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Encounters With Thrombus and Thrombosis in a Major Academic Center Chapter | 22 335
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FIGURE 22.25 Macroscopic picture of fresh thrombus removed from ulnar artery by thrombosuction.
FIGURE 22.26 A radiolucent area at diastole and systole at 6 o’clock (level at which inflow of the second valve touches the first implanted valve). Left:
cross-sectional images with corresponding longitudinal image on the right. Green and blue lines indicate levels of cross section.
336 Cardiovascular Thrombus
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(B)(A)
(C) (D)
FIGURE 22.27 A thrombus (13 6 cm) at the interface of two bioprostheses without affecting the bioprosthetic leaflets (which were slim and mobile)
was suspected, consequently, oral anticoagulant therapy was initiated (international normalized ratio target 2.5e3.0). This led to almost complete
resolution of the frame thrombosis (A and C, 1 month after transcatheter aortic valve replacement [TAVR]; B and D, 5 months after TAVR).
REFERENCES
[1] Koupenova M, Kehrel B, Corkrey H, Freedman J. Thrombosis and platelets: an update. Eur Heart J 2017;38:785e91.
[2] Buccheri S, Franchina G, Romano S, Puglisi S, Venuti G, D’Arrigo P, Francaviglia B, Scalia M, Condorelli A, Barbanti M, Capranzano P,
Tamburino C, Capodanno D. Clinical outcomes following intravascular imaging-guided versus coronary angiographyeguided percutaneous coronary
intervention with stent implantation. A systematic review and Bayesian network meta-analysis of 31 studies and 17,882 patients. J Am Coll Cardiol
Interv 2017;10:2488e98.
[3] Wiyono A, van Beusekom H, Ligthart J, van der Giessen W. Thrombotic complication during intracoronary imaging. Neth Heart J 2012;20:229e31.
[4] Lee R, Adlam D, Clelland C, Channon K. Lines of Zahn in coronary artery thrombus. Eur Heart J May 2012;33(9):1039.
[5] Regar E, Akasaka T, Tearney G. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography
studies. A report from the International Working Group for intravascular optical coherence tomography standardization and validation. J Am Coll
Cardiol 2012;59:1058e72.
[6] Kume TK, Akasaka T, Kawamoto T, Ogasawara Y, Watanabe N, Toyota E, Neishi T, Sukmawan R, Sadahira Y, Yoshida K. Assessment of coronary
arterial thrombus by optical coherence tomography. Am J Cardiol 2006;97:1713e7.
[7] Kumar V, Abbas A, Fausto N. Robbins, Cotran textbook pathologic basis of diseasevol. 27. Elsevier Health Sciences; August 2014.
FURTHER READING
[1] Van Gils L, Budde R, de Jaegere PPT, van Mieghem N. Early stent frame thrombosis complicating transcatheter valve in valve implantation. Eur Heart
J 2017;38:2231.
Chapter 23
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Thrombosis in Atrial Fibrillation
Gregory K. Jones
Charles George Veterans Affairs Medical Center, Asheville, NC, United States
ATRIAL FIBRILLATION: PREVALENCE, TYPES, AND CLINICAL IMPLICATIONS
Atrial fibrillation (AF) is the most common cardiac rhythm disorder afflicting humankind and is associated with both
increased morbidity and increased mortality [1]. It is an irregular rhythm, often rapid in nature, of the upper chambers of the
heart (atria). The mechanism of AF is both complex and still not fully understood. It had been hypothesized in one model as
“chaotic wandering wavelets of elect rical activity” within the atrial chambers [2]. The wandering wavelets of electrical
activity self-extinguish and then reinitiate new wavelets in a recurring fashion. More recently, it is believed that AF requires a
trigger and a means of perpetuation. Its initiation is thought to be related to atrial ectopic beats or runs of atrial ectopics, of
which 90% originate from the muscular sleeves of the pulmonary veins [3]. Whether these are on the basis of triggered
activity, automaticity, or microreentry is still unclear. During AF complex electrical and muscular remodeling occurs within
the atrial chambers. These remodeled regions may serve as additional areas of atrial ectopic firings as well as localized regions
of reentry that help perpetuate AF (“rotors”). Rotors are of great interest in understanding the mechanism of persistent AF and
may potentially serve as a target for therapeutic radio-frequency ablation therapy [4].
