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TABLE 12.5 Grade 5 ThrombusdA New Modification of the Restratification Process: Distinctive Types of the
Occlusive Thrombus
Type A: Guidewire successfully crosses and recanalizes the occlusive thrombus with partial or complete restoration of forward flow.
Type B: Guidewire crosses the occlusive thrombus positioned distally but fails to restore any forward flow.
Type C: Guidewire fails to cross the occlusive thrombus and TIMI 0 flow persists.
stents. The rheolytic thrombectomy and the laser are described in a focused chapter in this book. As for stenting, when
required in a large thrombus load, a thrombus-capturing stent can be readily deployed [41,42]. The utility of the modified
reclassification extends beyond application in AMI, as it can be used in all patients with ischemic coronary syndromes
presenting with TIMI 0 antegrade flow caused by a totally occlusive thrombus grade 5. Nevertheless, over time it became
evident that the original Thoraxcenter’s thrombus grade 5 restratification method calls for a new modification, as it
assumed that every grade 5 thrombus can be restratified. In reality, not all grade 5 thrombi are alike and they do not
respond in unison to restratification. Accordingly, the authors of this chapter introduce herein an important modification to
the Thoraxcenter restratification process by defining three distinct types of grade 5 thrombus as presented in Table 12.5 and
illustrated in Fig. 12.3GeK.
The grade 5 type A occlusive thrombus enables a guidewire or a small balloon to cross and as a result at least partial
restoration of antegrade flow is achieved. Type B represents a thrombus that first allows a guidewire or a small balloon to
successfully cross and be placed distally; however, no antegrade flow ensues. The operator may then attempt to apply a
larger balloon or a thrombectomy tool. If successful, the target is regraded as type A, though the definition of grade 5 type
B holds if no restoration of antegrade flow occurs. Grade 5 type C represents complete failure of the guidewire to even
cross the occlusive thrombus. Consequently, there is no change in the morphology of the occlusion, no recanalization
occurs, and therefore, no antegrade flow is restored. This scenario suggests that the underlying plaque burden and immense
resistance of the large thrombus combine forces, thus practically acting as a nonpenetrable chronic total occlusion.
Another practical thrombus grading classification was published by Nicoli and colleagues [33]. This classification is
depicted in Table 12.6 and illustrated by Fig. 12.4AeB. Recognizing the challenge of exact differentiation between TIMI
grade 1 and grade 3, this bilevel classification incorporates only two grades for angiographically evident thrombus: a low
grade corresponding to TIMI thrombus grades 1e3 and a high grade corresponding to TIMI thrombus grades 4 and 5. Of
note, similar to the TIMI classification, this bilevel system is useful as well in the assessment of thrombus burden in old
saphenous vein bypass grafts. The simplicity of this classification is less useful when the thrombus is angiographically
assessed to be an “intermediate” size, i.e., between “small
” and “large” load, as demonstrated in Fig. 12.5.
Introducing another innovative classification, Aleong and colleagues combined edge detection and video-densitometrybased quantitative coronary angiography for enhanced quantitative assessment of thrombus load. Their experience with
this method suggests that it accurately quantified the thrombus volume [43]. Altogether, the usefulness and merit of the
contemporary angiography-based classifications of thrombus score are highly valuable [44,45], yet certain inherited
limitations should be recognized as well. First, reliance on visual interpretation of angiography carries inherent limitations
concerning the accuracy of the assessment. Accordingly, underestimation of thrombus presence and size occurs when
angiographic assessments are compared with more accurate tools such as optical coherence tomography, coronary
ultrasound, and angioscopy. Second, the current classifications fall short of differentiating between types of thrombus (i.e.,
white vs. red) and do not define the thrombotic content within chronic total occlusions. Third, classifications neither
describe nor take into account the underlying morphology and severity of the accompanying atherosclerotic plaque. This is
especially apparent when the target contains heavy calcification. Yet, it should be recognized that there is no other gold
standard practical method to be compared with angiography. Thus, angiography remains the most user-friendly and the
least expensive imaging modality currently available for decision-making during PCI. As such, angiog raphic thrombus
classifications are clinically relevant.
