CHAPTER 124
OVERVIEW OF HEMOSTASIS AND THROMBOSIS
Jeffrey I. Weitz
Hemostasis preserves vascular integrity by balancing the physiologic
processes that maintain blood in a fluid state under normal circum-
stances and prevent excessive bleeding after vascular injury. Preserva-
tion of blood fluidity depends on an intact vascular endothelium and
a complex series of regulatory pathways that maintains platelets in a
quiescent state and keeps the coagulation system in check. In con-
trast, arrest of bleeding requires rapid formation of hemostatic plugs
at sites of vascular injury to prevent exsanguination. Perturbation of
hemostasis can lead to bleeding or thrombosis. Bleeding will occur if
there is failure to seal vascular leaks either because of defective hemo-
static plug formation or because of premature breakdown of the
plugs. In contrast, thrombosis may occur if prothrombotic stimuli
are unregulated.
Thrombosis can occur in arteries or veins and is a major cause of
morbidity and mortality. Arterial thrombosis is the most common
cause of acute coronary syndromes, ischemic stroke, and limb
gangrene, but thrombosis in the deep veins of the leg leads to the
postthrombotic syndrome and to pulmonary embolism, which can
be fatal.
Most arterial thrombi form on top of disrupted atherosclerotic
plaques because plaque rupture exposes thrombogenic material in the
plaque core to the blood.1 This material then triggers platelet aggrega-
tion and fibrin formation, which results in the generation of a
platelet-rich thrombus that temporarily or permanently occludes
blood flow. Whereas temporary occlusion of blood flow in coronary
arteries may trigger unstable angina, persistent obstruction causes
myocardial infarction. The same processes can occur in the cerebral
circulation, where temporary arterial occlusion may manifest as a
transient ischemic attack and persistent occlusion can lead to a stroke.
Likewise, critical limb ischemia can occur if there is superimposed
thrombosis on ruptured atherosclerotic plaques in the major arteries
supplying blood to the lower extremities.
In contrast to arterial thrombi, venous thrombi rarely form at sites
of obvious vascular disruption. Although they can develop after surgi-
cal trauma to veins or secondary to indwelling venous catheters, they
usually originate in the valve cusps of the deep veins of the calf or in
the muscular sinuses, where there is stasis.2 Sluggish blood flow in
these veins reduces the oxygen supply to the avascular valve cusps.
Hypoxemia induces endothelial cells lining the valve cusps to express
adhesion molecules, which tether tissue factor-bearing leukocytes and
microparticles onto their surface. Tissue factor–bearing leukocytes
and microparticles adhere to these activated cells and induce coagula-
tion. Impaired blood flow exacerbates local thrombus formation by
reducing clearance of activated clotting factors. Calf vein thrombi
that extend into the proximal veins of the leg can dislodge and travel
to the lungs to produce pulmonary embolism.3
Arterial and venous thrombi contain platelets and fibrin, but the
proportions differ. Arterial thrombi are rich in platelets because of
the high shear in the injured arteries. In contrast, venous thrombi,
which form under low shear conditions, contain relatively few plate-
lets and consist mostly of fibrin and trapped red blood cells. Because
of the predominance of platelets, arterial thrombi appear white, but
venous thrombi appear red, reflecting the trapped red cells.
The antithrombotic drugs used for prevention and treatment of
thrombosis target components of thrombi, and include antiplatelet
1774
drugs, which inhibit platelets; anticoagulants, which attenuate coagu-
lation; and fibrinolytic agents that induce fibrin degradation (see
Chapter 151). With the predominance of platelets in arterial thrombi,
strategies to inhibit or treat arterial thrombosis focus mainly on
antiplatelet agents, although in the acute setting, strategies often
include anticoagulants and fibrinolytic agents. When arterial thrombi
are occlusive and rapid restoration of blood flow is required, mechani-
cal and pharmacologic methods enable thrombus extraction, com-
pression, or degradation (see Chapter 145). Although rarely used for
this indication, anticoagulants can also prevent recurrent ischemic
events after acute myocardial infarction. Anticoagulants are the main-
stay for prevention and treatment of venous thromboembolism
because fibrin is the predominant component of venous thrombi (see
Chapter 144). Antiplatelet drugs are less effective than anticoagulants
because of the limited platelet content of venous thrombi. Selected
patients with venous thromboembolism benefit from fibrinolytic
therapy—for example, patients with massive or submassive pulmo-
nary embolism achieve more rapid restoration of pulmonary blood
flow with systemic or catheter-directed fibrinolytic therapy than with
anticoagulant therapy alone. Selected patients with extensive deep
vein thrombosis in the iliac or femoral veins also may have a better
outcome with catheter-directed fibrinolytic therapy or mechanical
thrombus extraction in addition to anticoagulants (see Chapter 145).
This chapter provides an overview of hemostasis and thrombosis
and highlights the processes involved in platelet activation and aggre-
gation, blood coagulation, and fibrinolysis.
HEMOSTATIC SYSTEM
The major components of the hemostatic system are the vascular
endothelium, platelets, and the coagulation and fibrinolytic systems.
Vascular Endothelium
A monolayer of endothelial cells lines the intimal surface of the cir-
culatory tree and separates the blood from the prothrombotic suben-
dothelial components of the vessel wall (see Chapter 125). As such,
the vascular endothelium encompasses about 1013 cells and covers a
vast surface area. Rather than serving as a static barrier, the healthy
vascular endothelium is a dynamic organ (Fig. 124-1) that actively
regulates hemostasis by inhibiting platelets, suppressing coagulation,
promoting fibrinolysis, and modulating vascular tone and permeabil-
ity.4 Defective vascular function can lead to bleeding if the endothe-
lium becomes more permeable to blood cells, if vasoconstriction does
not occur, or if premature degradation of hemostatic plugs opens seals
in the vasculature.
Platelet Inhibition
Endothelial cells synthesize prostacyclin and nitric oxide and release
them into the blood.4 These agents not only serve as potent vasodila-
tors but also inhibit platelet activation and subsequent aggregation
 Chapter 124  Overview of Hemostasis and Thrombosis 1775

Antiplatelet Anticoagulant Profibrinolytic

Heparan
NO CD39 Prostacyclin sulfate TM EPCR TFPI t-PA u-PA

Endothelium

Figure 124-1  THE ANTITHROMBOTIC FUNCTIONS OF THE ENDOTHELIUM. The healthy

endothelium has (1) antiplatelet activity because of synthesis and release of prostacyclin and nitric oxide
(NO) and expression of CD39, a membrane-associated ectoADPase; (2) anticoagulant activity because of
heparan sulphate proteoglycan-mediated activation of antithrombin and expression of thrombomodulin
(TM) and endothelial protein C receptor (EPCR), which are involved in protein C activation, and surface-
bound tissue factor pathway inhibitor (TFPI); and (c) profibrinolytic activity because of release of tissue
and urokinase-type plasminogen activator (t-PA and u-PA, respectively).

