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Antithrombotic Drug Therapy in Cardiology: The Role of Coagulation in Arterial and Venous Thrombosis
In addition to production of fibrin, thrombin has wide-reaching functions that range from platelet activa-
tion to stimulation of endothelial cells, vascular smooth muscle cells (VSMC), monocytes, T lymphocytes,
and fibroblasts, so the production and inhibition of thrombin is tightly regulated (19,20).
The coagulation system comprises proenzymes that typically reside in the intravascular space in an
inactivated state together with cofactors, cations, and cell-associated phospholipid. Coagulation can
be activated by two principal mechanisms, the intrinsic and the extrinsic pathways that converge to
produce thrombin by the common pathway through a series of inter-related enzymatic reactions
(21,22) (See Fig. 2). These classical pathways form the basis of the two most frequently performed
coagulation tests, the prothrombin time (PT), which measures the extrinsic and common pathways;
and the activated partial thromboplastin time (APTT), which measures the intrinsic and common
pathways. However, the physiologic activation of coagulation in vivo is not so segregated, with the
initiation phase occurring through tissue factor exposed during vascular injury leading to a subsequent
propagation phase and further amplification of the process by thrombin, due to activation of factors,
V, VIII, XI (23).
The Intrinsic Pathway
One mechanism of coagulation activation is the intrinsic pathway, so called because its compo-
nents, factors XII, XI, IX, VIII, prekallikrein (PK), and high molecular weight kininogen (HMWK),
are all plasma proteins and are “intrinsic” to the lumen of the blood vessel (24). The intrinsic pathway
can be activated when factor XII undergoes autoactivation to factor XIIa on a negatively charged
surface through a process called “contact activation” (25,26) (See Fig. 3). Negatively charged surfaces
Fig. 1. The elements of the hemostatic system, with the relationship between endothelial cells, the vascular wall,
coagulation, coagulation inhibitors, and platelet activation. AT antithrombin, ProS protein S, APC activated protein C,
TFPI tissue factor pathway inhibitor, ECM extracellular matrix.
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Fig. 2. Diagram of the coagulation cascade, depicting the intrinsic and extrinsic pathways of activation. The extrinsic
pathway of activation is started with exposure of tissue factor (TF), coupled with factor VIIa that leads to the activa-
tion of factor X. The intrinsic pathway is started by the contact activation factors (factor XII, high molecular weight
kininogen (HMWK), and prekallikrein (PK)) with eventual activation of factor X by the tenase complex (factors IXa,
VIIIa, calcium (Ca++), and phospholipid). Activated factor X (Xa) participates in the prothrombinase complex (factor
Xa, Va, Ca++, phospholipids) for the conversion of prothrombin to thrombin, which converts fibrinogen to fibrin
monomer. Fibrin then polymerizes and is crosslinked by factor XIIIa. Further activation of coagulation is fostered by
thrombin’s activation of factors V, VIII, and XI.
Fig. 3. The contact activation and cell-based activation pathways of the intrinsic factors. Negatively charged surfaces
can activate the contact activation factors. Activation of factor XII leads to conversion of prekallikrein (PK) to kallikrein
(K), facilitated by the cofactor high molecular weight kininogen (HMWK), with kallikrein further stimulating the
activation of factor XII. Activated factor XII subsequently activates factor XI. The intrinsic pathway can also be acti-
vated in a cell-based process. HMWK-PK binds to a cell-based receptor complex, which includes a binding protein
for the globular head domains of complement component C1q, designated gC1qR, cytokeratin 1 (CK1) and urokinase
plasminogen activator receptor (u-PAR). Prolylcarboxypeptidase (PRCP) bound to the complex activates PK to form
plasma kallikrein, resulting in factor XII activation.
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include the artificial reagents in the APTT assay, such as kaolin, celite, and silica, which explains
the dependence of the APTT on the contact activation factors. However, the intrinsic pathway can be
activated in
vivo by substances such as articular cartilage, endotoxin, L-homocysteine, and the
developing thrombus
(27,28).
Activation of factor XII leads to conversion of PK to kallikrein, facilitated by the cofactor HMWK,
with kallikrein further stimulating the activation of factor XII
(27). Activated factor XII subsequently
activates factor XI, with factor XIa activating factor IX. Factor IXa, together with factor VIIIa, phos-
pholipids, and calcium form the tenase complex that activates factor X.
