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586 © Schattauer 2011
Venous and arterial thrombosis – pathogenesis and the rationale
for anticoagulation
Alexander G. G. Turpie1; Charles Esmon2
1Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 2Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, and Departments
of Pathology and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
Summary
Thromboembolic disorders are major causes of morbidity and mortality.
It is well-recognised that the pathogenesis is different for arterial and
venous thrombosis; however, both involve coagulation activation. Anti-
coagulants are used for the prevention and treatment of a wide variety
of thromboembolic and related conditions. Agents with anti-
inflammatory properties in addition to anticoagulation may be particu-
larly beneficial. Traditional anticoagulants, although effective, are as-
sociated with certain limitations. Understanding the pathological pro-
cesses associated with thrombosis and the rational target for anti-
coagulation is essential, not only for the development of safer and more
Correspondence to:
Dr. Alexander G. G. Turpie, MD
Department of Medicine, McMaster University
Hamilton Health Sciences-General Hospital
237 Barton Street East
Hamilton, Ontario L8L 2X2, Canada
Tel: +1 416 363 6726, Fax: +1 905 628 9505
E-mail: turpiea@mcmaster.ca
Introduction
Haemostasis is the normal physiological response that prevents
significant blood loss after vascular injury. Blood vessel injury
triggers a sequence of responses: vessel constriction to reduce
blood flow; platelet plug formation at the site of trauma involving
platelet adhesion, activation, and aggregation; and blood coagu-
lation involving a complex set of protease reactions. Although hae-
mostasis is essential for survival, inappropriate coagulation can
lead to the formation of a thrombus. Thromboembolic disorders
are major causes of morbidity and mortality. Anticoagulants are
used to prevent or treat a wide variety of conditions that involve ar-
terial or venous thrombosis, including the prevention and treat-
ment of venous thromboembolism (VTE), long-term prevention
of ischaemic stroke in patients with atrial fibrillation (AF), and sec-
ondary prevention of cardiac events in patients with acute coron-
ary syndrome (ACS) (1–4).
It is well-recognised that the pathogenesis of arterial thrombo-
sis differs from that of venous thrombosis, which is reflected by
their different management strategies. Understanding the patho-
genic processes that occur in the blood vessel wall and in the blood
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Review Article
effective agents, but also for better clinical management of patients
who require anticoagulation therapy. In recent years, new oral agents
that target single enzymes of the coagulation cascade have been devel-
oped – some of those are in advanced stages of clinical development.
Based on scientific rationale, both factor Xa and thrombin are viable
targets for effective anticoagulation.
Keywords
Anticoagulation, arterial thrombosis, factor Xa, thrombin, venous
thrombosis
Received: October 28, 2010
Accepted after minor revision: December 27, 2010
Prepublished online: January 12, 2011
doi:10.1160/TH10-10-0683
Thromb Haemost 2011; 105: 586–596
itself causing thrombosis is crucial, not only for developing more
effective and safer antithrombotic agents, but also for better man-
agement of patients with thromboembolic disorders. Traditional
anticoagulants are associated with limitations such as parenteral
administration with the heparins and the requirement for routine
coagulation monitoring and dose adjustment with the vitamin K
antagonists (5, 6). In recent years, small-molecule, oral agents that
target a single enzyme in the coagulation cascade have been devel-
oped. Some of these new oral agents (such as direct factor Xa in-
hibitors and direct thrombin inhibitors) have undergone extensive
evaluation for the prevention and treatment of thromboembolic
disorders (7).
After a brief description of haemostasis and blood coagulation,
this article will provide an overview of the pathogenesis of venous
and arterial thrombosis, and the rationale for using anticoagulants
in those thromboembolic and related disease conditions. The im-
pact of the protein C pathway on coagulation and inflammation,
and the potential role of new oral anticoagulants and other anti-
thrombotic agents in the management of thromboembolic dis-
orders will also be discussed.

Haemostasis and blood coagulation
The endothelium of the blood vessel wall plays a crucial role in
maintaining the integrity of the vasculature. When the vessel wall is
damaged or the endothelium is disrupted, collagen in the sub-
endothelial matrix becomes exposed to the flowing blood. Within
seconds, platelets bind to the exposed collagen, which causes pla-
telet activation, degranulation, and aggregation, leading to the
formation of a primary platelet plug. In conjunction, coagulation
is activated at the site of injury by the exposed subendothelial tissue
factor (TF), resulting in fibrin formation, which stabilises the pla-
telet plug (8, 9).
TF is an integral membrane protein that is constitutively ex-
pressed on fibroblasts and pericytes in the adventitia and medial
smooth muscle cells of the blood vessel wall (8). Under normal
conditions, the endothelium acts as a barrier to separate TF from
factor VII and factor VIIa in the circulating blood, which prevents
the initiation of coagulation in the absence of vessel injury. How-
ever, TF is also expressed in many non-vascular cells (such as
monocytes) and microparticles in the circulation. This blood-
borne TF is thought to participate in the processes of blood coagu-
lation (8, 10). Coagulation reactions occur on specific cell surfaces
such as activated platelets and TF-bearing cells.
For decades, the coagulation cascade was conceptualised as hav-
ing two distinct points of initiation – the extrinsic and intrinsic
pathways (11). However, it has become clear that these pathways do
not function in the body as independent systems. An increasing
understanding of the role of different factors and cells involved in
blood coagulation has led to a cell-based model of coagulation.
Unlike the older cascade model, the cell-based model represents
more accurately the interaction between coagulation enzymes and
cellular activity that leads to thrombin generation and clot
formation (12).
Initiation phase
The initiation phase is localised to cells that express TF (8, 12).
After binding to factor VIIa, the TF−factor VIIa complex activates
small amounts of factor IX and factor X. Factor Xa then activates
factor V on the TF-bearing cells and forms a complex with factor
Va, which then converts a small amount of prothrombin (factor II)
to thrombin (factor IIa; 씰Fig. 1) (12, 13).
Amplification phase
The small amount of thrombin generated on TF-bearing cells am-
plifies coagulation reactions. In addition to activating platelets, the
generated thrombin activates factor V and factor VIII on the pla-
telet surface, leading to a burst of thrombin-generating potential.
Thrombin also activates platelet-bound factor XI (씰Fig. 1) (8, 12).
