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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3720_Библиотеки_им_академика_М_И_Перельмана
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16 Cardiovascular Thrombus
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FIGURE 2.1 Virchow triad. Different etiologies causing arterial or venous thrombosis.
aligned in parallel formations at the site of rupture, indicating a path of travel toward the surface of the plaque [15].
Moreover, optical coheren ce tomography (OCT) used in benchtop studies and during percutaneous coronary intervention
has demonstrated the presence of cholesterol crystals perforating the plaque cap and those that were widely distributed at
the site of plaque rupture, respectively (Fig. 2.5) [16,17]. The arterial wall injury caused by crystals exposes underlying
collagen to the circulating blood and leads to thrombus formation. In fact, finite element analysis was used to confirm that
there was an increase in the plaque wall stress especially when crystals were modeled to be located at the plaque edges,
which are often seen as the site of fibrous cap rupture [18].
Certain triggers have been found to cause cholesterol crystallization [19]. These include an increase in the cholesterol
saturation, a drop in ambient temperature, hydration of the cholesterol molecule to the monohydrate species, and a local
alkaline pH. In fact, a combination of some of these local physiochemical conditions leads to a synergistic effect
(e.g., cholesterol saturation and drop in temperature). Specifically, a drop in temperature even by 1
C is sufficient to trigger
crystallization. This aspect of temperature drop is of particular interest because core temperature is lowest in the early
morning hours and may help explain why most cardiovascular events occur at that time [19e21].
If the cholesterol amount and saturation in the necrot ic core of the plaque are large, then the expansion of the volume
with crystallization of cholesterol will lead to an abrupt tear in the fibrous cap, causing rupture and acute thrombosis.
However, if the cholesterol amount in the necrotic core is small, then when the liquid cholesterol crystallizes it can
perforate the fibrous cap to cause erosion, but not enough to cause a tear. Eventually, this would lead to thrombus
formation in a protracted manner and result in a clinical presentation with atypical symptoms as often seen in women
[11,13] (Fig. 2.6).
TYPES OF THROMBI DURING ACUTE MYOCARDIAL INFARCTION
In general, thrombi are classified as predominantly “white,” platelet rich, or “red,” fibrin rich. White thrombi are typically
transparent, frosty, and glass-like, while red thrombi are shiny and glistening, rich in fibrin and red blood cells (Fig. 2.7).
Platelet-rich thrombi are reported to be more common in AMI [22]. However, angioscopic examination of coronary arteries
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(A)
(B)
FIGURE 2.2 Angioscopy and scanning electron microscopy of red and white thrombi. (A) Angioscopic image of occluded femoral artery in patient
presenting with cold lower extremity. Image demonstrates a glistening fibrin-rich red thrombus on top of a white mass, presumed a white thrombus,
surrounded by yellow plaque. (B) Angioscopic image of recanalized thrombus in artery. Scanning electron micrographs of (C) red thrombus with fibrin
and red blood cells and (D) white thrombus with platelet aggregates. (B) Reproduced with permission from Seeger JM and Abela GS. Angioscopy as an
adjunct to arterial reconstructive surgery: A preliminary report. J Vasc Surg 1986;4:315e20. (C,D) Courtesy of Dr. George Abela.
(C)
(D)
FIGURE 2.3 Activation and inhibition of platelets. Activation of platelets by exposure to collagen (transmission electron micrograph) in an injured
artery via glycoprotein VI and ab1 (GP VI, a2b1). Other receptors on the platelet include the Par-1 and GP IIbeIIIa. Pharmacological agents are designed
to block these receptors. Fibrinogen then attaches to the platelet receptors to form a complex of platelet aggregates and thrombus. SEM, scanning electron
micrograph; TXA2, thromboxane A2; vWf, von Willebrand factor. Modified and reproduced with permission from Phillips DR, Conley PB, Sinha U, Andre
