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Classically, the onset and progression of atherosclerosis
is related to inflammation
Macrophages, neutrophils, and lymphocytes play a
pivotal role in destabilizing and rupturing atherosclerotic
plaques, resulting in atherothrombosis
However, there has been recent linkage of the
inflammation and coagulation in atherosclerosis
While antiplatelet/anticoagulant therapy has not been
shown to produce regression of plaques, the hemostatic
modulators influence the composition of the arterial wall.

Hemostasis: slowed blood flow
› Due to…
 Normal vasoconstriction
 Abnormal obstruction (plaques)
 Coagulation/surgical means (ligation)
The goal is to achieve an equilibrium that
allows for proper blood flow and to stop
bleeding after vascular injury.
 When this balance is disrupted, it can lead to
thrombus formation or bleeding

Aside from their traditional hemostatic role,
platelets are also important in pro-inflammatory
conditions such as atherosclerosis
 Coagulation proteins are involved in disrupting
the endothelial barrier, leukocyte recruitment,
inflammation, migration and proliferation of
VSMCs, and angiogenesis
 Most of these actions are mediated by the TFFVIIa complex, factor Xa, and thrombin and
involve protease-activated receptors (PARs).
 PARs are located on vascular cells normally.
However, in atherogenesis these receptors are
overexpressed

When inflammation is present, the vascular
endothelium changes to a proatherogenic
phenotype (regardless of vascular wall injury)
 As a result, cell-adhesion molecules such as Pselectin are enhanced on the surface of both
platelets and endothelial cells. The upregulation of P-selectin causes platelets to
interact with circulating leukocytes, which is
critical in plaque formation and progression
 At the same time, platelets adhere to the
endothelium primarily via vWF, causing them to
secrete atherogenic mediators: cytokines,
chemokines, adhesion molecules, coagulation
factors, etc.

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Intact endothelium
has an anticoagulant
phenotype

Circulating platelets
and clotting factors
do not significantly
adhere

Vascular injury exposes
subendothelial matrix proteins
(collage, von Willebrand
factor) and changes to a
procoagulant phenotype

Matrix proteins cause platelet
adherence and activation and
subsequent secretion of…
› ADP: induces platelet
aggregation
› TXA2: plt. activator and
vasoconstrictor
› 5-HT: vasoconstrictor and plt.
aggregation

This results in platelets
binding to fibrinogen and
cross-linking to other
platelets– “platelet plug”
Coagulation proteins have been linked to
atherogenesis by increased thrombin-generating
activity in early atherosclerotic lesions
 The increased presence of these coagulation factors in
early atherosclerotic vessels will eventually contribute
plaque instability
 Also, clinical studies have shown that a more fibrous
plaque structure (rather than a lipid-rich structure with
inflammatory cells) is associated with thrombin
generation in coronary artery stenosis patients
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Tissue factor is considered to be
the primary starting point of the
coagulation pathway
TF is found to be higher in
atherosclerotic lesions from
patients with unstable angina or
MI vs. those with stable
conditions
Factor VII forms a complex with
TF, which takes part in: vascular
remodeling, angiogenesis,
chemotaxis, and inflammation.
Plasma levels of TF antigen are
associated with markers of
subclinical atherosclerosis
(increased carotid intima-media
thickness) and increased risk of
CV-related death
While this pathway is not essential in
hemostasis, it may be involved in arterial
thrombosis
Negatively charged surfaces in blood
trigger the cleavage of factor XII, which
activates proinflammatory kallikrein-kinin
and complement.
Factor XII-mediated formation of
bradykinin regulates vasodilation and
vascular permeabilities as well as
induces complement activation.
Levels of kallikrein in tissue and
prekallikrein in plasma have been
associated with CVD severity
If factor XII and the kallikrein-kinin
system are stimulated over a period of
time, this may encourage a
proatherogenic environment
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The intrinsic and extrinsic
pathways both activate factor X
to Xa
Factor Xa signals various cell
types of the CV system– this
contributes to the production of
proinflammatory cytokines, celladhesion molecule expression,
and up-regulation of TF
These signals may contribute
to the progression of
atherosclerotic plaques by
causing inflammation,
migration of leukocytes, and
angiogenesis
An important pharmacologic
finding is that factor Xa
inhibitors reduced vascular
remodeling and neointimal
formation
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Under normal circumstances, thrombin binds to
thrombomodulin to enhance the activation of protein C, an
endogenous anticoagulant and antiinflammatory.
During atherogenesis, thrombomodulin decays allowing
thrombin to potentiate endothelial dysfunction, oxidative
stress, inflammation, and activation of platelets and
leukocytes.
Thrombin (along with factors Xa, XIa, IXa, and plasmin)
also cleaves complement proteins C3 and C5 which
induce inflammation and chemotaxis of inflammatory cells.
Furthermore, Melagatran (a direct thrombin inhibitor)
reduces progression of atherosclerosis and promotes
plaque stability by inhibiting proinflammatory transcription
factors
› This effect shows a cross-linking between coagulation and
inflammation in atherosclerosis

