Coronary Thrombus

Pathophysiology of Thrombus

An understanding of the structure of thrombus and its multifaceted characteristics is essential for making proper management choices in the revascularization of atherosclerotic lesions and vessels. A thrombus-containing lesion is formed when the fibrous cap of an atherosclerotic plaque develops structural defects.9 Lipid-rich lesions are vulnerable to disruption or erosion because they consist of a crescentic mass of lipids either in close contact with the vessel lumen or separated from it by a discrete component of extracellular matrix.10 11 Plaque disruption occurs most frequently where the fibrous cap is thinnest, most heavily infiltrated by lipid-filled macrophages (foam cells), and therefore weakest, and for eccentric plaques, this tends to be the shoulder region between the plaque and the adjacent vessel wall.12 However, the process is not purely mechanical, but an active process is involved in the pathophysiology. Atherectomy specimens from patients with ACSs reveal areas very rich in macrophages,13 and these cells are capable of degrading extracellular matrix by phagocytosis or secretion of proteolytic enzymes; thus, enzymes such as plasminogen activators and matrix metalloproteinases (MMPs: collagenases, gelatinases, and stromelysins) may weaken the fibrous cap and predispose it to rupture. The ensuing contact of exposed, disrupted, and highly thrombogenic subendothelial matrix and plaque with circulating platelets and white blood cells activates the coagulation cascade. The resultant platelet adhesion and aggregation lead to thrombus formation. Furthermore, released tissue factor from the arterial injury directly activates the extrinsic coagulation cascade and promotes fibrin formation. Activated platelets release powerful promoters of vasoconstriction and aggregation, including serotonin, adenosine diphosphate, thromboxane A2, oxygen-derived free radicals, endothelin, and platelet-activating factor.14 As the thrombus accumulates to form a critical obstacle, impaired flow dynamics alongside and distal to the thrombotic lesion develop, frequently accompanied by dynamic vasoconstriction and resultant clinical ischemic events.15

Thrombosis–Substrate Dependent

There is striking heterogeneity in the composition of human atherosclerotic plaques, even in the same individual, and the disruption of plaques exposes different vessel wall components to blood. Data on the thrombogenicity of disrupted atherosclerotic lesions are limited. The lipid core, abundant in cholesterol ester, displayed by far the highest thrombogenicity.16

Thrombosis–Tissue Factor Dependent

Tissue factor (TF), a small-molecular-weight glycoprotein, initiates the extrinsic clotting cascade and is believed to be a major regulator of coagulation, hemostasis, and thrombosis. TF forms a high-affinity complex with coagulation factors VII/VIIa; TF/VIIa complex activates factors IX and X, which in turn lead to thrombin generation.17 TF antigen is normally present only in the arterial adventitia. Platelet deposition on lipid-rich atheromatous core was more than three times greater than on adventitia, with tunica media next, then foam-cell–rich matrix and collagen-rich matrix, and normal intima least thrombogenic. The lipid-rich core also exhibits the most intense TF staining, and this observation suggests that TF is an important determinant of the thrombogenicity of human atherosclerotic lesions after spontaneous or mechanical plaque disruption. Colocalization analysis of directional coronary atherectomy specimens from patients with unstable angina pointed to a strong relationship between TF and macrophages.18

Thrombus in Acute Coronary Syndrome: Acute Thrombosis

Disruption of a vulnerable or unstable plaque with a subsequent change in plaque geometry and thrombosis results in a complicated lesion.19 20 On occasion, the clinical consequence will be unstable angina or another ACS.19 However, it seems that such a thrombus more often causes no symptoms and, by self-organization, then contributes importantly to the progression of atherosclerosis.

