Abstract
Coronary angiography is the “golden standard” imaging technique in interventional cardiology and it is still widely used to guide interventions. A major drawback of this technique, however, is that it is inaccurate in the evaluation and quantification of intracoronary thrombus burden, a critical prognosticator and predictor of intraprocedural complications in acute coronary syndromes. The introduction of optical coherence tomography (OCT) holds the promise of overcoming this important limitation, as near-infrared light is uniquely sensitive to hemoglobin, the pigment of red blood cells trapped in the thrombus. This narrative review will focus on the use of OCT for the assessment, evaluation and quantification of intracoronary thrombosis.
Highlights
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Thrombotic burden in acute coronary syndromes Is not adequately evaluated by standard coronary angiography, whereas Optical Coherence Tomography is exquisitely sensitive to the hemoglobin contained in red blood cells and can be used to precisely quantify thrombus.
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Both research and clinical applications have been developed using the OCT-based evaluation of thrombus. In particular, whereas precise quantification scores are useful for comparing antithrombotic therapies in randomized trials, both pharmacological and mechanical, the most important practical applications for OCT-based assessment of thrombus are the individuation of culprit lesions in the context of diffuse atheromata in acute coronary syndromes, and the so-called “delayed stenting” strategies.
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Improvements in 3D rendering techniques are on the verge of revolutionizing OCT-based thrombus assessment, allowing extremely precise quantification of the thrombotic burden.
1
Introduction
Coronary angiography is accepted as the “golden standard” imaging modality in interventional cardiology, and it is commonly used to guide percutaneous coronary interventions (PCI). However, as physicians deal with increasingly complex procedures, they have come to appreciate a major drawback of this technique, namely its limitation in the evaluation and quantification of the thrombotic burden . Intracoronary thrombi are indeed a common occurrence in acute coronary syndromes (ACS) , and exhibit special physical properties and profoundly abnormal behavior . The response of thrombus to standard management with pharmacotherapy and mechanical displacement is variable and, at times, unpredictable. Large evidence has accumulated relating thrombus quantity and quality to intraprocedural complications and adverse prognosis . The introduction of optical coherence tomography (OCT), first as a research tool and more recently as a guide to complex interventions , however, holds the promise of allowing precise thrombotic burden evaluation, due to its high resolution (in the order of 10–20 μm) and to the peculiar optical properties of thrombus as compared to other components of atherosclerotic plaques .
This review will focus on the use of OCT for the assessment, evaluation and quantification of intracoronary thrombus.
2
How does OCT identify thrombus?
Intracoronary OCT is a high-resolution imaging modality that uses a light source with a near-infrared spectrum (wavelengths ranging from 1280 to 1350 nm) to produce cross-sectional images of coronary arteries by measuring the “echo time delay” and the intensity of backscattered light . OCT is not able to image under the condition of blood flow . The poor penetration of light through blood is mainly due to the RBCs (containing no nucleus or organelles, but transporting hemoglobin and delimited by a membrane), to the high concentration (40%) of these scatterers (RBCs) in blood, and to the different refractive index of plasma and RBCs . Thus, it is necessary to create a blood-free environment using a transparent media flush . The peculiar optical properties of RBCs, however, besides representing an obstacle for light propagation, allow the distinction of intracoronary thrombosis into white and red thrombi on OCT.
At histologic examination red thrombus appears as a dark red mass protruding into the vessel lumen, consisting of mainly RBCs and fibrin, while white thrombus can be observed as a willow-like structure composed by platelets and white blood cells (WBCs), with a small amount of RBCs . At OCT analysis red thrombus can be defined as high-backscattering, with signal-free shadowing protrusion ( Fig. 1 A ), while white thrombus is depicted as signal-rich, low-backscattering mass projecting into the lumen ( Fig. 1 B). However, a mixed thrombus with intermediate features is often observed ( Fig. 1 C) .
Due to its high content in RBCs, red thrombus is characterized by elevated values of total light attenuation coefficient, μ t . In a study by Kume et al. , OCT was able to differentiate between the two types of thrombi with high sensitivity (90%) and specificity (88%). In particular, the ½ width of signal intensity attenuation was greater in white than in red thrombus (324 ± 50 μm vs 183 ± 42 μm, p = 0.0001) and the cut-off value of 250 μm differentiated white from red with high sensitivity and specificity. Interestingly, no significant differences in peak intensity measured at the surface of the thrombus were found (145 ± 34 μm vs 130 ± 18 μm, p = 0.12) . In practical terms, this means that the penetration of light is more rapidly attenuated by red than by white thrombus, and that it is the presence of optical shadowing (and not the bright appearance at the trailing edge) which has to be used to identify red thrombi.
In comparison with other intracoronary imaging modalities such as angioscopy and IVUS, OCT is capable to detect and characterize coronary thrombosis with greater accuracy. In a study, OCT showed a sensitivity of 100% for the detection of intracoronary thrombus, similar to that of angioscopy but much higher than that of IVUS (33%), and, in addition, a higher sensitivity for the detection of plaque rupture as compared to both angioscopy and IVUS (respectively, 73% vs. 47% vs. 40%); moreover, plaque erosion was almost exclusively detected by OCT (23%) .
