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Pathology of Arterial Thrombosis: Characteristics and Thrombus Types Chapter | 2 25
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(A)
(C)
(B)
(D)
(E) (F)
FIGURE 2.11 Scanning electron microscopy of saline and cholesterol crystals Intimal surface of artery with saline control (A, C, E) and cholesterol
crystals (B, D, F). No intimal injury is present with saline control arteries, and extensive injury with surface abrasions is noted with cholesterol crystals.
(Bottom) Graph of lumen diameter following pharmacological challenges with acetylcholine (Ach) following norepinephrine (Ne) preconstruction.
Crystal-treated arteries vasoconstrict, while microspheres and saline-treated arteries do not. Reproduced with permission from Gadeela N, Rubinstein J,
Tamhane U, Huang R, Pathak DR, Hosein H-A, Rich M, Dhar G, Abela GS. The impact of circulating cholesterol crystals on vasomotor function:
implications for no-reflow phenomenon. J Am Coll Cardiol-Intv 2011;4:521e29.
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TREATMENT OF ARTERIAL THROMBOSIS
There are two commonly used methods to treat arterial thrombosis, including medical and interventional approaches.
Medical treatment to dissolve the red, or fibrin-rich, thrombus with thrombolytic therapy (i.e., Tenecteplase) is often used
to help to restore the blood flow, in addition to treating the underlying platelet thrombus using various antiplatelet agents
(e.g., aspirin, thienopyridine, glycoprotein IIbeIIIa inhibitors) [8]. Thrombolytic therapy is usually used for AMI, acute
stroke, and acute limb ischemia where thrombolytic agents could be delivered intravenously or applied directly to the site
of occlusion via a catheter approach. Antithrombin agents such as heparin, Argatroban, and Hirulog are usually used as
part of the treatment especially associated with interventional procedures [8]. Combinations of various medical treatments
are frequently used (i.e., aspirin and heparin). Each one of these treatments has its own risks and benefits as well as
limitations. The second approach is using percutaneous interventional techniques that can directly remove the thrombus by
catheter aspiration, balloon angioplasty, and stent deployment in the artery at the site of plaque rupture. Surgical
approaches include thrombus extraction via balloon or bypass surgery by grafting beyond the site of arterial occlusion as
another option.
FIBRINOLYSIS
The endogenous fibrinolytic system is a complex and dynamic protective mechanism that alters the stability and propagation of a thrombus in a vessel. Coronary angiography has shown that infarcted arteries were occluded with thrombus in
90% of cases in the first 6 h of an AMI but dropped to 57% by 12e24 h [60]. A similar drop was noticed in postmortem
examination of 78 cases, from 87.8% to 68.4% during the same time. Lower rates of clot detection in acute coronary
syndrome with passage of time can be attributed to endogenous lysis. The rate of spontaneous resolution in STEMI has
been reported to be 15%e22% [61]. Plasmin breaks down cross-linked fibrin into soluble fibrin degradation products.
Plasminogen is also converted to plasmin by both tPA and urokinase-type plasminogen activators. Plasmin cleaves tPA
and urokinase to more active two-chain polypeptides that degrade the fibrin in the circulation. Plasmin antagonist s like
a2-antiplasmin or plasminogen activator inhibitors can inhibit fibrinolysis. Plasminogen activator inhibitor 1 (PAI-1;
released from platelet granules predominantly) and thrombin-activatable fibrinolysis inhibitor are major inhibitor of
fibrinolysis. Thrombin helps to stabilize the clot by activating thrombin-activatable fibrinolysis inhibitor. Other nonplasmin-mediated fibrinolysis occurs from leukocytes present in a thrombus that release neutrophil membrane proteolytic enzymes (elastase, cathepsin G) that can break down fibrin directly and can help plasmin in fibrinolysis. Factor XIII
helps in cross-linking fibrin, increases fiber density, and makes clots resistant to lysis. Arterial (platelet-rich) thrombi are
more resistant to lysis than eryth rocyte-rich venous thrombi [62]. PAI-1 acts to prevent the action of plasmin, leading to
preservation of the thrombus and creating a prothrombotic state.
Clots composed of dense fibrin netw orks a re mor e re sista nt to lysi s and ar e foun d in acute c or onar y syn drome
patients compared with stable angina patients [63] and in patients with a history of the no-reflow phenomenon despite
successful opening of the infarct-related artery [64]. Undas et al. found that patients with in-stent stenosis had altered clot
properties: compact fibrin clots are more resistant to lysis compared with those in patients who did not experience this
complication [65].
