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42 Part 2 The cardiovascular system
In this book we mostly focus on common disorders—those most often encountered in
doctors’ surgeries, general hospitals, and pharmacies throughout the world. Frequently
these conditions are not life-threatening but remain serious, for example skin disorders
(Chapter 8) or most manifestations of depression (Chapter 19). By contrast, in this section
we will mainly be considering a set of conditions caused by disease of the heart or blood
vessels (the cardiovascular system) that are both common and life-threatening. What will
most of us die of? Well, the answer is very clear: most of us will die from cardiovascular
disease or from cancer. Taken together cardiovascular diseases will kill more of us than
any other set of conditions. As we discuss in Chapter 6, in the USA alone approximately
one person dies every minute as a result of diseased blood vessels in the heart.
For a large percentage of these people death will be sudden and unexpected. The most
common cause of these sudden deaths is heart attacks—the blood supply to part of the
heart is reduced by clogged-up vessels, oxygen supply to the heart is inadequate, and as
a result part of the heart tissue dies.
However, we are not helpless to reduce the likelihood of this happening. We can eat well,
exercise, and avoid cigarette smoke and stress. Taken together, these measures can have
a profound effect on cardiovascular risk reduction. Here we are concerned with
understanding how we can use drugs as therapeutic agents to reduce patients’ risk of
establishing diseases of the heart or blood vessels, and how we can modify the course of
such illnesses when they occur. The objective is to improve longevity and the quality of life.
In this section we will encounter a number of patients who develop a range of common
and serious cardiovascular conditions. Monique has developed a blood clot in a leg vein
following a long-haul flight (Workbook 1). For her, this creates discomfort, but also a risk of
more serious and potentially life-threatening consequences—the risk of these occurring is
reduced by the drugs she takes. Once her illness is resolved there is no reason to think her
long-term risk is increased. Andreas (Workbook 2) has high blood pressure (hypertension),
a condition in which, typically, the patient feels perfectly well. Despite the absence of
symptoms, Andreas will have to take antihypertensive drugs for the rest of his life—the
long-term reduction in blood pressure will substantially reduce Andreas’s risk of
developing serious cardiovascular conditions such as heart attacks and stroke.
Contrasting with this, poor Brian in Workbook 3 has already developed clogged-up
coronary arteries—we need to reduce his long-term risk with drugs that modify his blood
lipid profile, but in his case it is too late to prevent a heart attack. In Workbooks 3 and 4 we
will explore the pathology and blood treatment of patients with other common types of
heart disease (arrhythmias and heart failure). In every case we will describe the
physiological basis of these illnesses, and set out to understand how the action of the
drugs at a cellular and molecular level changes the physiology of the heart and blood
vessels, and why this results in a therapeutic outcome.
Chapter 4
Haemostasis and
thromboembolic disorders
Useful terms for this topic
Embolus: Part of a thrombus which has broken away
and is free oating in blood, or lodges at a site distal
to origin.
Fibrinolysis/thrombolysis: The dissolving of a blood
clot.
Haemostasis: Arrest of blood ow from a damaged
blood vessel.
Thromboembolic disorders: Collective term for
conditions arising from blood vessel occlusion by
thrombi or emboli.
Thrombosis: Process of thrombus formation. Involves
coagulation of blood and platelet plug formation.
Thrombus: A blood clot on the inside face of an intact
blood vessel.
Venous thromboembolism: Collective term for deep
vein thrombosis (DVT) and pulmonary embolism.
What happens when you cut yourself and bleed?
Eventually the ow of blood from the wound reduces
and a clot forms. e underlying mechanism behind
this arrest of blood loss from a damaged blood vessel is
called haemostasis. In this case, formation of a clot is
benecial. Some of the haemostatic processes, however,
can be activated inappropriately, and which can give
rise to serious pathological conditions such as heart
attack and stroke. In Workbook 1 at the end of this
chapter, our ctional patient Monique experiences pain
in one leg soon after a long-haul ight, and it is
concluded that a blood clot has formed on the inner
face of an intact vein.
• A clot on the inside of the wall of an intact blood vessel
is called a thrombus, and in this patient has led to a
condition called deep vein thrombosis (DVT); the
thrombus may block (occlude) or reduce blood ow at
its site of formation.
