LST and 15 matched T2DM patients who did not develop LST (non-LST). Overall, we identified a bioenergetic alteration in T2DM patients with LST characterized by an imbalanced NAD+/NADH redox state resulting from deficient mitochondrial complex I (NADH: ubiquinone oxidoreductase) activity, which led to reduced ATP-linked and maximal mitochondrial respiration, increased glycolytic flux, and platelet hyperactivation compared with non-LST patients. Congruently, platelets from LST patients exhibited downregulation of tricarboxylic acid cycle and NAD+ biosynthetic pathways as well as upregulation of the proximal glycolytic pathway, a metabolomic change that was primarily attributed to compromised mitochondrial respiration rather than increased glycolytic flux as evidenced by the integrative analysis of bioenergetics and metabolomics. Importantly, both bioenergetic and metabolomic aberrancies in LST platelets could be recapitulated ex vivo by exposing the non-LST platelets to a low dose of rotenone, a complex I inhibitor. In contrast, normalization of the NAD+/NADH redox state, either by increasing NAD+ biosynthesis or by inhibiting NAD+ consumption, was able to improve mitochondrial respiration, inhibit mitochondrial oxidant generation, and consequently attenuate platelet aggregation in both LST platelets and non-LST platelets pretreated with low-dose rotenone. These data, for the first time, delineate the specific patterns of bioenergetic and metabolomic alterations for T2DM patients who suffer from LST, and establish the deficiency of complex I-derived NAD+ as a potential pathogenic mechanism in platelet abnormalities.

Advances in the development of biodegradable coronary stents: A translational perspective.

Implantation of cardiovascular stents is an important therapeutic method to treat coronary artery diseases. Bare-metal and drug-eluting stents show promising clinical outcomes, however, their permanent presence may create complications. In recent years, numerous preclinical and clinical trials have evaluated the properties of bioresorbable stents, including polymer and magnesium-based stents. Three-dimensional (3D) printed-shape-memory polymeric materials enable the self-deployment of stents and provide a novel approach for individualized treatment. Novel bioresorbable metallic stents such as iron- and zinc-based stents have also been investigated and refined. However, the development of novel bioresorbable stents accompanied by clinical translation remains time-consuming and challenging. This review comprehensively summarizes the development of bioresorbable stents based on their preclinical/clinical trials and highlights translational research as well as novel technologies for stents (e.g., bioresorbable electronic stents integrated with biosensors). These findings are expected to inspire the design of novel stents and optimization approaches to improve the efficacy of treatments for cardiovascular diseases.

Frequency, Risk Factors, and Outcome of Definite Stent Thrombosis: A Single-Center Experience.

Introduction Stent thrombosis (ST) is a serious and potentially life-threatening complication of primary or complex high-risk percutaneous coronary intervention (PCI). Multiple factors are said to precipitate ST, related to the patient's clinical comorbidities, lesion characteristics, operative technique, and post-procedural care. The older-generation stents were thought to be involved in early ST. Though the new generation of drug-eluting stents decreases the incidence of early and late ST, patients are still at risk of very late stent thrombosis (VLST). Objective To evaluate the frequency, risk factors, and outcomes of definite ST in developing and resource-constrained countries like Pakistan, where PCIs, including primary PCI, complex PCI, and PCI in high-risk populations, are performed routinely. Methods This observational cross-sectional study included all patients who underwent primary and complex high PCI between 2012 and 2017 at TABBA Heart Institute (THI), Karachi, Pakistan. Results We included a total of 6587 patients in our study, and among the enrolled sample size, 22 (0.33%) had definite ST. Acute stent thrombosis (AST) was found in seven patients, sub-acute stent thrombosis (SAST) in 10, late stent thrombosis (LST) in two, and VLST were observed in three patients. The basic characteristics of our study ST population were as follows: mean age was 58 years, 95.5% were male, 4.5% were female, nine patients (40%) had diabetes mellitus, 15 patients (68%) had hypertension, 11 (50%) had dyslipidemia, and four patients were smokers (18%). Conclusion The frequency, risk factors, and rate of mortality of definite ST in the Pakistani population who underwent primary and complex high-risk PCI reflect nearly equal statistics observed in other studies. As seen in other international studies, the incidence rate of VLST was higher in our population.