by stimulating adenylate cyclase and increasing intracellular levels of
cyclic adenosine monophosphate (cAMP). In addition, endothelial
cells express CD39 on their surface, a membrane-associated ecto-
adenosine diphosphatase (ADPase). By degrading ADP, which is a
platelet agonist, CD39 attenuates platelet activation.
Anticoagulant Activity
Intact endothelial cells play an essential part in the regulation of
thrombin generation through a variety of mechanisms. Endothelial
cells produce heparan sulfate proteoglycans, which bind circulating
antithrombin and accelerate the rate at which it inhibits thrombin
and other coagulation enzymes. Tissue factor pathway inhibitor
(TFPI), a naturally occurring inhibitor of coagulation, binds heparan
sulfate on the endothelial cell surface.5 Administration of heparin or
low-molecular-weight heparin (LMWH) displaces glycosaminoglycan-
bound TFPI from the vascular endothelium, and released TFPI may
contribute to the antithrombotic activity of these drugs.
Endothelial cells regulate thrombin generation by expressing
thrombomodulin and endothelial cell protein C receptor (EPCR) on
their surfaces. Thrombomodulin binds thrombin and alters this
enzyme’s substrate specificity such that it no longer acts as a proco-
agulant but becomes a potent activator of protein C (see Chapter
129). Activated protein C serves as an anticoagulant by degrading
and inactivating activated factor V and factor VIII (factors Va and
VIIIa, respectively), key cofactors involved in thrombin generation.
Protein S acts as a cofactor in this reaction, and EPCR enhances this
pathway by binding protein C and presenting it to the thrombin–
thrombomodulin complex for activation. In addition to its role as an
anticoagulant, activated protein C also regulates inflammation and
preserves the barrier function of the endothelium.6
Fibrinolytic Activity
Vascular Tone and Permeability
In addition to synthesizing potent vasodilators, such as prostacyclin
and nitric oxide, endothelial cells also produce a group of counter-
regulatory peptides known as endothelins that induce vasoconstric-
tion. Endothelial cell permeability is influenced by the connections
that join endothelial cells to their neighbors. Macromolecules traverse
the endothelium via patent intercellular junctions, by endocytosis, or
through transendothelial pores. Vasodilatation, severe thrombocyto-
penia, and high doses of heparin can increase endothelial permeabil-
ity, which may contribute to bleeding. Activated protein C may also
contribute to the barrier function of the endothelium.
Platelets
Platelets are anucleate particles released into the circulation after
fragmentation of bone marrow megakaryocytes (see Chapter 126).
Because they are anucleate, platelets have limited capacity to synthe-
size proteins. Thrombopoietin, a glycoprotein synthesized in the liver
and kidneys, regulates megakaryocytic proliferation and maturation
as well as platelet production. After they enter the circulation, plate-
lets have a life span of 7 to 10 days.
Damage to the intimal lining of the vessel exposes the underlying
subendothelial matrix. Platelets home to sites of vascular disruption
and adhere to the exposed matrix proteins (see Chapter 127). Adher-
ent platelets undergo activation and not only release substances that
recruit additional platelets to the site of injury but also promote
thrombin generation and subsequent fibrin formation (Fig. 124-2).
A potent platelet agonist, thrombin amplifies platelet recruitment and
activation. Activated platelets then aggregate to form a plug that seals
the leak in the vasculature.7 An understanding of the steps in these
highly integrated processes helps pinpoint the sites of action of the
antiplatelet drugs and rationalizes the utility of anticoagulants for the
treatment of arterial thrombosis and venous thrombosis.

