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4 Cardiovascular Thrombus
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(A)
(D)
LM
LAD
LCX
B
RI
C
D, E
(B)
(E)
(C)
(F)
NC
Thr
Thr
CD68
Movat
FIGURE 1.3 Ruptured plaque associated with nonocclusive luminal thrombus. A 45-year-old man with a history of hypertension, diabetes mellitus,
and hyperlipidemia died suddenly after jogging during his lunch break. (A) A postmortem angiography showed mild luminal narrowing with haziness at
proximal RI. (BeD) Serial OCT images revealed the presence of plaque rupture (in C, D) with nonocclusive luminal thrombus (white arrowhead in D)
and an adjacent distinct superficial signal-rich region (thin white arrows in B) with rapid attenuation (white arrowheads in B), indicating thin-cap
fibroatheroma. Disrupted fibrous cap also shows distinct superficial signal-rich region (thin white arrows in C and D). (E) Histology confirmed the
presence of plaque rupture with an acute fibrin-rich thrombus (shown as Thr) overlying the NC (section stained with Movat pentachrome). (F) Immunostaining for CD68-positive macrophages demonstrated substantial infiltration of foamy macrophages within the disrupted fibrous cap (thin black ar-
rows). LAD, left anterior descending artery; LCX, left circumflex artery; LM, left main coronary artery; NC, necrotic core; OCT, optical coherence
tomography; RI, ramus intermedius. Reprinted from Otsuka F, et al. Clinical classification of plaque morphology in coronary disease. Nat Rev Cardiol
2014;11:379e89 with permission from Elsevier.
plaque burden. Lesions from type 2 diabetic subjects have larger mean necrotic cores (P < .01), and macrophages, T cells,
and HLA-DR are significantly greater in diabetic subjects (P ¼ .03, P ¼ .0 03, and P < .0001, respectively) compared with
nondiabetics [19].
Several OCT studies have demonstrated that plaque rupture is the most frequent cause of acute coronary syndromes
[20,21]. These studies reported the mean thickness of the fibrous cap as 54 mm (interquartile range 50e60 mm); in 67% the
thickness was <70 mm, and 95% had a cap thickness <80 mm. These clinical data are consistent with our histological
autopsy data, considering tissue shrinkage is a well-known phenomenon of fixation and dehydration during preparation of
paraffin sectioning and staining. Moreover, there are important differences between OCT and histology in terms of
definition of plaque rupture, specifically the presence of intraplaque cavity. The OCT definition of plaque rupture includes
presence of a disrupted thin fibrous cap but also intraplaque cavity; the latter is likely an artifact of aspiration thrombectomy along with contrast flushing. Histopathology studies have never reported intraplaque cavity in autopsy studies in
patients who had never undergone any intervention. In addition, it is possible that intraplaque cavities may also be
associated with distal embolization into intramyocardial coronary arteries.
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NECROTIC CORE EXPANSION (PLAQUE FISSURE AND INTRAPLAQUE HEMORRHAGE)
Two factors contribute to the sudden increase in lesion enlargement prior to plaque rupture. These include plaque hemorrhage with or without plaque fissure and silent, asymptomatic plaque ruptures. In the 1960s, Constantinides and colleagues put forth the concept of cracks or fissures communicating with the luminal as one of the pathways by which blood
could enter lesions (Fig. 1.4A) [22]. In the 1980s, Michael Davies expanded this concept and described this lesion as
plaque fissures, which were observed in 63% of patients dying of coronary thrombosis. The fissure occurred at the junction
of the plaque cap with the more normal intima, communicating with the underlying necrotic core that occupied <15% of
the vessel circumference [23,24]. Davis highlighted that fissures should be distinguished from plaque ruptures. Plaque
ruptures are usually surrounded by an obvious luminal thrombus. On the other hand, fissures are most likely to involve an
intraintimal thrombus composed of fibrin and platelets with interspersed erythrocytes. In addition, even if thrombi exist,
luminal thrombi related to fissures are most commonly very small. In fact, plaque fissure is characterized as a tear in an
eccentric plaque with underlying small necrotic core, and the fibrous cap is not thin. The path of the fissure is generally
derived from the necrotic core reaching the lumen, lined by a few macrophages, and red blood cells a nd fibrin are observed
in the tract and within the necrotic core. In our hands the incidence is <10%.