The platelets sustain and amplify the coagulant response at the plaque site and release procoagulant platelet-derived microparticles. Various biochemical processes and interactions between activated platelets, red blood cells, fibrinogen, vasoconstrictors, atherosclerotic material, and the vessel wall all have a substantial impact on the fibrin network. These constituents account for the thrombus's level of activity, stability, or instability and for the overall “aggressiveness” of the thrombus as encountered during intervention. The presence and ratio of the aforementioned components lead to the formation of distinct thrombus types, each with unique rheolytic and mechanical properties. The two most prominent are the red and white thrombi. They can be detected by angioscopy,21 and their angiographic characteristics correlate with the histology of extracted thrombi.22 The red thrombus has a dense surface with a loose inner core. Transmission or scanning electron microscopy demonstrates loosely packed fibrin and many interspersed red blood cells. The white thrombus consists of a dense structure lacking loose inner spaces, yet it contains a high concentration of platelets with fibrin and only few red blood cells.23 Based on the histopathologic analysis of aspirated thrombotic content, erythrocyte-rich (red) thrombus is found in approximately 35% of patients, predominately in those presenting with low Thrombolysis In Myocardial Infarction (TIMI) flow. The platelet-rich (white) thrombus is identified in 65% of cases, especially in the early hours of acute myocardial infarction.24

However, the fact is that in many patients the occlusive thrombus is a mixture of red and white clot, and the frequent resistance upon extraction attempts suggests that certain clots contain layers upon layers of one thrombus type interspersed with the other.25 26 From a clinical management viewpoint, coronary risk factors such as hypercholesterolemia, smoking, and male sex adversely influence plaque morphology in patients with ACSs and are associated with a higher frequency of thrombus.

Complications during Percutaneous Coronary Intervention

Dislodgment of friable thrombotic material by balloon and stent deployment is an issue of significant concern, especially in heavy thrombus burden (grades 3–5) lesions. Embolization of fragmented thrombotic particles obstructs flow within distal arterial segments, side branches, and myocardial microvessels. Overall, distal embolization occurs in the range of 6 to 15% of standard PCI for all lesion types in ACSs and is associated with up to a sevenfold increase in the rate of periprocedural MI. In most instances, resultant severe ischemia, microinfarctions, inflammatory response, and contractile dysfunction reduce coronary reserve and cause deleterious effects on recovery and salvage.34 These complications are especially encountered among patients who undergo primary PCI for acute myocardial infarction (AMI). When compared with the revascularization of thrombus-free lesions, embolization also significantly increases the need for emergency bypass surgery as well as the procedure-related death rate.35 The considerably limited yield of standard PCI in thrombus-containing lesions is further elucidated by the phenomenon of “illusion of reperfusion.”36 Essentially, this term describes a marked discrepancy between primary PCI-gained TIMI 3 flow versus the disappointing, suboptimal degree of myocardial salvage. Notably, the desired grade 3 myocardial blush score is gained in only 28 to 35% of patients in whom the standard PCI induces a TIMI 3 epicardial flow.37 The main causes of this marked discrepancy include the prevalent intracoronary thrombus and related distal embolization, microvessel obstruction, no reflow, and myocardial necrosis. Clearly, patients who develop procedure-related “no reflow” sustain larger-sized infarcts, significantly worse left ventricular (LV) function, and a greater risk of adverse cardiac events and death.38 Thus the deleterious impact of thrombus as a hazardous material that promotes adverse coronary events and suboptimal outcome should be anticipated and dealt with promptly before, during, and after PCI.

Indications for a Targeted Thrombus Strategy

In the absence of an apparent thrombus or when only a small thrombus (corresponding to grades 1–2) is detected, the recommended PCI strategy includes standard pharmacotherapy, balloon angioplasty, and stenting.39 Aspiration catheters can be useful as well in this situation. The management of a significant (grade 3) or heavy thrombotic burden (grades 4–5) is considerably more challenging.40 Targeted thrombus strategy is warranted in such situations, especially when the below mentioned pathologic, clinical featured demand. Table 4.

Pharmacotherapy

The mainstay pharmacologic treatments for the management of thrombus-containing lesions include aspirin, heparin, glycoprotein IIb/IIIa platelet receptor antagonists, thienopyridines (clopidogrel, prasugrel, ticlopidine), and direct thrombin inhibitors. Interestingly, a beneficial decrease in the thrombotic burden can be gained with the mainstay agents even before the initiation of an intervention, with resultant improved PCI results and reduced risk of distal thrombotic embolization.