Several biomarkers of thrombosis have been investigated, including D-dimer, PAI-1, thrombin-activatable fibrinolysis
inhibitor, and lipoprotein(a); however, their usefulness as predictors of cardiovascular events remains in doubt [66].
However, only 62%e83% of arteries were opened with fibrinolysis and the reocclusion rate within 60e90 min following
thrombolysis is about 45%, suggesting that the underlying pathology is still active [28,66].
CLOT RETRACTION AND FIBRINOLYSIS
Platelets play a key role in thrombin generation, clot formati on, retraction, and lysis. Clot retraction is caused by normal
or hyperactive platelet function and measured in vitro by measuring the volume of serum extruded from the clot or a
decrease in size of the clot mass [67]. Different techniques are used to measure clot retraction: the Hemodyne hemostasis
analyzer (Hemodyne, Inc., Richmond, VA, USA) measures the platelet contractile force generated during clot retraction,
and the Sonoclot analyzer (Sienco, Morrison, CO, USA) measures clot retraction-induced change in the ultrasound
signal. Thromboelasto gr aphy measures the viscose and elastic changes that occur in clots with fibrin polymerization,
thus allowing evaluation of clot formation from initiation to st abilization. TEG thromboelastography (Haemonetics
Corp., Braintree, MA, USA) and thromboelastometry (ROTEM; Tem Inte rnat iona l GmbH, Munich, Germany) measure
clot strength by measuring clot amplitude. Clot strength is mainly derived from platelet and fibrin/fibrinogen/factor XIII
Pathology of Arterial Thrombosis: Characteristics and Thrombus Types Chapter | 2 27
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interaction; platelets bind and tighten fibrin fibers [68]. When platelets bind to fibrin through the glycoprotein IIbeIIIa
receptor, cytoplasmic motility proteins inside the platelets cause clot retraction. Platelets contribute about 80% and fibrin
contribute about 20% to clot strength. The platelet component of clot strength is calculated by the difference in shear
modulus measured with and without platelets [68]. The TEG and ROTEM techniques utilize a plunger (central pin),
immerged in blood contained in a cylindrical cup, that can oscillate, and a blood clot forms a bond between the cup and the
plunger. Formation of the clot entraps the pin, leading to pin motion, and shear force increases as the clot strengthens and
decreases when the clot lyses. The rotational motion of the plunger is recorded in numerical and graphical representation.
The TEG device gives clot amplitude, while resistance to central pin rotation is measured by the ROTEM device.
Clinical studies are needed to validate the role of thromboelastography in the management of clinical thrombosis/
bleeding. Currently point-of-care thromboelastography/thromboelastometry devices are used in surgical or trauma settings
to predict postoperative bleeding. Samos et al. studied the use of thromboelastometry (ROTEM) in a point-of-care test to
compare hemostasis in acute STEMI patients (n ¼ 56) who were on dual antiplatelet therapy with healthy blood donors
[69]. They found that clot firmness was significantly increased in patients with STEMI prior to percutaneous intervention
(PCI) (after a loading dose of dual antiplatelet therapy) or after PCI on dual antiplatelet therapy compared with controls. In
this study platelet reactivity on treatment showed potent platelet inhibition with prolonged antiplatelet therapy after PCI.
Prolonged clot firmness in STEMI patients was hypothesized to be an indicator of fibrinogen disorder or fibrin polymerization defect rather than insufficient antiplatelet response. Maximum amplitude of the TEG expressed as clot strength
is used to assess the effect of antiplatelet therapy. It is well established that there exists individual variability in platelet
responsiveness to antiplatelet agents, especially clopidogrel [70].
TEG platelet mapping can measure maximum clot strength, clot strength by fibrin alone, clot strength under an ADP
receptor antagonist like clopidogrel, clot strength under a thromboxane A2 receptor antagonist like aspirin, and percentage
platelet inhibition [71]. Clopidogrel, an ADP antagonist at the P2Y12 receptor on the platelet surface, is known to have
varied antiplatelet effects due to genetic variation in cytochrome P450 activity. Light transmittance aggregometry and
vasodilator-stimulated phosphoprotein phosphorylation are the gold standard tests to evaluate platelet reactivity.
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[73] 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.
[74] Tian J, Ren X, Vergallo R, Xing L, Yu H, Jia H, Soeda T, McNulty I, Hu S, Lee H, Yu B, Jang IK. 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.
[75] Abela GS. The role of cholesterol crystals in myocardial infarction and stroke: a review. Clin Lipidol 2010;5:57e69.