P. Therapeutic approaches in arterial thrombosis. J Thromb Haemost 2005;3:1577e89.
during acute coronary syndrome has demonstrated the presence of both red and white thrombi. Using angioscopy as a
“gold standard,” angiography was able to detect occlusive red thrombi with a specificity and sensitivity of 100%; however,
white thrombi could not be distinguished from plaque in 50% of the cases evaluated [23] (Fig. 2.8). Other evaluations by
angioscopy used staining of thrombi by Evans blue dye. Uchida et al. semiquantitatively characterized thrombi as fibrin
rich (blue surface area) noted in 2/3 of cases, fibrin poor (1/3), or intermediate (between 1/3 and 2/3) of the entire
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(A)
(C)
(D)
(E)
(F)
(B)
(G)
(H)
FIGURE 2.4 Volume expansion of cholesterol during crystallization. (A, B) Ruptured arterial plaques from human carotid arteries (arrows indicate
torn fibrous cap). (C) Cholesterol crystals are seen growing above the edge of the test tube after crystallization. (D, E) Scanning electron micrographs
demonstrate sharp-tipped crystal geometries. (FeH) When a fibrous membrane is placed over the mouth of the test tube, crystals perforate the membrane
(F) as noted by scanning electron microscopy (G, H) (bars, 5 ¼ mm). Reproduced with permission from Abela GS, Vedre A, Janoudi A, Huang R, Durga S,
Tamhane U. Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am J Cardiol 2011;107:1710e17. Abela GS. The role
of cholesterol crystals in myocardial infarction and stroke: a review. Clin Lipidol 2010;5:57e69.
surface of the proximal end of the thrombus [24]. Fibrin-poor thrombi had platelets, red blood cells, or debris. The authors
described fibrin-rich thrombus in 60% of unstable angina and NSTEMI (Non ST-segment elevation myocardial infarction)
cases and 29% of STEMI patients.
More recent studies have gone beyond these findings and demonstrated that a great portion of the occlusive materials in
the arterial lumen obtained during AMI consists of cholesterol crystals released during plaque rupture (Fig. 2.9) [25]. This
was confirmed by scanning electron microscopy from aspirates obtained from culprit coronary arteries during AMI.
Furthermore, higher concentrations of cholesterol in the arterial wall have been associated with greater serum inflammation
and arterial thrombosis [26,27]. Thus, these findings suggest a new paradigm of what constitutes a major component of the
occlusive materials in the culprit coronary arteries during AMI. Aspirates obtained during AMI demonstrate that much of
the obstruction includes large cholesterol crystals with or sometimes without thrombi [25] (Fig. 2.10). Moreover, the larger
cholesterol crystal clusters were associated wi th reduced Thrombolysis in Myocardial Infarction (TIMI) flow and blush
scores. This may help explain in part why there is an up to 40% reocclusion rate after successful thrombolytic therapy [28].
METHODS TO DETECT THROMBI
Techniques that detect and differentiate platelet-rich or fibrin-rich thrombi are currently not available. Although angioscopy
is consi dered the gold standard for defining intraluminal pathology, angiography is the predominant practical utilized
method. Histopathological correlations of angiographic lesion morpholog ies have shown that lesions with intraluminal
lucency and irregular borders corresponded to complex plaque with thrombosis. Other technologies include intravascular
ultrasound (IVUS) and OCT. OCT is safe and has high-resolution intravascular imaging that allows detailed in vivo
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(A) (B)
(C)
FIGURE 2.5 Optical coherence tomography (OCT) images. (A, B) OCT of human coronary arteries during percutaneous intervention. Cholesterol
crystals (arrows) are defined as thin, linear regions of high intensity frequently associated with a fibrous cap or necrotic core within the plaque. (C, D)
Evidence of cholesterol crystals (cc) perforating the fibrous cap and intima of a human plaque. Micro-OCT images of human carotid plaque with (C) dense
concentration of cc beneath a bulging fibrous cap and (D) cc perforating the fibrous cap (arrow). nc, necrotic core. (A, B) Reproduced with permission
from Nakamura S, Inami S, Murai K, Takano M, Takano H, Asai K, Yasutake M, Shimizu W, Mizuno K. Relationship between cholesterol crystals and
culprit lesion characteristics in patients with stable coronary artery disease: an optical coherence tomography study. Clin Res Cardiol
2014;103:1015e21. Tian J, Ren X, Vergallo R, Xing L, Yu H, Jia H, Soeda T, McNulty I, Hu S, Lee H, Yu B, Jang K. Distinct morphological features of
ruptured culprit plaque for acute coronary events compared to those with silent rupture and thin-cap fibroatheroma: a combined optical coherence
tomography and intravascular ultrasound study. J Am Coll Cardiol 2014;63:2209e16. (D) Courtesy of Tearney GJ and reproduced with permission from
Liu L, Gardecki JA, Nadkarni SK, Toussaint JD, Yagi Y, Bouma BE, Tearney GJ. Imaging the subcellular structure of human coronary atherosclerosis
using microoptical coherence tomography. Nat Med 2011;17:1010e14.