• Chronic aspirin therapy has been shown to decrease the thrombotic burden before stent deployment.

• Heparin reduces fibrin formation and abolishes platelet contractile forces.41

• Glycoprotein IIb/IIIa receptor antagonists dramatically reduce platelet aggregate size as well as to improve thrombolytic access to the platelet-rich clot's fibrin.42

However, these agents are less effective in an already formed, active, unstable thrombus,43 especially when it is a high-grade thrombus. For example, significant limitations of these useful pharmacologic therapies are quite apparent during the revascularization of old saphenous vein grafts (SVGs) with a large thrombotic content.44

Thrombus Aspiration Catheters

Manual thrombus aspiration of the infarct-related vessel has attracted intense interest as a useful method for the rapid reduction in thrombotic burden, prevention of thrombus embolization, preservation of microvascular integrity, and reduction in infarct size.46 Most aspiration-based catheters are available in 4- to 6F sizes; they contain an extraction lumen and aspiration syringe. They are user-friendly because of their low crossing profile, hydrophilic coating, flexibility, and tapered distal tip47 (Fig. 3).

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Fig. 3 Rheolytic thrombectomy system. Double vessel acute thrombotic occlusion in ACS patients. (A) Mid-LAD thrombotic occlusion with establishment of flow after wiring. (C) Usage of thrombuster. ACS, acute coronary syndromes; LAD, left anterior descending artery.

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Fig. 3 Rheolytic thrombectomy system. Double vessel acute thrombotic occlusion in ACS patients. (A) Mid-LAD thrombotic occlusion with establishment of flow after wiring. (C) Usage of thrombuster. ACS, acute coronary syndromes; LAD, left anterior descending artery.

Meta analysis of randomized studies on catheter thrombus aspiration shows a significant benefit of reducing mortality compared with PCI alone, 2.7% versus 4.4% (p = 0.05), respectively.48 However, some investigators failed to find any advantage to the routine use of aspiration catheters in STEMI patients, observing that this approach does not increase myocardial salvage and, in fact, may increase final infarct size.49 In the TOTAL (Thrombectomy with PCI versus PCI Alone) trial, patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, showed no reduction in the risk of cardiovascular death, recurrent MI, cardiogenic shock, or the New York Heart Association (NYHA) class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days.50 Among the limitations of aspiration catheters are the difficult delivery along tortuous vessels and reduced ability to aspirate at the distal coronary segments; there is also the risk of dissection/perforation in cases in which the guidewire is not located within the true lumen. The low, negative aspiration pressure and the small evacuation holes also limit the yield of these catheters in the presence of a large thrombotic volume. Commonly, the application of aspiration catheters results in inadequate clot extraction, leaving at least 30 to 50% residual thrombus volume.47 The considerable risk of catheter-induced distal embolization, especially during a hurried maneuver, and the need to repeatedly pass across a large thrombus, should be taken into account in planning clot extraction. It is noteworthy that even the sequential use of thrombus aspiration catheters and distal protection filters is associated with insufficient thrombus removal.47 48 49

Power-Sourced Thrombectomy Devices

This group of mechanical tools includes the rheolytic thrombectomy, the excimer laser, and the X-Sizer (eV3, Plymouth, Minnesota, United States). The question of whether power-based mechanical thrombectomy offers any advantage over aspiration catheters is relevant to practical management, although there are no prospective studies with direct comparisons between these two modalities. Overall, there is a strong clinical impression that the larger the target thrombus, the higher the extracting yield of a power-based mechanical thrombectomy device.46 51

The X-Sizer thrombectomy system is used mainly in Europe (Fig. 4). It consists of a helical cutter enclosed in a protective housing attached to a dual-bore catheter shaft containing a guidewire and vacuum/extraction lumens. Activation of the handheld controller simultaneously rotates the helical cutter at 2,100 rpm (revolutions per minute), which entraps and macerates soft atherosclerotic plaque and thrombus and channels to a vacuum collection bottle. The device operates cutters 1.5, 2, and 2.3 mm in diameter and is compatible with 0.014-in guidewires.52 53 The large, prospective X-Sizer in Acute Myocardial Infarction Patients for Negligible Embolization (X-AMINE) multicenter study that followed demonstrated a success rate for the device of 87% and adequate thrombus removal in 95% of the lesions.54

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Fig. 4 AngioJet rheolytic thrombectomy.