The literature refers to different types of AF. The American Heart Association classifications for AF are outlined
below [5].
l Paroxysmal AF: This describes episodes of AF that terminate spontaneously or with intervention within 7 days; they
may recur with variable frequency.
l Persistent AF: This is episodes of continuous AF that last more than 7 days. AF can still terminate spontaneously or
with intervention; it may recur.
l Long-standing persistent AF: This refers to episodes of continuous AF that last more than 12 months
l Permanent AF: This applies when a joint physician/patient decision has been made to accept the presence of AF and
stop further attempts to restore and/or maintain sinus rhythm (as this represents clinical acceptance rather than an
inherent pathophysiological attribute of AF, it is understood that acceptance of AF may change as symptoms, efficacy
of interventions, and patient/physician preferences evolve).
In the United States, AF has become almost epidemic. This largely correlates with an aging population as well as a
population in which there is increased body size\obesity [6,7]. It is currently estimated that there are 2.7e6.1 million
patients with AF in the United States [8]. The percentage of Medicare fee-for-service beneficiaries with AF is reported to
be 2% for those <65years old, and 9% for those over the age of 65 years [8]. This finding is consistent with an increased
prevalence with age. Worldwide, the number of patients with AF exceed 33 million, with over 5 million new cases per year
globally [9]. This number may be an underestimation due to a significant number of individuals with cryptogenic AF. The
prevalence of AF in the United States and Europe exceeds that of Asian countries, probably as a consequence of a lower
incidence of risk factors such as hypertension (HTN), atherosclerotic heart disease, diabetes, and obesity [10]. Although the
No. 1 risk factor for AF is still HTN, body mass index (BMI) now ranks sixth and is rising. Obese individuals have an up to
2.4-fold increased risk of AF [7]. In addition, the risk of AF increases progressively with increasing BMI. There are also
observational data showing incre ased likelihood of transitioning from paroxysmal to permanent AF with progressive
increases in BMI [11].
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00023-5
Copyright © 2018 Elsevier Inc. All rights reserved.
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Cost and care issues of AF are astronomical. More than 750,000 hospitalizations are related to AF each year in the
United States [12,13]. AF causes 15%e20% of ischemic strokes, lending to high cost and mortality issues that contribute
to approximately 130,000 deaths each year. On average this disease adds over $8705 to medical costs per patient per year
[14]. It is estimated that the cost per year of AF in the United States is over $6 billion annually. If “tota l cost” due to loss of
productivity is considered, costs may exceed $15e$26 billion annually [15].
Clinical manifestations of AF are variable but important. It leads to impairment in cardiac output due to the loss of atrial
contraction as well as reduced diastolic filling times as a consequence of increased and irregular ventricular rate response.
These factors can produce a sensation of dyspnea and reduced exercise tolerance in many patients, but not all. Left unchecked, rapid ventricular rates increase myocardial oxygen demand, potentially leading to myocardial ischemia and
anginal symptoms. Importantly, continuous rapid ventricular rates can lead to depletion of myocardial energy stores,
leading to myocardial cellular injury and tachycardia-induced cardiomyopathy. Its most problematic issue, however, remains its propensity to lead to thromboembolism. With embolic cerebrovascular accidents being one of the most detrimental consequences of AF, understanding AF and thrombus formation is imperative to appropriate and optimal
treatments. The causes of thromboembolism formation are both intrinsic to the unique structure of the atrium and a
multitude of complex systemic factors.
DETERMINANTS OF THROMBOEMBOLISM FORMATION IN ATRIAL FIBRILLATION
Thrombus formation in patients with AF is a well-known entity. Factors involved in atrial thrombus formation are
numerous. They include mechanical factors that may lead to chamber enlargement and promotion of abnormal blood stasis,
endothelial injury, and abnormal hemostasis, and more recently there is evidence that inflammation may play a role
(Fig. 23.1).