Furthermore, intraplaque vasa vasorum in our experience is the dominant cause of intr apla qu e hemorrhag e
(Fig. 1.4). In 1938 Wartman suggested that intraplaque hemorrha g e is a major contributor to the progressi on of c oron ar y
lesions. These studies involved injection of silicon polymer into atherosclerotic human coronary arteries, which
demonstrated an elaborate microvascular network (the vasa vasorum) extending from the adventitia through the media
into the thick ene d intima, whereas nonatherosclerotic vessels rarely had vasa vasorum. We believe intraplaque hemorrhage ar ise s from disruption of thin-walled microvessels that are lined by a discontinuous endothelium without
supporting pericytes [25]. Moreover, we and others have suggested that intraplaque hemorrhage and rupture of the
fibrous cap are associated with an increased density of microvessels [12,26,27]. Intraplaque vasa vasorum reaches the
intima most frequently from the adventitia. Kumamoto et al. have shown that intraplaque hemorrhage is 28 times more
likely to o riginate from the adventitia compared with the lumen [28]. In addition, highly calcified and fibrotic arteries
(stable plaque) generally had low vascular density, and luminal stenosis and inflammation. We r ep orte d that hemorrhage
into a p reexisting necrotic core plays an important role in its expansion [29]. The free cholesterol in the necrotic core
(A) (B)
Plaque fissure
FIGURE 1.4 Plaque morphologies that can lead to necrotic core expansion. Histological and schematic images are shown for (A) plaque fissure and
(B) intraplaque hemorrhage. Arrowheads indicate neoangiogenesis. Reprinted from Yahagi K, et al. Nat Rev Cardiol 2015;13:79e98 with permission
from Elsevier.
Intraplaque
hemorrhage
Macrophage foam cells
Cholesterol clefts
Necrotic core
Calcified plaque
Collagen
Hemorrhage
Thrombus
Healed thrombus
Angiogenesis
Fibrin
6 Cardiovascular Thrombus
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may arise from the red cell membranes, which are the richer in free cholest erol than any other cell membrane in the
body. Furthermore, i n our previous study we showed that intraplaque hemorrhage is probably derived from the leaky
vasa vasorum [29,30]. The intraplaque vasa vasorum lacks competent endothelial junctions and is usually not supported
by pericytes, which is not true of the adventitial vasa vasorum. The endothelium of neoangiogenic vessels also showed
intracytoplasmic vacuoles, membrane blebs, and basement membrane detachments [25,31]. Inadequate endothelial
junctions promote red cell leakage and are associated with indicators of inflammation, such as macrophages and T
lymphocytes [31,32].
Erosion
Erosions are the second most prevalent cause of coronary thrombosis (Fig. 1.1B and C). Erosion lesions have a luminal
thrombus and the underlying plaque, which shows a lack of endothelium but is rich in smooth muscle cells and proteoglycans with very few macrophages and T cells [5]. The lesions underlying plaque erosion are mostly characterized as
early lesions with rare calcification compared with the advanced lesions of plaque ruptures. The type of plaque located
underneath erosions consists of pathological intimal thickening (16%) without necrotic core and hemorrhage, early
fibroatheroma (34%), and a late fibroatheroma (50%) [33]. In addition, the underlying media is intact, with well-defined
internal and external elastic lamina (IEL and EEL) observed in 32% of cases; focally disrupted IEL (from inflammation and
angiogenesis) is seen in 52%, and cases in which both IEL and EEL are disrupted are uncom mon (16%). The medial
smooth muscle cells behave more like a normal vessel (mildly stenotic), with highest expression of smooth muscle a-actin,
followed by smooth muscle myosin heavy chain and smoothelin, thus supporting the concept that erosions may be a result
of vasospasm. The types of proteoglycan underneath the erosions are mostly composed of versican and hyaluronan,
whereas PRs show a minimum of proteoglycan and hyaluronan, but are rich in type I collagen. At the interphase of
thrombus and underlying plaque in erosions there is a high expression of CD44, which promotes thrombosis [34].