Plasma fibrinogen levels are a major
indicator of the amount of formed thrombin.
› In the presence of thrombin, fibrinogen is
converted to fibrin, forming a fibrin clot

The effects of fibrinogen on the plaque
phenotype…
› Favors permeability of endothelial cells,
accumulation of LDL, and formation of foam cells
› Induces monocyte and VSMC migration
› Increases platelet reactivity and aggregation
› Enhances inflammation
Factor XIII is also known as “fibrin stabilizing
factor” because it cross-links fibrin to form
fibrin chains, creating an insoluble clot
 Factor XIII also enhances the formation of
angiotensin II receptors, worsening
atherosclerosis by continually sensitizing
circulating monocytes and enhacing
inflammation.
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Tissue Factor Pathway Inhibitor (TFPI) acts on
factor VIIa and Xa to decrease thrombin formation,
resulting in decreased angioenesis, vascular
remodeling, inflammation, and increased clearance
of lipoproteins
TFPI co-localizes with TF, regulating its effects
within atherosclerotic lesions
TFPI also inhibits matrix metalloproteinases which
play a pivotal role in destabilizing plaques
Studies have shown that TFPI-deficient mice have
significantly more plaques than control mice and
that overexpression of TFPI is associated with
lower cholesterol levels and reduced plaque
development
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Thrombin, despite its many procoagulant effects, also
acts as an anticoagulant. It activates protein C by
binding to protein C receptors.
Protein C then dissociates and forms a complex with
protein S leading to inactivation of factors Va and VIIIa,
therefore down-regulating additional generation of
thrombin
Studies have indicated that atherosclerotic vessels have
decreased protein C receptor expression, leading to
decreased anticoagulant activity/regulation of thrombin

There is an intimate cross-linkage between
hemostasis and inflammation in atherosclerosis

While anticoagulant therapy is important in
prevention of thrombosis, it has not yet
demonstrated regression of plaque growth

However, while long-term warfarin
administration has not shown any visible effect
on plaque progression, patients who under went
CABG showed a 35% reduction in mortality 3
years after discontinuation. This evidence leads
to the possibility of warfarin therapy to alter
plaque phenotypes

With traditonal vascular imaging using ultrasound, it has
been difficult to accurately examine phenotypes and
changes of plaques due to poor tissue penetration.

The use of high-resolution MRI in assessing plaque
characteristics will support the phenotyping of vasculature
walls as a method of determining the role of hemostasis in
atherosclerosis

Currently, very few medications target relevant molecules
of hemostasis. With this potential, new research and
therapeutic options should be investigated
› Oral direct inhibitors of Xa and thrombin
› Small molecules that can access vessel walls and potentially
alter plaques
 DX-9065A
 Pradaxa
Borissoff, Julian I., Henri M. Spronk, and Hugo
Ten Cate. New England Journal of
Medicine 2011; 364:1746-760.
 Dipiro, Joseph T., Terry L. Schwinghammer,
and Cecily V. Dipiro. “Venous
Thromboembolism.” Pharmacotherapy
Handbook. By Barbara G. Wells. 7th ed.
New York: McGraw-Hill Companies, 2009.
163-65.
 Katzung, Bertram G., Susan B. Masters, and
Anthony J. Trevor. "Drugs Used in Disorders
of Coagulation." Basic and Clinical
Pharmacology. 11th ed. New York:
McGraw-Hill Companies, 2009. 587-91
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The Hemostatic System as a Modulator of Atherosclerosis