The vascular endothelium promotes fibrinolysis by synthesizing and

releasing tissue-type and urokinase-type plasminogen activator (t-PA
and u-PA, respectively), which initiate fibrinolysis by converting plas-
minogen to plasmin (see Chapter 129). Endothelial cells in most
vascular beds synthesize t-PA constitutively. In contrast, perturbed
endothelial cells produce u-PA in the settings of inflammation and
wound repair.
Endothelial cells also produce type 1 plasminogen activator inhib-
itor 1 (PAI-1), the major regulator of both t-PA and u-PA. Therefore,
net fibrinolytic activity depends on the dynamic balance between the
release of plasminogen activators and PAI-1. Fibrinolysis localizes to
the endothelial cell surface because these cells express annexin II, a
coreceptor for plasminogen and t-PA that promotes their interaction.
Therefore, healthy vessels actively resist thrombosis and help main-
tain platelets in a quiescent state.
Adhesion
Platelets adhere to exposed collagen and von Willebrand factor (vWF)
and form a monolayer that supports and promotes thrombin genera-
tion and subsequent fibrin formation. These events depend on con-
stitutively expressed receptors on the platelet surface, α2β1 and
glycoprotein (GP) VI, which bind collagen, and GPIbα and GPIIb/
IIIa (αIIbβ3), which bind vWF. The platelet surface is crowded
with receptors, but those involved in adhesion are the most abundant:
every platelet has about 40,000 to 80,000 copies of GPIIb/IIIa
and 25,000 copies of GPIbα. Receptors cluster in cholesterol-
enriched subdomains, which render them more mobile, thereby
increasing the efficiency of platelet adhesion and subsequent activa-
tion (see Chapter 127).
 1776 Part XII  Hemostasis and Thrombosis
Plaque disruption
Tissue Collagen vWF
factor
Platelet adhesion
and secretion
Aspirin COX-1
Thrombin TXA2 ADP
Ticlopidine
Clopidogrel
Prasugrel
Ticagrelor
Platelet recruitment
and activation
Vorapaxar
GPIIb/IIIa activation
Abciximab
Eptifibatide
Tirofiban
Platelet aggregation
Figure 124-2  SITES OF ACTION OF ANTIPLATELET DRUGS. Aspirin
inhibits thromboxane A2 (TXA2) synthesis by irreversibly acetylating
cyclooxygenase-1 (COX-1). Reduced TXA2 release attenuates platelet activa-
tion and recruitment to the site of vascular injury. Ticlopidine, clopidogrel,
and prasugrel irreversibly block P2Y12, a key adenosine diphosphate (ADP)
receptor on the platelet surface; ticagrelor is a reversible inhibitor of P2Y12.
Apciximab, eptifibatide, and tirofiban inhibit the final common pathway of
platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF)
binding to activated glycoprotein (GP) IIb/IIIa. Vorapaxar inhibits thrombin-
mediated platelet activation by targeting protease activated receptor-1 (PAR-
1), the major thrombin receptor on platelets.
Under low shear conditions, collagen can capture and activate
platelets on its own. Captured platelets undergo cytoskeletal reorga-
nization that causes them to flatten and to adhere more closely to the
damaged vessel wall. Under high shear conditions, however, collagen
and vWF must act in concert to support optimal platelet adhesion
and activation. vWF synthesized by endothelial cells and megakaryo-
cytes assembles into multimers that range from 550 to more
than 10,000 kDa. When released from storage in the Weibel-Palade
bodies of endothelial cells or the α-granules of platelets, most of
the vWF enters the circulation, but the vWF released from the ablu-
minal surface of endothelial cells accumulates in the subendothelial
matrix, where it binds collagen via its A3 domain. This surface-
immobilized vWF can simultaneously bind platelets via its A1
domain. In contrast, circulating vWF does not react with unstimu-
lated platelets. This difference in reactivity likely reflects vWF con-
formation; whereas circulating vWF is in a coiled conformation that
prevents access of its platelet-binding domain to vWF receptors on
the platelet surface, immobilized vWF assumes an elongated shape
that exposes its A1 domain. In this extended conformation, large
vWF multimers serve as the molecular glue that tethers platelets to
the damaged vessel wall with sufficient strength to withstand higher
shear forces.8 Large vWF multimers provide additional binding sites
for collagen and heighten platelet adhesion because platelets have
more vWF receptors than collagen receptors. Adhesion to collagen
or vWF results in platelet activation, the next step in platelet plug
formation.
Activation and Secretion
Adhesion to collagen and vWF initiates signaling pathways that result
in platelet activation. These pathways induce cyclooxygenase-1
(COX-1)–dependent synthesis and release of thromboxane A2, and
trigger the release of adenosine diphosphate (ADP) from storage
granules. Thromboxane A2 is a potent vasoconstrictor, and similar to
ADP, locally activates ambient platelets and recruits them to the site
of injury. This process results in expansion of the platelet plug. To
activate platelets, thromboxane A2 and ADP must bind to their
respective receptors on the platelet membrane. The thromboxane
receptor (TP) is a G-protein coupled receptor that is found on plate-
lets and on the endothelium, which explains why thromboxane A2
induces vasoconstriction as well as platelet activation.9 ADP interacts
with a family of G protein–coupled receptors on the platelet mem-
brane. Most important of these is P2Y12, which is the target of the
thienopyridines, but P2Y1 also contributes to ADP-induced platelet
activation, and maximal ADP-induced platelet activation requires
activation of both receptors. A third ADP receptor, P2X1, is an
adenosine triphosphate (ATP)–gated calcium channel. Platelet
storage granules contain ATP as well as ADP; ATP released during
the platelet activation process may contribute to the platelet recruit-
ment process in a P2X1-dependent fashion.
Although TP and the various ADP receptors signal through dif-
ferent pathways, they all trigger an increase in the intracellular
calcium concentration in platelets. This in turn induces shape change
via cytoskeletal rearrangement, granule mobilization and release, and
subsequent platelet aggregation. Activated platelets promote coagula-
tion by expressing phosphatidylserine on their surfaces, an anionic
phospholipid that supports assembly of coagulation factor complexes
(see Chapter 128). After being assembled, these clotting factor com-
plexes trigger a burst of thrombin generation and subsequent fibrin
formation. In addition to converting fibrinogen to fibrin, thrombin
amplifies platelet recruitment and activation and promotes expansion
of the platelet plug. Thrombin binds to protease-activated receptors
types 1 and 4 (PAR1 and PAR4, respectively) on the platelet surface
and cleaves their extended amino-termini, thereby generating new
amino-termini that serve as tethered ligands that bind and activate
the receptors (Fig. 124-3). Whereas low concentrations of thrombin
cleave PAR1, PAR4 cleavage requires higher thrombin concentra-
tions.10 Cleavage of either receptor triggers platelet activation.
In addition to providing a surface on which clotting factors assem-
ble, activated platelets also promote fibrin formation and subsequent
stabilization by releasing factor V, factor XI, fibrinogen, and factor
XIII (see Chapter 127). Thus, there is coordinated activation of
platelets and coagulation, and the fibrin network that results from
thrombin action helps anchor the platelet aggregates at the site of
injury. Activated platelets also release adhesive proteins, such as vWF,
thrombospondin, and fibronectin, which may augment platelet adhe-
sion at sites of injury, as well as growth factors, such as platelet-
derived growth factor (PDGF) and transforming growth factor-β
(TGFβ), which promote wound healing. Platelet aggregation is the
final step in the formation of the platelet plug.
Aggregation
Platelet aggregation links platelets to each other to form clumps.
GPIIb/IIIa mediates these platelet-to-platelet linkages. On nonacti-
vated platelets, GPIIb/IIIa exhibits minimal affinity for its ligands.
Upon platelet activation, GPIIb/IIIa undergoes a conformational
transformation, which reflects transmission of inside-out signals from
its cytoplasmic domain to its extracellular domain.11 This transforma-
tion enhances the affinity of GPIIb/IIIa for its ligands; fibrinogen;
and, under high shear conditions, vWF (see Chapter 127). Arginine–
glycine–aspartic acid (RGD) sequences located on fibrinogen and
vWF, as well as a platelet-binding lycine–glycine–aspartic acid (KGD)
sequence on fibrinogen, mediate their interaction with GPIIb/IIIa.
When subjected to high shear, circulating vWF elongates and exposes
its platelet-binding domain, which enables its interaction with the