Calcification is not observed in more than half of erosions (56%), microcalcification is detected in 40% of erosions, and
fragmented calci fication and sheets of calcification are in less than 2% [33]. Erosion is generally associated with negative
remodeling, whereas plaque rupture is associated with positive remodeling [35]. Usually erosions are observed at a single
site (96%), and only rarely are observed at multiple sites (4%). Most erosions are eccentric (82%), whereas ruptures are
equally eccentric and concentric (54% and 46%, respectively) [36]. At the time of presentation, the thrombus has been
shown more frequently to be older, showing signs of early healing, i.e., nuclear breakdown of leukocytes, and/or
proliferation of smooth muscle and endothelial cells especially in 88% of plaque erosions, compared with 54% of PRs
(P < .0001). Plaque erosions frequently show more distal emboli than plaque ruptures (71% vs. 42%, respectively) [15].
The lesions of erosi ons are less stenotic (70 11%, in cross section) compared with those of ruptures (78 12%, in cross
section P < .03).
The tissue at the interface of thrombus involves activated smooth muscle cells, which are present in a proteoglycanrich matrix composed mainly of hyaluronan, versican, and collagen type III. By contrast, the fibr ous cap of plaque
ruptures consists of primarily collagen type I, biglycan, and decorin [36,37]. Usually, erosions show minimal inflammation with a few or absent macrophages and T lymphocytes and the plaque is not disrupted [37]. A previous study
reported that 68% of erosions showed absent or minimal inflammation within the transition zone between thrombus and
underlying plaque and the remaining 32% had mild inflammation. In addition, 34% of erosions show no or minimal
inflammation in the advent itial/medial border, whereas inflammation is mild in 50% and rarely moderate or severe, in
18% of cases (14% and 4%, respectively) [38]. Morphological features of the underlying lesions of erosions are poorly
understood. In addition, plaque erosions were more commonly seen in women, with over 80% of coronary thrombi seen
at autopsy in women <50 years of age being plaque erosions, whereas the frequency of erosion in older women
(>
50 years) is rare. Patients with acute coronary syndromes undergoing OCT who have evidence of erosion are also
younger than those identified as having plaque rupture or calcified nodule (53.8 13.1 years vs. 60.6 11.5 and
65.1 5.0 years, respectively; P < .01). Furthermore, only 40% of plaque erosions showed severe narrowing (>75%
cross-sectional area narrowing), whereas 48% had 51%e75% narrowing, while the remaining 12% had <50% narrowing [36,38].
It was not possible to diagnose plaque erosion in patients presenting with acute coronary syndrome in the catheterization lab until the introduction of OCT in clinical practice. As the use of OCT has been expanded, it has become
possible to observe the underlying plaques with ruptured fibrou s ca ps or intact fibr ous ca p s lea di ng t o coro na r y
thrombotic events [39].Definite OCT plaque erosion was defined as the presence of no disruption of underlying plaque
with an acute luminal thrombus [7]. Also, the diagnosis of probable OCT erosion requires a luminal irregular surface or
attenuation of underlying plaque b y thrombus with no superficial lipid or calcification at the proximal or distal sections
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(A)
(C)
(D)
RCA
LAD
Diagonal
LCX
Th
Th
(B)
NC
MФ
MФ
L
OFDI
Th
*
OFDI
*
H&E
FIGURE 1.5 Multiple plaque erosions in three major coronary arteries. (A) Postmortem radiography showed mild focal calcification in all major
coronary arteries. (B) Histologic examination showed the left circumflex artery (LCX) with a nonocclusive platelet-rich organizing thrombus (Th) with
underlying late fibroatheroma. (C) The right coronary artery (RCA) showed a luminal fibrin-rich organizing thrombus with an underlying late fibroatheroma. (D) The diagonal branch artery also showed a luminal fibrin-rich organizing thrombus with an underlying pathological intimal thickening. Highpower images from boxes in (C) and (D) are shown. Fibrin-rich thrombi with a few inflammatory cells are seen on the luminal surface. Corresponding
