General Considerations
Despite the essential role of platelets in arterial thrombogenesis, personalized antiplatelet
therapy based on platelet function tests (PFTs) did not improve clinical outcome after
coronary revascularization1 and did not predict recurrent ischemic or bleeding events
in individual patients.2,3 To understand why these point-of-care PFTs have yielded
so little clinical benefit, we scrutinized their mechanism of thrombus assessment
for its relevance to the pathomechanism of arterial thrombogenesis.
Fundamental differences exist between thrombus generation at high shear in native
blood in vivo and agonist-induced platelet aggregation at low shear in anticoagulated
blood ex vivo. Most PFTs in current use reproduce the second scenario. These tests,
which are variants of the classical platelet aggregometer, are based on the assumption
that the secretion of agonists from activated platelets is the major determinant of
thrombus growth. Accordingly, various soluble agonists are used (adenosine diphosphate
[ADP], thromboxane A2 [TXA2], or α-thrombin) to activate platelets in citrate-anticoagulated
whole blood at very low shear, and the formation of small platelet aggregates (attached
to fibrinogen-coated beads to obtain better optical signals) are measured. Under physiological
conditions, at arterial shear rates (≈420 s−1), platelet aggregation occurs only in
response to activation by agonists; however, in vivo, at sites of turbulent flow near
the site of a severe stenosis and thus high shear (above ≈10 000 s−1), long-lasting
adhesion and aggregation occur without any requirement for platelet activation. Consequently,
the main soluble agonists are not involved in the initial shear-induced platelet aggregation
but rather contribute to stabilization of the unstable platelet aggregate. There are
also essential differences between platelet aggregation in citrated blood and native
blood. In citrated blood, in response to activation of platelets by ADP, collagen,
or arachidonic acid, soluble agonists are released from platelet storage granules
or generated by platelets (release reaction), which substantially enhances the initial
platelet reaction (secondary aggregation). In contrast, in native blood, whether in vivo
or in vitro, only activation by α-thrombin binding to platelet surface glycoprotein
Ibα receptors can induce platelet adhesion, dense granule secretion, and aggregation.
Under pathological conditions, thrombin is essential not only for initiation and propagation
of the initial platelet aggregation but importantly for stabilization of the platelet
thrombus through enzymatic and structural effects. By releasing plasminogen activator
inhibitor 1, the main inhibitor of the fibrinolytic system, from the storage granules
of platelets and activating thrombin-activatable fibrinolysis inhibitor, thrombin
confers resistance on the arterial thrombus against endogenous fibrinolysis. Thrombin
also anchors unstable platelet aggregates, together with fibrin, to the site of vascular
injury, imparting structural stability to the thrombus, thereby preventing downstream
embolization due to the effects of arterial flow (Figure 1).
Figure 1
Contribution of high shear forces and thrombin to arterial thrombogenesis. Exposed
to high shear, platelets with clustered membrane glycoprotein Ibα interact with the
exposed A1 domains of vWF, and loose platelet aggregates are formed. High shear also
induces formation of platelet-derived microparticles, which generate thrombin. Acting
on the loose primary platelet aggregates, thrombin (1) propagates aggregation by releasing
ADP from platelet granules and allowing the formation of thromboxane A2, (2) provides
structural stability to the thrombus by enmeshing the tight platelet aggregate with
a fibrin network, and (3) makes the platelet-rich thrombus resistant to endogenous
fibrinolysis by releasing the main fibrinolysis inhibitor PAI-1 from platelets and
inducing the formation of TAFI. ADP indicates adenosine diphosphate; PAI-1, plasminogen
activator inhibitor 1; TAFI, thrombin-activatable fibrinolysis inhibitor; TXA2, thromboxane
A2; vWF, von Willebrand factor.
Importance of High Shear Forces
Evidence shows that shear gradient–dependent platelet aggregation is the primary mechanism
initiating thrombus formation under conditions of pathological high shear, such as
those that exist in a severely stenosed artery. Soluble agonists play only a secondary
role, serving to stabilize the initial platelet aggregates.