IIa
IIa
IIa
LDPR
SFLLR
R
LDP
RLLF
S
C C C C
Response
Figure 124-3  ACTIVATION OF PROTEASE-ACTIVATED RECEPTOR
(PAR)-1 BY THROMBIN. Thrombin (IIa) binds to the amino terminus of
the extracellular domain of PAR-1, where it cleaves a specific peptide bond.
Cleavage of this bond generates a new amino-terminus sequence that acts as
a tethered ligand and binds to the body of the receptor, thereby activating it.
Thrombin then dissociates from the receptor. Analogs of the first five or six
amino acids of the tethered ligand sequences, known as thrombin receptor
agonist peptides, can independently activate PAR-1.
conformationally activated GPIIb/IIIa. Divalent fibrinogen and mul-
tivalent vWF molecules serve as bridges and bind adjacent platelets
together. After being bound to GPIIb/IIIa, fibrinogen and vWF
induce outside–inside signals that augment platelet activation and
result in the activation of additional GPIIb/IIIa receptors, creating a
positive feedback loop. Because GPIIb/IIIa acts as the final effector
in platelet aggregation, it is a logical target for potent antiplatelet
drugs (see Chapters 132 and 151). Fibrin, the ultimate product of
the coagulation system, tethers the platelet aggregates together and
anchors them to the site of injury.
Coagulation
Coagulation results in the generation of thrombin, which converts
soluble fibrinogen to fibrin. Coagulation occurs through the action
of discrete enzyme complexes, which are composed of a vitamin
K-dependent enzyme and a non-enzyme cofactor, and assemble on
anionic phospholipid membranes in a calcium-dependent fashion
(see Chapter 128). Each enzyme complex activates a vitamin
K–dependent substrate that becomes the enzyme component of the
subsequent complex. Together, these complexes generate a small
amount of thrombin, which amplifies its own generation by activat-
ing the non-enzyme cofactors and platelets, which then provide an
anionic surface on which the complexes assemble. The three enzyme
complexes involved in thrombin generation are extrinsic tenase,
intrinsic tenase, and prothrombinase (Fig. 124-4). Although extrinsic
tenase initiates the system under most circumstances, the contact
system also plays a role in some situations.
Extrinsic Tenase
This complex forms upon exposure of tissue factor-expressing cells
to the blood.12 Tissue factor exposure occurs after atherosclerotic
plaque rupture because the core of the plaque is rich in cells that
express tissue factor. Denuding injury to the vessel wall also exposes
Chapter 124  Overview of Hemostasis and Thrombosis 1777
tissue factor constitutively expressed by subendothelial fibroblasts and
smooth muscle cells. In addition to cells in the vessel wall, circulating
monocytes and monocyte-derived microparticles (small membrane
fragments) also provide a source of tissue factor. When tissue factor–
bearing monocytes or microparticles bind to platelets or other leuko-
cytes and their plasma membranes fuse, tissue factor transfer occurs.
By binding to adhesion molecules expressed on activated endothelial
cells or to P-selectin on activated platelets, these tissue factor-bearing
cells or microparticles can initiate or augment coagulation.13 This
phenomenon likely explains how venous thrombi develop in the
absence of obvious vessel wall injury.
Tissue factor is an integral membrane protein that serves as a
receptor for factor VIIa. The blood contains trace amounts of factor
VIIa, which has negligible activity in the absence of tissue factor.12
With tissue factor exposure on anionic cell surfaces, factor VIIa binds
in a calcium-dependent fashion to form the extrinsic tenase complex,
which is a potent activator of factors IX and X. After being activated,
factor IXa and factor Xa serve as the enzyme components of intrinsic
tenase and prothrombinase, respectively.
Intrinsic Tenase
Factor IXa binds to factor VIIIa on anionic cell surfaces to form the
intrinsic tenase complex.14 Factor VIII circulates in blood in complex
with vWF. Thrombin cleaves factor VIII and releases it from vWF,
converting it to its activated form.15 Activated platelets express
binding sites for factor VIIIa. After being bound, factor VIIIa
binds factor IXa in a calcium-dependent fashion to form the intrinsic
tenase complex, which then activates factor X. The change in catalytic
efficiency of factor IXa–mediated activation of factor X that occurs
with deletion of individual components of the intrinsic tenase
complex highlights their importance. Absence of the membrane or
factor VIIIa almost completely abolishes enzymatic activity, and the
catalytic efficiency of the complete complex is 109-fold greater than
that of factor IXa alone.14 Because intrinsic tenase activates factor X
at a rate 50- to 100-fold faster than extrinsic tenase, it plays a critical
role in the amplification of factor Xa and subsequent thrombin gen-
eration (see Chapter 128).
Prothrombinase
Factor Xa binds to factor Va, its activated cofactor, on anionic phos-
pholipid membrane surfaces to form the prothrombinase complex.
Activated platelets release factor V from their α-granules, and this
platelet-derived factor V may play a more important role in
hemostasis than its plasma counterpart.16 Whereas plasma factor
V requires thrombin activation to exert its cofactor activity, the par-
tially activated factor V released from platelets already exhibits
substantial cofactor activity. Activated platelets express specific factor
Va binding sites on their surface, and bound factor Va serves as a
receptor for factor Xa. The catalytic efficiency of factor Xa activation
of prothrombin increases by 109-fold when factor Xa incorporates
into the prothrombinase complex.14 Prothrombin binds to the pro-
thrombinase complex, where it undergoes conversion to thrombin in
a reaction that releases prothrombin fragment 1.2 (F1.2). Plasma
levels of F1.2, therefore, provide a marker of prothrombin
activation.
Fibrin Formation
The final effector in coagulation is thrombin. Thrombin converts
soluble fibrinogen into insoluble fibrin. Fibrinogen is a dimeric mol-
ecule, each half of which is composed of three polypeptide chains—
the Aα, Bβ, and γ chains. Numerous disulfide bonds covalently link
the chains together and join the two halves of the fibrinogen molecule
(Fig. 124-5). Electron micrographic studies of fibrinogen reveal a
trinodular structure with a central E domain flanked by two D
 1778 Part XII  Hemostasis and Thrombosis
Extrinsic
tenase
Figure 124-4  COAGULATION SYSTEM. Coagulation occurs
through the action of discrete enzyme complexes, which are composed
of a vitamin K–dependent enzyme and a non-enzyme cofactor. These
complexes assemble on anionic phospholipid membranes in a calcium-
dependent fashion. Vascular injury exposes tissue factor (TF), which
binds factor VIIa to form extrinsic tenase. Extrinsic tenase activates
factors IX and X. Factor IXa binds to factor VIIIa to form intrinsic
tenase, which activates factor X. Factor Xa binds to factor Va to form
prothrombinase, which converts prothrombin (II) to thrombin (IIa).
Thrombin then converts soluble fibrinogen into insoluble fibrin.
domains. Crystal structures show symmetry of design with the central
E domain, which contains the amino termini of the fibrinogen
chains, joined to the lateral D domains by coiled-coil regions.
Fibrinogen circulates in an inactive form. Thrombin binds to the
amino termini of the Aα and Bβ chains of fibrinogen, where it cleaves
specific peptide bonds to release fibrinopeptide A and fibrinopeptide
B and generates fibrin monomer (see Fig. 124-5). Because they are
products of thrombin action on fibrinogen, plasma levels of these
fibrinopeptides provide an index of thrombin activity. Fibrinopeptide
release creates new amino termini that extend as knobs from the E
domain of one fibrin monomer and insert into preformed holes in
the D domains of other fibrin monomers. This creates long strands
known as protofibrils, consisting of fibrin monomers noncovalently
linked together in a half-staggered overlapping fashion.17
Noncovalently linked fibrin protofibrils are unstable.17 The stabil-
ity of the fibrin network is enhanced by platelets and procoagulant
cells.18 Platelets not only bind fibrin via GPIIb/IIIa and promote the
formation of a dense fibrin network, but they also release factor XIII.
By covalently cross-linking the α and γ chains of adjacent fibrin
monomers, factor XIIIa stabilizes the fibrin in a calcium-dependent
fashion and renders it relatively resistant to degradation. Factor XIII
circulates in blood as a heterodimer consisting of pairs of A and B
subunits. The active and calcium binding sites on factor XIII are
localized to the A subunit. Platelets contain large amounts of factor
XIII in their cytoplasms, but platelet-derived factor XIII consists only
of the A subunits (see Chapter 127). Both plasma and platelet factor
XIII are activated by thrombin.
Contact Pathway
Current thinking is that tissue factor exposure represents the sole
pathway for activation of coagulation and that the contact system—
which includes factor XII, prekallikrein, and high-molecular-weight
kininogen—is unimportant for hemostasis because patients deficient
in these factors do not have bleeding problems (see Chapter 139).
The physiologic role of factor XI is more difficult to assess because
the plasma level of factor XI does not predict the propensity for
bleeding (see Chapter 139). Although the capacity of thrombin to
Vascular Contact
injury activation
TF VIIIa VIIIaH
VIIIaL
IXa
IX X IXa X Intrinsic
tenase
Xa Xa
VaH
VaL II
Xa
Prothrombinase
IIa
Fibrinogen Fibrin
feed back and activate platelet-bound factor XI may explain this
phenomenon, platelet-derived factor XI may be more important for
hemostasis than circulating factor XI.
We cannot ignore the contact pathway, however, because coronary
catheters and other blood-contacting medical devices, such as stents
or mechanical valves, likely trigger clotting through this mechanism.
Factor XII bound to the surface of catheters or devices undergoes a
conformational change that results in its activation. Factor XIIa con-
verts prekallikrein to kallikrein in a reaction accelerated by high-
molecular-weight kininogen, and factor XIIa and kallikrein then
feedback to activate additional factor XII. Factor XIIa propagates
coagulation by activating factor XI (Fig. 124-6).
In addition to its role in device-related thrombosis, the contact
pathway may also contribute to the stability of arterial and venous
thrombi.19,20 DNA and RNA released from damaged cells in athero-
sclerotic plaques activates factor XII, and mice given DNA- or RNA-
degrading enzymes exhibit attenuated thrombosis at sites of arterial
injury. Polyphosphates released from activated platelets also activate
factor XII and may provide another stimulus for contact pathway
activation. Mice deficient in factor XII or factor XI form small
unstable thrombi at sites of arterial or venous damage, suggesting that
factor XII and factor XI contribute to thrombogenesis (see Chapter
139). It is unknown whether the same is true in humans. Patients
with unstable angina have increased plasma levels of factor XIa, but
it is unclear whether this reflects activation by factor XIIa or by
thrombin. Although the contribution of the contact pathway to
thrombin generation remains uncertain, the final product of coagula-
tion is fibrin. Hemostasis depends on the dynamic balance between
the formation of fibrin and its degradation. The fibrinolytic system
mediates fibrin breakdown.
Fibrinolytic System
Fibrinolysis initiates when plasminogen activators convert plasmino-
gen to plasmin, which then degrades fibrin into soluble fragments.
Blood contains two immunologically and functionally distinct plas-
minogen activators, t-PA and u-PA. Whereas t-PA mediates intravas-
cular fibrin degradation, u-PA binds to a specific u-PA receptor
 Chapter 124  Overview of Hemostasis and Thrombosis 1779