A case of "very" very late stent thrombosis: More than 12 years after DES.

A rare but possibly catastrophic consequence of drug-eluting stents (DES) is very late stent thrombosis. We report a case of 74-year-old male who sustained a ST elevation myocardial infarction (STEMI) 12 years after initial Paclitaxel eluting stent implantation (PES). This is the longest time between stent placement and the development of an acute coronary event due to very late stent thrombosis that we are aware of (VLST). The implications for prognosis and therapy are significant because they highlight the uncertainty around the recommended duration of antiplatelet medication in patients with DES. Clinicians face challenges in treating those patients particularly when competing medical conditions demand the discontinuation of antiplatelet therapy. VLST is concerning since the underlying pathophysiology is unknown, and the best preventive treatments and duration of antiplatelet medication after stent implantation are unknown.

Very Late Stent Thrombosis after Discontinuation of Antiplatelet Agents during Anticoagulation Therapy in a Patient with Peri-stent Contrast Staining after Implantation of a Second-generation Drug-eluting Stent.

A 54-year-old man was admitted to our hospital due to intermittent chest pain. He had a history of acute myocardial infarction, and peri-stent contrast staining had been observed at the stent implantation site. The patient previously underwent anticoagulation therapy for left ventricular thrombus and antiplatelet therapy to prevent stent thrombosis. More than one year after implantation of a drug-eluting stent, antiplatelet drugs were discontinued, and anticoagulant alone was prescribed according to the guidelines, which resulted in very late stent thrombosis. The risks of both bleeding and thrombosis must be fully considered when deciding whether or not to discontinue antiplatelet therapy during anticoagulation therapy.

Management of Stent Thrombosis Post-Percutaneous Coronary Intervention and Associated Rare Complications.

Stent thrombosis is a devastating complication of percutaneous coronary intervention (PCI) associated with significant morbidity and mortality. Progressive technical advancements from balloon angioplasty to bare-metal stent and drug-eluting stent placement have reduced the incidence of stent thrombosis. Definitive management and preventive methods are still negligible. Here, we describe two cases of definite subacute stent thrombosis of the right coronary complicated by pericarditis and very late left anterior descending stent thrombosis after the intervention in the right coronary artery. In both cases, antiplatelet treatment with clopidogrel showed excellent compliance. Therefore, after successful PCI, we switched both cases from clopidogrel to potentially more potent antiplatelet treatment, such as ticagrelor, to reduce the occurrence of stent thrombosis in the future.

Primary Percutaneous Coronary Intervention in Patients With Type 2 Diabetes With Late/Very Late Stent Thrombosis and de novo Lesions: A Single-Center Observational Cohort Study of Clinical Outcomes and Influencing Factors.