(D)
assessment. It can identify plaque rupture, fibrous cap erosion, intracoronary thrombus, macrophage infiltration, cholesterol
crystals, and thin-cap fibroatheroma. Red thrombi can be recognized as high-backscattering protrusions inside the lumen of
the coronary artery, with signal-free shadowing in the OCT image. White thrombi are identified by low-backscattering
projections. There are no significant differences in peak intensity of the OCT signal between red and white thrombi [29,30].
IVUS has been used to identify plaque rupture and vulnerable plaques. In prospective trials using IVUS, ruptured
plaques had an echo lucent area representing the lipid core cavity that was 4.1 3.2 mm
2
, a ratio of echo lucent area to
plaque >38.5 17.1%, and a fibrous cap thickness <0.7 mm [31]. In addition, at an average of 3 years follow-up of
patients who had myocardial infarction, recurren ce of events occurred equally at the site of the initial culprit and at
subsequent nonculprit lesions. The nonculprit lesions typically had thin-cap fibroatheromas or large plaque burden with
small luminal area [32]. The differentiation of red and white thrombus by IVUS may be feasible using backscatter of the
echo signals [33]. Near-infrared spectroscopy has also been used to detect areas of large lipid deposits in the arterial wall
[34]. However, long-term studies have yet to demonstrate its predictive value in detecting unstable plaques. Computed
tomography angiography (CTA) is also upcoming as a noninvasive approach to help in detecting the severity of stenosis
using fractional flow reserve [35]. All imaging techniques have some benefits and limitations (Table 2.1). However, blood
tests with D-dimer and troponin-I have limited use in confirming the presence of arterial thrombosis.
RISK FACTORS FOR ARTERIAL AND VENOUS THROMBOSIS
There are numerous risk factors for thrombosis, including both hereditary and acquired factors. Hereditary risk factors are
caused by gene mutations that can result in either loss or gain of function. Examples of loss-of-function mutations include
deficiency of antithrombin, protein C, and protein S, which act as anticoagulants. Gain-of-funct ion mutations include factor
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FIGURE 2.6 Proposed mechanism of plaque hemorrhage, rupture, and/or erosion induced by cholesterol crystallization with phase transition
and volume expansion of the necrotic core. In the case of a large necrotic core (top), the plaque cap is torn rapidly, leading to rupture, whereas in the
case of a small necrotic core (bottom), it leads to erosion. Human plaques with rupture and erosion are shown with corresponding scanning images from
human coronary arteries. Furthermore, trauma to the vasa vasorum caused by expanding cholesterol crystals within the plaque causes intraplaque
hemorrhage. Modified with permission from Abela GS. Cholesterol crystals piercing the arterial plaque and intima triggers local and systemic
inflammation. J Clin Lipidol 2010;4:156e64; Abela GS, Aziz K. Cholesterol crystals rupture biological membranes and human plaques during acute
cardiovascular events: a novel insight into plaque rupture by scanning electron microscopy. Scanning 2006;28:1e10; Abela GS, Aziz K, Vedre A, Pathak
D, Talbott JD, DeJong J. Effect of cholesterol crystals on plaques and intima in arteries of patients with acute coronary and cerebrovascular syndromes.
Am J Cardiol 2009;103:959e68; Abela GS. The role of cholesterol crystals in myocardial infarction and stroke: a review. Clin Lipidol 2010;5:57e69.