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Turpie, Esmon: Anticoagulation in thrombosis 587
Propagation phase
On the surface of activated platelets, factor XIa activates factor IX.
This factor IXa, together with the factor IXa generated by the TF−
factor VIIa complex, forms the tenase complex with factor VIIIa.
This factor IXa−factor VIIIa complex activates factor X, which
forms the prothrombinase complex with factor Va and produces a
burst of thrombin generation.
Clot formation
The generated thrombin cleaves soluble fibrinogen to insoluble fi-
brin. Fibrin monomers polymerise to form the fibrin mesh that is
stabilised and cross-linked by thrombin-activated factor XIIIa
(씰Fig. 1) (12, 14).
Recent evidence suggests that cellular injury can release mRNA
from the cells, which in turn can activate coagulation by triggering
factor XII activation. The physiological relevance of this pathway is
demonstrated by the observation that vessel occlusion in the ferric
chloride model of arterial thrombosis has been reduced by RNAase
treatment (15). Cell injury can also release histones that are cytot-
oxic to cells and elicit fibrin and platelet deposition along with leu-
cocyte accumulation in the tissues. The trigger for these responses
is probably the release of RNA from the cells and the exposure of
TF (16). The relevance of these observations is supported by the
finding that the blockade of histone toxicity protects animals from
the lethal responses to endotoxin.
The role of endothelial cells in the control of
blood coagulation
The endothelium of the blood vessel wall plays a crucial role in
maintaining the integrity of the vasculature. By releasing sub-
stances such as nitric oxide, prostacyclin, and the ectonucleotidase
CD39, the endothelium keeps the platelets in their inactivated state
and impairs their adhesion in the absence of vessel injury (8, 17).
The endothelial cells also produce coagulation inhibitors, includ-
ing tissue factor pathway inhibitor (TFPI) and heparan sulphate.
TFPI inhibits the TF−factor VIIa/factor Xa complex (9), thus elim-
inating the generation of both factor Xa and factor IXa, and in-
hibiting the initiation of coagulation. Free thrombin and factor Xa
are inhibited by antithrombin (AT), and this inhibitory activity of
AT is markedly enhanced by heparan sulphates present on the sur-
face of endothelial cells (18). In addition, free thrombin in the cir-
culation binds to the endothelial surface-bound thrombomodulin
(TM) and activates the protein C system – a major negative control
mechanism of coagulation (18, 19).
The protein C anticoagulant system is initiated when thrombin
binds TM and forms the thrombin−TM complex, which decreases
free thrombin levels, thus preventing thrombin from cleaving fi-
brinogen or activating platelets. Furthermore, this complex masks
Thrombosis and Haemostasis 105.4/2011
588 Turpie, Esmon: Anticoagulation in thrombosis

Figure 1: An overview of blood

coagulation. TF, tissue factor; TFPI, tissue
factor pathway inhibitor; vWF, von Willebrand
factor.

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Figure 2: The anticoagulant effect of the
activated protein C system. Thrombin (IIa)
binds to thrombomodulin (TM) and activates
protein C (PC), which is reversibly bound to the
endothelial cell protein C receptor (EPCR). Acti-
vated protein C (APC) binds to protein S (PS)
and inactivates factor Va and factor VIIIa.
Figure 3: The cytoprotective effects of
activated protein C. IL, interleukin; MCP,
monocyte chemoattractant protein; TF, tissue
factor.
the binding sites of thrombin for fibrinogen and the platelet
thrombin receptor (20, 21). Protein C is a vitamin K-dependent
protein, and is activated after binding to the endothelial protein C
receptor and interacting with the thrombin−TM complex. Acti-
vated protein C (APC), together with its cofactor protein S, inacti-
vates factor Va and factor VIIIa, thereby decreasing the formation
of factor Xa−factor Va (the prothrombinase complex) and factor
IXa−factor VIIIa (the intrinsic tenase complex), which results in
the inhibition of coagulation (9, 21) (씰Fig. 2). The APC system
also enhances fibrinolysis by inactivating plasminogen activator
inhibitor-1 (which inhibits clot lysis or fibrinolysis) (20, 21). In ad-
dition, thrombin within the thrombin−TM complex is more sensi-
tive to inhibition by circulating AT than free thrombin (20). Under
normal conditions, natural anticoagulants and the fibrinolytic sys-
tem ensure that thrombus formation is a controlled and balanced
process. Deficiency or any impairment of these systems may result
in a hypercoagulable state.
Relationship between coagulation and
inflammation, and the role of activated
protein C
Thrombosis and inflammation share some pathophysiological
processes that involve inflammatory mediators, the activated
endothelium, TF expression on monocytes, and circulating TF-
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Turpie, Esmon: Anticoagulation in thrombosis 589
bearing microparticles derived from activated platelets and en-
dothelial cells (8, 21). Inflammation can trigger a coagulation re-
sponse in a number of ways, such as inducing TF synthesis in in-
travascular cells and stimulating blood-borne TF, increasing pla-
telet numbers and reactivity, causing the exposure of negatively
charged phospholipids (22), and downregulating the natural anti-
coagulant systems.
The protein C pathway is particularly sensitive to downregu-
lation by inflammatory responses (22). For example, endotoxin,
tumour necrosis factor (TNF)-α and interleukin (IL)-1β can
downregulate TM and endothelial protein C receptor – the APC
complex co-factors (23, 24). Acquired protein C deficiency is
prevalent in the majority of septic patients (>85%) and is associ-
ated with increased morbidity and mortality in patients with se-
vere sepsis and septic shock (25). On the other hand, APC exhibits
anti-inflammatory activity by decreasing proinflammatory cyto-
kines such as TNF-α, IL-1β, IL-6, IL-8, and MCP-1, reducing in-
flammatory mediator-induced TF expression on leucocytes, in-
hibiting neutrophil adhesion to the endothelium, and upregulat-
ing anti-inflammatory mediators (e.g. IL-10) (21, 24). In addition,
APC can also reduce endothelial cell apoptosis and help maintain
endothelial cell barrier functions (21, 24). Accumulating evidence
suggests that the APC system protectively modulates a variety of
disease processes, including diabetic nephropathy (26), stroke
(27), tumour metastasis (28), multiple sclerosis (29), reperfusion-
induced coronary (30), and renal injury (31). These effects are
thought to be attributed to its cytoprotective properties (씰Fig. 3).