• Furthermore, part of the thrombus may break away
from the vessel wall, forming an embolus, which could
then block a smaller blood vessel downstream, for
instance in the lungs.
In this chapter we explore thrombus formation and
removal, and the serious and common illnesses to which
thrombus formation contributes. We then look at the
cellular and molecular basis of action of the drugs used to
manage these pathologies, and the way this helps us to
understand the pattern of use of these drugs in practice.
We will concentrate on the most widely used drugs, such
as heparin, aspirin, and warfarin. In addition, some less
well-known classes of drugs that are becoming more
common in clinical practice will be introduced, such as
the novel oral anticoagulants dabigatran, rivaroxaban,
and apixaban.
In Monique’s case the thrombus causing the blockage
dislodges and moves to her lungs, occluding blood
vessels there. is creates a further dangerous condition
called pulmonary embolism (PE). e process by which
blood clots occur and travel through the veins is called
venous thromboembolism (VTE) and comprises both
44 Chapter 4 Haemostasis and thromboembolic disorders
DVT and PE. ese common and potentially serious
conditions associated with blood vessel occlusion by
thrombi and emboli are known collectively as
thromboembolic disorders. Stroke, angina, and
Table 4.1 Thromboembolic disorders
Thromboembolic
disorder
Deep vein thrombosis Deep veins, most commonly in
myocardial infarction (MI; heart attack) are also
thromboembolic disorders; these are summarized in
Table 4.1. Patients with conditions in which thrombus
formation plays a role are also encountered in the
workbooks at the end of Chapters 6 and 7.
Pulmonary embolism Lung arterial vessels
Ischaemic stroke Brain arterial vessels
Myocardial infarction
Unstable angina
4.1 How thrombi are formed and destroyed:
the targets for drug action
Numerous drugs are available to modify the processes of
haemostasis which underlie thromboembolic disorders.
ese are mainly antithrombotic drugs. However, under
some conditions, agents that increase thrombus
formation or stability (haemostatic or antibrinolytic
drugs) are clinically useful. To understand the use of
these drugs you must develop a working picture of how
thrombi are formed and removed. e mechanisms
discussed below are those that underlie thromboembolic
disorders. From a clinical perspective these are the events
which can be precipitated in dierent ways by the risk
factors set out in Table 4.2. ese include prolonged
periods of immobilization with consequent abnormality
of blood ow—one condition which has most likely
contributed to the development of a DVT in Monique’s
leg after her long-haul ight.
4.1.1 Platelet activation and coagulation
in thrombus formation
One event contributing to haemostasis when you cut
yourself is vascular spasm; the contraction of smooth
muscle in the wall of small arterioles supplying blood to
the damaged area reduces blood ow and loss. is
occurs rapidly and is important in resolving a wound. e
remaining events leading to formation of a clot which
stems blood loss are coagulation and platelet processes.
So haemostasis, the arrest of blood ow from a broken
blood vessel, has three components:
1) vascular spasm
2) coagulation cascade
3) platelet activation and plug formation.
e last two of these clotting processes also occur in an
intact vessel in thrombus formation. It is these
coagulation/platelet events that are targeted by the
antithrombotic drugs.
Although they are part of the same process, we will
introduce the elements of the coagulation cascade and
platelet activation separately.
1) Coagulation: is is the conversion of blood into a gel,
and is the end result of two convergent coagulation
cascades, intrinsic and extrinsic1, as set out in Box 4.1.
1 e intrinsic cascade is so named because all required components for
its activation are present in the blood. By contrast the extrinsic cascade is
initiated by tissue factor, a component from outside the blood, with which
it comes into contact in areas of damage to the blood vessel.
Site affected
the leg (particularly calf) and pelvis
Heart arterial vessels
Table 4.2 Risk factors for thromboembolism classied according to the abnormality they cause
Abnormality of blood flow (e.g.
pooling of blood)
Immobilization (e.g. long plane flights) Heart valve disease/replacement Oestrogen therapy (oral contraceptives)
Bed rest Acute myocardial infarction Pregnancy
Paralysis Indwelling catheters Malignancy
Atrial fibrillation Previous DVT/PE Thrombocytosis (high platelet count)
Venous obstruction from obesity,
pregnancy, tumour
Myocardial infarction Tumour invasion Antithrombin III or activated protein C deficiency
Abnormality of surface in
contact with blood
Fractures Protein C and S deficiency
Abnormality relating to clotting proteins
45
Contact pathway (e.g. collagen or glass)
Box 4.1
Coagulation and platelet activation are integrated processes
(intrinsic pathway)
XII XIIa
XI XIa
IX IXa
Figure a Interaction between coagulation cascades and platelet activation as the coagulation factors
assemble on the surface of activated platelets.