The intrinsic pathway can also be activated in a cell-based process, as the components can assem-
ble on endothelial cells, platelets, and granulocytes (27,29). HMWK-PK binds to a cell-based receptor
complex, which includes a binding protein for the globular head domains of complement component
C1q, designated gC1qR, cytokeratin 1 (CK1) and urokinase plasminogen activator receptor (u-PAR)
(27) (See Fig. 3). Prolylcarboxypeptidase (PRCP) bound to the complex activates PK to form plasma
kallikrein, resulting in factor XII activation
(30). Apart from activation of factor XI, this complex is
involved in other physiologic activities through formation of bradykinin, which participates in fibri-
nolysis activation and the production of antiplatelet molecules, nitric oxide and prostacyclin, from
endothelial cells
(27).
The role of the contact activation factors, XII, HMWK, and PK, has traditionally been discounted in
physiological hemostasis, as patients with deficiencies of these proteins do not manifest a bleeding dia-
thesis
(31). Studies have shown that factor IX is principally activated not by the contact factors but by the
tissue factor/factor VIIa complex, as described later, and physiologic hemostasis is thought to proceed
principally through that extrinsic pathway (32). However, recent studies with factor XI and XII knockout
mice have indicated that deficiency of these factors may impair formation of occlusive thrombi in arterial
injury models and may be attractive targets for new antithrombotic agents (26,28,33).
The Extrinsic Pathway
The so-called Extrinsic Pathway of coagulation, comprising tissue factor and factor VII, is acti-
vated by tissue injury or cellular activation and is likely the primary mechanism for in
vivo hemostasis
(2,34). Tissue factor, complexed with activated factor VIIa in the presence of calcium and phospholipids,
activates coagulation through conversion of factor X to Xa and also through activation of factor IX to
IXa (35) (See Fig. 4).
Tissue factor is an intrinsic membrane glycoprotein expressed on many vascular wall cells, such as
smooth muscle cells, pericytes, and fibroblasts (34,36). Constitutively expressed cell-based tissue factor
can be exposed to the blood following vascular injury, but tissue factor expression can also be induced on
vascular endothelial cells and leukocytes by thrombin and inflammatory stimuli (34,37,38). This induc-
tion is well described for monocytes, but also may occur in neutrophils and eosinophils and is thought to
play a role in the thrombotic consequences of disseminated intravascular coagulation and sepsis (37,39).
Activation of many cells leads to production of minute membrane-bound microparticles, which may be a
source of circulating tissue factor activity (40). Platelets may also play a role, as recent studies have shown
that platelets can be stimulated to produce TF mRNA and synthesize TF protein (34,41).
Fibrin Formation and Common Pathway Activation
The purpose of coagulation is the formation of an insoluble fibrin polymer as a hemostatic plug.
To this end, the transformation of plasma-based fibrinogen to crosslinked fibrin is accomplished by
several mechanisms and is tightly regulated.
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Fibrinogen is a large plasma protein that is a dimer composed of two mirror-image groups of three
polypeptide chains, the Aa, Bb, and g chains
(42) which are held together by a group of central
disulfide bonds. Fibrinogen has a trinodular structure, with the central disulfide bonded area forming
the central E domain, and the flanking polypeptides forming two lateral D domains (43) (See Fig. 2).
The serine protease thrombin cleaves off small fibrinopeptides from the Aa and Bb chains, converting
fibrinogen to fibrin monomer. Binding sites in the central region of the fibrin monomer, termed
A-knobs and B-knobs, are exposed. This allows the “knobs” on one monomer to bind to gC and bC
“holes” in the D domains in another monomer in a half-staggered overlap pattern, facilitating noncova-
lent assembly into a fibrin protofibril polymer (44,45). The protofibrils then associate laterally into
bundles that form thicker fibers. Concurrent with the conversion of fibrinogen to fibrin, thrombin cata-
lyzes the activation of factor XIII, a transglutaminase enzyme that stabilizes the fibrin polymer by
forming covalent crosslinks between g chains in the D domains of adjacent fibrin molecules (46).
Thrombin, which plays a key role in the formation of fibrin and its crosslinking, is a serine protease
that is formed from prothrombin by the action of factor Xa and the prothrombinase complex, a
phospholipid membrane-based complex consisting of factors Xa and Va together with calcium (20).
