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8 Computational Fluid Dynamics intheArterial System: Implications forVascular…
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formation, growth, and rupture [53, 54]. The effect of arterial geometry plays a
vital role in stress distribution and consequently rupture risk of the aneurysm [55].
Greater geometric tortuosity can increase arterial WSS [56].
CFD simulation can be employed to identify the relationship between haemodynamic changes resulting from dilatation and aneurysm growth, risk and location of
rupture [55]. CFD modelling results indicate that the highest WSS occurs at the
entrance or inlet of blood ow into the aneurysm where it is confronted with higher
pulsatile blood ow forces and the lowest WSS is located at the widest part of the
aneurysm wall [57]. In regions of low WSS, ow recirculation and thrombus deposition occur probably from prolonged interaction between the blood and the vascular endothelium leading to wall degeneration. An understanding of the interplay
between wall shear stress and vascular remodelling will ultimately lead to a better
understanding of AAA development, growth, and rupture potential [58].
193
8.8.4 Aortic Dissection
CFD and FEA are also useful in studying why and where are the most likely points
in the aortic arch for spontaneous and traumatic dissections to occur. The subsequent behaviour of the false lumen might be predicted rather than only observed and
management planned accordingly.
Thrombosis of the false lumen in aortic dissection is essential to reduce the longterm risk of aneurysmal change. Maintenance of ow and increase in diameter of
the false lumen is due to the relatively high diastolic pressure in the false lumen due
to higher outow resistance and a ow gradient from false to true lumens during
diastole. If this is reduced by treatment closing inow to the false lumen, then the
false lumen diastolic pressure falls and the lumen collapses. Thrombosis will occur
when blood ow velocity and arterial WSS are low [59].
In complex dissection where the stent graft landing zone is critical, CFD can be
used to predict the effects of various lengths of coverage on false lumen exclusion
so that the treating surgeon can weigh up the risks of longer coverage and false
lumen exclusion with the increased risk of paraplegia [60, 61].
8.8.5 Stents
Stent thrombosis and in-stent stenosis following arterial stenting is the result of
complex interactions between the owing blood, altered wall geometry, compliance
mismatch, radial force and stent structure [62]. CFD modelling can be used to predict the effects of stenting in different vascular beds by providing detailed analysis
of blood ow and the interaction forces and displacements between the blood ow
and the stented artery. This can be used to inuence stent design and improve treatment strategy.
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S. Mishani et al.
8.9 CFD Benets andChallenges
CFD is a quick and cost-effective means of studying blood ow conditions which
enable us to investigate blood pressure variations and induced arterial wall stresses
which cannot be achieved by bench top testing. Furthermore, CFD post-processing
provides comprehensive visual images from vectors, contours, or animations which
generate an insight into the interpretation of arterial diseases and treatment strategies.
Despite the benets, some inherent limitations and challenges of CFD should be
understood. CFD converts physical data to small numerical fragments to simplify
complex problems which creates inaccuracies when compared to analytical equations [44]. Time consuming numerical calculations in complex CFD models may
necessitate simplication of variables and parameters as well as modelling of only
a few cases rather than large numbers, and this can introduce error [63, 64].
8.10 Conclusion
Clinical image-based CFD modelling and haemodynamic parameters, particularly
those related to arterial WSS, can hold a prominent position in the patient-specic
quantitative evaluation of arterial disease and treatment effects [64]. Using accurate
properties of blood and arterial walls in modern CFD is enhancing our understanding compared to earlier techniques which assumed Newtonian properties and nonpulsatile vessels for example. This is serving to provide more accurate prediction of
behaviour which can be informative in the clinical setting.
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Further Reading
Versteeg HK, Malalasekera W.An introduction to computational uid dynamics: the nite volume
method. Pearson Education; 2007.