Background: This study compared differences in the risk factors and clinical outcomes of primary percutaneous coronary intervention (PCI) in type 2 diabetes mellitus (DM) and non-DM patients with de novo lesions (DNLs) and late or very late stent thrombosis (LST/VLST). Methods: We used angiography to screen 4,151 patients with acute coronary syndrome for DNL and LST/VLST lesions. Overall, 3,941 patients were included in the analysis and were allocated to the DM (n = 1,286) or non-DM (n = 2,665) group at admission. The primary endpoint was a composite of major adverse cardiovascular events (MACEs), defined as death, myocardial infarction, revascularization, and ischemic stroke, within a median follow-up period of 698 days. Results: In the group with a total white blood cell count >10 × 109/L (P = 0.004), a neutral granular cell count >7 × 109/L (P = 0.030), and neutrophil-lymphocyte ratio >1.5 (P = 0.041), revascularization was better for DNL than for LST/VLST lesions. Among DM patients with DNLs, each unit increase in age was associated with a 53.6% increase in the risk of MACEs [hazard ratio (HR): 1.536, 95% confidence interval (CI), 1.300-1.815, P < 0.0001]. Older age (≥65 years) was associated with a significantly greater risk of MACEs (P < 0.0001). Furthermore, each standard deviation (SD) increase in the level of peak white blood cell counts was associated with a 50.1% increase in the risk of MACEs (HR, 1.501; 95% CI, 1.208-1.864; P = 0.0002). When stratifying the DM population with DNLs according to the D-dimer baseline and peak levels <0.5 vs. ≥0.5 mg/L, the high D-dimer group at baseline had a 2.066-fold higher risk of MACEs (P < 0.0001), and the high peak level D-dimer group had a 1.877-fold higher risk of MACEs (P = 0.001) compared to the low-level groups. Among DM patients with LST/VLST, each unit increase in age was associated with a 75.9% increase in the risk of MACEs (HR: 1.759, 95% CI, 1.052-2.940, P = 0.032). Furthermore, for each SD increase in the peak D-dimer level, the risk of MACEs increased by 59.7% (HR, 1.597; 95% CI, 1.110-2.295; P = 0.041). Conclusion: Following successful primary PCI, the measurement of baseline and peak D-dimer values may help identify individuals at high cardiovascular risk. This suggests a potential benefit of lowering D-dimer levels among T2DM patients with DNL. Furthermore, age and the peak D-dimer values may facilitate the risk stratification of T2DM patients with LST/VLST.

Pathological assessment of very late bare metal stent thrombosis in the left main coronary artery: a case report.

BACKGROUND: Late catch-up phenomenon following stent implantation is a well-known complication. However, no report has evaluated thrombosis after 9 years with multi-modality and pathological evaluation. CASE SUMMARY: A 71-year-old man with stable angina underwent elective percutaneous intervention of the left main coronary artery with implantation of a bare metal stent (BMS) 9 years ago. At the 9-year follow-up, coronary computed tomography (CCT) and coronary angiography (CAG) findings revealed a thrombus-like structure in the BMS slightly protruding into the sinus of Valsalva. Therefore, the previously prescribed double-antiplatelet therapy was replaced with an anticoagulant and clopidogrel, and a potent statin treatment was initiated. After the changes in drug treatment, follow-up examinations with CCT at 1 and 3 months suggested a decrease in the size of the thrombus; however, it appeared to increase after 6 months. Subsequently, the patient underwent surgical intervention. Pathological assessment of the explanted stent showed a proteoglycan-dominated extracellular matrix with few smooth muscle cells suggesting an organized thrombus. DISCUSSION: It should be emphasized that multiple factors might be responsible for very late stent thrombosis, such as peri-stent strut chronic inflammation involving proteoglycans, stent protrusion, and poorly controlled type 2 diabetes mellitus, possibly further inducing inflammatory cells.

Optical coherence tomographic insights of very late stent thrombosis of a second-generation drug-eluting stent: a case report.

BACKGROUND: Very-very late stent thrombosis (VVLST) occurring more than 5 years after implantation of drug-eluting stent (DES) is extremely rare, being restricted to few case reports. Mainly described with first-generation stents, this life-threatening complication has not been described with later-generation stents. We describe the first case of VVLST occurring 3309 days (>9 years) after implantation of second-generation DES. CASE SUMMARY: A 62-year-old man presented with the acute coronary syndrome. He has a history of percutaneous coronary intervention (PCI) to the right coronary artery using the three second-generation DES more than 9 years ago. Coronary angiogram revealed in-stent restenosis (ISR) with doubtful angiographic thrombus. Optical coherence tomography (OCT) confirmed the diagnosis of stent thrombosis (STh) localized to the stent overlap zone with underlying ISR. Patient underwent OCT-guided PCI with DES implantation and was discharged on dual antiplatelet therapy including ticagrelor. He is doing well on follow-up at 6 months. DISCUSSION: Stent thrombosis can occur in second-generation stents nearly a decade after implant. Stent overlap segment is more prone to neo-atheroma formation and vulnerable plaque leading to STh. In addition to confirming the diagnosis, OCT provides exciting insights into the underlying mechanism. This has implications for long-term antiplatelet therapy in patients implanted with multiple stents.