Chapter 3
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Fibrin Clot Structure and Function: A
Novel Risk Factor for Arterial and Venous
Thrombosis and Thromboembolism
Stephen R. Baker and Robert A.S. Arie¨ns
University of Leeds, Leeds, United Kingdom
INTRODUCTION
A thrombus is formed from a mesh network of fibrin fibers and platelets that have aggregated to form a blood clot.
The insoluble fibrin found in a thrombus is produced from its soluble precursor fibrinogen, which is synthesized in the liver
[1]. Physiologically, fibrinogen plays an important role in wound healing and hemostasis. Found at normal concentrations
of 2e4 g/L, fibrinogen is among the most abundant proteins found in blood plasma. This concentration, however, is very
sensitive to significant changes, some of which are caused by inflammation. Increased levels of fibrinogen have been linked
to cardiovascular disease and thrombosis [2e10].
Human fibrinogen is a 340-kDa (45 nm in length) protein first found to have a trinodular structure in 1959 [11].
Since then, the structure has been confirmed using different form s of high-resolution microscopy and X-ray crystallography [12,13].Eachfibrinogen molecule consists of two identical sets of three polypeptide chains, Aa,Bb,and
g (Aa
2Bb2g2
[14,15]. A total of 29 disulfide bonds hold these chains to gether [16]. The structure of fibrinogen is shown in Fig. 3.1
(top). In normal fibrinogen, each polypeptide chain has a well-known amino acid sequence, with the Aa,Bb,andg
chains consisting of 610, 461, and 411 residues, respec tively [17]. The C terminu s of the Bb and g chains is f ound in
the D-region, while the Aa ch ain continues for another loosel y structured 350 residues, foldin g back onto the E-region
[18,19].
Calcium plays an important role in the structure of fibrinogen. Often neglected in the past because of its role in various
other parts of the coagulation cascade, calcium has been shown to stabilize and protect fibrinogen from denaturing due to
heat and pH or even proteolysis [20,21]. It also plays an important role in accelerating fibrin formation by elevating lateral
aggregation of individual fibrin molecules. Calcium binding sites have been located in the D-region on both the g and the
Bb chains, with two being on the former and one being on the latter near the holes associated with moleculeemolecule
interactions and polymerization of fibrin [22,23]. Interestingly, as we will discuss later, calcium also plays a major role in
fibrinolysis and proteolysis of a stabilized clot into its fragments by plasmin.
In addition to disorders related to increased concentrations of plasma fibrinogen, studies since the turn of the 21st
century have found a link between changes in fibrinogen structure and atherothrombotic diseases [7,24e29]. A common
variant found from the alternative splicing of the g chain mRNA leads to the final four residues in the C terminus being
replaced by 20 highly negatively charged residues [30e32]. The resulting variant, gA/g
of 8%e15% in blood plasma. Increased gA/g
eases (CADs), and myocardial infarction (MI), while decreased concentrations have been linked to deep vein thrombosis
(DVT) [33e35].
), with a central globular E-region attached to two distal globular D-regions by a coiled-coil region
0
0
concentrations are linked to diseases such as stroke, coronary artery dis-
, is found at normal concentrations
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00003-X
Copyright © 2018 Elsevier Inc. All rights reserved.
31
FIGURE 3.1 Fibrinogen structure, clot formation, and branching. Schematic of a fibrinogen molecule (top). Located in the central globular E-region
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are the N-terminal ends of each of the Aa (red), Bb (blue), and g chains (green). The N-terminal ends of the Aa and Bb chains extend out from the
E-region to fibrinopeptides A (FpA) and B (FpB), respectively. The E-region is connected to the distal globular D-region by the coiled-coil region. The
D-region consists of the C-terminal ends of the Bb and g chains, while the Aa chain extends further, folding back to the E-region where its C-terminal end
(aC) interacts with FpB. The addition of thrombin and calcium initiates polymerization in a stepwise fashion. First, FpA is cleaved by thrombin, allowing
for interactions between the newly formed A knob and hole a, which is located on the g chain in the D-region. This forms trimers (middle) and protofibrils
consisting of half-staggered fibrin molecules. At a later time, thrombin þ calcium further enhances polymerization by cleaving FpB, allowing for
interactions between the newly formed B knob and hole b, which is located on the Bb chain, also simultaneously releasing the aC domain. The release of
FpB and the aC domain allows for lateral aggregation of protofibrils (bottom). Also shown are the different types of branching that can occur during
polymerization. Bilateral branching occurs when two protofibrils interact laterally to form a four-stranded fibril, while equilateral branching occurs when
three protofibrils interact to form three double-stranded fibrils.