High wall shear rates are considered pathological in the range 2500 to 200 000 s−1,
and the maximum shear rate across a severe short stenosis can exceed 250 000 s−1.4
An average 10% decrease in vessel diameter at the stenosis site can increase shear
rates by 40% to 90% and initiate platelet activation and thrombus formation.5 Earlier
investigators of fluid mechanics characterized the hemodynamics, specifically, the
wall shear rates, in a severely stenosed coronary artery and proposed a cardinal role
for high shear in initiating thrombus formation6–9; however, these basic studies could
not explain the interaction between shear and thrombus growth. Although confirming
earlier findings, later studies provided strong evidence for the threshold and mechanism
of high shear–induced platelet activation.4,10–12
Variables affecting the actual shear rates in a severely stenosed artery are shown
in Figure 2. From a detailed analysis, stenosis length, height, and roughness emerged
as the main determinants of the local shear rates, whereas stenosis eccentricity or
flow pulsatility were not significant contributors to local hemodynamics.12 The extended
length of stenosis reduced the shear rate by a factor of 4. Compared with a smooth
surface, roughness of the plaque or thrombus surface greatly increased shear rate.
Even at an early stage of atherosclerosis, the luminal surface of the arterial wall
becomes rough because of accumulation of lipid-filled macrophages within the intima
and detachment of endothelial cells.
Figure 2
Variables affecting local shear rates in a severely stenosed artery. The definition
of shear rate (γ) is shown, in which Q is the flow rate and r is the radius of the
vessel. Streamline pattern of blood flow through a stenotic vessel is shown. The peak
shear in the apex of the stenosis is reduced with increasing length of the stenosis,
whereas surface roughness of the stenosis increases shear rates. In the poststenotic
recirculation zone, shear rate is low and flow of turbulent; small eddies cause hemolysis
by dissipating shear energy to the membrane of red cells.
Under normal flow conditions, von Willebrand factor (vWF) and platelets circulate
together without interacting, and their interaction to form thrombi is regulated by
changes in shear stress. At physiological arterial shear rates (≈420 s−1), platelet
aggregation occurs only after activation by agonists; however, if shear rates exceed
10 000 s−1, glycoprotein Ibα receptors on the platelet surface form clusters, and
plasma vWF undergoes conformational transformation exposing its A1 domain. As a result
of these structural changes, platelets interact with vWF, and aggregates are formed
just downstream in the poststenotic segment, at which there is low shear (shear deceleration
zone) and turbulent flow (Figure 1). At these high shear rates, platelet aggregation
occurs independently of ADP, TXA2, and thrombin and is mediated exclusively by vWF–glycoprotein
Ibα adhesive bonds.6–8 In addition, above threshold shear rates of >10 000 s−1, microvesicles
(microparticles) are formed on the platelet surface and are responsible for abundant
thrombin generation.13 Furthermore, in the poststenotic region at low shear and turbulent
flow, small eddies can induce hemolysis (Figure 2), and the disrupted red cell membrane
fragments also contribute to thrombin generation. The significance of shear-induced
thrombus formation in a stenotic artery is supported by increased platelet reactivity
due to vWF release after coronary angioplasty.14 Because of this key role in arterial
thrombogenesis, vWF is regarded as a risk factor, mediator, and pharmacological target
in antithrombotic strategy.15
Point-of-Care Platelet Function Tests That Use High Shear
Presently, 3 commercially available point-of-care PFTs claim to test platelet reactivity
under high shear stress: the PFA-100 (Siemens Inc), the Global Thrombosis Test (GTT;
Thromboquest Ltd), and the PlaCor Platelet Reactivity Test (PlaCor Inc).
In the PFA-100, shear rates of 5000 s−1 are described in the 147-μm aperture of the
collagen-coated membrane impregnated with specific platelet agonists; however, histology
of the occluded aperture revealed that adhesion and aggregation of platelets take
place on the proximal (and not distal) surface of the membrane around the aperture,
and the arrest of flow was caused by the extension of those proximally formed platelet
aggregates into the aperture. This is important because the platelets, which react
with the collagen-coated membrane and form occlusive aggregates, were exposed to shear
only in the capillary conduit (200-μm diameter) on their way to the membrane16,17
and had not passed through the 147-μm aperture. Because shear rate is inversely proportional
to the cube of the arterial radius, the true initial shear rate in the PFA-100 is
likely to be <2500 s−1.
The manufacturer of the PlaCor Platelet Reactivity Test claims that a shear rate of
1500 s−1 exists in the restricted segment of the capillary conduit and that platelet-rich
thrombus formation on the steel coil, which forms the restriction, is a reflection
of high shear–induced thrombosis. In fact, deposition of platelets and leukocytes
on stainless steel surfaces at low shear and low flow rates is a recognized phenomenon
on cardiac catheters18 and has little relevance to the thrombotic occlusion of a stenotic
artery at high flow and shear rates.