V Leiden and prothrombin mutation G20210A, which lead to a hypercoagulable state with increased risk of clot formation
[36]. These factors will either cause hypercoagulability or decrease fibrinolysis, both of which will promote thrombosis.
Acquired risk factors include smoking, obesity, hypertension, hypercholesterolemia, diabetes, metabolic syndrome, and
physical inactivity; lifestyle modifications can diminish the risk for thrombosis associated with these acquired risk factors.
Another major risk factor for both arterial and venous thrombotic events is age [37]. Several coagulation factors in
plasma increase with age, while fibrinolytic activity decreases with age, resulting in an increased risk of thrombosis [38].
The metabolic syndrome defined as abdominal obesity, high triglyceride levels, reduced high-density lipoprotein
cholesterol, hypertension, and elevated fasting blood glucose carries a risk for thrombosis [39]. In particular, tissue
plasminogen activator (tPA), von Willebrand factor, and coagulation factors VII, VIII, and IX are significantly associated
with insulin resistance. There are several observational studies on smoking cessation that show smoking has a causative
role in arterial disease and thrombosis. Studies have shown that smok ing cessation, regular exercise, and weight loss play a
critical role in reduction of platelet activity and coagulability [35].
ATHEROSCLEROSIS, INFLAMMATION, AND THROMBOSIS
It is also important to mention that a greater amount of atherosclerosis increases both local and systemic inflammation and
is associated with more thrombosis in a model of plaque rupture and thrombosis [27]. Furthermore, in the same model only
arterial wall cholesterol was found to be an independent predictor of thrombosis [26]. As mentioned earlier, cholesterol
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(A)
(C)
(E)
(B)
(D)
(F)
FIGURE 2.7 Gross view of a predominantly white thrombus as often seen in the atherosclerotic model of plaque disruption and thrombosis.
(A) Gross view of a predominantly white thrombus. (B) Correlation between thrombus surface area and cholesterol content in atherosclerotic arterial wall
(r ¼ 0.71, P < .002). (C) Light micrograph of a white thrombus overlying a plaque on the intimal surface of the aorta (Movat’s pentachrome stain,
platelets stain red, original magnification 160). (D) Transmission electron micrograph of a white thrombus demonstrating a high concentration of
platelets with fibrin and few red blood cells (original magnification 3.4 2.5). (E) Light micrograph of a red thrombus overlying a plaque on the intimal
surface of the aorta (Movat’s pentachrome stain, original magnification 180). This demonstrates a dense surface thrombus layer with loose inner core.
(F) Transmission electron micrograph of red thrombus with loosely packed fibrin with many interspersed red blood cells (original magnification 3.4 2.5). Reproduced with permission from Ma H, Aziz KS, Huang R, Abela G. Arterial wall cholesterol content is a predictor of the development
and severity of arterial thrombosis. J Thromb Thrombol 2006;22;5e11; Johnstone E, Friedl SE, Maheshwari A, Abela GS. Distinguishing characteristics
of erythrocyte-rich and platelet-rich thrombus by intravascular ultrasound catheter system. J Thromb Thrombolysis 2007;24:233e239.