Blood Stasis
AF represents a chaotic nonuniform electrical rhythm. As such, there is loss of organized atrial systole, which promotes blood
stasis and thrombus formation in and of itself. Early in the course of AF, complex electrical remodeling as well as structural
remodeling occurs, promoting chamber enlargement (Fig. 23.2). Electrical changes occur relativel y quickly and include a
reduction in myocardial voltage and a decrease in both the effective refractory period and the absolute refractory period [16].
One of the main mechanisms of cellular remodeling is related to rate-induced intracellular calcium overload (Fig. 23.3) [17].
AF promotes continuous atrial depolarization that inhibits sarcoplasm reticulum calcium reuptake, resulting in increased
levels of intracellular calcium, which impair excitationecontraction coupling and subsequent contractile function. At the
cellular level, changes are characterized by volume increases, myolysis (loss of cellular myofibril structure), accumulation of
glycogen, and mitochondrial changes [18]. Eventually there is atrial cell death and necrosis and subsequent replacement with
collagen and fibrosis. This in turn leads to additional volume expansion of the left atrium. Stasis of blood flow is enhanced as
the left atrium enlarges. Chamber enlargement is further promoted by prolonged time periods of AF, suggesting greater
fibrosis deposition over time. This is confirmed by late gadolinium-enhanced MRI studies. Gadolinium diffuses rapidly out of
capillaries into tissue but cannot cross intact cellular membranes. Both abnormal and normal myocardium passively accumulates gadolinium. With time, because of the slower kinetics and a larger volume of distribution, abnormal myocardium
(scar) possesses a slightly larger amount of gadolinium per unit volume. Thus late enhancement of gadolinium on MRI
confers fibrosis and scarring in this setting. Gadolinium cardiac MRI (CMRI) studies show a good correlation to atrial tissue
late enhancement and the time duration of AF [19]. These enhanced uptake regions, representing fibrosis and scar, also serve
to form areas of slow conduction that can perpetuate reentry circuits. Regions of atrial tissue where reentry occurs may serve
as rotors for persistent AF. The degree of fibrosis correlates to the effectiveness of radio-frequency ablation and pulmonary
vein isolation (PVI). The Utah score classification utilizes delayed enhancement (DE) CMRI to categorize the degree of
fibrosis: Utah stage I, representing minimal fibrosis, up to Utah stage IV, extensive fibrosis. The degree of fibrosis increases
the likelihood of AF recurrence following radio-frequency ablation [20].
Additional clinical factors can promote chamber enlargement and blood stasis. HTN and valvular heart disease, for
example, increase atrial pressure or volume loads and subsequently promote myocardial cellular stretch and fibrosis that
lead to atrial enlargement. There seems to be a direct correlation between left-atrial (LA) size and subsequent thrombotic
formation, as studies show that LA size serves as an independent risk factor for stroke [21,22].
The unique anatomy of the LA chamber itself also promotes blood stasis. The left-atrial appendage (LAA) is an open inlet
with variable flow dynamics depending upon size, length, and contractile state. This structure serves as the most common site
for intraatrial thrombus formation in AF as well as patients in sinus rhythm [23]. In echocardiographic studies, there is a
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Atrium Atrial tissue
Platelet activation
↑β-thromboglobulin
Thrombus formation
Thromboembolism and stroke
Coagulation cascade acivation
↑ D-dimer
↑ Prothrombin 1 and 2
↑ Thrombin-antithrombin complex
Endothelial damage/dysfunction
Hemoconcentration
↑ Hematocrit
Blood stasis
Wall motion abnormalities
Atrial tissue changes
• Myocytic hypertrophy
• Sclerosis
• Fibroelastosis
• Extracellular matrix
abnormal changes
Re-entry foci
formation
Atrial fibrillation
FIGURE 23.1 Complex determinants of thrombogenesis: blood stasis, endothelial dysfunction, coagulation activation, and platelet activation. Com-
ponents of Virchow’s triad for thrombogenesis in atrial fibrillation are shown. Abnormal changes are shown in the vessel wall (e.g., atrial tissue changes,
endothelial damage, and dysfunction), in flow (stasis, e.g., in the left atrial appendage), and in blood constituents (e.g., hemoconcentration, platelets,
coagulation cascade activation, inflammation); all factors contribute to a propensity for thrombus formation (thrombogenesis) in atrial fibrillation. vWf, von
Willebrand factor. Reprint with permission. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited.