Chapter 9
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Physiological Haemostasis
SimonMcRae
Key Learning Points
The haemostatic response involves complex interactions between multiple pro-
•
teins and cell types, and can be divided into primary and secondary haemostasis
• Primary haemostasis results in platelet plug formation and results from interac-
tions between platelets and subendothelial adhesive proteins (von Willebrand
factor and collagen)
• As part of the primary haemostatic response, platelets go through a sequence of
events that involves initial platelet adhesion, resulting in intracellular signalling
that triggers platelet shape change, activation with granule release, and nally
aggregation.
•
Secondary haemostasis results in sequential conversion of zymogens to active
enzymes as part of the coagulation cascade, leading to the formation of a mesh-
like network of cross-linked brin.
• The brinolytic system is responsible for the dissolution of thrombus composed
of cross-linked brin, and plays a major role in helping maintain a patent vascu-
lar system
9.1 Introduction
Physiological haemostasis involves complex interactions between endothelial cells,
platelets, and coagulation proteins, that result in a platelet plug and localised thrombus formation at the site of a break in vascular integrity. Numerous regulatory processes prevent widespread activation of coagulation, ensuring that blood remains
uid in the absence of vascular injury or other pathology. All components of the
S. McRae (*)
Department of Haematology, Launceston General Hospital, Launceston, Australia
e-mail: Simon.McRae@ths.tas.gov.au
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_9
199© Springer Nature Switzerland AG 2020
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haemostatic process can be disturbed resulting in either a pro-thrombotic or bleeding tendency, and drugs that modify the haemostatic process are commonly used,
particularly in patients with vascular disease. An understanding of normal haemostasis is therefore important for all clinicians that deal with this patient group.
S. McRae
9.2 Primary Haemostasis
Primary haemostasis is the initial response of the body to vascular injury, and
involves interaction between platelets, adhesive proteins located in the subendothelial matrix (including collagen and von Willebrand factor), and circulating brinogen [1]. The end result of primary haemostasis is the formation of a stable platelet
plug around which a brin network can then be built. This same process is responsible for the pathogenic thrombus formation in patients with arterial disease.
Disorders of primary haemostasis tend to manifest as mucosal bleeding, including
epistaxis, oral bleeding and menorrhagia, and often result in immediate difculty
with haemostasis in the post-operative setting.
9.2.1 Platelets
Platelets are small fragments of megakaryocyte cytoplasm that, in the resting state,
are small discoid structures. The normal range for circulating platelet count in adults
is between 150 and 400× 109/L.Although anucleate, platelets are metabolically
active, and interact with the local environment through the binding of surface glycoprotein receptors to specic ligands (for more detail on these interactions, see
Chap. 10). Platelets go through a predictable cycle of response to vessel wall injury
that involves initial platelet adhesion to the sub-endothelium, subsequent intracellular signalling that triggers platelet shape change and activation with granule
release, and nally aggregation (Fig.9.1) [2].
9.2.1.1 Platelet Adhesion andvon Willebrand Factor
Endothelial injury results in the exposure of circulating blood to the subendothelial
matrix that is rich in a number of adhesive proteins. von Willebrand factor (vWF) is
a large adhesive glycoprotein produced by endothelial cells and megakaryocytes
that play a central role in initial platelet adhesion [3]. The mature vWF molecule
consists of disulphide-linked multimers of high molecular weight of up to 20,000,000
daltons [4]. When secreted into the plasma, these high molecular weight (HMW)
vWF multimers are digested into smaller forms by the metalloprotease ADAMTS13
(a disintegrin and metalloprotease with a thrombospondin type 1 motif, member
13). These smaller soluble forms bind less readily to platelet receptors, reducing the
GP IIb/IIIa Fibrinogen
Collagen
s
n
GP Ia/IIa
9 Physiological Haemostasis
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201
Adhesion
Fig. 9.1 Mechanism of platelet aggregation
chance of spontaneous platelet aggregation. However, vWF secreted into the subendothelial space binds to other molecules such as collagen, resulting in a conformational change that exposes the binding site for platelet glycoprotein (GP) receptor Ib
[4]. Subendothelial vWF is therefore “primed” to interact with circulating platelets
in the event of endothelial injury. Other important adhesive proteins include collagen type 1 and type 4, bronectin, thrombospondin, laminin and vitronectin.