Thrombosis and Haemostasis 105.4/2011
590 Turpie, Esmon: Anticoagulation in thrombosis
Venous thrombosis
VTE comprises deep-vein thrombosis (DVT) and pulmonary em-
bolism. DVT occurs most often in the large veins of the legs. When
part of the thrombus breaks away, it can travel to the lungs and dis-
rupt or block the blood flow in a pulmonary artery. Over 150 years
ago, Rudolph Virchow proposed a triad of causes for venous
thrombosis: venous stasis, vascular endothelial injury, and hyper-
coagulability of blood. This triad still applies, with one or more
factors participating in the development of DVT (씰Fig. 4).
Venous stasis (or reduced blood flow in the veins) can be caused
by many medical conditions, including immobility (e.g. hospital
or nursing home confinement), major orthopaedic surgery (e.g.
during and after surgery), or increased venous pressure (e.g. in
heart failure). The majority of venous thrombi form in regions
with a slow blood flow (32) and reducing venous stasis in the legs
has been found to reduce the risk of VTE (33). Venous stasis pro-
motes thrombus formation by failing to clear activated coagu-
lation factors quickly from the site of vascular injury. In addition,
local hypoxia and distension of the vessel wall as a result of venous
stasis can activate the endothelium, causing the expression of ad-
hesion molecule selectins on its surface (17). Accumulating evi-
dence suggests that circulating TF-bearing microparticles may play
important roles in venous thrombosis (8, 17) – similar to that of
platelets in arterial thrombosis (34). These microparticles attach to
the activated endothelial cells and transfer TF to them, initiating
coagulation reactions and clot formation (17). An increase in en-
dothelial microparticles and leucocyte activation has been found
in patients with VTE (35).
It has also been suggested that TF-bearing microparticles may
also contribute to the hypercoagulable state associated with disease
conditions with an increased risk of DVT (such as cancer, inflam-
mation, and congestive heart failure) (8, 17, 36). Elevated numbers
of tumour-derived TF-bearing microparticles in plasma have been
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found in cancer-associated thrombosis (8). Although surgery or
trauma can directly cause vascular wall injury, and coagulation is
activated via the exposed subendothelial TF, deep vessel wall injury
is not a common feature in non-surgical patients with DVT.
Factors that may allow a small, silent thrombus to enlarge, or a
new thrombus to develop, include the prolonged impairment of
venous function (37), sustained hypercoagulability (38), and im-
pairment of the endogenous anticoagulant or fibrinolytic systems
(39, 40). Venous thrombi consist of mostly red blood cells and large
amounts of fibrin. Activation of the coagulation system is the pri-
mary cause of venous thrombosis, and precedes platelet activation
and aggregation (17). This explains why anticoagulation therapy
has become the primary management strategy for VTE, and evi-
dence-based guidelines strongly recommend the use of anticoagu-
lants for the prevention and treatment of VTE (3, 4, 41).
Arterial thrombosis
The primary trigger for arterial thrombosis is the rupture of an
atherosclerotic plaque, causing a complete or partial vessel occlu-
sion. When plaque rupture occurs, its lipid core is exposed to the
circulating blood in the arterial lumen. The core area of the plaque
contains TF and fragments of collagen, which are highly thrombo-
genic (42, 43). Circulating TF is also increased in patients with car-
diovascular disease and might contribute to thrombosis after
plaque rupture (44). In the initial stage of plaque rupture, platelets
are rapidly recruited to the site, followed by aggregation and the re-
sulting rapid growth of the thrombus. The coagulation cascade is
also activated at this stage with the formation of thrombin, which
activates platelets. Activated platelets promote further platelet re-
cruitment, adhesion, aggregation, and activation (44). Thus, an ar-
terial thrombus is platelet-rich and exposed to fast flowing blood.
Figure 4: Venous thrombosis. Pathogenic
processes that can trigger venous thrombosis
include: abnormal blood flow (e.g. venous
stasis), vessel wall damage or alterations in the
endothelium, and hypercoagulability of blood.
© Schattauer 2011

Figure 5: Arterial thrombosis. An athero-
sclerotic plaque develops through the accumu-
lation of lipid deposits and foam cells. The rup-
ture of an atherosclerotic plaque is the primary
trigger of arterial thrombosis. The core area of
the plaque contains tissue factor and collagen
(highly thrombogenic), which are released into
the lumen of the blood vessel upon rupture.
The fibrin component of the thrombus increases as it extends into
the arterial lumen, although the surface area of the thrombus that
is exposed to the blood in the lumen will be covered by activated
platelets. A loose network of fibrin with large numbers of trapped
red blood cells also form part of the thrombus in the final stage of
thrombosis (43) (씰Fig. 5).
ACS is usually the outcome of atherosclerosis and thrombosis
in the coronary arteries. Most acute myocardial infarctions are
caused by thrombosis developed on a culprit coronary athero-
sclerotic plaque. Thrombosis is also the major initiating factor in
unstable angina. Studies have suggested that a new thrombotic cor-
onary event accounts for 50–70% of sudden deaths caused by is-
chaemic heart disease (43). An arterial thrombus that is rich in fi-
brin is often fully occlusive and results in ST-elevated myocardial
infarction, whereas a platelet-rich arterial thrombus is often par-
tially occlusive, resulting in unstable angina and non-ST-elevated
myocardial infarction.
It is now well recognised that inflammation plays a key role in
the pathogenesis of coronary artery disease and other manifes-
tations of atherosclerosis. Blood-borne inflammatory and im-
mune cells constitute an important part of an atheroma. Many of
these cells are activated, producing several types of molecules (in-
cluding inflammatory cytokines and proteases), which can des-
tabilise the plaque, resulting in plaque rapture and ACS (45). The
levels of C-reactive protein and IL-6, as well as other inflammatory
markers, are elevated in patients with unstable angina and myo-
cardial infarction (24, 45, 46). Interestingly, it has been suggested
that some beneficial effects of statins may be partly attributed to
their anti-inflammatory properties (47–49). However, results from
a meta-analysis have indicated that most of the anti-inflammatory
effect of statins is related to the magnitude of low-density
lipoprotein (LDL) reduction, and the potential non-LDL effects of
statins on inflammation are relatively small (50). Nevertheless, it is
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Turpie, Esmon: Anticoagulation in thrombosis 591
likely that LDL lowering may be a primary driver for the reduction
in inflammation that contributes to lower cardiovascular risk (50).