The orange shaded areas indicate events occurring on the surface of activated platelets. The scheme shows changes in
structure (e.g. to activated form of factor) with blue arrows, and stimulating influences on these reactions with black
arrows. The numbered steps are referred to in the text.
In vivo pathway (extrinsic pathway)
Tissue factor
VII VIIa
Ca2+/VIIIa
XXa
II (prothrombin)
4
Platelet aggregation
& GPIIb/IIIa expression
Fibrinogen
5
6
2+
Ca
Fibrin
monomer
Activated
platelet acidic
phospholipid
2+
Ca
/Va
IIa (thrombin)
XIIIa XIII
scaffold
Platelet
activation
2+
Ca
Cross-linked
brin polymer
1
2
3
Setting the stage e coagulation cascades are
conventionally described as the intrinsic pathway (or
more usefully the contact pathway) and the extrinsic
pathway (described here as the in vivo pathway),
which converge at the level of factor X activation and
have in common the sequence of events beyond this
point (Figure a). is part of the pathway, from
activation of factor X to the formation of the crosslinked brin polymer, may therefore be described as
the common pathway. e role of platelet activation/
aggregation in thrombus formation cannot be
separated from coagulation—they are part of an
integrated process.
Role of platelets e involvement of platelets is
shown in Figure a as numbered steps: 1 platelet
activation leads to the exposure of acidic
phospholipids; 2 these phospholipids are essential
for the enzymatic steps enclosed in the shaded area,
and so act as scaolds for the assembly of complexes
of coagulation factors, leading to thrombin
formation; 3 the enhanced thrombin availability
itself stimulates (via platelet thrombin receptors)
more platelet activation leading to 4, increased
expression of platelet glycoprotein IIb/IIIa (GPIIb/
IIIa) receptors; 5 platelets are brought together in
aggregates, linked by the binding of brinogen to
these GPIIb/IIIa receptors on their surfaces; 6 this
brinogen can then be converted to brin by the
action of thrombin. In this way, the platelet–
coagulation cascade forms a functional unit for the
formation of a thrombus.
46 Chapter 4 Haemostasis and thromboembolic disorders
Each cascade comprises a series of clotting factors.
ese factors are proteins, which are synthesized in
the liver and released into the bloodstream as inactive
precursors. Specically, each protein is a proteolytic
enzyme, i.e. an enzyme which catalyses the breakdown
of other proteins. As such, each member of the cascade
in turn cleaves and activates the next factor. e signal
being transmitted by the cascade is amplied at each
step, since each active factor formed can activate a
very large number of molecules in the next step.
For example, as shown in Box 4.1, the inactive factor X is
activated to factor Xa, which then cleaves inactive factor II
(also known as prothrombin) to form the active enzyme,
factor IIa (thrombin). Fibrinogen is another soluble protein,
which is made in the liver and circulates in the blood. When
thrombin is activated, it cleaves brinogen to form
insoluble brin. In addition, thrombin activates local factor
XIII to XIIIa, which cross-links and stabilizes the brin,
forming a mesh and creating the scaold for a thrombus.
rombin also acts to stimulate its own formation. It does
this by activating factor XI and also factors V and VIII, both
of which are themselves cofactors which greatly enhance
the action of factors Xa and IXa respectively. e net eect
is an amplication of the cascade by its end product,
thrombin. e coagulation cascades and the ways in which
they are initiated are described in Box 4.1.
2) Platelet recruitment: is is characterized by platelet
adhesion to the vessel wall, platelet activation with a
change in shape and release of active chemical
mediators, and platelet aggregation, in which
platelets clump together (Box 4.2). ree important
themes for understanding drug action are:
• thetwo-waycommunicationbetweenplateletsand
local vascular endothelial cells (Box 4.3)
• theroleplayedbythebiosynthesis,andrelease
from platelets, of thromboxane A2 (TXA2),
adenosine diphosphate (ADP), and other chemical
mediators (Box 4.2)
• thecontrolofexpressionofcertainreceptorsonthe
surface of platelets, notably the central role of
glycoprotein IIb/IIIa (GPIIb/IIIa) receptors (Box 4.2).