The GTT uses native blood and an initial shear rate of ≈16 000 s−1 as the sole agonist
to activate platelets and initiate the thrombotic occlusion of narrow channels. When
platelets are exposed to such high shear, they become activated, aggregate, form microparticles,
and generate thrombin. Because the shear rate in the GTT is higher than the threshold
of >10 000 s−1, there is no requirement for the use of any chemical agonist. Because
only fibrin-stabilized thrombi can cause the measured occlusion and arrest of flow,
the GTT measurement reflects both platelet reactivity to pathologically relevant high
shear stress and thrombin generation. At elevated shear stress, platelet thrombus
formation depends entirely on the binding of vWF to platelet glycoprotein Ibα and
glycoprotein IIb/IIIa receptors. This is reflected in the GTT, in which occlusion
time was inversely correlated with plasma vWF antigen and vWF ristocetin cofactor
activity,19 and antagonism of vWF with the glycoprotein Ib inhibitor aurin tricarboxylic
acid significantly inhibited occlusion,20 showing that vWF is essential for thrombosis
formation in this system.
It has to be emphasized that despite the vast theoretical knowledge accumulated in
this field, the many variables make it extremely difficult to simulate hemodynamics
that occur in vivo in a stenosed atherosclerotic coronary artery. Based on evidence
from theoretical studies, however, a PFT should claim relevance to the coronary situation
in vivo only if it exerts high shear stress (>10 000 s−1) on platelets and a shear
gradient (flow deceleration zone with turbulence) is created in which the propagation
and stabilization of the initial shear-induced platelet aggregates could take place.
Importance of Thrombin Generation
The formation of procoagulant phospholipids (microparticles) on the membranes of platelets
and subsequent thrombin generation are cardinal features of arterial thrombogenesis
(Figure 1). The crucial contribution of thrombin to arterial thrombosis is thought
to be 2-fold. First, thrombin, the most powerful platelet agonist, accelerates the
initial aggregation both by direct action and by releasing potent agonists (ADP, TXA2,
platelet activating factor 4) from platelets. Second, by forming fibrin, thrombin
imparts structural stability to the initially unstable thrombus mass.
As stated earlier, in vivo, only thrombin activation can induce a platelet release
reaction, namely, the release of ADP and formation of TXA2 (ie, the agonists often
used in PFT assays), and generate microparticles on the platelet surface.21 It has
been shown that patients with stable ischemic heart disease on dual antiplatelet therapy
express high levels of the thrombin receptor protease-activated receptor 1 (PAR-1)
that are associated with profound thrombin-inducible platelet activation. Nonetheless,
neither ex vivo PAR-1 expression nor in vitro thrombin-inducible PAR-1 activation
was correlated with ADP-inducible platelet aggregation,22 and no interaction was observed
between PAR-1 or P2Y12 antagonist treatment after acute coronary syndromes on efficacy
or safety of outcomes.23 Measurement of platelet thrombus formation on collagen fibrils
in flowing blood did not reveal a correlation between inhibition of thrombus formation
and the level of P2Y12 inhibition.24 Furthermore, the relative importance of agonist-induced
platelet activation, release reaction, and contribution to thrombus growth at pathological
high shear rates has been challenged.25,26
Evidence now points to thrombin as the main player at an early stage by providing
firm attachment of platelet aggregates to the vessel wall and later by stabilizing
the loose platelet aggregates with fibrin and rendering the thrombus resistant to
fibrinolysis. Activation of thrombin receptors PAR-1/PAR-4 by thrombin results in
the synthesis and secretion of plasminogen activator inhibitor 1 from aggregated platelets27
and activation of thrombin-activatable fibrinolysis inhibitor, conferring resistance
on the arterial thrombus against endogenous fibrinolysis (Figure 1). Such fibrin-stabilized
thrombus can resist high arterial flow and, protected from endogenous thrombolysis,
can cause lasting occlusion of the artery.
Effect of Anticoagulation on Thrombin
Thrombin formation takes place only above a critical plasma calcium concentration.