macrophage (MF) stain and optical frequency domain imaging (OFDI) images (Terumo, Tokyo, Japan) are depicted. Moderate macrophage infiltration is
seen around the circumference of the vessel (red arrowheads); however, the culprit site (white arrows) is devoid of macrophages in the RCA. Note the
absence of macrophages in the diagonal branch (macrophage-stained section of D). OFDI showed luminal surface irregularity with minimal attenuation
because the thrombus had focal areas of platelets interspersed with large areas of fibrin in the RCA and the diagonal branch (white arrows), and a bright
layer with attenuation (red arrowheads) indicates presence of macrophages in the RCA (C). (Bottom) Serial sections at high power stained by hematoxylin
and eosin (H&E), platelet (PLT; CD61), fibrin (fibrin II), and macrophage (CD68) from the box in (D) are shown. Platelet stains (brown) show few
superficial and interspersed platelets with a predominance of fibrin (brown, adjacent section) and rare macrophage infiltration (brown). *Placement of the
guidewire. L, lumen; LAD, left anterior descending; NC, necrotic core. Reprinted from Yahagi K, et al. JACC Cardiovasc Imag 2014;7:1172e4 with
permission from Elsevier.
PLT
Fibrin
MФ
of culprit lesions. Previous OCT studies showed a 31% prevalence of plaque erosions in patients presenting with acute
coronary syndromes. However, an OCT-defined di stinc tio n b et ween erosion, plaque rupture, and calc ified nodule can be
difficult to make. Although OCT has good axial resolution, it cannot clearly identify differentiated cell types. In addition,
the presence of luminal thrombus attenuates the depth of light penetration of OCT in the presence of blood i n the lumen
(Fig. 1.5).
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Calcified Nodule
Calcified nodule is the least frequent cause of coronary thrombosis [9]. Calcified nodule is characterized as a luminal
surface disrupted by nodules of dense calcium with overlying thrombus and little or no underlying necrotic core in arteries
that are highly calcified and tortuous and often have large sheets of calcification (Fig. 1.1D). In 236 autopsy cases, the
prevalence of calcified nodule was only 5% [6]. Although the mechanism of calcified nodules remains unknown, it is
believed that fragmentation of calcified plates is the underlying mechanism. Fragments of calcified plates lead to small
nodules of calcification, which disrupt the overlying fibrous cap and endothelial lining, attracting platelets and fibrin that
lead to a luminal thrombus. Intraplaque fibrin is often observed in nodular calcification, possibly resulting from discontinuity of surrounding capillaries. Most eruptive calcified nodules are eccentric lesions where calcified nodules protrude
into the overlying lumen with endothelial disruption that initiates platelet adherence. The location of calcified nodules is
most frequently in the mid-right coronary artery or left anterior descending artery at sites of maximal tors ion [9].In
addition, calcified nodules are most frequent in older individuals with renal failure, diabetes, and coronary tortuosity. It is
important to recognize the difference between “eruptive calcified nodule” and “nodular calcification”; the latter occurs
within the plaque and does involve the fibrous cap or the lumen but is often associated with medial wall disruption with or
without extension into the adventitia.
In OCT studies, calcified nodular tissue has been de fined as an accumulation of nodular calcification (small calcium
deposits) with disruption of the fibrous cap on the calci fied plate and an overlying white thrombus. Calcium was defined as
a signal-poor or heterogeneous region with a sharply delineated border [40] (Fig. 1.6). A study by Lee et al. reported an
incidence of 4.2% in patients presenting with acute coronary syndrome (ACS) (48%) and stable angina (52%) with a high
incidence of diabetes (34%) and renal insufficiency (28%) [41]. Further studies are needed to validate the utility of OCT in
the identification of calcified nodules.