Cyclooxygenase (COX)-2 is the inducible form of cyclooxyge-
nase and has been shown to be involved in the proinflammatory re-
sponse of vascular tissue, participating in both atherosclerosis and
thrombosis (51). Increased inflammatory activity that involves
COX-2 may predispose patients to cardiovascular events. Recent
evidence also suggests that altered histone acetylation levels in in-
flammatory processes are associated with atherosclerosis and res-
tenosis, and histone hyperacetylation may have a protective mech-
anism in vascular injury and remodelling, possibly by reducing the
expression of factors involved in these pathological processes (52).
In acute arterial thrombotic events, drugs that reduce the
growth of a thrombus should be administered, with platelets as the
main target. Although antiplatelet agents are most commonly used
to prevent the incidence of arterial thrombosis and recurrent is-
chaemic events, coagulation is clearly activated after plaque rup-
ture, which provides a mechanistic rationale for anticoagulation
therapy. Clinical evidence has shown that the combination of anti-
coagulant and antiplatelet therapy is more effective than either
treatment alone (53). In addition, based on the role of inflam-
mation in the pathogenesis of ACS, anticoagulants with anti-
inflammatory properties may be beneficial. It has been shown that
the combination of vitamin K antagonists with acetylsalicylic acid
causes higher bleeding rates (42). New oral anticoagulants have
demonstrated effective anticoagulation in some clinical studies.
However, adequate dose-findings studies for the new oral agents to
be co-administered with antiplatelet drugs in this setting are
necessary to ensure that the potential benefit of the combination
therapy is not offset by any increase in bleeding complications.
Thrombosis and Haemostasis 105.4/2011
592 Turpie, Esmon: Anticoagulation in thrombosis
Thrombus formation in atrial fibrillation
AF is the most common significant cardiac arrhythmia and it in-
creases the risk of stroke four- to five-fold across all age groups
(54). Left atrial thrombus formation in patients with AF fulfils the
Virchow’s triad for thrombogenesis, with abnormal blood flow,
endothelial dysfunction, and a hypercoagulable state (55, 56).
Thrombi associated with AF occur most often in the left atrial ap-
pendage, and abnormal blood flow is evident in the left atrium. AF
is also associated with markers of coagulation and platelet acti-
vation that may reflect a systemic hypercoagulable or prothrom-
botic state (56). For example, systemic fibrinogen and fibrin
D-dimer levels are elevated in patients with persistent and paroxy-
smal AF, indicating the presence of active intravascular thrombo-
genesis (55). Both von Willebrand factor and TF are overexpressed
in the atrial endothelium in patients with AF who have a history of
cardiogenic thromboembolism (56). In addition, recent evidence
suggests that inflammation and various growth factors may also
play a potential role in driving the prothrombotic state in AF (56).
Based on the existing evidence, the pathogenesis of throm-
boembolism in AF seems to fulfil the Virchow’s triad for thrombo-
genesis. Thus, the thrombus may be a 'venous-type clot'. There-
fore, anticoagulation therapy is an important part of patient man-
agement strategies and is strongly recommended in evidence-
based guidelines (41). Numerous clinical studies have demon-
strated that anticoagulants can effectively reduce the incidence of
ischaemic stroke in patients with AF.
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Figure 6: Targets for anticoagulation.
Schematic representation of the coagulation
cascade demonstrating the inhibiting effects
of traditional and new anticoagulants on
coagulation factors. AT, antithrombin.
Targets for anticoagulation
The coagulation pathway provides many targets for potential anti-
coagulants (씰Fig. 6). Drugs that target the TF−factor VIIa com-
plex inhibit the initiation phase of coagulation, whereas those that
target factor IXa or factor Xa, or their co-factors (factor VIIIa and
factor Va), inhibit the propagation of coagulation. Thrombin in-
hibitors inhibit thrombin activities. Direct factor Xa inhibitors and
direct thrombin inhibitors are in the most advanced stage of clini-
cal development. These include rivaroxaban, apixaban, edoxaban,
betrixaban (oral, direct factor Xa inhibitors), and dabigatran etex-
ilate (an oral, direct thrombin inhibitor). Some of these agents
have already shown promise in providing safe, equivalent, or more
effective anticoagulation compared with traditional anticoagu-
lants, without the need for routine coagulation monitoring (7, 57,
58).
Direct factor Xa inhibition
Factor X is a key component of coagulation. As part of the pro-
thrombinase complex, factor Xa catalyses the conversion of pro-
thrombin to thrombin – one molecule of factor Xa results in the
generation of approximately 1,000 thrombin molecules (59, 60).
Whenever there is vessel damage, exposing subendothelial TF, fac-
tor Xa is generated after the formation of the TF−factor VIIa com-
plex. Thus, factor Xa inhibition would be desirable in both arterial
and venous thrombosis. Moreover, inhibiting factor Xa may also be
© Schattauer 2011

important in preventing platelet activation, deposition and re-
cruitment at the sites of vessel injury by preventing thrombin gen-
eration. In addition, direct factor Xa inhibition does not affect the
activity of preformed thrombin, which may allow the function of
the existing thrombin to continue (such as activating protein C)
(61–63).
Inhibition of factor Xa with new, oral, direct inhibitors may
have potential advantages over indirect factor Xa inhibitors. These
include their ability to inhibit factor Xa within the prothrombinase
complex, which the AT-dependent, indirect factor Xa inhibitors
(such as unfractionated heparin and low-molecular-weight hepa-
rin – which have anti-factor Xa activity – and fondaparinux, which
is an indirect factor Xa inhibitor) are unable to do. Direct factor Xa
inhibitors inhibit free, prothrombinase-bound, and clot-
associated factor Xa (61, 64, 65). Clot-associated factor Xa has been
shown to be enzymatically active in vitro and is able to activate pro-
thrombin to thrombin (66) thus contributing to clot-associated
procoagulant activity (67).Therefore, direct inhibition of clot-
associated factor Xa could be an effective and localised approach to
prevent thrombus growth. Recent evidence suggests that rivar-
oxaban, a direct factor Xa inhibitor, also affects clot structure by in-
creasing the permeability and degradability of the clot, thus pro-
moting clot lysis (68).