COOH NH2 NH2 COOH

Aα FPA FPA Aα

Bβ FPB FPB Bβ Fibrinogen

γ γ

D Coiled E Coiled D
domain coil domain coil domain

D E D Fibrinogen

Thrombin FPA, FPB

D E D Fibrin monomer

Figure 124-5  FIBRINOGEN STRUCTURE AND CONVER-

D E D D E D SION OF FIBRINOGEN TO FIBRIN. A dimeric molecule, each
Fibrin polymer half of fibrinogen is composed of three polypeptide chains—the
E D D E D D E Aα, Bβ, and γ chains. Numerous disulfide bonds (lines) covalently
link the chains together and join the two halves of the fibrinogen
molecule to yield a trinodular structure with a central E domain
Factor XIIIa linked via the coiled coil regions to two lateral D domains. To
convert fibrinogen to fibrin, thrombin cleaves specific peptide
bonds at the amino (NH2) termini of the Aα and Bβ chains of
fibrinogen to release fibrinopeptide A (FPA) and fibrinopeptide B
(FPB), thereby generating fibrin monomer. Fibrin monomers
D E D D E D Cross-linked polymerize to generate protofibrils arranged in a half-staggered
fibrin polymer overlapping fashion. By covalently cross-linking α and γ chains of
E D D E D D E adjacent fibrin monomers, factor XIIIa stabilizes the fibrin network
and renders it resistant to degradation.

(u-PAR) on the surface of cells, where it activates cell-bound plas-
minogen. Consequently, pericelluar proteolysis during cell migration
and tissue remodeling and repair are the major functions of u-PA.21
Regulation of fibrinolysis occurs at two levels (see Chapter 129).
PAI-1, and to a lesser extent, PAI-2, inhibit the plasminogen activators,
and α2-antiplasmin inhibits plasmin. Endothelial cells synthesize
PAI-1, which inhibits both t-PA and u-PA, whereas monocytes and the
placenta synthesize PAI-2, which specifically inhibits u-PA. Thrombin-
activated fibrinolysis inhibitor (TAFI) also modulates fibrinolysis and
provides a link between fibrinolysis and coagulation.22 Whereas throm-
bosis can occur if there is impaired activation of the fibrinolytic system,
excessive activation leads to bleeding. Therefore, a review of the mecha-
nisms of action of t-PA, u-PA, and TAFI is worthwhile.
Mechanism of Action of Tissue
Plasminogen Activator
Tissue plasminogen activator, a serine protease, contains five discrete
domains: a fibronectin-like finger domain, an epidermal growth
factor (EGF) domain, two kringle domains, and a protease domain.
Synthesized as a single-chain polypeptide, plasmin readily converts
t-PA into a two-chain form. Single- and two-chain forms of t-PA
convert plasminogen to plasmin. Native Glu-plasminogen is a single-
chain polypeptide with a Glu residue at its amino-terminus. Plasmin
cleavage at the amino-terminus generates lysine–plasminogen, a
truncated form with a Lys residue at its new amino terminus.21 t-PA
cleaves a single peptide bond to convert single-chain glutamine- or
lysine–plasminogen into two-chain plasmin composed of a heavy
chain containing five kringle domains and a light chain containing
the catalytic domain. Because its open conformation exposes the t-PA
cleavage site, lysine–plasminogen is a better substrate than glutamic
acid–plasminogen, which assumes a circular conformation that
renders this bond less accessible.
Tissue plasminogen activator has little enzymatic activity in the
absence of fibrin, but its activity increases by at least three orders of
magnitude when fibrin is present. This increase in activity reflects the
capacity of fibrin to serve as a template that binds t-PA and plasmino-
gen and promotes their interaction. Whereas t-PA binds to fibrin via
its finger and second kringle domains, plasminogen binds fibrin via
its kringle domains. Kringle domains are loop-like structures that
bind Lys residues on fibrin. As fibrin undergoes degradation, more
Lys residues are exposed, which provide additional binding sites for
t-PA and plasminogen. Consequently, degraded fibrin stimulates t-PA
activation of plasminogen more than intact fibrin.
α2-Antiplasmin rapidly inhibits circulating plasmin by docking to
its first kringle domain and then inhibiting the active site.21 Because
plasmin binds to fibrin via its kringle domains, plasmin generated on
the fibrin surface resists inhibition by α2-antiplasmin. This phenom-
enon endows fibrin-bound plasmin with the capacity to degrade
fibrin. Factor XIIIa cross-links small amounts of α2-antiplasmin onto
fibrin, which prevents premature fibrinolysis.18
 1780 Part XII  Hemostasis and Thrombosis