Thrombin has many functions apart from fibrin formation and is associated with propagation of
coagulation through activation of factors V and VIII, thus accelerating the activity of the prothrombi-
Vessel
Injury
TF/VIIa
X
Va/Xa/Prothrombin
(Prothrombinase
Complex)
Thrombin
Fibrinogen
Fibrin
IX
IXa/VIIIa
XI
XIa
TF
TFPI
+
+
Surface
XII
XIIa
HMWK
Monocyte Activation
Endothelial ActivatIon
TF
TF
TF
EXTRINSIC PATHWAY ACTIVATION
INTRINSIC PATHWAY ACTIVATION
COMMON PATHWAY
PKK
(Tenase Complex)
Fig. 4. Sources of tissue factor (TF) in the activation of coagulation. Tissue factor is expressed by many vascular wall
cells and is exposed upon vascular injury. It can also be expressed during activation of endothelial cells and leuko-
cytes, such as monocytes. Various cells, from endothelial cells to leukocytes and smooth muscle cells can produce
small membrane-bound vesicles, called microparticles, that may express tissue factor. Tissue factor/factor VIIa is
involved in the activation of coagulation through direct activation of factor X, but this is inhibited by tissue factor
pathway inhibitor (TFPI). Tissue factor/factor VIIa can also activate factor IX, which leads to factor X activation
through the tenase complex.
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nase and tenase complexes, respectively (47) (Fig. 2). Thrombin is further involved with amplification
of coagulation through its direct activation of factor XI. Indeed, individuals with factor XI deficiency
typically only have bleeding when large amounts of thrombin are formed, such as during surgical
procedures
(48).
Thrombin, through a series of G-coupled protease-activated receptors (PARs), also activates plate-
lets and other cells, such as endothelial cells and monocytes
(19). Upregulation of PARs in smooth
muscle cells is thought to play a key role in the pathogenesis of atherosclerosis and restenosis
(49).
Due to its wide-ranging effects, the activity of thrombin is closely regulated, as discussed later.
The activation of thrombin requires the action of factor Xa, another serine protease, in the
prothrombinase complex resulting in cleavage of a peptide fragment, prothrombin fragment F1 + 2,
from prothrombin (50). The formation of active factor Xa from the proenzyme factor X is considered
the start of the common pathway and can be triggered by both tissue factor/factor VIIa from the
extrinsic pathway and by the tenase complex (factors IXa, VIIIa, calcium, and phospholipids) from
the intrinsic pathway
(2). Having two separate mechanisms for factor Xa activation is thought to be
associated with two temporal stages of blood coagulation
(32,51), the initiation and propagation
stages. In the initiation stage, factor X is initially activated by tissue factor/factor VIIa. This produces
small amounts of thrombin, which activates factors V and VIII, leading to further thrombin produc-
tion
(47). After initiation, an inhibitor, tissue factor pathway inhibitor (TFPI), downregulates the ability
of tissue factor/VIIa to activate factor X
(52). Coagulation then enters the propagation phase, directing
the activity of tissue factor/VIIa toward activation of factor IXa, resulting in a switch of the pri-
mary activation of factor X to be via the intrinsic pathway tenase complex (51). Further thrombin
production leads to the activation of factor XIa, which amplifies the propagation phase further.
Lessons from Studying In Vivo Coagulation Activation
Most studies that have been used to define the coagulation process have been performed in vitro,
often with highly purified single protein components. While these have helped delineate the processes
involved, they may not necessarily indicate the relative importance of coagulation factors in hemos-
tasis, hemorrhage, or thrombosis
(145). For example, the processes of hemostasis and thrombosis
may differ, as in
vivo studies have shown defective thrombus formation in the absence of factors XII
and XI, while patients with factor XII deficiency do not display a hemostatic defect
(26,28). The clini-
cal phenotype for deficiency of factors VIII and IX is hemophilia, a significant bleeding disorder, so
this helps to indicate the importance of factor X activation by the tenase complex compared to tissue
factor/VIIa. Contrary to the dogma that tissue factor is extrinsic to the blood vessel lumen, circulating
tissue factor-bearing microparticles have been shown to be involved with in
vivo thrombus develop-
ment (53). It has been shown from in vivo studies that platelet thrombus formation and fibrin forma-
tion may occur more simultaneously than sequentially, and other studies question the crucial role of
platelet membrane phospholipids in the formation of fibrin (54,55). While these studies may challenge
the classical paradigm of coagulation and its relationship with platelets, they also serve to underscore
the complex and inter-related nature of the hemostatic process.
