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Antithrombotic Drug Therapy in Cardiology: The Role of Coagulation in Arterial and Venous Thrombosis
The Role of Coagulation in Arterial Disease
Links Between Coagulation and Atherosclerosis
Atherogenesis is a complex process involving endothelial cells, VSMC, macrophages, platelets,
lipids, the inflammatory system, and cytokines that leads to the development of lipid-rich atheroscle-
rotic plaques that result in vascular stenosis (9,125,126,148). Ongoing inflammation steers cellular
proliferation and extracellular matrix production toward apoptosis, matrix degradation, and accumula-
tion of necrotic material (9,126). Further disruption of a plaque made vulnerable by inflammation
often leads to an acute thrombosis and vascular occlusion, due to platelet thrombus formation (127–
129). Increased tissue factor expression by cells within the ruptured plaque can lead to coagulation
activation, thrombin activation, and fibrin formation (23). If vascular occlusion does not occur with
subclinical rupture, repetitive plaque rupture, thrombosis, and cellular proliferation lead to further
Table 1
Risk factors associated with venous thrombosis
Acquired Inherited
Major surgery Factor V Leiden
Trauma, accidental and surgical Prothrombin gene mutation G20210A
Solid and hematopoietic malignancies
Cancer therapies
Antithrombin deficiency
Central venous catheters Protein C deficiency
Limb immobilization
Hip, knee replacement
Prolonged cast or splinting
Stroke
Protein S deficiency
Bed ridden due to acute illness:
Cardiopulmonary disease
Infectious disease
Inflammatory disease
Malignancy
Hyperhomocysteinemia*
FVIII activity*
*Hereditary and environment contributions
Antiphospholipid antibody syndrome
Heparin-induced thrombocytopenia
Paroxysmal nocturnal hemaglobinuria
Disseminated intravascular coagulation/sepsis
Inflammatory bowel disease
Dysfibrinogenemia
Advancing age, especially >50
Obesity
Pregnancy, oral contraceptives, hormone replacement therapies
Long-haul airline travel Controversial:
Factors IX and XI
Plasminogen deficiency
Hypofibrinolysis
PAI-1 4G/5G mutation
ZPI deficiency
Factor XIII polymorphisms
Endothelial protein C receptor
Thrombomodulin
References: (107,116,117)
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Antihrombotic Drug Therapy in Cardiovascular Disease
luminal narrowing (130). The crucial role of both platelets and coagulation in the pathogenesis of
acute coronary atherothrombosis is shown by the success of pharmacologic intervention with
antiplatelet and anticoagulant drugs
(131,132).
Tissue factor plays several roles in atherogenesis. Many cells within the atherosclerotic plaque
express tissue factor
(23). That tissue factor may play a role in pathogenesis of plaque-associated
thrombosis is shown by animal studies demonstrating inhibition of thrombosis by treatment with
recombinant-activated factor VII or TFPI
(133,134). In addition, circulating tissue factor associated
with cellular microparticles may also play a role in atherothrombosis. Procoagulant microparticles
have been shown to be elevated in patients with acute coronary syndromes compared to patients with
stable angina
(79,135). However, other reports indicate that endothelial microparticles observed in
acute myocardial infarction may have an anticoagulant phenotype, through expression of TFPI and
activated protein C
(87). An observation of increased levels of leukocyte-derived microparticles in
subclinical atherosclerosis suggests a predictive value for microparticle measurement
(84,136). While
the role of circulating microparticles in atherothrombosis is not firmly established, drugs such as
statins, which have been shown to decrease microparticle release, may play an additional role in treat-
ment of coronary disease
(137).
Thrombin generation certainly plays a role in atherothrombosis through its stimulation of fibrin
production, but it has been shown to be an integral regulator as well due to its ability to activate
platelets, and mediate inflammatory signals to macrophages, smooth muscle cells and endothelial
cells (9,19,149). Thrombin, through action on endothelial PARs-1 and -2, stimulates expression of
leukocyte adhesion molecules and secretion of proinflammatory chemokines such as monocyte
chemotactic protein-1, platelet-derived growth factor (PDGF), IL-6 and IL-8 (9,138). Thrombin may
also play a role in matrix remodeling due to its ability to stimulate endothelial production of matrix
metalloproteinases (139). Further coagulation effects of thrombin on endothelial cells include release
of von Willebrand factor, factor VIII, and tPA
(19). Smooth muscle cells also express PAR-1 and -2,
and thrombin may stimulate their proliferation, production of growth factors, production of extra
-
cellular matrix proteins, and expression of tissue factor (9,140). Thrombin activation of platelets
through PAR-3 and -4 not only leads to platelet activation, but also to secretion of inflammatory
mediators (PDGF, platelet factor 4, RANTES) and expression of CD40 ligand, that serves to attract
leukocytes and activate them
(141). As discussed previously, thrombin’s protease activity is usually
short lived due to many inhibitory mechanisms. However, there is some evidence that thrombin may
be sequestered in atherosclerotic lesions, resulting in persistent thrombin activity with consequent
cellular effects and vascular remodeling
(19).
Role of Thrombophilia Risk Factors in Arterial Thrombosis
Thrombophilia risk factors, as described earlier, are typically associated with an increased risk
of venous thrombosis as most risk factors are due to increased function of coagulation proteins or
decreased function of the natural anticoagulants. There is, however, a modest association between
some of the thrombophilia risk factors with arterial thrombotic disease (142), especially in
younger individuals or in association with oral contraceptive use. The association between factor
V Leiden and myocardial infarction has been studied in several large meta-analyses, with an over-
all modestly increased relative risk of MI in factor V Leiden carriers of 1.17 (95% CI 1.08–1.28)
(143). Data from a meta-analysis of prothrombin G20210A and MI showed an increased odds ratio
of 1.28 that was nonsignificant (95% CI, 0.94–1.73) (144). Despite single case reports, prospec-
tive studies have not shown an association between deficiency of antithrombin, protein C, or
protein S and MI (142).