4.1.2 Coagulation and platelet
recruitment are part of the same process,
leading to platelet–fibrin plug formation
Although they are often presented as separate processes,
blood coagulation and platelet recruitment occur together
as a series of simultaneous and interconnected events
Initiating events, e.g. stasis,
endothelial damage, atherosclerosis
Coagulation
cascade
Platelet-fibrin plug
formation
Mature thrombus
Figure 4.1 Elements of thrombus formation.
Thrombus formation involves the concerted activation of both
the coagulation cascade and platelets; the two occur
together, with the coagulation cascade typically being
assembled on the surface of activating platelets. In this way,
platelet activation stimulates coagulation. Similarly, products
of coagulation such as thrombin directly stimulate platelets.
See also Box 4.1.
Platelet
recruitment
Coagulation and platelet
recruitment build a
thrombus together. The
balance between the 2
varies, e.g. platelet-rich
white thrombus, or
coagulation-dominated
red thrombus.
leading to platelet–brin plug formation, as illustrated in
Figure 4.1 and explored further in Boxes 4.1 and 4.2.
Activated platelets expose acidic phospholipids on their
surface, providing negatively charged sites where the
components of the coagulation cascade can assemble
and be activated (see Box 4.1 for those factors that require
this phospholipid contact to be active). During this phase
platelets are aggregating by binding through their GPIIb/
IIIa receptors to brinogen molecules, assembling a mass
of activating platelets and active coagulation factors along
with their nal substrate, brinogen. As thrombin is
formed on the surface of the brinogen-bound platelets,
it does two things: (1) it acts on protease-activated
receptors (PARs; see Box 4.3), to activate platelets and
recruit more of them into the thrombus-forming process,
and (2) it converts brinogen to insoluble brin, forming
a mesh of brin with platelets attached. is is the
platelet–brin plug. As the thrombus matures, the brin
becomes cross-linked by the action of factor XIIIa to form
a tighter mesh, and the platelets (which are packed with
actin/myosin) contract, compressing and strengthening
the thrombus.
4.1 How thrombi are formed and destroyed: the targets for drug action 47
Platelet GPlb
Platelets
Box 4.2
Platelets: their role in the haemostatic process
Setting the stage Platelet activation is a key event in
most strokes and heart attacks (Chapter 6), so the role
of platelets is clearly of importance to us. Platelets are
non-nucleated components of blood with a lifespan of
5–9 days. ey release a variety of chemical mediators
when activated, both those that are pre-stored in
granules and those released as they are synthesized.
ese mediators act on neighbouring platelets (and
local endothelial cells), recruiting them into the
formation of a thrombus. Platelets also become ‘sticky’
on activation, when they clump together and adhere
to the vessel wall. e activated platelets expose
surfaces which promote the coagulation cascade, so
that platelet plug formation and coagulation occur
together (platelet–brin plug formation) in the
development of a thrombus (see also Box 4.1). e
process of recruiting platelets into haemostasis,
leading to platelet plug formation, can be divided into
three steps: adhesion, activation, and aggregation.
Role of thrombin rombin is the main active
product of the coagulation cascade. It is also a potent
activator of platelets. As such it is a major point of
interaction between the coagulation cascade and
platelet plug formation (see also Box 4.1). rombin
acts upon a family of receptors called proteaseactivated receptors (PARs). Platelets stimulated by
thrombin expose acidic phospholipids on their
surface. Interaction with this phospholipid is required
for the action of several coagulation factors, and so
platelet surfaces become the sites of thrombin
formation by the coagulation cascade. is forms a
positive feedback system for thrombin formation (see
Box 4.1). In addition, thrombin stimulates its own
formation by activating factors higher up in the
coagulation cascade, adding another level of
amplication, and accelerating clot formation.
Platelet adhesion is describes the sticking of
platelets to the inner face (luminal aspect) of the
blood vessel. In a healthy blood vessel, there is active
communication between platelets and endothelial
cells which ensures that platelets pass freely over the
surface of blood vessels (see Box 4.3). However, when
endothelial function is compromised, by disease (e.g.
atherosclerosis; Chapter 6) or trauma, the antiplatelet
inuence is reduced and thrombotic inuences such
as von Willebrand factor take over.
von Willebrand factor
• is is a large protein, which plays a role in the
coagulation cascade as well as platelet recruitment.