REGULATION OF COAGULATION
Coagulation activation involves numerous proteins and amplification steps, so its activation and
propagation is closely regulated. The activities of thrombin and tissue factor, in particular, have
several well-studied inhibitors and/or regulatory mechanisms. These regulatory mechanisms are of
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clinical significance, as defective regulation due to congenital inhibitor deficiency may lead to clinical
thrombosis, while pharmacologic use of the inhibitors has successfully controlled thrombosis. The
endothelial cells that line the blood vessels also are able to regulate the function of many aspects of
hemostasis from coagulation to platelet activation to fibrinolysis
Regulation of Tissue Factor
Classically, since tissue factor was thought only to exist in locations extrinsic to the blood vessel
lumen, regulation of tissue factor activity has been thought to involve primarily vessel injury with exposure
of constitutively expressed tissue factor to flowing blood. While this process is undoubtedly involved,
other mechanisms for regulation of tissue factor exposure and activity likely play a role. Tissue factor
can exist in an encrypted, inactive form, or a decrypted, active form; decryption may involve conformational
or disulfide bonding changes (56,57). The major regulation of tissue factor/factor VIIa activity is through
tissue factor pathway inhibitor b (TFPIb), a Kunitz-type proteinase inhibitor
(52). TFPIb forms a
quaternary complex with tissue factor, factors VIIa and Xa; the factor Xa within the complex is deacti-
vated, but binding to adjacent tissue factor/factor VIIa prevents further factor X activation (38,58). TFPI
may also further downregulate coagulation by causing TF-expressing cells to internalize cell surface TF/
factor VIIa complexes (59). The importance of TFPI as a hemostatic regulator is highlighted by the
embryonic lethality due to hemorrhage observed in TFPI knockout mice
(60).
Regulation of Thrombin
The activity of thrombin is closely regulated by several direct and indirect mechanisms; these
involve antithrombin, a direct-acting inhibitor, or take advantage of thrombin’s proteolytic activities
through the activation of protein C. Several naturally occurring thrombin inhibitory molecules have
been developed by blood-sucking insects or envenoming snakes. One such molecule, hirudin, is a very
potent direct thrombin inhibitor (DTI); OTIs have been developed as successful commercial anti-
thrombotic agents, highlighting the importance of regulating endogenous thrombin activity (61).
Antithrombin (formerly called Antithrombin III) is a serine protease inhibitor that is a direct inhibitor
of thrombin and other serine proteases (2,20). The reactive site loop (P1–P17) of antithrombin includes
a scissile P
1
-P
1
¢ (Arg393-Ser394) bond that resembles the substrate for thrombin and other serine
proteases
(62,63). Once thrombin cleaves the bond, the protease is covalently linked to the P1 residue
and an inactive thrombin/antithrombin complex is formed (See Fig.
5). The ability of antithrombin to
inhibit thrombin is accelerated approximately 1000-fold by heparin binding to arginine residues in the
D-helix of antithrombin, with a resultant conformational change of the P1-P17 loop and exposure of the
P1-P1¢ reactive center (64,65). The inactivated thrombin/antithrombin complex dissociates from heparin,
allowing heparin to bind to another antithrombin molecule and catalyze the inactivation of yet more
thrombin. In vivo, the luminal surface of endothelial cells is rich in heparan sulfate; bound antithrombin
is thus maintained in an active conformation, ready to facilitate the rapid inactivation of thrombin.
Another thrombin regulatory mechanism is the thrombomodulin/protein C system, a multimolecular
system that regulates blood coagulation, principally through the proteolytic degradation of activated
factors V (fVa) and VIII (fVIIIa) (20,66,67) (See Fig. 5). Thrombin binds to an endothelial cell recep-
tor, thrombomodulin, via the anion-binding exosite (68) and through conformational changes leads to
a change in thrombin’s substrate specificity from fibrinogen to protein C with activation of protein C
(69). Protein C interacts with the thrombomodulin/thrombin complex by binding to endothelial cell
protein C receptor (EPCR), which appears to be an important step in physiological protein C activa-
tion (70). In addition to activating protein C, the thrombomodulin/thrombin complex also is able to
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activate thrombin activatable fibrinolysis inhibitor (TAFI), which results in inhibition of fibrin degra-
dation and may also have a broad anti-inflammatory role
(71,72). Activated protein C is released
from the EPCR, and combines with protein S, another vitamin K-dependent factor, on endothelial or
platelet phospholipid surfaces (66,67). This activated protein C complex is able to degrade factors Va
and VIIIa, thus slowing the procoagulant drive
(2).