Initial platelet adhesion, particularly in high shear conditions, involves interaction
between vWF and the GPIb/IX/V complex located on the platelet surface. This complex consists of four trans-membrane subunits GPIba, GPIbb, GPIX and GPV, with
the N-terminal globular domain of GPIba responsible for the interaction with the
A1-domain of vWF [1]. Binding of vWF to GP Ib is often reversible, and in animal
models platelets can be seen to initially slide or translocate along the subendothelial
surface due to cyclical attachment and then dissociation of the GP Ib/IX/V complex
to vWF [2]. However, nally through further platelet receptor ligand interactions the
platelet is stabilized on the subendothelial surface. The platelet glycoprotein Ia/IIa
receptor (integrin α
2ß1
tant in low-shear conditions [5]. Glycoprotein VI, a platelet surface receptor that
belongs to the immunoglobin superfamily, also directly binds collagen and further
activates the GPIa/IIa receptor via intracellular signaling [6]. Other ß1 integrins also
bind their respective subendothelial ligands (α6ß1—laminin; α5ß1—bronectin), and
there is increasing evidence that early binding of vWF to the glycoprotein IIb/IIIa
) receptor contributes to the initial adhesion process [2]. Finally there is evi-
(α
IIbß3
dence that formation of platelet membrane tethers, that consist of smooth cylinders
of lipid membrane pulled from the platelet surface under the inuence of hemodynamic drag forces, contribute to platelet adhesion in high shear conditions [7].
VWF
GP Ib/IX/V
Shape change, Activation
Granule release
Clotting factor
Aggregation
ADP, Serotoni
) binds collagen, an interaction that appears to be more impor-
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S. McRae
In addition to being involved in initial platelet adhesion as described above,
VWF also binds circulating factor VIII [8]. This signicantly prolongs the half-life
of the latter molecule. As a result, patients with reduced VWF levels will also have
reduced FVIII levels due to the acceleration in clearance of FVIII.
VWF has also been shown to be involved in the regulation of blood vessel formation, with lack of VWF leading to enhanced angiogenesis in some vascular beds [9].
As a result patients with von-Willebrand disease have been documented to have
increased rates of angiodysplasia that may result in intractable gastro-intestinal
bleeding.
9.2.1.2 Platelet Activation andShape Change
Following platelet adhesion, multiple pathways lead to platelet activation that
results in platelet shape change, platelet granule release, and conformational
change in the GP IIb/IIIa receptor that allows binding to brinogen and vWF, leading to platelet aggregation. Binding of vWF to the GP Ib receptor and collagen to
the GP VI during the adhesion process triggers intracellular signaling via a pathway that involves activation of Src family kinases (Src), Syk and PI 3-kinase
(PI3K). These events lead to the activation of phospholipase C-β (PLC), which
hydrolyses membrane phospholipids to generate inositol (1,4,5) trisphosphate
(IP3) [10]. The binding of IP3 to its receptors (IP3R) on the dense tubular system
(DTS) then results in mobilisation of intra-platelet calcium stores, which has a
number of consequences including;
1. Thromboxane A2 (TXA2) generation—the increase in intracellular calcium stim-
ulates the production of arachadonic acid by PLC and phospholipase A2.
Arachadonic acid is converted into TxA2 via the actions of the enzymes cyclo-
oxygenase 1 (COX-1) and Tx synthase. TxA2 is released from the platelet and
binds platelet receptors TPα and TPß. The effects of TxA2in platelets are medi-
ated primarily through TPα. Binding of TxA2 to this G-protein coupled receptor
results in further PLC activation, leading to further intracellular calcium increase
further reinforcing platelet activation [11]. Local diffusion of TxA2 also contrib-
utes to the recruitment to the site of injury and activation of further platelets.