Lancet. 2009 Jan 10;373(9658):155e66 doi: 10.1016/S0140-6736(09)60040-4.
correlation between LAA contractility and thrombus formation. Studies utilizing transesophageal echocardiography (TEE) to
measure “left-atrial appendage ejection fraction” found it to be an independent risk factor for thrombus formation beyond the
clinical CHADS
enlargement, and the unique structure of the appendage all are involved in the formation of static blood flow that promotes
thrombus formation. Multiple other factors, however, also play a role in thrombus formation.
Endothelial Damage
Endothelial injury and dysfunction are felt to be key components in thrombus formation in the vasculature. In patients with
AF, the left atrium undergoes structural changes resulting in significant endothelial or endocardial injury. Remodeling
Inflammation
↑ vWF, interleukin 6
scoring scheme [24]. Thus, the loss of LA contractility, structural remodeling issues with chamber
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FIGURE 23.2 Complex overview of both (A) electrical and (B) structural remodeling within the atrial chamber during atrial fibrillation. AF, atrial
fibrillation; APD, action potential duration; DADs, delayed after depolarization; ECM, extracellular matrix; RP, refractory period; SR, sarcoplasmic re-
ticulum. Reprint with permission. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation.
2011 Nov 15;124(20):2264e74. doi: 10.1161/CIRCULATIONAHA.111.019893.
effects include endothelial denudation with regions of atrial edema, fibrin thread deposits, neutrophil infiltration of
endocardium, and thrombotic aggregation. These effects can be seen by electron microscopy and surgical pathology
specimens in patients with AF [25,26].
Endothelial function can be indirectly assessed by circulating serum factors. Von Willebrand factor and soluble
E-selectin are indices of endothelial activation, dysfunction, and damage. Von Willebrand factor also serves as a marker of
prothrombotic risk [27]. Both of these factors are elevated in patients with AF compared with age-matched controls in
normal sinus rhythm [28,29]. Studies show a correlation between LA volume and plasma von Willebrand factor levels
[30]. This suggests that the source of elevated von Willebrand factor is the endothelial region of the left atrium. In addition,
there appear to be different levels of plasma-circulating von Willebrand factor in patients with paroxysmal AF compared
with those with persistent AF [28]. This would also support increased levels of endothelial damage with time and more
advanced forms of AF.
Additional evidence of endothelial dysfunction comes from studies looking at endothelial-dependent flow-mediated
dilation (FMD). Endothelial dysfunction is reflected by an impaired FMD response. In human vasculature, FMD can
be studied in the forearm and coronary circulation. A vasodilatory stimulus is applied to the downstream vascular bed,
eliciting a flow-dependent dilation of the upstream conduit vessel. This principle was studied in 40 patients with chronic
AF compared with 26 normal sinus rhythm controls [31]. Significant endothelial dysfunction was demonstrated in the
patients with AF. Elevated von Willebrand factor and E-selectin were found as well.
Abnormal Hemostasis
There is increasing evidence of a potential proth rombotic state in AF. This is in part put forth by studies showing increased
coagulation and platelet activation along with abnormal fibrinolysis in the AF patient population [32] . In a meta-analysis of
59 studies that looked at different prothrombotic factors, a number of elevated hemostatic markers correlated well to
patients with AF compared with normal sinus controls. This included coagulation activation factors where levels of
D-dimer, fibrinogen, thrombineantithrombin, prothrombin fragments 1 and 2, and antithrombin III were all elevated in
patients with AF compared with their normal sinus controls.