TABLE 12.6 The Bilevel TIMI Thrombus Grading Scale
Low thrombus content equal to TIMI thrombus grades 1e3
High thrombus content equal to TIMI thrombus grades 4 and 5
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(A) (B)
FIGURE 12.4 (A and B) The bilevel angiographic thrombus classification. (A) Two small thrombus burden lesions. The left main (upper ring) contains
a grade 2 thrombus and the obtuse marginal branch (lower ring) contains a tighter lesion with a grade 1 thrombus. (B) A large thrombus resides within a
dissected atherosclerotic plaque in the proximal circumflex artery (red ring).
FIGURE 12.5 Two thrombotic eccentric lesions located in the middle of the right coronary artery in a patient with acute inferior wall myocardial
infarction (red circles). Each thrombus can be assessed either as an “intermediate” load (i.e., between “small” and “large” size) or as a grade 2 or grade 3
thrombus. However, there is a certain likelihood that an angiographic assessment in this case underestimates the true burden of these thrombi and they, in
fact, consist of TIMI thrombus grade 4.
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THE “ANGRY THROMBUS” PHENOM ENON
The terms “angry throm bus” or “hostile thrombus” describe a unique, clinically worrisome pathologic vascular phenomenon with distinctive angiographic features. It is recognized during PCI and peripheral endovascular interventions
alike. The hallmark of this thrombus type is sudden, rapid, and aggressive large volume accumulation accompanied by
angiographic and clinical instability. This thrombus can be formed by sudden “natural” plaque rupture as demonstrated in
Fig. 12.6 or caused by mechanical provocation during percutaneous revascularization attempts, due to a guidewire and/or
other equipment crossing of an atherosclerotic thrombotic plaque as depicted in Fig. 12.7. In most instances the angry
thrombus process occurs in lesions that are considered angiographically as thrombus-containing plaques [37]. Nevertheless, it can be formed as well in “ clean” plaques, i.e., those with TIMI thrombus grade 0. This aggressive thrombotic
structure can be formed at any stage of the coronary (or peripheral) intervention, serving as an ominous marker for eminent
complications. Moreover, the angry thrombus can even abruptly develop upon completion of a seemingly routine, uncomplicated balloon inflation or stent deployment. In the vast majority of instances identification of an angry thrombus is
accompanied by rapidly developing deleterious clinical effects. Once an angry thrombus is formed it rapidly aggregates at
the target lesion and beyond, frequently expanding distally and even proximally into the treated vessel with devastating
effect on the ischemic myocardium [46].
Thrombus classification can assist in both recognition and management of this abnormal structure, as the angry
thrombus can rapidly expand to reach a TIMI thrombus grade of 4 or 5. Consequently, acute vessel closure can ensue, as
well as thrombus fragmentation, distal embolization, and occlusion of smaller arteries. The angry thrombus commonly
causes severe ischemia, dangerous arrhythmias, and conduction abnormalities due to cessation of antegrade flow, distal
embolization, and marked decrease in myocardial perfusion. This process frequently leads to AMI accompanied by severe
hemodynamic instability. From a technical point, the angiographic identification of such rapid increase in the thrombus
load should be followed by expeditious clot removal. Notably, the angry thrombus commonly resists treatment with
standard pharmacotherapy, balloon angioplasty, or aspiration catheters and standard stenting [37]. Specifically, in many
cases an aggressive, angry thrombus does not readily respond to aspiration catheters, thus requiring application of
motorized mechanical thrombectomy and administration of enhanced pharmacotherapy to restore antegrade flow and distal
perfusion for myocardial salvage [47,48].
THROMBUS SCORING IN NONCORONARY VASCULATURE
In addition to the aforementioned coronary thrombus grading systems, other clot scoring systems are used in the vascular
bed. For example, neurologists and neuroradiologists use angiographic computerized tomography (CT) for creation of a
clot burden score (CBS). This score serves as an important determinant of clinical and radiologic outcomes in stroke
patients [49]. The CBS defines the extent of the thrombus present in the proximal anterior circulation of the brain and is
scored on a scale of 0e10. A score of 10 is normal, implying the absence of a clot, while a score of 0 represents complete,
FIGURE 12.6 A “natural” occurrence of a rapidly forming “angry” or “hostile” thrombus (red circle). A large-size thrombotic accumulation occurred
within minutes following plaque rupture in the right coronary artery. The patient developed a complicated acute myocardial infarction.