In addition to coagulation, factor Xa also exhibits proinflam-
matory and proliferative activities. Factor Xa induces macrophage
migration inhibitory factor in endothelial cells and the expression
of IL-6, IL-8, and monocyte chemotactic protein, thus contribu-
ting to the inflammatory processes (69–71). Recent studies have
also indicated a potential role for factor Xa in the progression of
tissue fibrosis and wound healing (72). The binding of factor Xa to
vascular endothelial cells induces the release of platelet-derived
growth factor, which is involved in cell proliferation (73, 74). The
migration and proliferation of vascular smooth muscle cells in re-
sponse to endothelial injury contribute to the development of res-
tenosis and atherosclerosis. Preclinical evidence suggests that fac-
tor Xa inhibition could block some of the proinflammatory and
proliferative processes, such as the expression of proinflammatory
cytokines (75), and the proliferation of vascular smooth muscle
cells (76) and, thus, limit restenosis after balloon angioplasty (77,
78).
It has been shown recently that the oral, direct factor Xa in-
hibitor rivaroxaban concentration-dependently inhibited the pro-
coagulant activity of activated monocytes and macrophages,
whereas the indirect factor Xa inhibitor fondaparinux did not dis-
play this effect (79). This property could be attributed to the abil-
ity of rivaroxaban to inhibit factor Xa bound to monocytes. Inter-
estingly, both rivaroxaban and fondaparinux exhibited anti-
inflammatory activity by inhibiting the secretion of inflammatory
chemokines – an effect that was thought to be due to the inhibition
of thrombin generation (79); it is not yet known to what extent this
is attributed to the direct inhibition of factor Xa-mediated
proinflammatory activities.
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Turpie, Esmon: Anticoagulation in thrombosis 593
Direct thrombin inhibition
Thrombin has multiple effects on coagulation, including the con-
version of fibrinogen to fibrin and the activation of factor XIII and
platelet-bound factor XI. Thrombin is the most potent activator of
platelets, and also induces the synthesis and/or secretion of adeno-
sine diphosphate (ADP), endothelial platelet-activating factor, se-
rotonin, and thromboxane A2 (20). In addition, thrombin am-
plifies its own generation by activating factor VIII and factor V –
key co-factors for the tenase complex and the prothrombinase
complex, respectively (80). Moreover, thrombin mediates a
number of processes that promote anticoagulation and fibrinoly-
sis, via the thrombin−TM complex and APC system.
Fibrin-bound thrombin is an important potentiator of throm-
bus growth. Unlike indirect thrombin inhibitors, direct thrombin
inhibitors inactivate fibrin-bound thrombin and free thrombin
(81). In addition, because direct thrombin inhibitors do not bind
to platelet factor 4, their anticoagulant activity is not affected by the
large quantities of this chemokine released from activated platelets
in platelet-rich thrombi (7).
Thrombin is also involved in many other physiological and pa-
thophysiological processes such as inflammation and wound heal-
ing (20). Vascular endothelial growth factor (VEGF) is a specific
endothelial mitogen that initiates angiogenesis. It mediates en-
dothelial cell proliferation, cellular migration, and vascular tube
formation. Thrombin potentiates the effects of VEGF; clot-bound
thrombin, which is resistant to inhibition by AT, contributes to an-
giogenesis and tissue repair at the sites of injury. The effect of
thrombin on vascular permeability contributes to oedema and
swelling associated with inflammation (20). Furthermore, throm-
bin mediates inflammatory processes via increasing monocyte ad-
hesion to selectins (19) and the stimulation of proinflammatory
cytokine (e.g. IL-6 and IL-8) and chemokine production (20, 82,
83). These properties also present thrombin as a target for other
pharmacological interventions beyond coagulation. However,
thrombin also has anti-inflammatory properties via the thrombin−
TM complex and the APC system, and the APC system exhibits
other cytoprotective functions (such as anti-apoptosis and
endothelial barrier protection) (21). While inhibiting thrombin
activity may have anti-inflammatory potential by blocking throm-
bin-mediated proinflammatory activities, it is not known whether
long-term inhibition of the APC system (e.g. by thrombin
inhibition) would have any adverse consequences.
Inhibition of platelets
Platelets play a vital role in haemostasis and are key participants in
the pathogenesis of arterial thrombosis (84). When vascular injury
occurs (such as the rupture of an atherosclerotic plaque), platelets
are rapidly recruited to the site, followed by activation and aggre-
gation. Activated platelets then release the contents of granules,
which further promote platelet recruitment, adhesion, aggre-
gation, and activation. This results in the rapid growth of the
Thrombosis and Haemostasis 105.4/2011
594 Turpie, Esmon: Anticoagulation in thrombosis
thrombus (44). Antiplatelet agents are used for the prevention and
acute treatment of arterial thrombosis. The primary targets are
molecules involved in platelet activation and aggregation. The
commonly used agents include acetylsalicylic acid (a COX-1 in-
hibitor) and the thienopyridines (ADP receptor antagonists) (84).
Although the established efficacy has validated platelet COX-1 and
ADP receptors as clinically viable targets for antiplatelet therapy,
there are limitations with the use of these agents, such as the in-
complete inhibition of platelet aggregation and/or ongoing
thromboxane A2 production with the use of acetylsalicylic acid and
the delayed onset and offset of action with the thienopyridines (7).
Recent attention has focused on the protease activated receptor-1
inhibitors and novel ADP receptor antagonists (7).
Other pharmacological agents
In addition to anticoagulant and antiplatelet therapies, there are
also other agents that exhibit antithrombotic activity. For example,
statins have been shown to significantly reduce the risk of VTE in
recent clinical studies (85–87). The potential mechanisms that me-
diate the antithrombotic effect of statins include the reduction of
TF expression and thrombin generation, and thus the attenuation
of fibrinogen cleavage (88). In addition, statins have been shown to
promote TM expression on endothelial cells, thereby enhancing
the APC anticoagulant pathway (89, 90). Thus, the benefits of sta-
tins may be attributed not only to their effects on lipid levels and
anti-inflammatory properties, but also their potential influence on
coagulation (88, 91).
Conclusions
The aetiology and pathological mechanisms are different for ve-
nous and arterial thrombosis, which are reflected in their different
treatment strategies. Both oral, direct factor Xa inhibitors and oral,
direct thrombin inhibitors have demonstrated potential in clinical
studies to date (92–98), providing further evidence for both
factor Xa and thrombin being viable targets of anticoagulant ther-
apy. However, each drug or drug class may behave differently when
used in different clinical indications, likely due to the different
mechanisms of action of the drugs and differences in the patho-
genesis of disease conditions.