Some studies also show findings of increased platelet activation in the AF population. This is suggested by increased
circulating levels of certain indices of platelet activation. Platelet factor IV is a small cytokine released from activated
platelets during platelet aggregation and promotes blood coagulation. b-Thromboglobulin is a protein that is stored in alpha
granules of platelets and released in large amounts after platelet activation. Finally, P-selectin functions as a cell adhesion
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Na+/Ca2+-exchange
2+
T-type and
L-type
2+
Ca
-channel
2+
Ca
RyR
Sarcoplasmic
Reticulum
FIGURE 23.3 Calcium homeostasis and events related to calcium overload induced by atrial fibrillation (AF). A schematic representation of calcium
homeostasis and the events that may take place due to calcium overload induced by AF. Depolarization of the cardiomyocyte leads to inflow of calcium into
the cell via (1) L-type Ca
from the sarcoplasmic reticulum via ryanodine receptors (RyR) into the cytoplasm. Calcium, subsequently, binds to contractile elements and initiates
contraction. In the diastole, calcium leaves the cytoplasm via sarcoplasmic reticulum Ca
and via the Na
calcium overload can contribute to an altered signal transduction. Activation of Ca
calmodulin-dependent protein kinase II (CaMKII) may be increased. Activation of calpain may result in degradation of muscle proteins (myolysis). Increased
calcineurin activation activates nuclear factor of activated T cells (NFAT) by dephosphorylation and CaMKII activates myocyte enhancer factor 2 (MEF2)
signaling. Both lead to altered gene expression such as increased atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression and
hypertrophy. Calsarcin, a stretch-sensitive protein localized to the Z-disk, is an inhibitor of calcineurin. The plasma membrane calcium-ATPase fine-tunes
diastolic calcium levels and inhibits calcineurin via direct binding. Reprint with permission. De Jong AM, Maass AH, Oberdorf-Maass SU, Van Veldhuisen
DJ, Van Gilst WH, Van Gelder IC. Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res. 2011 Mar 1;89(4):754e65. doi: 10.1093/cvr/cvq357. Epub 2010 Nov 11.
þ
2þ
channels, (2) reverse-mode Naþ/Ca2þexchanger, and (3) T-type Ca2þchannels. This induces calcium-induced calcium release
/Ca2þexchanger and plasma membrane Ca2þ-ATPase. Ions can also leave and enter the cell via stretch-activated channels (SAC). During AF,
Ca2+Ca
+
Ca
2+
2+
SERCA
Ca
Plb
3 Na
Calpain
+
Myosin
+
Ca
+
+
Myolysis
Actin + troponin
SAC
2+
Contraction
Calsarcin
+
2þ
-ATPase (SERCA), which is regulated by phospholamban (Plb),
2þ
-dependent proteins such as calpain, calcineurin, and calcium/
Ca2+-ATPase
2+
-Calmodulin
Ca
+
CaMKII
2+
Ca
+
Calcineurin
+
Altered gene expression
Plasma
membrane
Cytosol
–
–
MEF2
+
Hypertrophy
p
-NFAT
+
NFAT
Nucleus
+
molecule on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets.
These indices have been found to be elevated in patients with AF compared with their normal sinus rhythm controls
[33,34]. Interestingly, levels tend to decrease after cardioversion back to normal sinus rhythm. In addition, mean platelet
volume (MPV) is a marker of platelet size, function, and activation. Increased MPV reflects active and large platelets that
release more thromboxane A
as a marker for enhanced atrial-chamber thrombus formation remains unclear, however. In one study in which patients with
TEE-documented atrial clot were compared with patients with AF and no evidence of clot, MPV did not correlate to the
presence or absence of LA thrombus [37]. Further evaluation appears to be necessary in terms of sorting out the role of
platelet activation in LA thrombus formation.
The fibrinolytic system plays an important function in preventing intravascular thrombosis (Fig. 23.4). Tissue plasminogen activator (tPA) is a protein involved in the breakdown of thrombus. Modified antithrombin III (ATM), D-dimer,
and plasminogen activator inhibitor-1 (PAI-1) are other components within the fibrinolytic system. ATM is a marker of
thrombin activity. Increased levels are indicative of an enhanced coagulable state. D-dimer is a fibrin degradation product
present in the blood after degradation by fibrinolysis. It serves as a marker of intravascular fibrin turnover and thrombus
formation. Finally, PAI-1 is a serine protease inhibitor (serpin) that functions as the principal inhibitor of tPA. As active
PAI-1 levels rise, active tPA levels decrease and thus thrombus breakdown declines.
than smaller ones. Several studies show MPV elevation in AF [35,36]. Whether MPV serves
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FIGURE 23.4 Overview of the fibrinolytic system and
its interactions. Dotted arrows reflect inhibitory influence.