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(A) (B)
(C) (D)
FIGURE 12.7 Provoked formation of an “angry” or “hostile” thrombus. (A) The left main coronary artery contains critically stenosed plaque with
accompanying grade 2 thrombus. (B) Percutaneous coronary intervention of a left main coronary artery stenosis: first, anticoagulation was provided with
GP IIb/IIIa platelet receptor antagonist, heparin, aspirin, and clopidogrel. Then while the guidewire crossed the left main plaque and was positioned in the
distal circumflex artery, very aggressive thrombus formation occurred from the left main coronary artery involving the entire circumflex artery, resulting in
severe spasm and slow flow. The patient experienced increased chest pain accompanied by profound ischemia and hypotension, necessitating immediate
thrombus dissolution with excimer laser catheter (Spectranetics, Colorado Springs, CO, USA). (C) Angiogram after laser thrombolysis and concomitant
plaque debulking demonstrates flow restoration, with reversal of the angry clot accumulation and mild residual clot remaining in the proximal segment of
the vessel. (D) Final angiographic results after stenting of the left main and the ostium of the circumflex artery. The patient made clinical recovery. From
Topaz O. The thrombus containing lesion. In: Topol EJ, Teirstein P, editors. Text book of interventional cardiology, 7th ed. Philadelphia: Elsevier; 2015.
pp. e, with permission.
multisegment thrombotic vessel occlusion. Interestingly, the location of the thrombus is taken into consideration by this
classification; for example, 2 points are subtracted from the idyllic score of 10 if the thrombus is found in each of the
supraclinoid internal carotid arteries or the proximal or distal part of the middle cerebral artery trunk. With the identification of thrombus, 1 point is subtracted from the top score of 10 if a thrombus is located in the infraclinoid internal carotid
artery, the anterior cerebral artery, or each affected middle cerebral segment M2 branch. Another angiographic thrombus
classification utilized for patients with acute ischemic stroke is based on a method by Qureshi et al. [50]. It creates a 5-point
scale, essentially constituting a modificati on of one of the earliest TIMI scales in use [51]. In another development, Barreto
and colleagues developed modified criteria for a simpler thrombus scaling system aiming to improve certain limitations of
the traditional scoring method [52]. According to their angiographic and clinical experience, an inherent difficulty in
distinguishing between two of the grades representing low thrombus burden, i.e., grade 2 versus grade 3, requires
introduction of a bilevel scoring system. It consists of a low grade spanning TIMI 0 to 3 (thus varying from no thrombus
present to a moderate-size clot of <2 vessel diameters) and a higher grade, which corresponds to a TIMI grade 4 clot (a
large thrombus of >2 vessel diameters). This classification system identifies the grade 4 thrombus as an independent risk
factor contributing to poor outcome.
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THROMBUS GRADING IN PERIPHERAL ARTERIAL DISEASE
In most instances of revascularization for peripheral arterial diseases the focus is on the morphologic features, the location,
and the degree of accompanyin g impaired flow [53]. Apparently the need to stratify an underlying thrombotic load in this
vascular bed is less evident compared with the coronary circulation. A case in point is the lack of an estab lished thrombus
grading scale for assessment of internal carotid artery disease. In part this can be explained based on the fact that an
intraluminal thrombus adjunct to an internal carotid plaque is a rare finding on traditional diagnostic imaging. Nevertheless,
when a specific need arises to accurately characterize a carotid artery thrombus, CT angiography is the tool of choice [54].
SUMMARY
Plaque disruption and subsequent thrombosis are critical, involving acute coronary and peripheral ischemic syndromes.