For convenience, so that samples can be stored and analyzed when convenient, most
PFTs are performed on citrate-anticoagulated blood, in which the calcium concentration
is well below the necessary threshold for thrombin generation.2 In citrated blood,
many common platelet agonists can cause secondary aggregation due to secretion of
ADP and formation of TXA2 (release reaction). In contrast, in native blood, only thrombin
can induce significant platelet granule secretion (ADP release, TXA2 formation).28
In the absence of thrombin generation due to citrate anticoagulation, all common point-of-care
PFTs (PFA-100, VerifyNow assay [Accumetrics], Plateletworks [Helena Laboratories])
that use citrated blood, in which there is an absence of thrombin generation, use
specific agonists to induce platelet aggregation. Only the GTT and the PlaCor Platelet
Reactivity Test use native blood, the former using venous blood and the latter using
fingerstick blood; however, PFTs using fingerstick blood have little relevance to
platelet reactivity in vivo. First, the most reactive platelets react and remain inside
the wound and are not present in the collected sample. This is confirmed by findings
showing fingerstick platelet counts to be systematically lower and to correlate poorly
with venous counts.29 Furthermore, release of tissue factor from the wound accelerates
coagulation; therefore, such a test at low shear rates more closely reflects coagulation
than pure platelet reactivity. Thrombin generated from activated platelets (procoagulant
activity) plays a pivotal role in GTT measurement. Microparticles derived from red
cells or platelets exert a common mechanism of triggering thrombin generation. To
assess endogenous thrombin potential, a technique of hemolysis-induced microparticle
formation was used with the GTT and shown to cause enhanced thrombotic occlusion,
a convenient model to assess total endogenous thrombin potential.30
Does the Specific Inhibition of TXA2 or ADP-Induced Platelet Aggregation Reflect the
Sole Mechanism of the Antithrombotic Effect of Aspirin and P2Y12 Inhibitors?
Dual antiplatelet therapy coupling aspirin with a P2Y12 inhibitor is currently the
therapy of choice for the prevention of recurrent thrombotic events following coronary
stent implantation. In such a combination, aspirin inhibits platelet TXA2 generation,
and the P2Y12 receptor inhibitor prevents ADP-induced platelet activation. Aspirin
and P2Y12 antagonists are regarded as “agonist-specific” drugs, selectively inhibiting
platelet activation by TXA2 or ADP, respectively. Nonetheless, several studies indicate
that these drugs exert antithrombotic effects that are unrelated to inhibition of
ADP- or TXA2-induced platelet aggregation.31–33 Recent findings suggest that 12-hydroxyleicosatetraenoic
acid, a procoagulant (tissue factor release) and proaggregatory eicosanoid that is
generated alongside TXA2 from arachidonic acid–stimulated platelets, may play a significant
role in variable sensitivity to aspirin.34 Intake of aspirin significantly delayed
and inhibited thrombin generation in native thromboplastin-activated blood, whereas
it had no such effect in citrated plasma.35 Aspirin appears to have a significantly
reduced effect on collagen-induced thrombus formation at high wall shear rates. In
a canine model of coronary artery stenosis, aspirin was effective only at low shear
rates of 500 s−1, whereas at shear rates of 2000 s−1, aspirin failed to prevent cyclic
flow reduction, even at high doses.5,36 Aspirin did not reduce platelet deposition
and thrombus formation with collagen in a model replicating an 80% stenosis at a shear
rate of 10 500 s−1.37 In contrast to its effects at low shear rates of 500 and 1500 s−1,
aspirin was unable to fully prevent occlusive thrombus formation at high shear rates
of 4000 and 10 000 s−1, even at doses 20 times the recommended daily oral dose of
100 mg.38 In patients with peripheral arterial disease on aspirin, platelet responsiveness
to various agonists was normal when tested under high shear–flow conditions, except
for inhibited platelet reactivity to PAR-1 stimulation.39
A marked reduction in thrombus formation with frequent thrombus detachment from collagen
surfaces after aspirin use38–40 indicates that at high flow and shear conditions,
it is the inhibitory effect of aspirin on thrombus stabilization, rather than inhibition
of platelet cyclooxygenase and TXA2 synthesis, that is responsible for much of its
therapeutic effect.