• It is released from endothelial cells and damaged
blood vessel walls.
• Its main function is to bind other proteins. For
example, it binds to subendothelial collagen
exposed as a result of endothelial damage, and to
receptor proteins on the surface of platelets (e.g.
GPIb receptors), thus causing platelets to adhere to
the blood vessel wall (Figure b).
receptors
von Willebrand
factor
Area of endothelial damage
Figure b von Willebrand factor acts as a bridge
between collagen, exposed in damaged blood vessels,
and the GPIb receptors on platelets.
This leads to the platelets adhering to the blood vessel wall at
the site of damage.
Lumen of
blood vessel
Endothelium
Collagen
Box 4.2 Platelets: their role in the haemostatic process
Platelet GPIIb/IIIa
Platelet activation e contact with collagen and
the process of adhesion initiates the activation of
platelets. Two components of platelet activation can
be identied: shape change and release of active
chemical mediators.
Shape change Platelets are normally discoid in
shape with a smooth surface, but on activation (e.g. by
binding to collagen) they become irregular in shape
with a somewhat spiky surface.
Release of mediators Numerous highly potent
chemical mediators are released from activating
platelets. ese can be classied into two groups.
1. Substances pre-stored in granules and released
by exocytosis. Here we are concerned with
adenosine diphosphate (ADP), which is released
from granules and acts on other local platelets via
their P2Y12 receptors. However, it should also be
noted that platelets release other stored
substances, such as adrenaline (epinephrine) and
5-hydroxytryptamine (serotonin).
2. Substances which are lipid soluble, not stored,
and leave the cell by passing through cell
membranes as they are synthesized. For this
group of substances it is the rate of synthesis that
determines the rate of release from platelets. e
important example here is thromboxane A2 (TXA2);
the enzymes responsible for its synthesis are prime
drug targets (see also Figure 4.6 and discussions
elsewhere of steroidal and non-steroidal antiinammatory drugs, e.g. Chapter 9, Section 9.3.1,
and Chapter 20, Section 20.3.2).
Key role of GPIIb/IIIa receptors in platelet–fibrin
plug formation e signicance of ADP and TXA2 is
that, together with thrombin formed as part of the
parallel coagulation cascade, they stimulate platelets
to express glycoprotein receptors, GPIIb/IIIa. ese
receptors are essential for platelet aggregation (see
receptors
Fibrinogen
Activated platelets
Figure c Activated platelets express GPIIb/IIIa
receptors; fibrinogen binds to these, pulling the
platelets together.
The fibrinogen is converted to insoluble fibrin strands by
thrombin produced on the surface of platelets (Box 4.1), and the
platelets themselves contract, forming a solid thrombus. Note
that the activated platelets binding fibrinogen are also attached
to the inner face of the blood vessel (Figure b), explaining why
the thrombus grows attached to the blood vessel wall.
Box 4.2 Platelets: their role in the haemostatic process
Factors II, VII, IX, & X
below). It is not surprising then, that these receptors
have also been the target of drug development
programmes, leading to the antiplatelet drugs
abciximab, eptifibatide, and tirofiban.
Platelet aggregation is refers to the process of
activated platelets sticking together with brin/
brinogen to form aggregates. Platelets which have
been exposed to thrombin, ADP, and TXA2 express
GPIIb/IIIa receptors on their surfaces; these receptors
There is further crosstalk between the mechanisms
of haemostasis
e processes underlying haemostasis interact at many
additional points. For example:
• the activating platelets being drawn into the
aggregating mass release vasoconstrictor substances
such as TXA2, causing vascular spasm
• thrombin formed in the coagulation cascade can
promote both platelet activation and vasoconstriction
(acting through PARs, see Box 4.3)
• activating platelets attenuate the anticoagulant
inuences of locally produced heparin (see below).
is crosstalk has important implications for
understanding drug action. It means, for example, that
antiplatelet drugs may be expected to modulate all three
mechanisms of haemostasis. is being the case, when
we consider Monique’s situation in Workbook 1, it may
lead us to ask whether she should have been advised to
take aspirin as part of her therapy, and if not, why?