Intravascular thrombus adhering to an underlying atherosclerotic plaque can severely impair coronary and peripheral
arterial flow dynamics. Thrombus is a formidable obstacle for percutaneous revascularization and its constituents serve as
important determinants of procedure success and prognosis. The most complex and dangerous vascular thrombotic
accumulation is termed the angry thrombus phenomenon. The thrombus serves as a recognized risk factor for short- and
long-term adverse cardiovascular events, distal embolization, and stent thrombosis. Paramount to the management of
cardiac and other vascular thrombotic syndromes is the use of contemporary thrombus classifications. Several classifications are available; the most widely applied is the TIMI thrombus grading method. It is an angiographic visual score
consisting of five distinctive thrombus grades whereby grade 0 contains no thrombus, while grade 5 defines a heavy
thrombus burden that totally occludes antegrade coronary flow. This specific grade undergoes further restratification and
characterization of its three distinctive types. Other thrombus classifications are described in this chapter as well. The
utilization of thrombus classifications can lead to safer decision-making concerning optimal treatment modalities, yield
desirable revascularization outcomes, and reduce risks and complications. Specific recognition should be given to identification and classification of postintervention residual thrombus, as it adversely affects procedure outcomes. Altogether,
from a practical patient management perspective, angiographic diagnostic procedures and percutaneous interventions for
acute coronary and peripheral ischemic syndromes should record and classify any thrombus load within the target lesions
and vessels.
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Chapter 13
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Impact of Thrombus Burden on
Myocardial Damage in the Setting of
Primary Percutaneous Coronary
Intervention
Massimo Napodano and Antonio Landi
University of Padua Medical School, Padova, Italy
THE ROLE OF THROMBUS IN THE PATHOPHYSIOLOGY OF ST-SEGMENT ELEVATION
MYOCARDIAL INFARCTION
Primary pe rcutaneous coronary intervention (PPCI) represents the pivotal treatment for ST-segment elevation myocardial
infarction (STEMI) [1], which is still the leading cause of death worldwide [2]. Coronary thrombosis represents the
pathophysiological basis of STEMI in patients and it is the result of a complex cellular and molecular cascade [3], which
brings partial or complete occlusion to a coronary artery.
The importance of coronary thrombosis in myocardial infarction was originally revealed between 1910 and 1940. Later
on, it became the subject of innumerable controversies in the cardiology community regarding its role as a result rather than
a cause of acute myocardial infarction. A direct relationship between coronary thrombus formation and the onset of acute
transmural ischemia was then well established by many elegant postmortem studies [4e6], which definitely clarified its
pivotal role. The evidence derived from autopsy has constituted a milestone in understanding the pathophysiological
mechanisms of STEMI; however, these studies presented a selection bias linked to postmortem a nalysis. Since 2008, the
development of thrombus aspiration systems has therefore allowed us to analyze in vivo the histopathological features of
thrombus, its dynamic composition, and its architecture.
Coronary thrombus can be classified according to microscopic characteristics, age, and size. It consists of platelets,
fibrin, erythrocytes, cholesterol crystals, and leukocytes (including monocytes, neutrophils, T cells, and B cells) in variable
amounts [7]. According to the microscopic characteristics, thrombi can be classified as white, red, or mixed. “White”
thrombus is platelet rich, often sessile, and nonocclusive. It is more frequent in non-STEMI patients [8] and particularly in
the early hours of STEMI [9]. “Red” thrombus is fibrin and erythrocytes rich, often occlusive, and more frequent in patients
with STEMI. This different composition seems to reflect two distinct thrombosis trigger mechanisms in acute coronary
syndromes: plaque rupture and superficial erosion [10,11]. Rupture of a thin fibrous cap overlying a lipid-rich atherosclerotic plaque is the most common mechanism in the setting of STEMI. The contact of blood with tissue factor, released
by macrophages, induces blood coagulation activation, platelet aggregation, and the formation of a red thrombus, a tangled
network of erythrocytes, inflammatory cells, and fibrin. Superficial erosion [12] represents a less common trigger of
coronary thrombosis and is characterized by a thick and intact fibrous cap with few inflammatory cells and abundant
extracellular matrix (collagen, proteoglycan, glycosaminoglycan). The contact of blood with collagen induces platelet
activation, the release of preformed mediators, proinflammatory cytokines (CD40 ligand), and ADP, which amplify platelet
aggregation. The result of this complex molecular and cellular cascade is the formation of a white, platelet-rich thrombus,
in contrast with the red, fibrin-rich thrombus more often associated with plaque rupture. In 2015, an in vivo
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00013-2
Copyright © 2018 Elsevier Inc. All rights reserved.