Because the potent antithrombotic effects of platelet P2Y12 receptor blockers are
attributed solely to antagonism of ADP-induced platelet aggregation, tests of ADP-induced
aggregation are used to monitor their therapeutic effectiveness; however, ADP-induced
platelet aggregation is also affected by aspirin and is not specific for P2Y12 receptor
inhibition. Furthermore, ADP release from dense granules after platelet stimulation
with ADP in citrated blood results in significantly increased peak aggregation compared
with the same stimulation with ADP in hirudin-anticoagulated blood, in which ADP activation
does not cause release and secondary aggregation. As such, ADP-induced platelet aggregation
tests underestimate the in vivo effect of P2Y12 inhibitors.41 The relationship between
circulating levels of P2Y12 inhibitors and inhibition of ADP-induced platelet aggregation
is nonlinear. The most specific method for assessing platelet P2Y12 receptor activity
is the flow cytometric analysis of the phosphorylation state of vasodilator-stimulated
phosphoprotein. Although ≈50% of patients were found to be clopidogrel resistant as
measured by ADP-induced platelet aggregation (VerifyNow), the vasodilator-stimulated
phosphoprotein assay identified only 11.7% of patients as nonresponders.42 Most PFTs
measuring ADP-mediated platelet aggregation use prostaglandin E1, which was shown
to overestimate the therapeutic response to platelet P2Y12 inhibitors.43 On these
grounds, the suitability of ADP-induced platelet aggregation for monitoring P2Y12
antagonist medication is questioned.44–46
Earlier claims that P2Y receptors on platelets could be activated only by nucleotides
(ADP) have been challenged. Several P2Y receptors display agonist promiscuity and
tissue specificity and can be activated not only by ADP but also by other agonists
such as leukotrienes in nanomolar concentrations. As such, P2Y12 inhibitors may exert
important effects on thrombotic and inflammatory processes through mechanisms that
are independent of inhibition of ADP-induced platelet aggregation or unrelated to
P2Y12 antagonism. Vessel wall (not platelet surface) P2Y12 receptors were shown to
be important in early atheroma formation, and the latter was not inhibited by platelet
P2Y12 inhibition.47 Activation of neutrophils and the release of active tissue factor
at the site of plaque rupture during acute myocardial infarction are important thrombogenic
stimuli. The P2Y12 receptor antagonist prasugrel metabolite has been shown to inhibit
neutrophil activation through a mechanism that does not involve P2Y12 receptors in
neutrophils.48
It has been shown recently that P2Y12 antagonism disrupts the stability of newly formed
platelet aggregates, promotes disaggregation, and reverses arterial thrombotic occlusion.
Consequently, in addition to activating platelets, signaling via P2Y12 receptors seems
to be required for stabilizing platelet thrombi.49,50 Nitric oxide released from vascular
endothelium is a powerful inhibitor of platelet aggregation. Blockade of P2Y12 receptors
dramatically enhanced the antiplatelet potency of nitric oxide, resulting in a 1000-
to 100 000-fold increase in inhibitory activity against platelet aggregation and release
reaction in response to activation by thrombin or collagen.51
These findings support the hypothesis that mechanisms other than inhibiting ADP-induced
platelet aggregation play the main role in the antithrombotic effect of P2Y12 antagonists.
Furthermore, inhibition of thrombin generation, which is unaffected by P2Y12 inhibitors,
is a common-denominator mechanism of effective antithrombotic therapies. The reevaluation
of the thrombin hypothesis is reflected in the proposed advantages of adding novel
oral anticoagulants that directly or indirectly inhibit thrombin to dual antiplatelet
therapy to further reduce cardiovascular thrombotic events.52–54 Although this approach
may reduce thrombotic events, it also increased bleeding risk and thus cannot be recommended
as a panacea for all comers.
Anticoagulation of Blood Prevents the Use of High Shear Stress and Assessment of Thrombin
Generation in Point-of-Care Platelet Function Tests
Thrombus stability, namely, its firm attachment to the vessel wall and resistance
to embolization by the arterial flow, is a major determinant of the outcome of arterial
thrombus formation. Thrombin formed at the site of thrombus growth plays a pivotal
role in both thrombus growth and stability. In citrate-anticoagulated blood, thrombin
is not formed from activated platelets due to very low concentrations of calcium;
in addition, citrate exerts a direct effect on platelet reactivity that is unrelated
to the effect on ionized calcium levels.2,55 In citrated blood at very low shear,
such as that which occurs in platelet aggregometry, only small, loosely packed aggregates
are formed in response to agonist stimulation. If higher, pathologically relevant
shear rate is applied to citrated blood, the adhesion of platelets to the subendothelium
is greatly reduced and, because of the weak attachment between platelets, aggregation
is abolished.56 In contrast to the effect in citrated blood, the effect of aspirin
on platelet thrombus growth was markedly attenuated in native blood subjected to high
shear rate.57
In the GTT, native blood is tested at high shear rates, and the measured occlusion
and arrest of flow is caused by fibrin-stabilized thrombi. As such, thrombin generation
is an essential part of the test. It is claimed that in a single measurement, the
GTT can detect major determinants of hemostasis including platelet reactivity, endogenous
fibrinolytic, and thrombin-generating potential.30 In the GTT, the occlusion time
is a reflection of platelet reactivity. Short occlusion times may represent enhanced
platelet reactivity such as that occurring in a prothrombotic state, whereas prolonged
occlusion times may reflect the effect of antiplatelet or anticoagulant medication.