Fibrin Clot Structure and Function: A Novel Risk Factor for Arterial and Venous Thrombosis Chapter | 3 33
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FIBRIN AND CLOT FORMATION
Clot formation is initiated by the interaction of thrombin with fibrinogen, converting it to fibrin. Thrombin cleaves the two
N-terminal ends of the Aa and Bb chains, commonly referred to as fibrinopeptide A (FpA) and fibrinopeptide B (FpB),
respectively [36]. This release of the fibrinopeptides occurs in a time-dependent manner [37]. First, FpA is released,
exposing the new N-terminal sequence Gly-Pro-Arg on the a chain, aptly named the A knob. This sequence can now bind
to hole a, located in the D-region on the g-chain of a neighboring fibrin monomer [38]. Studies have shown that the Aea
interaction is critical to the formation of fibrin fibers [39,40]. On a longer time scale, thrombin cleaves FpB, exposing a
new N-terminal sequence, Gly-His-Arg, on the b chain, commonly referred to as the B knob. The new N terminus can now
bind to the D-region of the b chain on a neighboring molecule at hole b. Unlike the Aea interaction, absence of the Beb
interaction still allows for clot formation, though the resulting clot has different structural and mechanical properties
compared with a normal clot [39e41]. Simultaneous to the cleavage of FpB, the aC domain is released from the E-region.
Studies by Litvinov et al. showed evidence of direct interactions between FpB and the aC domain [42].
The Aea and Beb interactions are electrostatically driven [12,43]. At the physiological plasma pH of 7.4, fibrinogen
has a net negative charge, with the majority of this charge located in the central E-region. FpA release causes the overall
charge of fibrinogen to change from 20 to 13, but, perhaps more importantly, causes the E-region to change from a
charge of 8to1. Furthermore, cleavage of FpB causes the E-region to adopt a net positive charge, changing from 1
to þ5, and the overall change in charge of the molecule is from 13 to 7. With a net charge of 3, the D-region is now
attracted to the net positive charge of a neighboring molecule’s E-region, allowing for an electrostatically favorable
interaction between these regions [43].
Binding of the E- and D-regions of neighboring molecules allows clot formation to continue. The A knob, with amino
acid sequence beginning Gly-Pro-Arg, binds to Gln329, Asp330, His340, and Asp364 on the g chain of a neighboring
molecule [44]. The Beb interaction occurs between the B knob sequence, Gly-His-Arg, and Glu397 and Asp398 on the
Bb chain of a neighboring molecule [45,46]. As the individual molecules associate, they form a half-staggered, doublestranded overlap of fibrin molecules (Fig. 3.1, middle) [47]. As association continues, a double-stranded polymer
known as a protofibril is formed. At a critical length of somewhere between 600 and 800 nm, protofibrils begin to laterally
aggregate with the help of aC domain association on neighboring protofibrils [48,49].
Lateral aggregation and branching can occur in two different forms termed bilateral and equilateral junctions
[48,50,51]. These junctions occur as two or more protofibrils interact to form fibrils and later fibers. Bilateral junctions
occur when two protofibrils interact laterally to form a four-stranded fibril. Equilateral junctions occur when three protofibrils interact to form three double-stranded fibrils (Fig. 3.1, bottom). It should be noted that the resulting fibril of each
of these forms can subsequently interact with other protofibrils and allow for more bilateral or equilateral aggregation
interactions. Clots containing more equilateral junctions tend to have more highly branched, thinner fiber networks that are
much less porous [52]. In contrast, clots with more bilateral junctions have thicker, less-branched fibers resulting in a more
porous clot.
The structure of the resulting network of fibers is extremely sensitive to fibrinogen, thrombin, and calcium concentrations as well as modifications to the release of each fibrinopeptide. Batroxobin, an enzyme derived from snake venom,
has been shown to selectively cleave FpA without cleaving FpB, resulting in the desA-fibrin monomer [41,53]. Clots
formed with desA-fibrin have thinner fibers with fewer pores than clots formed in the presence of normal fibrin. As
discussed earlier, Beb interactions alone are not sufficient for clot formation. We also alluded to the necessity of Aea
interactions for clot formation. Interestingly, it has been shown that blocking specific knobe
interactions that can occur in the following manner: Aea, Beb, and Aeb [54]. This Aeb interaction was also shown to be
similar to the Beb interaction, suggesting that Aeb interactions can occur physiologically. No direct evidence of Bea
interactions has been found.