crystals were a major component of the aspirated materials obstructing the coronary artery during AMI [25]. In fact, some
of the arteries were occluded entirely with cholesterol crystals, with little or no thrombus (Fig. 2.10) [10,13]. The
cholesterol crystal size was associated with reduced TIMI flow and blush scores and higher serum levels of interleukin-1b
(IL-1b) cytokine [25]. The latter is also associated with both myoca rdial injury and triggering of IL-6 and production of
C-reactive protein (C RP) [40]. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial
Evaluating Rosuvastatin Jupiter trial demonstrated that patients on statins had fewer events of deep venous thrombosis and
pulmonary emboli [41,42]. Also, in that study, elevation in CRP levels above 2 m g/dL had an independent benefit beyond
the LDL levels. Most recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study trial demonstrated that
treatment by suppressing inflammation by inhibiting IL-1b over and above the use of statins and achieving target
LDL level s was associated with a significant reduction in recurrent cardiovascular events [43]. Thus, the presence of
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(A)
Red Thrombus
FIGURE 2.8 (A) Angiography: Left anterior oblique view of right coronary artery demonstrating a 1-cm filling defect with a trace amount of contrast
agent crossing the obstruction (arrow). Angioscopy: A bulging red thrombus occluding the entire vascular lumen is noted with a guidewire crossing in the
left upper quadrant of the field of view. (B) Angiogram: Left anterior oblique view of left anterior descending coronary artery demonstrating a focal
smooth lesion in the midportion of the artery (arrow). Angioscopy: White thrombus is seen billowing from a yellow plaque into the arterial lumen with a
wedge-like appearance (two o’clock). (C) Angiogram: Left anterior oblique view demonstrating a hazy lesion in the proximal obtuse marginal branch just
distal to the bifurcation of the circumflex coronary artery ( arrow). Angioscopy: A white thrombus emerging from a yellow plaque within the arterial wall
(three o’clock). Reproduced with permission from Abela GS, Eisenberg JD, Mittleman MA, Nesto RW, Leeman D, Zarich S, Waxman S, Prieto AR, Manzo
KS. Detecting and differentiating white from red coronary thrombus by angiography in angina pectoris and in acute myocardial infarction. Am J Cardiol
1999;83:94e97.
(B)
White ThrombusWhite Thrombus
(C)
(A)
(C)
FIGURE 2.9 Cholesterol crystal in coronary artery aspirates during acute myocardial infarction (A) Right coronary artery with filling defect
during acute myocardial infarction (black arrowhead). Inset shows aspirates collected in a cup (arrows). (B) Heap of aspirated materials with extensive
cholester ol crystals embedded in debris. (C) Scanning electron micrograph of large cholesterol crystal cluster (0.187 mm
of merged individual plate crystals. (D) Dense aggregate of needle-shaped cholesterol crystals. Modified and reproduced with permission from Abela
GS, Kalavakunta JK, Janoudi A, Leffler D, Dhar G, Salehi N, Cohn J, Shah I, Karve M, Kotaru P, Gupta V, David S, Narisetty K, Rich M, Vanderberg
A, Pathak DR, Shamoun F. Frequency of cholesterol crystals in culprit coronary artery aspirate during acute myocardial infarction and their relation
to inflammation and myocardial injury. Am J Cardiol 2017;120:1699-07. August 31, 2017. pii: S0002e9149(17)31281-X. doi: 10.1016/j.amjcard.
2017.07.075.
(B)
(D)
2
)composedofmanylayers
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(A) (B)
(C)
FIGURE 2.10 Scanning electron micrographs of coronary arteries of patients who died during acute myocardial infarction. (A, B) (A) Circumflex artery
totally occluded with thrombus that is loaded with cholesterol crystals (arrows). (B) Higher magnification. (C) Example of plaque rupture from a
postmortem specimen illustrating dense cholesterol crystal mass protruding and obliterating the lumen without thrombus. The plaque ruptured (arrows at
frayed cap edges) with crystals filling the entire lumen (hematoxylin/eosin; original magnification 134). Crystals are noted extending into the arterial
lumen (inset original magnification 334). Reproduced with permission from Janoudi A, Shamoun FE, Kalavakunta JK, Abela GS. Cholesterol crystal
induced arterial inflammation and destabilization of atherosclerotic plaque. Eur Heart J 2016;37:1959e67; Abela GS, Aziz K. Cholesterol crystals
rupture biological membranes and human plaques during acute cardiovascular events: a novel insight into plaque rupture by scanning electron
microscopy. Scanning 2006;28:1e10.
atherosclerosis, including cholesterol and other crystalloids, can trigger a local and systemic inflammation to enhance the
risk of thrombosis. We had previously demonstrated that cholesterol crystals trigger IL-1b production via the NLRP3
inflammasome [12]. It is also important to recognize that cholesterol crystals were not the only crystalloid p resent in
coronary artery aspirates; calcium phosphate crystals were also a contributor to coronary obstruction [25].