Accumulating evidence suggests a strong link between coagu-
lation and inflammation. Inflammatory mediators trigger coagu-
lation responses, and coagulation factors mediate inflammatory
processes and cell proliferation. The APC system, which has
multiple cytoprotective roles, is downregulated in inflammation.
The biological and pathophysiological roles of factor Xa and
thrombin are far beyond coagulation. The anti-inflammatory and
metastatic inhibitory effects of heparin, for example, are believed
to be independent of their anticoagulation property (99). Al-
though there are no clinical data currently available, by directly
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blocking thrombin generation or activity, the new oral anticoagu-
lants might have potential anti-inflammatory effects, which could
contribute to their antithrombotic efficacy and the overall clinical
benefits. However, it is not yet known whether long-term suppres-
sion of the APC pathway (e.g. through inhibiting thrombin activ-
ity) could cause adverse consequences. Further studies examining
the influence of direct factor Xa inhibitors and direct thrombin in-
hibitors on the APC system, as well as inflammatory markers, may
provide further insight.
Acknowledgements
The authors would like to acknowledge Yong-Ling Liu who pro-
vided editorial support with funding from Bayer Schering Pharma
AG and Johnson & Johnson Pharmaceutical Research & Develop-
ment, L.L.C.
References
1. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic ther-
apy for ischemic stroke: American College of Chest Physicians evidence-based
clinical practice guidelines (8th Edition). Chest 2008; 133: 630S–669S.
2. Harrington RA, Becker RC, Cannon CP, et al. Antithrombotic therapy for non-
ST-segment elevation acute coronary syndromes: American College of Chest
Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;
133: 670S–707S.
3. Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107:
I22–I30.
4. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism:
American College of Chest Physicians evidence-based clinical practice guidelines
(8th Edition). Chest 2008; 133: 381S–453S.
5. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K
antagonists: American College of Chest Physicians evidence-based clinical prac-
tice guidelines (8th Edition). Chest 2008; 133: 160S–198S.
6. Hirsh J, Guyatt G, Albers GW, et al. Antithrombotic and thrombolytic therapy:
American College of Chest Physicians evidence-based clinical practice guidelines
(8th Edition). Chest 2008; 133: 110S–112S.
7. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of
Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest
2008; 133: 234S–256S.
8. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359:
938–949.
9. Seré KM, Hackeng TM. Basic mechanisms of hemostasis. Semin Vasc Med 2003;
3: 3–12.
10. Chou J, Mackman N, Merrill-Skoloff G, et al. Hematopoietic cell-derived micro-
particle tissue factor contributes to fibrin formation during thrombus propa-
gation. Blood 2004; 104: 3190–3197.
11. Mann KG. The biochemistry of coagulation. Clin Lab Med 1984; 4: 207–220.
12. Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler
Thromb Vasc Biol 2006; 26: 41–48.
13. Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3: 1843–1853.
14. Bates SM, Weitz JI. Coagulation assays. Circulation 2005; 112: e53–e60.
15. Kannemeier C, Shibamiya A, Nakazawa F, et al. Extracellular RNA constitutes a
natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007;
104: 6388–6393.
16. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death
in sepsis. Nat Med 2009; 15: 1318–1321.
17. Lopez JA, Kearon C, Lee AY. Deep venous thrombosis. Hematology Am Soc He-
matol Educ Program 2004; 439–456.
18. Tanaka KA, Key NS, Levy JH. Blood coagulation: hemostasis and thrombin regu-
lation. Anesth Analg 2009; 108: 1433–1446.
19. Esmon CT. Crosstalk between inflammation and thrombosis. Maturitas 2008; 61:
122–131.
© Schattauer 2011

20. Licari LG, Kovacic JP. Thrombin physiology and pathophysiology. J Vet Emerg
Crit Care (San Antonio) 2009; 19: 11–22.
21. Sarangi PP, Lee HW, Kim M. Activated protein C action in inflammation. Br J
Haematol 2010; 148: 817–833.
22. Esmon CT. Coagulation inhibitors in inflammation. Biochem Soc Trans 2005; 33:
401–405.
23. Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of
the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988; 8: 5588–5592.
24. Esmon CT. Inflammation and the activated protein C anticoagulant pathway.
Semin Thromb Hemost 2006; 32 (Suppl. 1): 49–60.
25. Fisher CJ, Jr., Yan SB. Protein C levels as a prognostic indicator of outcome in sep-
sis and related diseases. Crit Care Med 2000; 28: S49–S56.
26. Isermann B, Vinnikov IA, Madhusudhan T, et al. Activated protein C protects
against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.
Nat Med 2007; 13: 1349–1358.
27. Cheng T, Liu D, Griffin JH, et al. Activated protein C blocks p53-mediated apop-
tosis in ischemic human brain endothelium and is neuroprotective. Nat Med
2003; 9: 338–342.
28. Van Sluis GL, Niers TM, Esmon CT, et al. Endogenous activated protein C limits
cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated
vascular endothelial barrier enhancement. Blood 2009; 114: 1968–1973.
29. Han MH, Hwang SI, Roy DB, et al. Proteomic analysis of active multiple sclerosis
lesions reveals therapeutic targets. Nature 2008; 451: 1076–1081.
30. Loubele ST, Spek CA, Leenders P, et al. Activated protein C protects against myo-
cardial ischemia/reperfusion injury via inhibition of apoptosis and inflam-
mation. Arterioscler Thromb Vasc Biol 2009; 29: 1087–1092.
31. Mizutani A, Okajima K, Uchiba M, et al. Activated protein C reduces ischemia/
reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood
2000; 95: 3781–3787.
32. Kroegel C, Reissig A. Principle mechanisms underlying venous thromboembol-
ism: epidemiology, risk factors, pathophysiology and pathogenesis. Respiration
2003; 70: 7–30.
33. Lowe GD. Virchow's triad revisited: abnormal flow. Pathophysiol Haemost
Thromb 2003; 33: 455–457.
34. Sevitt S. The structure and growth of valve-pocket thrombi in femoral veins. J Clin
Pathol 1974; 27: 517–528.