Ex-vivo measurements of optical properties of human blood during coagulation with OCT might also provide unique information in experimental models of thrombosis and have been used for the study of anti-coagulation factors and for implementation of antithrombotic drugs. A strong linear correlation (R 2 = 0.998) was observed between thrombus volume measured by OCT and thrombus weight . Another group developed an OCT-derived parameter, the clotting time derived from the 1/e light penetration depth (d 1/e ) vs. time, applying it to the study of the effects of coagulation activators and anticoagulants at various concentrations .
2
How does OCT identify thrombus?
Intracoronary OCT is a high-resolution imaging modality that uses a light source with a near-infrared spectrum (wavelengths ranging from 1280 to 1350 nm) to produce cross-sectional images of coronary arteries by measuring the “echo time delay” and the intensity of backscattered light . OCT is not able to image under the condition of blood flow . The poor penetration of light through blood is mainly due to the RBCs (containing no nucleus or organelles, but transporting hemoglobin and delimited by a membrane), to the high concentration (40%) of these scatterers (RBCs) in blood, and to the different refractive index of plasma and RBCs . Thus, it is necessary to create a blood-free environment using a transparent media flush . The peculiar optical properties of RBCs, however, besides representing an obstacle for light propagation, allow the distinction of intracoronary thrombosis into white and red thrombi on OCT.
At histologic examination red thrombus appears as a dark red mass protruding into the vessel lumen, consisting of mainly RBCs and fibrin, while white thrombus can be observed as a willow-like structure composed by platelets and white blood cells (WBCs), with a small amount of RBCs . At OCT analysis red thrombus can be defined as high-backscattering, with signal-free shadowing protrusion ( Fig. 1 A ), while white thrombus is depicted as signal-rich, low-backscattering mass projecting into the lumen ( Fig. 1 B). However, a mixed thrombus with intermediate features is often observed ( Fig. 1 C) .
Due to its high content in RBCs, red thrombus is characterized by elevated values of total light attenuation coefficient, μ t . In a study by Kume et al. , OCT was able to differentiate between the two types of thrombi with high sensitivity (90%) and specificity (88%). In particular, the ½ width of signal intensity attenuation was greater in white than in red thrombus (324 ± 50 μm vs 183 ± 42 μm, p = 0.0001) and the cut-off value of 250 μm differentiated white from red with high sensitivity and specificity. Interestingly, no significant differences in peak intensity measured at the surface of the thrombus were found (145 ± 34 μm vs 130 ± 18 μm, p = 0.12) . In practical terms, this means that the penetration of light is more rapidly attenuated by red than by white thrombus, and that it is the presence of optical shadowing (and not the bright appearance at the trailing edge) which has to be used to identify red thrombi.
In comparison with other intracoronary imaging modalities such as angioscopy and IVUS, OCT is capable to detect and characterize coronary thrombosis with greater accuracy. In a study, OCT showed a sensitivity of 100% for the detection of intracoronary thrombus, similar to that of angioscopy but much higher than that of IVUS (33%), and, in addition, a higher sensitivity for the detection of plaque rupture as compared to both angioscopy and IVUS (respectively, 73% vs. 47% vs. 40%); moreover, plaque erosion was almost exclusively detected by OCT (23%) .
Ex-vivo measurements of optical properties of human blood during coagulation with OCT might also provide unique information in experimental models of thrombosis and have been used for the study of anti-coagulation factors and for implementation of antithrombotic drugs. A strong linear correlation (R 2 = 0.998) was observed between thrombus volume measured by OCT and thrombus weight . Another group developed an OCT-derived parameter, the clotting time derived from the 1/e light penetration depth (d 1/e ) vs. time, applying it to the study of the effects of coagulation activators and anticoagulants at various concentrations .
3
Angiographic thrombus scoring systems
Angiographic thrombus grading scales are commonly used for quantification of the thrombus burden. The widely employed TIMI scale, originally created by the Thrombolysis In Myocardial Infarction study group investigators , was conceived in the fibrinolysis era, and reflected the view that the size and burden of intracoronary thrombi affected the efficacy of this therapy. The TIMI classification relies on the relative estimated size of the thrombotic mass and of the affected vessel, using a simple score ranging from grade 0 (no thrombus), to grade 5 (very large thrombus content that completely occludes flow).
Whereas this classification is user-friendly and universally accepted, it has two obvious limitations. At one end of the scale, angiography may easily miss small or moderate-sized thrombi, whose appearance is often of an indefinite intracoronary “haziness”, difficult to differentiate from calcium, plaque rupture or dissection. The accuracy of the highest level (grade 5), on the other hand, is clearly subjective, as the ischemic vessel containing grade 5 thrombus is totally occluded. Thus, an important modification was introduced by the Thoraxcenter (Rotterdam, The Netherlands) investigators . Their method utilizes either a guide wire or a 1.5 mm balloon for crossing and recanalization of the occluding thrombus. This intervention re-establishes a certain degree of antegrade coronary flow to the extent that the exposed underlying thrombotic mass can be reclassified as either a small (grade 1–3) or a large thrombus burden (grade 4).