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pathophysiological study evaluating plaque morphology and features in STEMI, by means of optical coherence tomography (OCT), showed that superficial erosion counted as a substrate of STEMI in one-third of patients; compared with
plaque rupture, intact fibrous plaque was associated with higher rates of patent infarct-related artery (IRA), fewer lipid-rich
areas, and residual endoluminal thrombus [11].
Thrombus formation is a fast-evolving process regulated by flow, blood cells, and plasma proteins, and its composition changes along with ischemic time. Silvain et al. [7] assessed the impact of ischemic time on thrombus composition,
finding a positive correlation with fibrin content and a negative correlation with platelet content. In other words, “fresh”
thrombi have the highest proportion of platelets (21% at <3 h), whereas the content of fibrin increases with ischemic time
(ranging from 48% at < 3 h to 67% at >6 h), leading to an “old” thrombus. Ischemic time strongly predicted thrombus
composition, with a twofold increase in fibrin content per ischemic hour. These findings were later supported by another
study by Ramaiola et al. [13]. They also found a higher presence of infiltrating leukocytes and undifferentiated progenitor
cells and, more interestingly, a decrease in Profilin-1 (an actin-binding protein released by fully activated platelets) in the
coronary thrombi of STEMI patients with longer pain-to-percutaneous coronary intervention (PCI) time. These results are
in line with those reported by Rittersma et al. [14], who showed that in at least 50% of 199 STEMI patients the coronary
thrombus was days or weeks old (with lytic or organized changes). This discrepancy between coronary occlusion and the
onset of clinical symptoms highlights how plaque instability and thrombus formation can remain clinically silent for days
or weeks, providing, moreover, relevant prognostic implications. Indeed, even if a sharp correlation between ischemic
time and distal embolization (DE) has been never confirmed [15], the latter occurs more frequently in patients with older
thrombus [16]. Probably, patients with older thrombus may present with recurrent episodes of temporary occlusive
thrombosis and spontaneous lysis. As a result, recurrent thrombosis induces more extensive embolization of debris and
amplifies microvascular damage, worsening clinical outcomes. Moreover, erythrocyte-rich components in aspirated
coronary thrombi are independently associated with an giographically visible distal embolization (AVDE) during PPCI
[17]. Thus, the link between ischemic time and AVDE is strictly influenced by thrombus burden and composition and by
the complex interplay between thrombosis and spontaneous lysis: as ischemic time is prolonged, erythrocyte-rich
components as well as thrombus burden may increase and AVDE may occur. However, because coronary thrombosis
is characterized by a heterogeneous architecture and fast-evolving composition, ischemic time cannot represent by itself a
marker of DE hazard.
THROMBUS RECOGNITION AND CLASSIFICATIONS
Coronary angiography represents the gold standard imaging modality in interventional cardiology and is widely used to
guide interventions. However, angiography has shown poor sensitivity in thrombus detection. Nonetheless, its recognition
and grading are significant not only for a correct pati ent evaluation, but also for its therapeutic and prognostic implications.
The earliest data from DeWood and coworkers [18] in 1980 assessed that angiography during acute myocardial infarction
could not recognize the presence of thrombus in 25% of patients, in whom thrombus was detected at surgery. In the
contemporary major trials on thrombus aspiration, thrombus was not detectable by angiography in about 10% of STEMI
cases, a rate that increases to nearly 20% considering patients with “possible thrombus.” The most widely used angiographic classification of thrombus in coronary lesions was originally introduced by the TIMI (Thrombolysis in Myocardial
Infarction) study group investigators [19]: the TIMI thrombus score (TTS). The TIMI classification relies on the angiographic assessment of the presence and size of intracoronary thrombus, using a simple score ranging from grade 0 (G0, no
thrombus) to grade 5 (G5, very large thrombus content, which completely occludes vessel flow), as shown in Fig. 13.1A.