MMP, matrix metalloproteinase; PAI-1, tPA inhibitor; tPA,
tissue plasminogen activator. Reprinted with permission.
Marín F, Roldán V, Lip GY. Fibrinolytic function and
atrial fibrillation. Thromb Res. 2003 Mar 15;109(5
e6):233-40.
plasminogen
PAI -1
PAI-1: tissue-type plasminogen activator inhibitor; t-PA: tissue-type
plasminogen activator;
MMP: matrix metalloproteinase. Dotted arrows reflect inhibitory influence.
t-PA
α
-antiplasmin
2
plasmin
Pro-MMP
fibrin
Active MMP
Fibrin degradation
products
ATM, D-dimer levels, and PAI-1 levels were evaluated in 36 patients with AF and compared with 20 healthy patients
in normal sinus rhythm [38]. Patients with AF had higher levels of ATM, D-dimer, and PAI-1 compared with controls.
Elevated PAI-1 levels have also been shown, in a retrospective analysis, to be significantly associated with subsequent
stroke in patients with AF [39]. One potential conclusion from these data is that the AF population shows a hypofibrinolytic state and increased thrombogenesis, which may increase the risk of thrombosis formation.
Inflammation
An array of data linking inflammation to AF and thrombus formation exists. The interpretation is hampered, however, by
uncertain data. The difficulty is in determining if the inflammation is the initiator of AF or a reflection of the disease
process itself. Certainly, AF is seen in situations in which inflammation is present. This would include inflammatory states
such as postoperative cardiovascular surgery, forms of myocarditis, and pericarditis. Inflammation being present is supported by increased circulating levels of C-reactive protein (CRP) and other inflammatory markers in these patients [40].
CRP is produced in the liver in response to factors released by macrophages and fat cells. CRP is classified as an acutephase reactant, which means that its levels will rise in response to inflammation. CRP is elevated in patients who have
postoperative AF compared with surgical controls [40]. In many cases, if AF was not an antecedent finding, when the
primary inflammatory insult resolves, often so does the AF.
Inflammation may play a role in other forms of AF as well. In patients with lone AF, histological data show atrial
myocarditis and/or patchy fibrosi s present compared with patients in normal sinus rhythm [16]. Here it remains unclear,
however: does AF cause these findings or is the substrate abnormal, leading to development of AF?
Several inflammatory markers are elevated in patients with AF unrelated to prior surgical intervention. These include
CRP, interleukin (IL)-6, and IL-8 [41,42]. IL-6 acts as both a proinflammatory cytokine and an antiinflammatory myokine.
In humans, it is secreted by T cells and macrophages to stimulate the immune response. High IL-6 levels have been
correlated with the presen ce of AF, the duration of AF, and individuals with increased LA diameter [43]. IL-8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells, and endothelial
cells. It is an important mediator of the immune reaction, acting as a chemoattractant for neutrophil granulocytes. Levels
have been found to be elevated in patients with advanced AF [44].
Clinically it is important to understand the potential role of inflammation in AF, but also in thrombus formation itself
(Fig. 23.5). If a strong association can be found between inflammation and AF thrombus formation, this would open up
potential targets for therapeutic treatment in the future. First, many of the inflammatory biomarkers found in patients with
AF, noted earlier, also have been shown to correlate with prothrombotic indices: CRP to fibrinogen and IL-6 to tissue
factor. Both CRP and IL-6 stimulate tissue factor production from monocytes in vitro. Furthermore, IL-6 increases platelet
production and sensitivity to throm bin, stimulating transcription of fibrinogen. This process is linked to both endothelial
activation and damage. In one retrospective study, higher plasma IL-6 levels were an independent predictor of stroke and
the composite end point of stroke and death [45]. Second, there also appears to be a correlation between inflammatory
markers such as CRP and standard stroke risk stratification schemes. In a study of 880 patients with AF, CRP levels were
the highest in patients with higher CHADS
In another study of 190 patients with nonrheumatic AF undergoing TEE, the presence of LA thrombus correlated well to
CRP levels [47].
scores as well as patients with raised BMI and peripheral vascular disease [46].