35. Chirinos JA, Heresi GA, Velasquez H, et al. Elevation of endothelial micropar-
ticles, platelets, and leukocyte activation in patients with venous thromboembol-
ism. J Am Coll Cardiol 2005; 45: 1467–1471.
36. Esmon CT. Basic mechanisms and pathogenesis of venous thrombosis. Blood Rev
2009; 23: 225–229.
37. McNally MA, Mollan RA. Total hip replacement, lower limb blood flow and ve-
nous thrombogenesis. J Bone Joint Surg Br 1993; 75: 640–644.
38. Dahl OE, Aspelin T, Arnesen H, et al. Increased activation of coagulation and
formation of late deep venous thrombosis following discontinuation of thrombo-
prophylaxis after hip replacement surgery. Thromb Res 1995; 80: 299–306.
39. Lindahl TL, Lundahl TH, Nilsson L, et al. APC-resistance is a risk factor for post-
operative thromboembolism in elective replacement of the hip or knee – a pros-
pective study. Thromb Haemost 1999; 81: 18–21.
40. Meltzer ME, Doggen CJ, de Groot PG, et al. The impact of the fibrinolytic system
on the risk of venous and arterial thrombosis. Semin Thromb Hemost 2009; 35:
468–477.
41. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibril-
lation: American College of Chest Physicians evidence-based clinical practice
guidelines (8th Edition). Chest 2008; 133: 546S–592S.
42. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treat-
ment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;
28: 1598–1660.
43. Davies MJ. The pathophysiology of acute coronary syndromes. Heart 2000; 83:
361–366.
44. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451:
914–918.
45. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl
J Med 2005; 352: 1685–1695.
46. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholi-
pase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart
disease in middle-aged men and women in the Atherosclerosis Risk in Commu-
nities (ARIC) study. Circulation 2004; 109: 837–842.
© Schattauer 2011
Downloaded from www.thrombosis-online.com on 2015-12-28 | IP: 54.152.109.166
For personal or educational use only. No other uses without permission. All rights reserved.
Turpie, Esmon: Anticoagulation in thrombosis 595
47. Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases
collagen content and decreases lipid content, inflammation, metalloproteinases,
and cell death in human carotid plaques: implications for plaque stabilization.
Circulation 2001; 103: 926–933.
48. Lefer DJ. Statins as potent antiinflammatory drugs. Circulation 2002; 106:
2041–2042.
49. Stewart RA. Predicting benefit from statins by C-reactive protein, LDL-choleste-
rol or absolute cardiovascular risk. Future Cardiol 2009; 5: 231–236.
50. Kinlay S. Low-density lipoprotein-dependent and -independent effects of choles-
terol-lowering therapies on C-reactive protein: a meta-analysis. J Am Coll Cardiol
2007; 49: 2003–2009.
51. Wang K, Tarakji K, Zhou Z, et al. Celecoxib, a selective cyclooxygenase-2 inhibitor,
decreases monocyte chemoattractant protein-1 expression and neointimal hy-
perplasia in the rabbit atherosclerotic balloon injury model. J Cardiovasc Phar-
macol 2005; 45: 61–67.
52. Chen SS, Jenkins AJ, Majewski H. Elevated plasma prostaglandins and acetylated
histone in monocytes in Type 1 diabetes patients. Diabet Med 2009; 26: 182–186.
53. Goodman SG, Menon V, Cannon CP, et al. Acute ST-segment elevation myo-
cardial infarction: American College of Chest Physicians evidence-based clinical
practice guidelines (8th Edition). Chest 2008; 133: 708S–775S.
54. Lip GYH, Boos CJ. Antithrombotic treatment in atrial fibrillation. Heart 2006; 92:
155–161.
55. Fuster V, Rydén LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the manage-
ment of patients with atrial fibrillation. A report of the American College of Car-
diology/American Heart Association Task Force on Practice Guidelines and the
European Society of Cardiology Committee for Practice Guidelines and Policy
Conferences (Committee to develop guidelines for the management of patients
with atrial fibrillation) developed in collaboration with the North American So-
ciety of Pacing and Electrophysiology. Eur Heart J 2001; 22: 1852–1923.
56. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibril-
lation: Virchow's triad revisited. Lancet 2009; 373: 155–166.
57. Olsson SB, Rasmussen LH, Tveit A, et al. Safety and tolerability of an immediate-
release formulation of the oral direct thrombin inhibitor AZD0837 in the preven-
tion of stroke and systemic embolism in patients with atrial fibrillation. Thromb
Haemost 2010; 103: 604–612.
58. Perzborn E. Factor Xa inhibitors – New anticoagulants for secondary haemosta-
sis. Hamostaseologie 2009; 29: 260–267.
59. Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Hae-
most 2003; 1: 1504–1514.
60. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost
2007; 5 (Suppl. 1): 60–64.
61. Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel
antithrombotic agent BAY 59-7939 − an oral, direct Factor Xa inhibitor. J Thromb
Haemost 2005; 3: 514–521.
62. Leadley RJ, Jr. Coagulation factor Xa inhibition: biological background and
rationale. Curr Top Med Chem 2001; 1: 151–159.
63. Orvim U, Barstad RM, Vlasuk GP, et al. Effect of selective factor Xa inhibition on
arterial thrombus formation triggered by tissue factor/factor VIIa or collagen in
an ex vivo model of shear-dependent human thrombogenesis. Arterioscler
Thromb Vasc Biol 1995; 15: 2188–2194.
64. Depasse F, Busson J, Mnich J, et al. Effect of BAY 59-7939 − a novel, oral, direct
Factor Xa inhibitor − on clot-bound Factor Xa activity in vitro. J Thromb Hae-
most 2005; 3 (Suppl. 1): Abstract P1104.
65. Jiang X, Crain EJ, Luettgen JM, et al. Apixaban, an oral direct factor Xa inhibitor,
inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost 2009;
101: 780–782.
66. Eisenberg PR, Siegel JE, Abendschein DR, et al. Importance of factor Xa in deter-
mining the procoagulant activity of whole-blood clots. J Clin Invest 1993; 91:
1877–1883.
67. Prager NA, Abendschein DR, McKenzie CR, et al. Role of thrombin compared
with factor Xa in the procoagulant activity of whole blood clots. Circulation 1995;
92: 962–967.