Nevertheless, the accuracy of the highest level (G5) is subject to interpretation challenges: because of total occlusion of the
vessel, the relation between the underlying plaque burden and the thrombus content is unknown, yet this grade supposedly
represents the highest thrombus load. To overcome this drawback, an important modification was introduced by Sianos and
coworkers [20], who provided a reclassification of TTS after antegrade flow restoration by either guidewire positioning or
undersized (2 mm) balloon predilation, to make it more reliable in the case of occluded vessels. This intervention, reestablishing a certain degree of coronary flow, may be really helpful for restratification into either small thrombus burden
(G1eG3) or large thrombus burden (LTB) (G4, Fig. 13.1B). The prognostic relevance of the Sianos classification was
proven in a large study [20] , in which LTB independently predicted major adverse events and stent thrombosis in patients
treated with drug-eluted stents. TTS and its reclassification represent a unique angiographic tool to weigh thrombus amount
in coronary lesions. However, in the presence of a thrombotic occlusion, the recognition of other angiographic features,
such as occlusion pattern, reference vessel diameter (RVD) of the IRA, and lesion length, may play a crucial role in
understanding the thrombus amount [21]. Occlusion of the IRA may be differentiated on the basis of three patterns,
according to the modified Yip classification [15,22]: “cutoff pattern” in the case of abrupt artery occlusion, “tapered
Impact of Thrombus Burden on Myocardial Damage in the Setting of PPCI Chapter | 13 191
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FIGURE 13.1 Angiographic thrombus grading scale (by TIMI study group investigators) and reclassification (by Sianos and coworkers). (A)
Intracoronary thrombus is angiographically identified and scored in five grades according to the TTS [19]. (B) In patients with occluded IRA at baseline
angiography, TTS is reassessed after guidewire crossing or a small deflated balloon (diameter 1.5 mm) passage or dilation: if antegrade flow is restored,
G5 is reclassified as G1 to G4 according to thrombus burden [20]. This reclassification is able to stratify patients into two main groups: small thrombus
burden (G1eG3) and large thrombus burden (G4). IRA, infarct-related artery; TIMI, thrombolysis in myocardial infarction; TTS, TIMI thrombus score.
occlusion” when there is a progressive narrowing of the vessel before occlusion, and “persistent dye,” characterized by
contrast impregnation proximal and/or distal to the lesion.
Recently, OCT has provided a high-resolution tool to analyze atherosclerotic plaque and lumen filling defects. Its
usefulness in assessing thrombus presence and extent has been evaluated in STEMI patients to overcome angiography
limitations (Fig. 13.2): intracoronary thrombus is observ ed in almost all cases [23], allowing also the identification of
plaque rupture, fibrous cap erosions, and thin cap fibroatheroma. Using OCT, several thrombus scores (TSs) have been
proposed to better evaluate thrombus amount and to provide reliable and universal assessment of thrombotic lesions
(Fig. 13.3). For instance, in the COCTAIL trial [24], Prati et al. measured a score for each cross section according to the
number of thrombus-involved quadrants (absent ¼ 0, a quadrant ¼ 1, etc.). The sum of each cross section score represents
the TS. Another useful score has been elaborated by Magro et al. [25] for the evaluation of in-stent residual thrombus after
PPCI. In-stent thrombus area (TA) is calculated by subtracting the lumen area (LA) from the stent area (SA), adding in
cases the free thrombus area (FTA) and incomplete strut apposition (ISA):
TA ¼ SA LA þ FTA þ ISA
Thrombus volume (TV) is defined as the mean TA at each interval, normalized by the length of the stent. Thrombus
burden is the ratio between the TV and the stent volume (TV/SV). An LTB (above the median) is associated with an
increased rate of no reflow and DE compared with patients with low thrombus burden. However, despite the high
sensitivity of OCT in identifying thrombus presence and amount in STEMI lesions, as well as residual thrombus after
coronary stenting during PPCI, it represents a time and contrast-consuming procedure and its application is currently
limited by availability and costs.
RELATIONSHIP BETWEEN THROMBUS BURDEN AND DISTAL EMBOLIZATION
DE of thrombus and plaque debris has been identified as one of the major drawbacks of PPCI in STEMI, limiting the
effectiveness of myocardial reperfusion and leading to larger myocardial damage and worse prognosis [26,27]. AVDE has
been reported in about 6%e15% of STEMI undergoing PPCI. However, as recognized by high-intensity signals using
intracoronary Doppler wire [28], embolization of microscopic debris (50 mm) occurs in almost all patients undergoing
PPCI, but coronary flow is reduced only when the total number of high-intensity signals is great. The clinical relevance of
this phenomenon remains poorly understood, because only a minority of these patients showed worse clinical outcomes
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