Similar to fibrin, annexin II on endothelial cells binds t-PA and
plasminogen and promotes their interaction. Cell-surface ganglio-
sides and α-enolase also may bind plasminogen and promote its
activation by altering its conformation into the more readily activated
open form. Plasminogen binds to endothelial cells via its kringle
domains. Lipoprotein a, which also possesses kringle domains,
impairs cell-based fibrinolysis by competing with plasminogen for
cell-surface binding. This phenomenon may explain the association
between elevated lipoprotein a levels and atherosclerosis.
Mechanism of Action of Urokinase-Type
Plasminogen Activator
Synthesized as a single-chain polypeptide, single-chain u-PA (scu-PA)
has minimal enzymatic activity. Plasmin converts scu-PA into a two-
chain form that is enzymatically active and capable of binding u-PAR,
the u-PA receptor on cell surfaces. Further cleavage at the amino-
terminus of two-chain u-PA yields a truncated, lower-molecular-
weight form that lacks the u-PAR binding domain.
Two-chain forms of u-PA readily convert plasminogen to plasmin
in the absence or presence of fibrin.21 In contrast, scu-PA does not
activate plasminogen in the absence of fibrin, but it can activate
fibrin-bound plasminogen because plasminogen adopts a more open
and readily activatable conformation when immobilized on fibrin.
Similar to the higher-molecular-weight form of two-chain u-PA,
scu-PA binds to cell surface u-PAR, where plasmin can activate it.
Many tumor cells elaborate u-PA and express u-PAR on their sur-
faces. Plasmin generated on these cells endows them with the capacity
for metastasis.
Mechanism of Action of TAFI
Thrombin-activated fibrinolysis inhibitor, a procarboxpeptidase
B–like molecule synthesized in the liver, circulates in blood in a latent
form where thrombin bound to thrombomodulin can activate it (see
Chapters 128 and 129). Unless bound to thrombomodulin, throm-
bin activates TAFI inefficiently.22 TAFIa attenuates fibrinolysis by
K PK
HK HK
XII XIIa
cleaving lysine residues from the carboxy termini of chains of degrad-
ing fibrin, thereby removing binding sites for plasminogen, plasmin,
and t-PA. TAFI links fibrinolysis to coagulation because the
thrombin–thrombomodulin complex not only activates TAFI, which
attenuates fibrinolysis, but also activates protein C, which mutes
thrombin generation.
Activated TAFI (TAFIa) has a short half-life in plasma because the
enzyme is unstable.22 Genetic polymorphisms can result in synthesis
of more stable forms of TAFIa. Persistent attenuation of fibrinolysis
by these variant forms of TAFIa may render patients susceptible to
thrombosis.
DISORDERS OF HEMOSTASIS OR THROMBOSIS
A physiologic host defense mechanism, hemostasis focuses on arrest
of bleeding by forming hemostatic plugs composed of platelets and
fibrin at sites of vessel injury. In contrast, thrombosis reflects a patho-
logic process associated with intravascular thrombi that fill the lumens
of arteries or veins.
Hemostatic Disorders
Bleeding can occur if there is abnormal platelet plug formation or
reduced thrombin generation and subsequent fibrin clot formation
at the site of vascular injury; disorders of primary and secondary
hemostasis, respectively. Bleeding also can occur if the platelet or
fibrin clot is prematurely degraded because of excessive fibrinolysis;
a disorder of tertiary hemostasis, the features distinguishing disorders
of primary, secondary, and tertiary hemostasis are outlined in Table
124-1. Hemorrhagic disorders can be inherited or acquired, and the
clinical and laboratory evaluation of such disorders is detailed in
Chapters 130 and 131, respectively.
Disorders of Primary Hemostasis
Platelet plug formation, the first step in the arrest of bleeding at sites
of injury, requires three key components (1) an adequate number of
functional platelets; (2) vWF, the molecular glue that mediates plate-
let adhesion to the damaged vessel wall even in the face of high shear;
and (3) a normal blood vessel that constricts in response to injury
(Table 124-2). Because the platelet plug provides the first line of
defense against bleeding, patients with disorders of primary hemosta-
sis often present with immediate bleeding after injury and petechiae,
pinpoint hemorrhages, may be noted. In addition to skin bleeding,

Table 124-1  Comparison of the Features of Disorders of Primary,

Secondary, or Tertiary Hemostasis

XI XIa Features Primary Secondary Tertiary

Components Platelets, vWF, Coagulation Fibrinolytic
involved and vessel wall factors
IX IXa
Site of Skin and Muscles, joints, Wounds and
bleeding mucocutaneous and deep genitourinary
and soft tissues tissues tract
Common Physical Petechiae and Hematomas and Hematuria and
pathway findings ecchymoses hemarthroses menorrhagia

Figure 124-6  CONTACT SYSTEM. Factor XII (XII) is activated by contact Timing of Immediate Delayed Delayed
with negatively charged surfaces. XIIa converts prekallikrein (PK) to kalli- bleeding
krein (K) and can feed back to activate more XII. Likewise, XIIa also can feed Inheritance Autosomal Autosomal or Autosomal
back to amplify its own generation. About 75% of circulating PK is bound dominant X-linked recessive
to high-molecular-weight kininogen (HK), which localizes it to anionic sur- recessive
faces and promotes PK activation. XIIa propagates clotting by activating XI,
which then activates IX. The resultant IXa assembles into the intrinsic tenase vWF, von Willebrand Factor
complex, which activates X to initiate the common pathway of coagulation.