Aspirin or acetyl salicylic acid exerts its antiplatelet effect by blocking TXA2
synthesis, due to the irreversible acetylation of Serine-529in COX-1. Because
platelets are anucleate, no new COX can be generated, explaining why aspirin
has a persistent functional effect that lasts the lifespan of the platelet (approxi-
mately 7days).
2. Granule release—intracellular calcium mobilization also results in the release
from the platelet of both the dense and alpha-granules. The dense granules con-
tain high concentrations of the small molecules adenosine diphosphate (ADP)
and serotonin, which further act to reinforce local platelet activation by binding
to specic platelet surface membrane receptors upon release. ADP is a central
player in sustained platelet activation. The receptors for ADP, the P2Y
and
1
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203
P2Y12 are seven transmembrane receptors that are coupled via heterotrimeric
G-proteins to numerous intracellular effector molecules. P2Y1 links to the
G-protein Gq resulting in further activation of PLC and also protein kinase C
activation. P2Y12 is linked to the G-protein Gi that has an inhibitory effect on
adenylate cyclase. ADP induced activation of the P2Y1 receptor induces platelet
shape change and rapid transient aggregation [12], whereas activation of the
P2Y12 receptor results in sustained irreversible aggregation [13]. The thienopyri-
dine class of antiplatelet agents, ticlopidine, clopidogrel, prasugrel and ticagrelor
all exert their antiplatelet effect by blocking the P2Y12 receptor. The active
metabolites of all agents have a free thiol moiety that forms a disulde bridge
with the extracellular cysteine residues Cys17 and Cys270 [14]. Released sero-
tonin also binds to a G-protein coupled platelet surface receptor, the 5-HT2A
receptor. Binding is also associated with Gq-dependent activation of PLC, result-
ing in amplication of platelet activation, platelet shape change, and weak
reversible platelet aggregation [15].
3. Activation of the GP IIb/IIIa receptor—in its resting state the GP IIb/IIIa recep-
tor is unable to bind its ligands, namely brinogen and vWF.The above platelet
signaling events through the activation of the small GTPase Rap1b and its
interaction with a Rap1-GTP interacting adapter molecule (RIAM), lead to the
binding of the proteins talin and kindlin to ß3 tail of GP IIb/IIIa receptor [16].
This leads to activation of the receptor and the resulting change in conforma-
tion allows the surface portion of the receptor to bind readily to brinogen and
vWF. The binding of talin to the receptor tail also links it to the underlying
actin cytoskeleton of the platelet, enhancing adhesive strength and platelet
cohesion [17].
4. Platelet shape change—the normally discoid-shaped platelet with a smooth sur-
face membrane undergoes dramatic shape change with stimulation, including
extension of lopodia, and attening or spreading on the subendothelial surface.
The platelet cytoskeleton is primarily responsible for regulating the platelet’s
shape. Platelet activation leads to the rapid reorganization and polymerization of
actin into laments, resulting in the above conformational change [18].
Along with ADP, the serine protease thrombin plays an important role in sustaining platelet activation leading to irreversible platelet aggregation. Thrombin specic
receptors, the protease-activated receptors (PARs), are located on the platelet surface. Two main PARs, PAR1 a high afnity receptor and PAR4, a low afnity receptor, are involved in thrombin mediated platelet activation [19]. Thrombin activates
PARs by cleaving the N-terminal of the receptor, unmasking a hidden receptorlinked ligand. This ligand then interacts with the remainder of the receptor leading
to G-protein coupled signaling that results in further platelet activation.
Finally platelet activation also results in the surface expression of a number of
adhesion molecules, such as the glycoprotein P-selectin which is involved in interaction with both endothelial cells and also the recruitment of inammatory cells to
the area of injury, via binding of P-selectin to P-selectin glycoprotein ligand 1
(PSGL-1) located on the surface of leucocytes [20]. Platelets also secrete
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