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Fig. 4 AngioJet rheolytic thrombectomy.

The AngioJet rheolytic thrombectomy system (AngioJet, Possis/Medrad, Minneapolis, Minnesota, United States) is a Food and Drug Administration (FDA)–approved device for thrombus-containing lesions encountered in coronary and peripheral interventions. The principle of activation is based on the creation of saline jets inside the catheter that travel backward at high speed to create a negative pressure zone (Venturi effect). Side windows along the catheter tip optimize fluid flow, drawing thrombus into the catheter for fragmentation and removal (Figs. 4, 5).

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Fig. 5 Thrombus extracted from coronary.

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Fig. 5 Thrombus extracted from coronary.

In the FAST (Florence Appraisal Study of rheolytic Thrombectomy) study, AngioJet was used in 116 AMI patients with extensive thrombus loads, leading to significant improvements in perfusion, as compared with a control group with similar thrombus loads who received standard PCI.55 The JetStent trial exclusively focused on AMI patients with angiographically visible thrombus, using only slow, single-pass, antegrade thrombectomy and a narrower temporal definition of early ST-segment resolution (> 50% within 30 minutes).56 It enrolled 501 STEMI patients with visible thrombus (grades 1–4) or with a totally occluded infarct-related vessel (thrombus grade 5 with subsequent restratification). A significant difference in MACE rate was observed between the groups at 1 and 6 months: 3.1% AngioJet versus 6.9% direct stenting (p = 0.05), and 12% versus 21% (p = 0.01), respectively. No difference was found between the two approaches regarding myocardial blush score and corrected TIMI frame count. Multivariable regression analysis showed that randomization to rheolytic thrombectomy was a predictor of ST-segment resolution (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.03–2.8, p < 0.039) and 6 months MACE rate. Despite the encouraging outcomes of the JetStent study, skepticism regarding the interpretation of results and the chance for wider use of this modality remains.

Lasers are mainly used for debulking lesions deemed unsuitable for standard PCI and can be applied for the revascularization of thrombus-containing lesions.57 The pulsed-wave ultraviolet-wavelength excimer laser (Spectranetics, Colorado Springs, Colorado, United States) has been successfully applied in patients with ACSs, including AMI.58 The excimer laser light interacts favorably with several components of the occluding thrombus. Laser-generated acoustic shock waves dissolve fibrin fibers and suppress platelet aggregation.59 The thrombus-dissolution capability of this laser was further examined by the Excimer laser angioplasty in acute myocardial infarction (CARMEL) multicenter study.60

A baseline TIMI 0 flow of 1.2 ± 1.1 increased to 2.8 ± 0.5 with the laser energy and was followed by final TIMI flow of 3.0 ± 0.2 (p < 0.001 vs. baseline) with adjunctive stenting. Total MACE was relatively low at 13%. Thus this study provided the first scientific, quantitative evidence of the considerable benefit of a dedicated mechanical thrombectomy device in thrombus-removal strategy and particularly in AMI.

Ultrasound-induced thrombus dissolution can be offered as adjunctive therapy aimed at increasing the efficacy of common thrombolytic therapies.61 Ultrasound-producing devices are defined by their different acoustic intensity and frequency, ranging from low (20–400 KHz) to high (0.5–3 KHz). The two main approaches to sonication therapy rely on an external device delivering transcutaneous therapeutic ultrasound energy62 and on the invasive, intravessel catheter, which delivers sonication directly to the targeted thrombus.