Increased fibrinogen concentration in plasma is a risk factor for thrombosis. This increase in concentration leads to clots
that are more densely packed with smaller pores. The resulting tightly packed structure, as will be discussed later, leads to
an increased resistance to fibrinolysis. Similar to fibrinogen concentrations, thrombin concentrations play an important role
in fiber thickness and clot density. Increased thrombin concentrations result in clots made of smaller fibers that are more
densely packed and less porous [52,55]. In contrast, clots formed with decreased thrombin concentrations lead to thicker
fibers and more porous clots. Calcium concentration is also quite important due to its binding with fibrinogen. Decreased
calcium concentrations cause clots to be formed more slowly, resulting in a less densely packed clot [56]. Increases
in calcium concentration drive the clot to form more quickly, resulting in more densely packed fibers. Directly related,
calcium also plays an important role in fibrinolysis, which we will discuss further later.
hole interactions leads to
34 Cardiovascular Thrombus
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FACTOR XIII
Resistance to mechanical and proteolytic stimuli is critical for clot stability and protection against bleeding. This stabilization is performed by the activated form of the 320-kDa transglutaminase, factor XIII (FXIII), which covalently binds
two or more fibrin monomers. FXIII circulates in the blood as a heterodimer consisting of two A- and two B-subunits
(A
) [57,58]. The B-subunit acts to protect and transport the hydrophobic A-subunit, which contains the active site
2B2
of the enzyme, while circulating in the blood. It should be noted that the B-subunit, on its own, is found at concentrations
roughly twofold higher than the A-subunit, and so approximately only half of the B- circulates in complex with the A-subunit
as an A
A-subunit, but also mediates other protein interactions with FXIII [60]. A schematic of FXIII is shown in Fig. 3.2.
Activation of FXIII occurs in two steps. First, thrombin cleaves a 37-amino-acid activation peptide (AP) from the
A-subunit, followed by calcium-induced dissociation from the B-subunit. This exposes the A-subunit active site and
produces the activated enzyme FXIIIa. The reaction is further enhanced by the presence of polymerizing fibrin [61]. In the
presence of thrombin, fibrinogen FpA is normally cleaved much faster than FXIII AP. The B-subunit of FXIII binds tightly
to fibrinogen, which accounts for nearly all FXIII circulating in the blood. As FXIII dissociates into A
remain bound to fibrin.
Already bound to fibrin as protofibrils are forming, FXIIIa can now form covalent cross-links between side chains from
ε-lysine donors and g-glutamine acceptors. Cross-linking of fibrin occurs only on the a and g chains, though at different
rates for each chain. To start, g-chai ns are cross-linked near the C terminus at residues Gln398 and/or Gln399 and Lys406
[62]. More slowly, a chains are cross-linked at residues Gln221, Gln237, Gln328, Gln366, and several lysine residues
[63,64]. The geg cross-links act to stabilize protofibrils, while aea cross-links stabilize the laterally aggregated structures
[65]. While cross-linking between chains is occurring, FXIIIa also incorporates a
a chain at Lys303 [27]. a
the clot. This interaction acts to further enhance fibrin’s resistance to lysis. In addition, other proteins are incorporated into
the clot to further stabilize and enhance resistance to lysis, including thrombin-activatable fibrinolysis inhibitor (TAFI),
fibronectin, collagen, and von Willebrand factor [66e69].
Stabilizing the clot with the addit ion of FXIII, not surprisingly, stiffens the clot through moleculeemolecule
interactions, continuing to single fibers and all the way to the whole clot level. As we will discuss further in a later section,
clots made only in the presence of thrombin and not FXIIIa are less stiff than those formed in the presence of FXIIIa [70].
Structurally, the presence of FXIIIa produces clots that are more densel y packed and less porous than those formed in its
absence [71]. FXIII binds to fibrinogen prior to being activated and remains bound when converted to its activated form,
heterotetramer, while the remainder circulates free [59]. It is believed that the B-subunit not only protects the
2B2
and B2, FXIIIa can
2
-antiplasmin (a2-AP) into the clot on the
2
-AP is a well-known inhibitor of plasmin, the major enzyme responsible for breaking down
2
FIGURE 3.2 Factor XIII structure. Schematic of the tetrameric factor XIII (FXIII) molecule made up of two A-subunits and two B-subunits (left).
In the presence of thrombin and calcium, the activation peptide (AP) is removed from each A-subunit and the A- and B-subunits dissociate (right).
This process exposes the active site on the A-subunit, which can cross-link fibrin. Activation of FXIII by thrombin and calcium is enhanced by the
presence of fibrin.
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