Protein Z System
Another inhibitory mechanism of the coagulation system has been described, namely the protein
Z system. Protein Z is a vitamin-K dependent protein, with an inhibitor, known as protein Z-dependent
protease inhibitor (ZPI)
(73). ZPI has been shown to inhibit factor Xa in a process that requires protein
Z, calcium, and phospholipids (74). ZPI has further been shown to inhibit factors XIa and IXa in a
mechanism not requiring protein Z, calcium, or phospholipids (75,76). This inhibitory mechanism has
been shown to play a role in hemostasis from in vitro studies and mouse models, but the role of ZPI
and protein Z as an anticoagulant system in humans remains to be fully elucidated (73).
Role of Endothelium
Endothelial cells are involved in many aspects of coagulation regulation. As indicated earlier,
heparan sulfate and thrombomodulin are involved in inhibition of thrombin activity. Endothelial cells
also inhibit platelet function through release of nitric oxide and prostacyclin and have profibrinolytic
function through release of tissue plasminogen activator (tPA) (77). However, when activated by
thrombin or inflammatory cytokines, endothelial cells can facilitate coagulation through expression
of tissue factor, expression of procoagulant lipids, release of procoagulant microparticles, downregu-
lation of thrombomodulin, and release of von Willebrand factor (78).
Fig. 5. Inhibition of thrombin. Thrombin (Factor IIa) is inhibited by antithrombin (AT) bound to heparans on endothe-
lial surfaces. It is also regulated by binding to thrombomodulin (TM) on endothelial cells, where it converts protein
C (Pro C) to activated protein C (APC). APC is a protease that degrades factors Va and VIIIa, thus decreasing further
thrombin production.
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Role of Microparticles
Microparticles are minute membrane-bound vesicles released from cell membranes by an exocyto-
sis process
(79). They have been shown to arise from a wide variety of cells, including endothelial
cells, platelets, monocytes, and erythrocytes
(80). Microparticles are released from the surface of cells
following apoptosis or activation; the release can be stimulated by a wide variety of agonists, such as
cytokines, thrombin, and endotoxin, but also physical stimuli such as shear stress or hypoxia
(79,81).
During the formation of microparticles, membrane asymmetry is lost, with an exposure of anionic
phospholipids, for example, phosphatidyl serine, to the external microparticle membrane
(82). This
provides a binding site for coagulation complexes, such as the tenase and prothrombinase complexes.
Because microparticles arise from the cell membrane, their protein antigen composition is characteristic
of their cell of origin and can be used to identify their source.
Circulating microparticles may contribute to the support of coagulation and development of throm-
bosis or may have anticoagulant properties, depending on their number and cell of origin or the pro-
ducing stimuli. The microparticle’s anionic phospholipid surface has been shown to support thrombin
generation through assembly of procoagulant complexes, and may be associated with clinical proco-
agulant states and other diseases (83,84,146). Tissue factor can be expressed by microparticles’
release by some cell types and may further contribute to their procoagulant activity
(38,85). Depending
on their cell surface antigens, microparticles may also contribute to the recruitment of cells to devel-
oping thrombi. For example, monocyte microparticles expressing tissue factor and P selectin glyco-
protein ligand-1 have been shown to bind to endothelial cells and platelets and to accumulate with the
developing thrombus (86). However, not all microparticles are necessarily procoagulant. Microparticles
arising from endothelial cells have been shown to have anticoagulant properties in some circum-
stances, with increased expression of TFPI and expression of activated protein C (79,87).
Elevated microparticle levels have been described in many cardiovascular and thrombotic disorders
and are often reported to correlate with clinical events (79–81). However, until the laboratory methods
for quantifying and characterizing microparticles are more standardized, their use as a diagnostic or
prognostic tool will be limited (79,88).