Although the morphology and histopathology of the culprit lesion have been extensively evaluated, little is known
about the relationship between the onset of thrombus maturation and acute coronary events [44]. Coronary thrombi have
been classified into four stages of healing [45] : early, late, infiltrating, and healing. Stage 1, the early healing stage
(<1 day), is composed of alternating layers of platelets mixed with fibrin and neutrophils. Stage 2, the late stage, is
characterized by a lytic phase (1e3 days), identified in about 69% of culprit plaques, composed of an acute thrombus with
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TABLE 2.1 Comparison of Available Endovascular Techniques for Identification of Intraluminal Pathology
Endovascular Diagnostic Advantages Disadvantages
Angiography l Detects arterial stenosis
l Degree of stenosis can be evaluated
l Detects calcification
l Guidance for intervention
Intravascular
ultrasound (IVUS)
Angioscopy
Optical coherence
tomography
l Quantification of plaque, wall thickness, and
lumen size
l Tissue characterization
l 360 degrees topographic view
l Validity confirmed by prospective studies
l Good surface imagery (i.e., thrombus, color)
l Forward viewing
l High resolution (10e50 mm)
l Validity confirmed by prospective studies
l High resolution (10e20 mm) of arterial surface
morphology
l Small probe size
l May be able to detect thin cap, lipid pool, possibly
l Risk of dissection
l Risk of distal embolization
l Cannot differentiate white thrombus
from plaque
l Risk of contrast agent
l No forward viewing
l May cause vascular damage
l Low resolution (80e120 mm)
l Cannot detect thrombus
l Needs blood displacement
l May cause vascular injury
l May cause ventricular arrhythmias
l Needs blood displacement
l Less depth of view than IVUS
macrophage content and cholesterol crystals
Infrared spectroscopy
l Detection of lipid burden in artery
l Possible identification of unstable atheromatous
l No evidence of long-term benefit
and prognosis
plaque
l Can image through whole blood
l Help in stent covering entire atherosclerotic plaque
degraded acute inflammatory cells without evidence of cellular organization. Stage 3 is the infiltrating thrombus
(4e7 days). This stage shows a basal ingrowth of smooth muscle cells and/or endothelial cells without an accumulated
proteoglycan matrix. Stage 4 is the healing thrombus (>7 days), which shows smooth muscle cells and endothelial cells
with an accumulated proteoglycan matrix [46,47]. The frequency of thrombus, plaque rupture, and plaque hemorrhage in
the coronary arteries among patients with unstable angina pectoris and sudden coronary death was similar to and
significantly less than in patients with AMI [48].
In the specific case of thrombosis in drug-eluting stents there was evidence of both inflammation and hypersensitivity
reaction. It showed eosinophilic and giant cell infiltrates, which suggest that a reaction to the polymer may have caused late
stent thrombosis [49].
TREATMENT OF ATHERO-CRYSTALLOIDS
Currently there is not a well-defined approach to the treatment of crystalloid emboli in the distal circulation during AMI.
Crystalloids can induce vasospasm by scraping the intimal surface as they travel downstream and contribute to no-reflow
conditions following intervention (Fig. 2.11) [50]. Moreover, crystalloids can also trigger muscle inflammation leading to
myositis and necrosis independent of ischemic obstruction [51]. This is not different from what is noted in the distal
circulation, with cholesterol crystal emboli from ruptured plaques in the aorta noted with livedo reticularis. Also, another
common example of cholesterol crystal embolic conditions includes emboli from the carotid arteries, so-called Hollenhorst
plaques, that occlude the retinal circulation and can cause transient ischemic attacks and strokes [52]. Preliminary studies
have suggested that alcohol and statins can dissolve cholesterol crystals [53,54]. Also, statins and aspirin have been shown
to prevent cholesterol crystal expansion [53,55]. Some clinical studies support this concept, because the use of statins prior
to coronary interventions, as well as with AMI, seems to provide additional benefits, and alcohol has been shown to help
reduce acute cardiovascular events [56]. Aspirin has been well established as a beneficial treatment during AMI [57]. Other
potential drugs include colchicine and urodeoxycholic acid [58,59]. However, further studies are needed to determine how
best to treat crystalloid emboli.
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