Table 124-2  Disorders of Primary Hemostasis
Components Affected Causes
Platelets Quantitative or qualitative platelet disorders
vWF Inherited or acquired deficiency or
dysfunction of vWF
Vessel wall Vasculitis or abnormalities of connective tissue
supporting the vasculature
vWF, von Willebrand factor
mucocutaneous bleeding, which may manifest as epistaxis, bleeding
gums, or hematochezia, is common as is excessive menstrual bleeding
in women (see Chapter 130).
Disorders of primary hemostasis may be inherited or acquired.23
Thrombocytopenia or congenital or acquired disorders of platelet
function are common causes of bleeding. Thrombocytopenia can be
the result of decreased production, which can occur because of failure,
infiltration, or fibrosis of the bone marrow (see Chapters 27 and 28);
increased platelet destruction; or abnormal distribution because of
platelet pooling in the spleen (see Chapter 134). Increased destruc-
tion of platelets can occur via immune mechanisms, such as immune
thrombocytopenic purpura (ITP), alloimmune thrombocytopenia,
posttransfusion purpura and drug-induced thrombocytopenia (see
Chapter 133), or nonimmune mechanisms, which include microan-
giopathic disorders, such as thrombotic thrombocytopenic purpura
and hemolytic uremic syndrome (see Chapter 136), as well as con-
sumption because of activation of coagulation, such as occurs with
disseminated intravascular coagulation (see Chapter 141).
Platelet function disorders include disorders of (1) platelet adhe-
sion, such as von Willebrand disease (see Chapter 140) and Bernard-
Soulier syndrome (see Chapter 127); (2) thromboxane synthesis;
(3) secretion, such as alpha or dense granule deficiency or aspirin-like
secretion defects; (4) aggregation, such as Glanzmann thrombasthe-
nia (see Chapter 127); or (5) procoagulant activity (Scott syndrome)
in which the platelets fail to support clotting factor complex assembly
(see Chapter 128). Acquired disorders of platelet function can occur
in patients taking drugs that impair platelet function, such as aspirin
or nonsteroidal antiinflammatory drugs, or in patients with uremia,
paraproteins, or myelodysplastic or myeloproliferative disorders (see
Chapter 132).
Bleeding can also occur with inflammation or malformations of
the blood vessels or abnormalities of the connective tissue supporting
the blood vessels. Inflammatory disorders include Henoch-Schonlein
purpura (see Chapter 152) and the vasculitis that occurs with para-
proteins or cryoglobulins or in patients with systemic lupus erythe-
matosus or other immune disorders.24 Hereditary hemorrhagic
telangiectasia is an inherited disorder associated with malformations
of the capillaries. Telangiectatic vessels can often be seen in the oral
and nasal cavities of patients with this disorder and bleeding episodes,
primarily from the nose and gastrointestinal tract, are common.
Abnormalities of the connective tissue matrix supporting the blood
vessels include Marfan syndrome, Ehlers-Danlos syndrome, and
pseudoxanthoma elasticum.25 Patients with these disorders frequently
report easy bruising.
Disorders of Secondary Hemostasis
Secondary hemostasis depends on rapid generation of sufficient
amounts of thrombin to generate a fibrin mesh that not only con-
solidates the platelet aggregates that form at sites of vascular injury
but is also stable enough to provide a barrier that prevents leakage of
blood from the damaged blood vessel.18 Secondary hemostasis can be
compromised by (1) impaired thrombin generation because of con-
genital or acquired deficiencies of coagulation factors or cofactors or
intake of drugs that inhibit one or more steps in the coagulation
Chapter 124  Overview of Hemostasis and Thrombosis 1781
Table 124-3  Disorders of Secondary Hemostasis
Component Affected Causes
Coagulation factors Congenital deficiency, autoantibodies, increased
consumption, or drugs that attenuate
thrombin generation or thrombin activity
Fibrinogen Decreased production; increased consumption
or synthesis of an abnormal protein
Impaired fibrin polymerization because of
fibrin(ogen) degradation products or
paraproteins
Fibrin cross-linking Congenital or acquired factor XIII deficiency
pathways, (2) congenital or acquired fibrinogen deficiency or dys-
function, or (3) impaired cross-linking of fibrinogen because of con-
genital or acquired deficiency of factor XIII (Table 124-3).
Examples of inherited deficiencies of coagulation factors include
hemophilia A and B, deficiencies of factor VIII and factor IX, respec-
tively (see Chapter 137). Because of redundancy in the coagulation
system, only patients with a factor VIII or factor IX level less than
1% have severe disease characterized by spontaneous bleeding or
bleeding with minimal trauma. Whereas those with factor levels
between 1% and 5% have an intermediate phenotype, patients with
factor VIII or IX levels above 5% usually have mild disease and bleed
only with trauma or surgery. The frequency of bleeding episodes in
patients with severe hemophilia can be reduced by prophylactic
administration of the appropriate factor concentrate; such treatment
is also administered to those with hemophilia who have overt bleed-
ing or in preparation for surgery or other major interventions. Man-
agement of hemophilia becomes more complicated if patients develop
inhibitory antibodies that attenuate or abolish the activity of the
infused factor (see Chapter 138). Congenital deficiencies of pro-
thrombin (factor II), factors V, VII, X, or XI (hemophilia C) or
fibrinogen are less common causes of bleeding (see Chapter 139). In
contrast, deficiencies of components of the contact pathway (factor
XII, high-molecular-weight kininogen, and prekallikrein) are not
associated with bleeding. The clinical and laboratory evaluation of
such patients are detailed in Chapters 130 and 131, respectively, and
their treatment is outlined in Chapter 116.
Acquired deficiencies of coagulation factors can result from
decreased synthesis because of severe liver disease, vitamin K defi-
ciency or intake of drugs that interfere with vitamin K metabolism,
consumption because of excessive activation of coagulation (e.g., dis-
seminated intravascular coagulation; see Chapter 141), or accelerated
clearance caused by adsorption by paraproteins or amyloid (see Chap-
ters 85 and 86) or caused by autoantibodies that shorten the half-life
or attenuate or abolish clotting factor activity.
Congenital disorders of fibrinogen include absence or low levels
of fibrinogen (afibrinogenemia and hypofibrinogenemia, respectively)
or synthesis of a dysfunctional protein (dysfibrinogenemia). Acquired
disorders of fibrinogen include decreased synthesis or production of
an abnormal fibrinogen and increased fibrinogen consumption or the
presence of inhibitors that interfere with fibrin polymerization, such
as paraproteins or autoantibodies, particularly in patients with sys-
temic lupus erythematosus or other immune disorders or elevated
levels of fibrin(ogen) degradation products.
Stabilization of fibrin requires cross-linking of the α and γ chains
of adjacent fibrin monomers to yield a polymer that is resistant to
premature breakdown. Factor XIIIa, a transglutaminase, performs
this function by catalyzing the condensation of lysine residues on one
chain with glutamic acid residues on another chain.26 Congenital or
acquired deficiency of factor XIII can impair cross-linking, resulting
in bleeding. The hallmarks of severe factor XIII deficiency include
umbilical stump bleeding in the neonatal period (see Chapter 152);
intracranial hemorrhage with little or no trauma; recurrent soft tissue
hemorrhages; and, in women, recurrent spontaneous miscarriages.
 1782 Part XII  Hemostasis and Thrombosis
Table 124-4  Disorders of Tertiary Hemostasis
Component Affected Causes
Plasminogen activators Increased t-PA or u-PA release in the GU tract
or other tissues
Plasmin Deficiency of PAI-1 or α2-antiplasmin, resulting
in an increased plasmin concentration
Plasminogen activation Enhanced plasminogen activation secondary to
activation of coagulation by procoagulants,
such as cancer cells, artificial surfaces, or
snake venoms
GU, Genitourinary; PAI-1, plasminogen activator inhibitor 1; t-PA, tissue
plasminogen activator; u-PA, urokinase-type plasminogen activator.
Disorders of Tertiary Hemostasis
Tertiary hemostasis depends on the generation of plasmin, which
degrades fibrin and restores blood flow in damaged vessels. Premature
lysis of fibrin in hemostatic plugs can lead to bleeding; this can occur
systemically or can be localized (Table 124-4). Systemic fibrinolysis
that occurs in the absence of activation of coagulation, so-called
primary hyperfibrinolysis, is rare but can occur with inherited defi-
ciency of PAI-1 or α2-antiplasmin, the inhibitors of the plasminogen
activators and plasmin, respectively; advanced liver disease; and some
snake bites. More commonly, systemic hyperfibrinolysis is secondary
to activation of coagulation by procoagulants such as tissue factor
(e.g., in patients with metastatic cancer) or artificial surfaces (e.g., in
cardiopulmonary bypass surgery or with cardiac assist devices). Exam-
ples of localized hyperfibrinolysis include menorrhagia or hematuria
after prostatectomy triggered by excessive plasmin generation induced
by the high concentrations of t-PA and u-PA in the uterus and geni-
tourinary tract, respectively.
Thrombotic Disorders
Thrombosis may occur in arteries, in the chambers of the heart, or
in the veins. Factors contributing to thrombosis in these sites include
endothelial injury or activation, reduced blood flow, and hypercoagu-
lability of the blood, the so-called Virchow triad.
Arterial Thrombosis
Most arterial thrombi occur on top of disrupted atherosclerotic
plaques. Plaques with a thin fibrous cap and a lipid-rich core are most
prone to disruption. Erosion or rupture of the fibrous cap exposes
thrombogenic material in the lipid-rich core to the blood and triggers
platelet activation and thrombin generation. The extent of plaque
disruption and the content of thrombogenic material in the plaque
determine the consequences of the event regardless of whether it
occurs in the cerebral circulation (see Chapter 147), the coronary
circulation (see Chapter 148), or the major arteries of the legs (see
Chapter 150), but host factors also contribute. Breakdown of regula-
tory mechanisms that limit platelet activation and inhibit coagulation
can augment thrombosis at sites of plaque disruption.
Decreased production of nitric oxide and prostacyclin by diseased
endothelial cells can trigger vasoconstriction and platelet activation.
Proinflammatory cytokines lower thrombomodulin expression by
endothelial cells, which promotes thrombin generation, and stimulate
PAI-1 expression, which inhibits fibrinolysis.
Products of blood coagulation contribute to atherogenesis, as well
as to its complications (see Chapter 146). Microscopic erosions in
the vessel wall trigger the formation of tiny platelet-rich thrombi.27
Activated platelets release PDGF and TGFβ, which promote a
fibrotic response. Thrombin generated at the site of injury not only
activates platelets and converts fibrinogen to fibrin but also activates
PAR-1 on smooth muscle cells and induces their proliferation, migra-
tion, and elaboration of extracellular matrix. Incorporation of thrombi
into plaques promotes plaque growth, and decreased endothelial cell
production of heparan sulfate—which normally limits smooth-
muscle proliferation—contributes to plaque expansion.27 The mul-
tiple links between atherosclerosis and thrombosis have prompted the
term atherothrombosis (see Chapter 146).
Intracardiac Thrombosis
Thrombi can form in the left ventricle after transmural myocardial
infarction or with an aneurysm or dyskinetic ventricle or in the left
atrial appendage, particularly in patients with atrial fibrillation (see
Chapter 149). Damage to the endothelium after myocardial infarc-
tion and abnormal blood flow are the major triggers for left ventricu-
lar thrombus formation. With rapid atrial fibrillation, there also is
stasis and turbulent blood flow in the left atrial appendage, which is
a long, blind-ended trabeculated pouch.28 This may lead to localized
activation of endothelial cells and subsequent loss of their anticoagu-
lant phenotype, a process amplified by adhesion of leukocytes and
subsequent elaboration of proinflammatory cytokines. The genera-
tion of thrombin creates a local hypercoagulable state that likely
promotes thrombus formation on the abnormal endothelium. Embo-
lization of these thrombi to the brain is a common cause of ischemic
stroke and is the major cause of mortality and morbidity in patients
with atrial fibrillation.
Venous Thrombosis
The causes of venous thrombosis include those associated with hyper-
coagulability, which can be genetic or acquired, and the mainly
acquired risk factors, such as advanced age, obesity, or cancer, which
are associated with immobility (see Chapters 142 and 144). Inherited
hypercoagulable states and these acquired risk factors combine to
establish the intrinsic risk of thrombosis for each individual.2 Super-
imposed triggering factors, such as surgery, pregnancy, or hormonal
therapy, modify this risk, and thrombosis occurs when the combina-
tion of genetic, acquired, and triggering forces exceed a critical
threshold.29
Some acquired or triggering factors entail a higher risk than
others. For example, major orthopedic surgery, neurosurgery, multi-
ple trauma, and metastatic cancer (particularly adenocarcinoma) are
associated with the highest risk; prolonged bed rest, antiphospholipid
antibodies (see Chapter 143), and the puerperium period are associ-
ated with an intermediate risk; and pregnancy, obesity, long-distance
travel, and the use of oral contraceptives or hormonal replacement
therapy are mild risk factors. Up to half of patients who present with
venous thromboembolism before the age of 45 years have inherited
hypercoagulable disorders—so-called thrombophilia (see Chapter
142)—particularly those whose event occurred in the absence of risk
factors or with minimal provocation, such as after minor trauma or
a long-haul flight or with estrogen use.30
REFERENCES
1. Lippi G, Franchini M, Targher G: Arterial thrombus formation in car-
diovascular disease. Nat Rev Cardiol 8:502, 2011.
2. Reitsma PH, Versteeg HH, Middledorp S: Mechanistic view of risk
factors for venous thromboembolism. Arterioscler Thromb Vasc Biol
32:563, 2012.
3. Morris TA: Natural history of venous thromboembolism. Crit Care Clin
27:869, 2011.
4. van Hinsbergh VW: Endothelium: Role in regulation and coagulation
and inflammation. Semin Immunopathol 34:93, 2012.
5. Crawley JT, Lane DA: The haemostatic role of tissue factor pathway
inhibitor. Arterioscler Thromb Vasc Biol 28:233, 2008.