Interaction Between Coagulation and Platelet Activation
A striking feature of the hemostatic system is the degree of redundancy and interdependence of the
activation and regulatory processes involved. Not only are there multiple ways for coagulation to
become activated, but there are also numerous and bidirectional associations between the coagulation
system and platelets.
The coagulation system supports platelet activation and function in several ways. Thrombin is a
potent activator of platelets through activation of PARs (19,89). Fibrinogen provides the bridge for
platelet-platelet aggregation through its bivalent binding to the platelet glycoprotein IIb/IIIa (a
IIb
/b
3
)
receptor (90). Von Willebrand factor, a hemostatic protein released from endothelial cells, supports
both platelet adhesion under shear and platelet aggregation (91).
On the other hand, activated platelets play a vital procoagulant role that serves as a link between
platelet function and coagulation activation (92). Platelet membrane phospholipids undergo a rear-
rangement during activation with a transfer of phosphatidyl serine from the inner table to the outer
table of the platelet membrane, providing a binding site for phospholipid-dependent coagulation
complexes that activate both factor X and prothrombin. Additionally, the GPIb/V/IX complex is thought
to participate in activation of factors XI and XII. The platelet alpha granules release many procoagulant
factors during platelet activation, including fibrinogen, von Willebrand factor, and factor V.
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COAGULATION DYSREGULATION IN ARTERIAL AND VENOUS THROMBOSIS
The pathophysiology of arterial thrombotic diseases, mainly centered around cardiovascular
atherosclerotic sequelae, is largely considered distinct from that of venous thrombotic disorders,
such as deep vein thrombosis (DVT). Inflammation, the metabolic syndrome, lipid dysregulation,
endothelial dysfunction, and platelet activation are characteristics of arterial thrombotic syndromes.
Dysregulation of the coagulation system is thought to play a major role in the pathophysiology of
venous thrombosis, highlighted by the well-described association between deficiency of the natural
anticoagulants and venous thrombosis
(93). However, evaluation of the risk factors for both disor-
ders shows some similarities, particularly age and obesity, and there is some evidence that patients
with venous thrombosis have a higher risk of cardiovascular disease
(94,95). Indeed, some disorders
such as antiphospholipid antibodies and HIT are complicated by both arterial and venous thrombo-
sis, suggesting a unifying mechanism.
Coagulation Dysregulation and Venous Thromboembolic Disease
Venous thrombosis typically manifests as a DVT, usually in the lower extremities, or as a pulmo-
nary embolism
(PE) due to embolization of the thrombus to the pulmonary vasculature. A combina-
tion of vascular stasis and coagulation dysregulation is thought to be principally involved in the
pathophysiology of venous thrombosis, as there is usually little underlying vascular pathology.
However, inflammatory and fibrinolytic mechanisms and production of tissue factor-bearing micro-
particles may contribute (96). Venous thrombosis is relatively common, with an average annual inci-
dence rate of 121.5 per 100,000 person-years in the USA and is the third most prevalent cardiovascular
disease after coronary artery disease and stroke (97). The risk factors for venous thrombosis have been
well studied and include both acquired and congenital risk factors (See Table
1). In general, venous
thrombosis is considered a multifactorial or multigenetic disease, with the combination of more than
one risk factor increasing the risk of developing venous thrombosis (98).
Congenital Thrombophilia
Recognition of familial tendencies for thrombosis initially led to a search for genetic abnormalities
in the coagulation system. The genetic abnormalities first to be described in association with throm-
bophilia were mutations leading to loss-of-function of natural anticoagulants, such as antithrombin,
protein C, or protein S (99–101). These disorders are rare and heterozygous individuals have an
increased risk for venous thromboembolism. In addition, elevated plasma levels of several coagulation
proteins, including fibrinogen, factors VIII, IX, and XI, have been described to be associated with an
increased risk of venous thrombosis (102). Furthermore, genetic polymorphisms associated with
venous thrombosis and arterial vascular disease have been found in many of the procoagulant
proteins, including prothrombin, fibrinogen, factors V, VII, XI, and XIII (103,147). Polymorphisms
of EPCR, Z Protein inhibitor, fibrinolytic proteins, and enzymes in the transsulfuration pathway lead-
ing to high homocysteine levels have also been described, but their association with venous throm-
botic disease is not well established. The following discussion will concentrate on the two most well-
described venous thrombotic risk factors, Factor V Leiden and the prothrombin G20210A mutation
Factor V Leiden
Patients resistant to the activity of APC were described by Dahlback in 1993 (104), and the molec-
ular basis for this defect was shown to be a point mutation in the factor V gene located on chromo-
some 1 (1691G-A), which was called Factor V Leiden (FVL) (105). The FVL mutation results in an
arginine-glutamine substitution at amino acid 506 (Arg506Gln), the site of the first molecular cleav-
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age of factor Va by APC. This results in diminished activated protein C cleavage of factor Va and
continued formation of thrombin by the prothrombinase complex (i.e., APC resistance).