The second phase of the test assesses lysis time, a measurement that reflects the
rapidity of lysis of the platelet thrombus formed in the first phase. The more prolonged
the lysis time, the less effective the endogenous thrombolytic activity, and this
appears to correlate with an increased risk of thrombotic events.
The GTT has limitations, including the need for timely prompt assessment of blood
immediately on withdrawal because native blood is used. Although providing a clear
physiological advantage, this approach could be seen by some as an inconvenience in
the present era of collecting anticoagulated blood samples and testing them later
in specialized laboratories. Furthermore, the instrument should be situated close
to the patient, and this may not be always possible or practicable. Delays in starting
the measurement or prolonged or difficult blood draws could have important effects
on the results of the occlusion and lysis times. Importantly, the GTT has not been
assessed and validated in large clinical trials, so its value in guiding personalized
antithrombotic therapy or predicting ischemic and bleeding events after coronary intervention
is largely unknown.
Assessment of Endogenous Thrombolytic Status
The overall clinical outcome of a thrombotic stimulus will be determined not only
by the strength of the stimulus for promoting thrombus formation and stabilization
but also by the efficacy of the natural protective endogenous thrombolytic enzymes.
The GTT is the only available PFT that measures thrombolytic status.58 That the lysis
time measured in the GTT is specific for thrombolysis is shown by the fact that plasminogen
activator streptokinase and tissue-type plasminogen activator dose-dependently enhanced
thrombolysis (lysis time) without affecting platelet function (occlusion time). The
plasmin inhibitor tranexamic acid prevented plasminogen activator–induced thrombolysis,
whereas inhibition of clot retraction by cytochalasin B did not affect the lysis time.20
The potential clinical relevance of assessing lysis time has been shown in patients
with recent acute coronary syndromes58,59 and with renal failure58,60 in whom impaired
endogenous thrombolysis, as demonstrated by prolonged lysis time, was associated with
an increased risk of myocardial infarction and cardiovascular death. In a small cohort
of patients presenting with ST-elevation myocardial infarction, those with spontaneous
ST resolution and normal coronary flow before intervention had very short lysis times
(efficient endogenous lysis), and those with markedly impaired (prolonged) lysis times
had higher incidence of no-flow and future adverse events.61
Conclusion
In the mechanism of coronary atherothrombosis, high shear stress and thrombin play
the cardinal roles. Although some PFTs claim to subject blood to high shear, actual
shear rates are well below the threshold required for direct platelet activation and
inducing thrombin generation. Furthermore, for convenience, these tests are carried
out on anticoagulated blood, in which thrombin is not generated. Current antiplatelet
therapy and thus PFTs target thromboxane A2 and the ADP–P2Y12 platelet activation
pathways. In vivo, however, only thrombin-induced platelet activation results in ADP
release and TXA2 formation, and even this makes little contribution to thrombus growth
at pathological shear rates. The most important function of thrombin in atherothrombosis
is to impart structural stability to the thrombus mass. Experimental evidence points
to reduced thrombus stability at the sites of severe stenoses, as one of the most
important therapeutic effects of antiplatelet drugs.
Disregarding the importance of both high shear forces, as primary activators of platelets
in a stenosed artery, and thrombin generation, which is responsible for thrombus stability,
has great negative impact on the clinical usefulness and physiological relevance of
many currently available PFTs.
Disclosures
Gorog is related through family to a company director in Thromboquest Ltd, but neither
she nor her spouse or children have any shares or financial interests or receive any
benefits from this company. She has received no grants, honoraria or financial sponsorship
from this company. There are no other conflicts of interest to disclose. Jeong has
received honoraria for lectures from AstraZeneca, Sanofi-Aventis, Daiichi Sankyo/Lilly,
Haemonetics, Otsuka and Yuhan Pharmaceuticals; and research grants or support from
AstraZeneca, Korean Society of Interventional Cardiology, Han-mi Pharmaceuticals,
and Haemonetics.