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Endothelium
activation
↑ IL-1
↑ TNF-α
E-selectin
IL-6
IL-1
IL-8
AF
PAI -1
AF
Complement
system
PAF
Fibrin
Thrombosis
C3, C5-9
P-selectin
AF
Inflammation
Thrombin
(IIa)
AF
Prothrombin
AF
vWF
Activated
platelets
AF
?
Fibrinogen
AF
↑ IL-1
AF
↑ TNF-α
Leukocytes
Xa factor
Tissue factor
AF
Macrophages
CD40
↓ TNF-γ
CD40L
CD4+
lymphocytes
IL-6
FIGURE 23.5 The relationship between
AF, inflammation, and thrombosis. The AF
boxes indicate areas where AF can affect or is
affected by the mechanisms linking inflammation and thrombosis. AF, atrial fibrillation;
IL, interleukin; PAI-1, plasminogen activator
inhibitor-1; TNF, tumor necrosis factor; vWF,
von Willebrand factor. Reprinted with
permission. Juan Carlos Kaski , Antonio L.
Arrebola-Moreno Inflammation and Thrombosis in Atrial Fibrillation. Juan Carlos
Kaski, Antonio L. Arrebola-Moreno Rev Esp
Cardiol. 2011;64:551e3 - Vol. 64 Num.07
DOI: 10.1016/j.rec.2011.03.014.
Determinants of Thrombus Formation: Summary
Thrombus formation in AF involves many modalities. Over 150 years ago, a “triad” of events was proposed for thrombus
formation. This included the phenomena of interrupted blood flow, irritation of the blood vessel, and factors that promoted
blood coagulation. Named after the German physician Rudolph Virchow, this became known as Virchow’s triad for
thrombosis formation. Today this can be interpreted in the setting of AF as abnormal blood stasis, endothelial injury, abnormal
hemostasis, and inflammation. It is difficult to assess which of these processes is more important to thrombus formation. More
likely, future treatment of thrombus formation will address elements of all these factors for optimal clinical benefit.
CLINICAL FACTORS IN THROMBOSIS FORMATION IN ATRIAL FIBRILLATION
AF increases the risk of stroke and thromboembolism by fivefold [48]. The risk, however, is not uniform among patients.
Numerous studies since the 1970s have looked at independent risk factors for stroke in patients with AF. Consistently the
strongest predictors of thromboembolic events in AF have been prior history of stroke or transient ischemic attack (TIA),
HTN, age, and diabetes mellitus (DM) [49].
A history of stroke or TIA has consistently been among the strongest independent risk factors for additional stroke in
the AF population. In patients with a prior history of stroke, the relative risk for additional stroke across multiple studies is
2.5, with a 95% CI 1.8e3.5 [49]. Due to the high prevalence of HTN in the population, HTN accounts for more cases of
AF than any other risk factor. HTN, in multiple studies, carries a relat ive risk of stroke of approximately 2.0, 95% CI
1.6e2.5 [48,49]. Furthermore, systolic blood pressure greater than 160 in some studies has been shown to be an additional
independent risk factor [50]. The prothrombotic risk of DM in AF is only partially understood. In a substudy to the Stroke
Prevention in Atrial Fibrillation (SPAF-III) trial, Varughese et al. showed that DM independently contributed to endothelial
damage/dysfunction in patients with AF, and that this effect was exaggerated further in individuals with congestive heart
failure (CHF) and increasing BMI [51]. The combination of DM and AF carries a stroke relative risk of 1.7, 95% CI
1.4e2.0 [46,48]. Finally, age itself is a progressive risk for stroke, with a relative risk of 1.5 in each decade of life after
65 years of age, relative risk (RR) 1.5, 95% CI 1.3e1.7 [49].
More recently, additional risk factors for stroke in the AF population have been found. Vascular disease, including
peripheral vascular and myocardial infarction, share many common risk factors with AF. Thus, it is not surprising that
vascular disease overall could serve as a risk factor for stroke in patients with AF. Multiple studies have shown prior
myocardial infarction to increase the risk of stroke in patients with AF [52,53]. Aortic plaquing, as assessed by TEE,
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increases a patient’s risk of stroke fourfold compared with patients who are plaque free and have underlying AF [54].In
one of the largest studies as of this writing, 87,202 patients with AF, of which 15,212 had vascular disease (17.4%), the risk
of thromboembolism was significantly elevated compared with patients with AF and no history of vascular disease (hazard
ratio 1.93, 95% CI 1.7e2.19) [55]. Importantly, the presence of vascular disease was found to be an “independent” risk
factor for stroke that enhanced the predictive value of the then CHADS
thus morphed into the more commonly use CHA
-VASc of today.