Stents with Thrombus Capturing Mechanisms

During PCI, direct stenting of thrombus-containing lesions with either bare metal or drug-eluting stents is a common strategy.63 Conceptually, a dedicated thrombus-trapping stent could offer a targeted approach to the management of thrombus and reduction in embolization. The MGuard stent (Inspire-MD, Tel-Aviv, Israel) was developed for providing a unique stainless steel bare metal stent covered with an ultrathin, micrometer-level (150 × 180 µm), flexible mesh net fabricated by circular knitting. During stent deployment, the net stretches and slides over the expanding stent struts, creating custom-designed pores parallel to the vessel wall. Once deployed, the MGuard stent seals the thrombus and accompanying plaque and captures potential embolic debris between the fiber net and the arterial wall.64

Power Thrombectomy

This unique reperfusion strategy is aimed at the treatment of ischemic lesions and vessels laden with very heavy thrombotic burdens and accompanying slow antegrade flow. It combines power-sourced mechanical thrombectomy with selective injection of thrombolytic agents into the target vessels. The thrombolytic agents can be selectively administered during the intervention through a dedicated perfusion balloon such as the ClearPath (Unisys) device.

Stent Thrombosis

Early, late, and very late stent thrombosis is an ominous clinical development that has a significant impact on clinical outcome.65 Stent thrombosis is often multifactorial.66 One of the major causes is post-PCI residual thrombus, which then either gradually accumulates over time or rapidly aggregates to form a fully occlusive thrombus. Stent thrombosis can become manifest by serious complications such as nonfatal and fatal AMI67 68 and marked hemodynamic instability. Expedient thrombus management is key to a favorable outcome, especially for patients who present with STEMI.66 Primary PCI, including additional stenting with or without thrombectomy, is effective in restoring vessel patency, but reocclusion and restenosis are frequent.69 The often raised practical question as to which device is best for the management of stent thrombosis can be addressed according to the amount of occlusive thrombus and associated clinical findings.70 71 While a small to medium thrombus load in a stable patient can be managed with combination therapy of pharmacological agents and an aspiration catheter, a large burden, especially in the presence of hemodynamic instability and ongoing ischemia, calls for enhanced removal by a power-based mechanical thrombectomy device. Nevertheless, even successful PCI for stent thrombosis is associated with a larger infarct and poorer outcome than in patients with de novo STEMI.

Multivessel Coronary Thrombosis

This is an uncommon occurrence that poses a considerable management challenge. Patients with simultaneous multivessel thrombosis frequently present with ACS, mostly with either STEMI or non-STEMI, accompanied by severe hemodynamic compromise. The pathophysiologic process that accounts for this situation begins when plaque ruptures, and resultant acute thrombosis of a single artery leads to the development of cardiogenic shock. This, in turn, further decreases coronary perfusion pressure; consequently, multivessel thrombus is formed on other preexisting lesions as well.72 Another mechanism of multivessel coronary thrombosis involves thrombotic embolization and the occlusion of multiple coronary vessels from a left chamber cardiac tumor.73 The optimal treatment approach to multivessel coronary thrombosis is unknown, varying considerably from PCI to urgent coronary artery bypass grafting (CABG). In instances in which the most critical culprit lesion can be identified with certainty, selective treatment with aspiration catheter, aggressive pharmacotherapy, and subsequent stenting can be beneficial. However, in a case of PCI failure or in patients with continuous global ischemia due to thrombus-laden lesions in the other coronary arteries (especially with accompanying hemodynamic deterioration), urgent CABG is the preferred management option.

Bypass Grafts

Myocardial ischemia occurring early after CABG is typically caused by graft thrombosis resulting from surgery-related mechanical issues, whereas late ischemic events are caused by progression of soft, friable atheromatous plaques in the grafts.74 75 Collagen-rich (firm) or collagen-poor (soft) thrombus superimposition, an integral component of this process, is found in as many as 80% of old bypass grafts.76 The thrombotic content is often much greater in vein grafts than in native arteries because of the greater caliber of vein grafts and the lack of side branches, conditions that promote blood stagnation and coagulation. SVG sculpturing can be used to facilitate revascularization of totally occluded grafts through maximal removal of their thrombus content and subsequent stenting (Table 6).