The FVL mutation is fairly common in the Caucasian population with a frequency of 2–15%, but
is uncommon in African blacks and Asians
(106,107). The mutation is detected in up to 40% of
patients with venous thrombosis
(103). FVL alone imparts approximately a five to eightfold increased
risk for venous thrombosis in heterozygotes and 80-fold in homozygotes
(108,109). Clinical studies
have shown FVL to be a risk factor for deep venous thrombosis, pulmonary embolism, cerebral vein
thrombosis, and superficial thrombophlebitis
(110).
Prothrombin G20210A
Due to the central role of thrombin, increased prothrombin levels are a likely risk factor for venous
thrombosis. In studying patients from families with unexplained thrombophilia, Poort et
al. identified
a G-A transition at nucleotide 20210 in the 3¢-untranslated portion of the prothrombin gene in 5 of 28
patients (111). The mutation is associated with increased levels of functionally normal prothrombin,
with heterozygotes having a level about 50% higher than unaffected individuals
(111). Prothrombin
G20210A results in elevated prothrombin levels and a two to fivefold increased risk of venous throm-
bosis (108,111)
Acquired Thrombophilia
Venous thrombosis is predominantly a disease of the aging, with the annual incidence increasing
rapidly after age 45 to approximately 1,000 per 100,000 person-years by age 80 (112). Other acquired
risk factors associated with venous thrombosis include malignancy, obesity, surgery, trauma, immo-
bilization, central venous catheters, prior venous thrombosis, pregnancy, and hormone therapy
(112,113) (See Table 1). Apart from age, malignancy has the strongest association with venous throm-
bosis, with 20% of venous thromboembolic events occurring in the setting of malignancy, most com-
monly with malignant brain tumors and cancer of the ovary, pancreas, colon, stomach, lung, and
kidney
(112,114). There has been a great deal of recent press regarding an increased risk of thrombo-
sis associated with long-haul airplane travel, and epidemiologic studies have shown approximately a
two to fourfold increased risk (115).
Two acquired risk factors for thrombosis, APS and HIT, merit discussion, as they are autoimmune-
based disorders and are associated clinically with both venous and arterial thrombosis (17). HIT is a
syndrome associated with thrombocytopenia and thrombosis developing approximately 5–14
days
following heparin therapy
(18). The inciting antigen in HIT is thought to be heparin/platelet factor 4
(116), with complexes of antibodies/heparin/platelet factor 4 binding to the FcgIIa receptor on plate-
lets and endothelial cells, triggering platelet and endothelial activation with release of prothrombotic
microparticles (117). In the APS, the antigen is variable, but is typically a protein associated with
phospholipid membranes or cardiolipin; common antigens include b2-glycoprotein I and prothrombin
(118), resulting in laboratory detection of anticardiolipin antibodies, anti-b2 glycoprotein I antibodies
and/or the lupus anticoagulant. The APS is associated clinically with arterial thrombosis, venous
thrombosis, and pregnancy complications in the setting of persistence of antiphospholipid antibodies
for more than twelve weeks
(119). The mechanism of thrombosis in patients with APS is still a matter
of debate, but proposed mechanisms include platelet activation through binding b2 glycoprotein I,
disruption of the Annexin V anticoagulant shield, and upregulation of endothelial cell tissue factor
activity (17,120,121). Since both APS and HIT involve activation of platelets, coagulation, and
endothelial cells, it is not surprising that both populations of patients demonstrate similar indicators
of a hypercoagulable and inflammatory state, including increased thrombin generation, markers of
platelet activation, endothelial cell dysfunction, and increased microparticles (17,79,122–124).
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