The Biolimus A9-coated BioFreedom™ stent: from clinical efficacy to real-world evidence.

In this state-of-the-art review, we present the findings and a critical analysis of the Leaders Free trial program, evaluating outcomes of a new stent-generation based on polymer-free technology, in this case the BioFreedom™ (Biosensors Europe, Switzerland), in patients at high bleeding risk (HBR). Polymer-free drug-coated stents were designed to obtain a device with the antirestenotic benefits of drug-eluting stents but without the polymer coating as potential trigger for delayed arterial wall healing and subsequent late ischemic adverse events, causing a prolonged dependence on dual antiplatelet therapy after stenting. This offers therefore the potential of a promising device-based strategy in a complex growing population of patients with combined HBR and high thrombosis risk, due to the possible reduction of antithrombotic duration.

Meta-analysis of Duration of Continuous Dual Antiplatelet Therapy and Late Stent Thrombosis After Second-Generation Drug Stent Implantation.

INTRODUCTION: The aim of the present study was to perform a systematic comparison of the incidence of late and extremely late stent thrombosis (ST) with short-term and long-term dual antiplatelet therapy (DAPT) after a second-generation drug-eluting stent (DES) implantation. METHODS: Randomized controlled trials using short-term and long-term DAPT and reporting late ST (30 days-1 year) and extremely late ST (longer than 1 year) after a percutaneous coronary intervention (PCI) with DES were searched and compared in the Life Sciences and Biomedical Information Bibliographic Database (MEDLINE), EMBASE, Cochrane Central, and ClinicalTrials.com. ST was used as the primary endpoint of the therapeutic outcome, and the fixed-effects model (I2 < 50%) or random-effects model (I2 ≥ 50%) was adopted for the combined analysis. The odds ratio (OR) and 95% confidence interval (CIs) were used to represent the results. P < 0.05 in the combined result indicated that the difference was statistically significant. RESULTS: A total of five randomized controlled trials consisting of 7142 patients were included, with 3556 cases of short-term DAPT (at most 6 months), and 3586 cases of long-term DAPT (at least 12 months). There was no significant difference between late ST and administration duration of DAPT (OR 0.98, 95% CI 0.30-3.18; P = 0.97, I2 = 0%). There was also no significant difference between the incidence of extremely late ST and the duration of DAPT application (OR 0.30, 95% CI 0.03-2.95; P = 0.31). CONCLUSION: The duration of continuous DAPT application had no effect on the occurrence of late and extremely late ST.

A case report of Kounis syndrome presenting with a rash, very late stent thrombosis and coronary evaginations.

BACKGROUND: Very late stent thrombosis (ST) is a concern in the era of drug-eluting stents (DESs), and ST is associated with peri-DES coronary artery aneurysmal lesions or coronary evaginations. An increasing number of cases of concurrent systemic allergic reaction and ST have been reported as Kounis syndrome (KS) in the literature. The number of patients with very late ST caused by KS is small, and further investigation of the potential pathophysiology is required. CASE SUMMARY: We report a case of KS that manifested as systemic urticaria followed by very late ST 14 years after placement of two sirolimus-eluting stents (SESs). Three months after the event of ST, coronary evaginations at the stented segments were detected on intravascular optical coherence tomography. DISCUSSION: Coronary evaginations are associated with local hypersensitivity, stent malapposition, uncovered strut, and flow disturbance that may predispose to ST. Systemic allergic reactions are known to promote platelet adhesion and aggregation. This case of KS suggests a pathophysiology in which the synergic effects between the coronary evaginations and a systemic allergic reaction may contribute to very late ST. For patients with Type 3 KS, performing follow-up intracoronary imaging tests may be important to confirm potential coronary evaginations, especially in patients with SESs.