Healed Plaque Rupture
Healed plaque ruptures (HPRs) are healed lesions of a disrupted fibrous cap with an overlying organized thrombus, which
was nonocclusive, that shows the presence of type III collagen in a proteoglycan-rich matrix and an underlying disrupted
thin cap that is made up of type I collagen (Fig. 1.7) [11]. In the early 1990s, Mann and Davies described the concept of
HPRs that were responsible for the progression of luminal narrowing through episodic rupture with healing in individuals
who had died from acute coronary syndromes (Fig. 1.7A and B) [42]. Of the 130 subjects who died suddenly of ischemic
heart disease, 314 episodes of coronary thrombosis were found: an average of 2.4 per patient [42]. Silent luminal thrombi
are most likely to be nonocclusive thrombi that can result from silent plaque ruptures or erosions. However, if they become
occlusive and heal, that constitutes a chronic total occlusion (Fig. 1.7C). Generally, the provisional matrix at healed lesions
is an organized thrombus that may or may not show the presence of fibrin, but is infiltrated by smooth muscle cells,
granulation tissue with proteoglycans, and type III collagen. The propagated thrombus away from the ruptured site, i.e.,
proximal and distal to the plaque rupture, is replaced by a fibrous plaque (Fig. 1.8).
As the process of healing advances, type III collagen is gradually replaced primarily by type I collagen with complete
endothelialization of the lumen. Healed ruptures may occur from a single rupture at one site or may evolve from multiple
ruptures that show layers of necrotic core surrounded by fibrous tissue where the deepest rupture site represents the oldest
rupture site [11]. We have shown that the percentage stenosis increases as the number of healed rupture sites increases [11].
Mann and Davies have shown that lesions with <20% diameter stenosis have the smallest percentage of HPRs, 16%; those
with 21%e50% narrowing had an intermediate percentage of HPRs, 19%, whereas those with >51% diameter stenosis had
the highest percentage of HPRs, 73%. In our sudden coronary death autopsy studies, HPRs were observed in 61% of cases.
However, it is difficult to identify sites of healed erosions. Findings of multilayered appearance of dense collagen with
alternating layers of smooth muscle cells and proteoglycans may represent healed plaque erosions.
Currently, in the general population, the prevalence of silent ruptures remains unknown. Culprit lesions of stable
plaques had the highest prevalence (80%), the second was acute rupture (75%), and the third was plaque erosion (9%) [43].
Multiple HPRs with layering were most commonly located in the proximal coronary arteries. In addition, the underlying
percentage of luminal narrowing in acute ruptures was significantly higher than that in HPRs (79 15% vs. 66 14%;
Histopathology of Cardiovascular Thrombus Chapter | 1 9
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(A) (B)
(D)
(C)
(E)
(F) (G) (H) (I)
(M)(L)(K)(J)
FIGURE 1.6 Calcified nodule. A 57-year-old man underwent percutaneous coronary intervention in the left anterior descending artery for stable angina.
The left circumflex artery was evaluated for the presence of significant lesions by OCT, and subsequent 3D reconstruction of OCT images was performed.
(A) Coronary angiography of the left circumflex artery. Black lines indicate the studied segment. (BeE) Upstream fly-through views (distal to proximal) of
3D reconstructions of OCT images indicating the sites corresponding to (F)e(M). (FeM) OCT images showing presence of red thrombus (arrows in F, H,
I, K, and M) in areas of fibrocalcific plaque (asterisks in F, G, I, J, and L) in the absence of plaque rupture. Sharp protrusions of calcium into the lumen are
seen in (G), (J), and (L) (asterisks) with very thin, or absent, overlying intimal layer. OCT, optical coherence tomography; P, posterior; A, Anterior; R,
Right; L, Left; F, Forward. Reproduced with permission from Karanasos A, Ligthart JM, Witberg KT, Regar E. Calcified nodules: an underrated
mechanism of coronary thrombosis? JACC Cardiovasc Imag 2012;5(10):1071e2.
P ¼ .0001), which is suggestive of the culmination of multiple previous silent events in sudden coronary death with
thrombosis. Also, sites of virgin acute plaque ruptures had less stenosis, 70%, and were observed in 25% of cases dying
with acute plaque rupture.