In the early 2000s, Yip and colleagues employed six angiographic predictors of large thrombus burden, namely (1) a cutoff pattern of occlusion, (2) accumulated thrombus proximal to the occlusion, (3) a reference lumen diameter of the IRA of > 4.0 mm, (4) an incomplete obstruction with an angiographic thrombus with the greatest linear dimension more than 3 times the reference lumen diameter, (5) the presence of floating thrombus proximal to the lesion, and (6) a persistent dye stasis distal to the occlusion, showing that the first three were independent predictors of slow flow/no reflow in STEMI patients .
In another recent development, Aleong et al. innovatively combined edge detection and video densitometry-based quantitative coronary angiography for enhanced quantitative assessment of thrombus. Their early experience suggests that it accurately quantifies thrombus volume .
4
OCT thrombus scoring systems
Several OCT scoring systems have been developed in order to quantify the amount of thrombus within a coronary vessel, with or without the presence of a stent. So far, they have mainly found application in the research field.
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Prati thrombus score
In the COCTAIL (ClearwayRx System to reduce intracoronary thrombus in patients with acute coronary syndromes according to Optical Coherence Tomography after Abciximab Intracoronary Local infusion) trial, Prati et al. showed that the local delivery of abciximab by means of a dedicated perfusion catheter is more effective than intracoronary infusion through the guiding catheter in reducing thrombus burden . They calculated a thrombus score (TS) as the sum of each cross-section score, obtained by measuring the number of involved quadrants and classifying thrombus as absent (TS = 0) or subtending 1, 2, 3 or 4 quadrants (respectively, TS = 1, 2, 3 or 4) ( Fig. 1 ). In another study by the same group , OCT was performed in STEMI and NSTEMI patients before and after manual thrombectomy (TB). The TS before TB was 91.6 while it was reduced to 46.7 afterwards (p < 0.01), with a percentage of thrombus removal of 53% (the % of thrombus removal was defined as: TS before TB/TS after TB × 100). The variation of TS (ΔTS) was reasonably correlated with the planimetry-measured surface area of the actual aspirated material at histology (r = 0.54; p < 0.01). Moreover, the authors found an inverse correlation between the ΔTS and the in stent thrombus area (r = − 0.50; p = 0.02), suggesting that the greater the amount of thrombus removal, the lower the residual amount of in stent atherothrombotic material. The validity of the method applied in the COCTAIL trial to calculate the thrombus score was recognized in the international Expert Review document .
In another important development, Parodi et al. took advantage of this score to compare the efficacy of manual and rheolytic TB. As a main finding, he showed that both techniques allow only incomplete removal of thrombus. The study failed to meet its primary end point, since the number of quadrants containing thrombus after stenting was lower in the rheolytic as compared to manual TB arm, but this difference did not reach statistical significance (median value 53 and 65, respectively; p = 0.083). However, patient selection was not based on the angiographic amount of thrombus.
Finally, in another ongoing study by the Prati group, the COCTAIL II, the post-stenting number of cross-sections with thrombus area more than 10% was selected as the primary endpoint to compare, in a 2 × 2 fashion, abciximab infusion with ClearWay catheter (with or without manual thrombus aspiration) with intravenous or intracoronary abciximab (also with or without thrombectomy) .
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Magro criteria
The residual amount of atherothrombotic material post-stenting is an important surrogate endpoint for studies aiming at comparing different procedures or treatments in the setting of emergency angioplasty. Indeed, the amount of in-stent residual thrombus, even if evaluated by low-resolution angiography, has been demonstrated to predict short-term adverse events in both primary PCI and after PCI for stent thrombosis . Magro et al. used OCT to measure in-stent thrombus area (TA) by subtracting the lumen area (LA) from the stent area (SA) and adding the Free Thrombus Area (FTA), while taking into account Incomplete Strut Apposition [TA = SA − LA + FTA + ISA]. Subsequently the thrombus volume (TV) was calculated by multiplying the mean TA by the length of stented segment within which thrombus material was deemed present at the OCT long-axis reconstruction. Eventually, TV was used to calculate the atherothrombotic burden, defined as the ratio between TV and stent volume ( Fig. 2 ). Patients with a high atherothrombotic burden (above the median) were more likely to have incomplete ST-segment resolution (odds ratio: 2.51, p = 0.008) and to develop no-reflow phenomenon (30% vs 0%, p = 0.02), angiographic embolization (33% vs 4%, p = 0.008) and distal occlusion (27% vs 4%, p = 0.03) when compared with those with low atherothrombotic burden. TB, interestingly, was associated with only a trend towards lower atherothrombotic burden. This method has been also validated for pre-stenting evaluation of thrombus amount in a study by Kajander et al. . A good correlation between intra-observer and inter-observer measurement was found, suggesting that measurement of pre-stent TB by OCT in STEMI patients treated with primary PCI is feasible and repeatable.
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TROFI trial criteria