6. Danese S, Vetrano S, Zhang L, et al: The protein C pathway in tissue
inflammation and injury: Pathogenic role and therapeutic implications.
Blood 115:1121, 2010.
7. Nieswandt B, Pleines I, Bender M: Platelet adhesion and activation
mechanisms in arterial thrombosis and ischaemic stroke. J Thromb
Haemost 9:92, 2011.
8. Di Stasio E, De Cristofaro R: The effect of shear stress on protein con-
formation: Physical forces operating on biochemical systems: The case
of von Willebrand factor. Biophys Chem 153:1, 2010.
9. Hechler B, Gachet C: P2 receptors and platelet function. Purinergic
Signal 7:293, 2011.
10. Adams MN, Ramachandran R, Yau MK, et al: Structure, function and
pathophysiology of protease activated receptors. Pharmacol Ther 130:248,
2011.
11. Bennett JS, Moore DT: Regulation of platelet beta 3 integrins. Haema-
tologica 95:1049, 2010.
12. Owens AP 3rd, Mackman N: Tissue factor and thrombosis: The clot
starts here. Thromb Haemost 104:432, 2010.
13. Owens AP 3rd, Mackman N: Microparticles in hemostasis and throm-
bosis. Circ Res 108:1284, 2011.
14. Mann KG: Thrombin generation in hemorrhage control and vascular
occlusion. Circulation 124:225, 2011.
15. Fay PJ: Factor VIII structure and function. Int J Hematol 83:103,
2006.
16. Fager AM, Wood JP, Bouchard BA, et al: Properties of procoagulant
platelets: Defining and characterizing the subpopulation binding a
functional prothrombinase. Arterioscler Thromb Vasc Biol 30:2400,
2010.
Chapter 124  Overview of Hemostasis and Thrombosis 1783
17. Lord ST: Molecular mechanisms affecting fibrin structure and stability.
Arterioscler Thromb Vasc Biol 31:494, 2011.
18. Wolberg AS: Plasma and cellular contributions to fibrin network forma-
tion, structure and stability. Haemophilia 16:7, 2010.
19. Gailani D, Renne T: The intrinsic pathway of coagulation: A target for
treating thromboembolic disease? J Thromb Haemost 5:1106, 2007.
20. Muller F, Renne T: Novel roles for factor XII-driven plasma contact
activation system. Curr Opin Hematol 15:516, 2008.
21. Schaller J, Gerber SS: The plasmin-antiplasmin system: Structural and
functional aspects. Cel Mol Life Sci 68:785, 2011.
22. Heylen E, Willemse J, Hendriks D: An update on the role of carboxy-
peptidase U (TAFIa) in fibrinolysis. Front Biosci 17:2427, 2011.
23. Broos K, Feys HB, DeMeyer SF, et al: Platelets at work in primary
hemostasis. Blood Rev 25:155, 2011.
24. Eby C: Pathogenesis and management of bleeding and thrombosis in
plasma cell dyscrasias. Br J Haematol 145:151, 2009.
25. Malfait F, DePaepe A: Bleeding in the heritable connective tissue disor-
ders: Mechanisms, diagnosis and treatment. Blood Rev 23:191, 2009.
26. Komaromi I, Bagoly Z, Muszbek L: Factor XIII: Novel structural and
functional aspects. J Thromb Haemost 9:9, 2011.
27. Borissoff JI, Spronk HM, ten Cate H: The hemostatic system as a modu-
lator of atherosclerosis. N Engl J Med 364:1746, 2011.
28. Watson T, Shantsila E, Lip GY: Mechanisms of thrombogenesis in atrial
fibrillation: Virchow’s triad revisited. Lancet 373:155, 2009.
29. Tchaikovski SN, Rosing J: Mechanisms of estrogen-induced venous
thromboembolism. Thromb Res 126:5, 2010.
30. Anderson JA, Weitz JI: Hypercoagulable states. Crit Care Clin 27:933,
2011.