2DS2
assessment scheme. This predictive scheme has
2
Clinical congestive heart failure has shown inconsistent findings among studies as an independent risk factor for stroke
in AF [49]. The variability in the diagnosis of congestive heart failure probably plays a role in this inconsistent finding
among studies. Moderate-to-severe left-ventricular systolic dysfunction as assessed by 2D echo, however, was a powerful
independent predictor in a meta-analysis of three clinical trials [56]. These trials found that moderateesevere leftventricular dysfunction by 2D echo was a strong independent predictor of stroke among patients with nonvalvular AF
(relative risk of 2.5, P < .001).
Female gender its elf conveys risk for thromboembolism in AF [57]. The ATRIA study was a prospective study of
13,559 patients with AF. Gender was assessed after controlling for other clinical risk factors. Multivariate analysis revealed
that women had a higher annual rate of thromboembolism off warfarin than did men (3.5% vs. 1.8%; adjusted rate ratio
(RR) 1.6; 95% CI 1.3e1.9). The etiology of an increased risk of stroke among women with AF remains unclear. Certainly
hormonal differences exist between men and women and may be a factor. Although some prothrombotic factors have been
shown to have different levels among women and men, it remains unclear if this has a direct role in the observed stroke
difference. Certainly, further study is indicated. What should be evident, however, is that female sex is an important factor
in decision-making on the use of oral anticoagulation (OAC) therapy in nonvalvular AF.
Enhanced risk of thromboembolism in patients with chronic kidney disease (CKD) is a less appreciated risk factor but
important given the high association of kidney disease with cardiovascular disease. AF itself increases the risk of ischemic
stroke and systemic thromboembolism and increases the risk of cardiovascular death. In patients with “both” AF and CKD,
stroke and mortality risk is further exacerbated, with a 66% increase in relative risk of death [58,59]. Thi s is not surprising,
given that patients with CKD show all the elements of enhanced thrombogenesis, including (1) blood stasis with reduced
LAA emptying velocity and formation of dense spontaneous echo contrast, (2) endothelial damage as assessed by FMD as
well as increased endothelin and von Willebrand factor levels, and (3) abnormal platelet coagulation abnormalities [60].
Most recently low-density lipoprotein cholesterol (LDL-C) has been demonstrated as a potential independent risk factor
for ischemic stroke in patients with nonvalvular AF [61]. In this study, a total of 424 patients with nonvalvular AF with
ischemic stroke were compared with 391 patients without ischemic stroke. No patient received antithrombotic therapy.
LDL-C was found to be an independent predictor of ischemic stroke in patients with nonvalvular AF and CHA
2DS2
-VASc
score of 5 or less (adjusted odds ratio 2.004; 95% CI 1.6e2.4; P < .001). The authors concluded that LDL-C may offer
further refinement of prospective stroke risk in addition to the standard CHA
-VASc scoring scheme.
2DS2
Putting the aforementioned risk factors together, numerous classification schemes have tried to predict thromboembolic
risk in patients with AF. The two frequently sited classification schemes are the CHADS
and CHA2DS2-VASc. The
2
clinical factors include congestive heart failure, HTN, age, DM, history of stroke\TIA, vascular disease, and female gender.
When put together, a prospective numerical risk assessment can be obtained (Tables 23.1 and 23.2).
TABLE 23.1 CHA2DS2-VASc Scoring System
CHA2DS2-VASc Score
l Congestive heart failure 1
l Hypertension 1
l Age >65 years/age >75 years 1/2
l Diabetes 1
l Stroke/transient ischemic attack 2
l Vascular disease 1
l Sex female 1
Max 9
Each clinical factor is assigned a numerical value. Risk sco re is additive with
maximum score 9.
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