With OCT imaging, healed ruptures can be identified by the presence of a multilayered appearance with different
optical densities of the necrotic core and healed rupture sites vs. fibrous cap (Fig. 1.9). However, as the process of healing
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(A) (C)(B)
Single-layer
Multiple-layers
Cholesterol clefts
Necrotic core
Calcified plaque
Collagen
Hemorrhage
NC
NC
NC
FIGURE 1.7 Episodic rupture and healing can lead to chronic total occlusion. Histological and schematic images are shown for (A) single-layer healed
plaque rupture, (B) multiple-layer healed plaque rupture, and (C) chronic total occlusion. Arrowheads indicate neoangiogenesis. NC, necrotic core.
Histological image in (A) reprinted Otsuka, F. et al. Clinical classification of plaque morphology in coronary disease. Nat Rev Cardiol
2014;11(7):379e89 © with permission from Nature Publishing Group. Histological image in (C) reprinted from Yahagi K, et al. Sex differences in
coronary artery disease: pathological observations. Atherosclerosis 2015;239(1):260e7 © with permission from Elsevier.
Healed thrombus
Angiogenesis
Fibrous plaque
FIGURE 1.8 Nonocclusive propagated thrombi that heal can contribute to the formation of fibrous plaques. Histological and schematic images are
shown for a fibrous plaque. Reprinted from Yahagi K, et al. Nat Rev Cardiol 2015;13:79e98 with permission from Elsevier.
continues, the type III collagen is replaced by type I collagen; therefore it is probably more difficult to differentiate by OCT
between fibroatheromas and HPRs. In acute plaque rupture and early HPR the lesion sites are positively remodeling with or
without severe stenosis; however, as healing progresses, the lesions begin to shrink from cross-linking of type I collagen
and therefore HPR may eventually show negative remodeling.
Collagen
Hemorrhage
Thrombus
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(A)
(C)
(B)
Movat
(D)
NC
(E)
NC
FIGURE 1.9 Healed plaque rupture. (A) An ex vivo OCT image shows a layered pattern of the signals and underlying signal-poor region with diffuse
border (white arrowheads) and focal signal-rich confluent punctate area with rapid attenuation (white arrows). (B) A corresponding histological section of
the human coronary plaque (stained with Movat pentachrome) shows healed plaque rupture and underlying NC with extensive hemorrhage and the
presence of foamy macrophages close to the luminal surface (black arrows). (C) The layered pattern of the OCT signals is highlighted in a high-power
image (white double arrows). (D) A high-power histological section (stained with Movat pentachrome) shows numerous smooth muscle cells within the
newly formed proteoglycan-rich neointima (black double arrows close to the luminal surface), with clear demarcation from the underlying old collagenrich fibrous cap. (E) In a high-power image of a Sirius red-stained section (taken with polarized light) that corresponds to the image in D, dense (type I)
collagen forms a fibrous cap, seen as a reddish-yellow region, and is overlaid with newer (type III) collagen, detected as a greenish area. NC, necrotic core;
OCT, optical coherence tomography. Reprinted from Otsuka F, et al. Clinical classification of plaque morphology in coronary disease. Nat Rev Cardiol
2014;11:379e89 with permission from Elsevier.
NC
CONCLUSION
Luminal thrombus in coronary arteries is platelet rich and grossly appears as a white thrombus, whereas a red thrombus that
is rich in red cells separated by lines of Zahn is a propagated thrombus and is located at the proximal ends of culprit sites.
Coronary artery thrombus can result from three different mechanisms; the most frequent is plaque rupture (65%e70%),
followed by erosion (25%e30%), and calcified nodule is the least frequent (2%e7%). Patients presenting with acute
coronary syndromes with or without ST-segment elevation myocardial infarction at culprit sites have rupture, erosion, or
calcified nodule, whereas those presenting with unstable angina may have all three types of thrombosis but the thrombus is
nonocclusive. Also, such culprit sites may have plaque hemorrhage or plaque fissure. Patients with stable angina have
severe stenosis (>75% cross-sectional area narrowing) and the plaques at these sites are usually heavily calcified, with or
without a necrotic core, but the fibrous cap is thick.
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