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Antithrombotic Drug Therapy in Cardiology: The Role of Coagulation in Arterial and Venous Thrombosis
SUMMARY
The coagulation proteins have a vital role in the hemostatic process, defending the body from
exsanguination during trauma. However, it is clear that dysregulation of the coagulation system can
variously lead to venous thrombosis and contribute to the development of arterial atherothrombotic
disease. Indeed, in arterial thrombosis, the effects of thrombin may extend far beyond coagulation
activation and play an important role in activation of a wide variety of cells and the inflammatory
processes. Venous thrombosis and arterial thrombotic diseases have traditionally been thought of as
separate processes; however, they share many similarities in pathophysiology and risk factors. The
activation of the coagulation cascade underlies both arterial and venous thrombosis, and biological
triggers, such as inflammation, prothrombotic microparticles, and endothelial activation provide a
plausible link between the two.
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3 The Link Between Inflammation
and Thrombosis
John H. Cleator and Mark Robbins
Co n t e n t s
Pathobiology of Inflammation, Atherosclerosis, and ACS
Markers and Mediators of Inflammation
The Future of Inflammation Control in ACS
Closing Thoughts and Cautionary Accounts from Previous
Anti-Inflammatory Strategies
References
Ab s t r a c t Atherosclerosis is an inflammatory disease. This fact is now strongly supported by clini-
cal, basic, and pathological research which has caused an evolution in thought concerning the evalu-
ation and treatment of acute coronary syndromes (ACS). The initial insult is endothelial injury and
subsequent dysfunction via the deleterious effects of the known cardiac risk factors such as oxidized
LDL, hyperglycemia, hypertension, hyperhomocystinemia, and smoking. Irrespective of the cause of
endothelial damage, the resultant activation and proliferation of inflammatory cells, smooth muscle
cells, and generation of cytokines and growth factors lead to the progression of atherosclerosis. The
presence and extent of inflammation, procoagulant state and composition of the atherosclerotic plaque
have been strongly associated with an increased risk of future cardiac events. Thus, the perpetuation
of the inflammatory response likely plays a pivotal roIe in the pathobiology and vulnerability of the
atherosclerotic plaque. Inflammatory markers once thought to be passive observers are now being
investigated as active participants in the progression of atherosclerosis and therefore targets for future
pharmacologic intervention.
Key words: CAD; Thrombosis; Inflammation; ACS; Adhesion Molecules; Chemokines; Cytokines;
C reactive protein; MPO; Interleukins; von Willebrand factor; P-selectin; Serum amyloid A; A2
Phospholipases; Tumor necrosis factor-a; NF-kB; HMG-CoA reductase inhibitors; PPAR agonists;
Aspirin; Cyclooxygenase-2; Protease-activated receptors; Thrombin receptor antagonist
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI :10.1007/978-1-60327-235-3_3
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
PATHOBIOLOGY OF INFLAMMATION, ATHEROSCLEROSIS, AND ACS
Endothelial Function
The endothelium lies in a critical location between the remaining vascular wall and the circulating
blood, thereby functioning as the pivotal barrier that protects the arterial wall from injury. This critical
monolayer of cells is pluripotential, carrying out the following functions; (1) provision of a nonthrom-
botic surface; (2) maintenance of vascular tone through the production and release of nitric oxide
(NO), prostacyclin, and endothelin; (3) regulation of growth factors and cytokines; (4) provision of a
nonadherent surface for leukocytes and platelets; and (5) the modification of lipoproteins as they
transverse its permeable barrier
(5). Injury to this monolayer plays a key role in the initiation and
progression of the atherosclerotic lesion by increasing adhesive cell surface glycoproteins, adherence,
migration, and activation of leukocytes, and smooth muscle cells, production of cytokines, chemok-
ines, and growth factors, as well as the reversal from an antithrombotic to a prothrombotic state
(1–4,7,9–12) (Fig. 1).
Adhesion Molecules
Cell-cell interactions are a vital component in the pathogenesis of inflammation and propagation
of atherosclerosis. Collectively known as cell adhesion molecules, three distinct families exist
(selectins, integrins, and the immunoglobulin superfamily) each with its own specific role in the
inflammatory process. The process entails tethering and rolling of leukocytes on the activated
endothelium, leukocyte activation, and ultimately firm adhesion and transendothelial migration along
a chemotactic gradient generated by mediators of inflammation (13,14).
Selectins are expressed on the cell surface of leukocytes (L-selectin), platelets (P-selectin), and
endothelial cells (E-selectin). Upon activation from inflammatory cytokines, mainly tumor necrosis
factor-a (TNF-a) and IL-1, cell surface expression of each selectin is enhanced
(15–17). This process
is vital in the early phase of inflammation mediating leukocyte recruitment and transient endothelial
Site of injury
(Plaque rupture or
erosion)
vWF
Leukocyte
Adhesion
Molecules
P-selectin
E-selectin
VCAM
ICAM
Platelet
Activation
Endothelial
Cell
NO
Prostacyclin
Vascular Smooth
Muscle Cell
Atherosclerotic Core
MMPs
Plaque Rupture
Angiogenic Growth
Factors
sCD40L
sP-selectin
MPO
sPLA2
LP-PLA2
a
b
c
d
Chemokines
Inactive Platelet
Active Platelet
Fig. 1. Schematic of the protective role the endothelium in preventing the progression of atherosclerosis.
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