68. Varin R, Mirshahi S, Mirshahi P, et al. Effect of rivaroxaban, an oral direct Factor
Xa inhibitor, on whole blood clot permeation and thrombolysis: critical role of
red blood cells. Blood (ASH Annual Meeting Abstracts) 2009; 114: Abstract 1064.
69. Bachli EB, Pech CM, Johnson KM, et al. Factor Xa and thrombin, but not factor
VIIa, elicit specific cellular responses in dermal fibroblasts. J Thromb Haemost
2003; 1: 1935–1944.
Thrombosis and Haemostasis 105.4/2011
596 Turpie, Esmon: Anticoagulation in thrombosis
70. Shimizu T, Nishihira J, Watanabe H, et al. Macrophage migration inhibitory fac-
tor is induced by thrombin and factor Xa in endothelial cells. J Biol Chem 2004;
279: 13729–13737.
71. Busch G, Seitz I, Steppich B, et al. Coagulation factor Xa stimulates interleukin-8
release in endothelial cells and mononuclear leukocytes: implications in acute
myocardial infarction. Arterioscler Thromb Vasc Biol 2005; 25: 461–466.
72. Borensztajn K, Stiekema J, Nijmeijer S, et al. Factor Xa stimulates proinflamma-
tory and profibrotic responses in fibroblasts via protease-activated receptor-2 ac-
tivation. Am J Pathol 2008; 172: 309–320.
73. Blanc-Brude OP, Chambers RC, Leoni P, et al. Factor Xa is a fibroblast mitogen via
binding to effector-cell protease receptor-1 and autocrine release of PDGF. Am J
Physiol Cell Physiol 2001; 281: C681–C689.
74. Ko FN, Yang YC, Huang SC, et al. Coagulation factor Xa stimulates platelet-de-
rived growth factor release and mitogenesis in cultured vascular smooth muscle
cells of rat. J Clin Invest 1996; 98: 1493–1501.
75. Joo SS, Won TJ, Kim JS, et al. Inhibition of coagulation activation and inflam-
mation by a novel Factor Xa inhibitor synthesized from the earthworm Eisenia
andrei. Biol Pharm Bull 2009; 32: 253–258.
76. Walenga JM, Jeske WP, Hoppensteadt D, et al. Factor Xa inhibitors: today and
beyond. Curr Opin Investig Drugs 2003; 4: 272–281.
77. Ragosta M, Gimple LW, Gertz SD, et al. Specific factor Xa inhibition reduces res-
tenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.
Circulation 1994; 89: 1262–1271.
78. Schwartz RS, Holder DJ, Holmes DR, et al. Neointimal thickening after severe cor-
onary artery injury is limited by a short-term administration of a factor Xa in-
hibitor. Results in a porcine model. Circulation 1996; 93: 1542–1548.
79. Laurent M, Varin R, Joimel U, et al. A novel mechanism of action of rivaroxaban:
inhibition of monocyte and macrophage procoagulant activity and consequence
on inflammatory process. Blood (ASH Annual Meeting Abstracts) 2009; 114:
Abstract 3124.
80. Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arte-
rioscler Thromb Vasc Biol 2003; 23: 17–25.
81. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics
and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in
healthy male subjects. Br J Clin Pharmacol 2007; 64: 292–303.
82. Bar-Shavit R, Kahn A, Fenton JW, et al. Chemotactic response of monocytes to
thrombin. J Cell Biol 1983; 96: 282–285.
83. Scholz M, Vogel JU, Hover G, et al. Thrombin stimulates IL-6 and IL-8 expression
in cytomegalovirus-infected human retinal pigment epithelial cells. Int J Mol
Med 2004; 13: 327–331.
84. Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest
Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;
133: 199S–233S.
Thrombosis and Haemostasis 105.4/2011
Downloaded from www.thrombosis-online.com on 2015-12-28 | IP: 54.152.109.166
For personal or educational use only. No other uses without permission. All rights reserved.
View publication stats
85. Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the
prevention of venous thromboembolism. N Engl J Med 2009; 360: 1851–1861.
86. Ramcharan AS, Van Stralen KJ, Snoep JD, et al. HMG-CoA reductase inhibitors,
other lipid-lowering medication, antiplatelet therapy, and the risk of venous
thrombosis. J Thromb Haemost 2009; 7: 514–520.
87. Sørensen HT, Horvath-Puho E, Søgaard KK, et al. Arterial cardiovascular events,
statins, low-dose aspirin and subsequent risk of venous thromboembolism: a
population-based case-control study. J Thromb Haemost 2009; 7: 521–528.
88. Undas A, Celinska-Lowenhoff M, Brummel-Ziedins KE, et al. Simvastatin given
for 3 days can inhibit thrombin generation and activation of factor V and enhance
factor Va inactivation in hypercholesterolemic patients. Arterioscler Thromb Vasc
Biol 2005; 25: 1524–1525.
89. Sen-Banerjee S, Mir S, Lin Z, et al. Kruppel-like factor 2 as a novel mediator of sta-
tin effects in endothelial cells. Circulation 2005; 112: 720–726.
90. Masamura K, Oida K, Kanehara H, et al. Pitavastatin-induced thrombomodulin
expression by endothelial cells acts via inhibition of small G proteins of the Rho
family. Arterioscler Thromb Vasc Biol 2003; 23: 512–517.
91. Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactive pro-
tein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a random-
ized trial and cohort study. J Am Med Assoc 2001; 286: 64–70.
92. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients
with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151.
93. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for
thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765–2775.
94. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus
short-term enoxaparin for the prevention of venous thromboembolism after
total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;
372: 31–39.
95. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for throm-
boprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776–2786.
96. Lassen MR, Gallus AS, Pineo GF, et al. The ADVANCE-2 study: a randomized
double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis
after total knee replacement. J Thromb Haemost 2009; 7 (Suppl 2): Abstract
LB-MO-005.
97. Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for
thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised
trial. Lancet 2009; 373: 1673–1680.
98. Olsson SB, Executive Steering Committee of the SPORTIF III Investigators.
Stroke prevention with the oral direct thrombin inhibitor ximelagatran com-
pared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF
III): randomised controlled trial. Lancet 2003; 362: 1691–1698.
99. Ludwig RJ. Therapeutic use of heparin beyond anticoagulation. Curr Drug Dis-
cov Technol 2009; 6: 281–289.
© Schattauer 2011