Further features of thrombus formation affect our
understanding of drug use
bind brinogen. is pulls the platelets together in
aggregates (Figure c). e brinogen is then a
substrate for the local thrombin being formed by the
coagulation cascades, which converts it to insoluble
brin. ese brin strands become cross-linked
(under the inuence of factor XIIIa) and stabilized to
form a mesh. is, together with the attached
platelets, forms the platelet–brin plug, which is the
basis of a platelet-rich thrombus.
Maturation of coagulation factors requires reduced
vitamin K e coagulation factors II, VII, IX and X (see
Box 4.1) are proteins in which the amino acid chain is
chemically modied after it has been synthesized. is
modication involves the -carboxylation of some of the
glutamic acid residues which form part of the protein
structure of these factors. Without this modication these
factors cannot be activated, and so coagulation cannot
take place. e -carboxylation reaction requires reduced
vitamin K; during carboxylation the reduced vitamin K is
converted to its oxidized form. e enzyme vitamin K
reductase restores the vitamin to its reduced form to
enable another round of -carboxylation (Figure 4.2). It is
this -carboxylation of clotting factors, and specically
the enzyme vitamin K reductase, that is the target for the
Unmodified
Vitamin K
Reduced
Vitamin K
Oxidized
WARFARIN
γ-carboxylated
e processes of coagulation and platelet plug formation
are major targets for the action of antithrombotic drugs,
and in Monique’s case we shall see how knowledge of
drugs which modify the thrombotic process allows us to
understand and plan her drug treatment. In addition,
drugs which promote thrombus dissolution (‘clotbusters’) have an important clinical role. Before
discussing the action and use of these drugs, there are
some interesting topics to consider that will improve our
ability to manage the clinical conditions presented by
Monique and other patients we will encounter later.
Vitamin K reductase
Figure 4.2 Role of vitamin K in clotting factor maturation.
Reduced vitamin K is necessary for the -carboxylation of a
number of clotting factors. Without this modification, the clotting
factors cannot later be activated to take part in the coagulation
cascade. The reduction of vitamin K is inhibited by warfarin,
preventing the synthesis of mature clotting factors, and eventually
leading to decreased levels of these factors in the blood.
Box 4.3
Two examples of endothelial–platelet interactions
Quiescent
platelets
PGI
P2Y
2
PAR
Activated
platelet
Thrombin
Heparin AT-III Endothelial cells Collagen-rich
Figure d Two examples of the communication between platelets and endothelial cells.
Endothelial cells inhibit platelet adhesion and activation, stopping platelets from sticking to the inside of the healthy blood
vessel, and consequently preventing thrombus formation and maintaining blood flow.
e activation of platelets by thrombin is
illustrated on the left of Figure d. Activation of
platelets by thrombin is considered to be one of the
most potent mechanisms for platelet recruitment
into thrombus formation. is activation then leads
to exposure of further acidic surfaces on the platelets,
which promotes the coagulation cascade and so
produces more thrombin (Box 4.1). If this process
progresses unchecked, there will be accelerating
brin formation and platelet–brin plug
development. However, in a healthy blood vessel this
sequence is blocked by the binding of antithrombinIII (AT-III) to heparin. e AT-III–heparin complex
inhibits thrombin activity, thereby preventing the
PAR-mediated activation of platelets. e heparin in
Figure d is native heparin, produced by endothelial
cells, and is one of the ways in which these cells
inhibit coagulation in healthy blood vessels. When
heparin is administered as a drug it supplements the
action of native heparin; this is particularly important
when heparin production is lowered as a result of
damage to the endothelium.
e role of ADP in prostacyclin (PGI2) and nitric
oxide (NO) production is illustrated on the right of
Figure d. As platelets activate they release a range of
mediators, including ADP (see Box 4.2) which acts on
platelets via P2Y1 and P2Y12 receptors to contribute to
thrombus formation. However, in a healthy blood vessel
this is prevented, as the ADP released from platelets
also stimulates endothelial cells, where it acts on P2Y1
receptors to enhance synthesis and release of PGI2 and
nitric oxide (NO). ese then act directly on platelets to
prevent progression towards platelet plug formation.
Many additional mechanisms operate in healthy
blood vessels to prevent platelets from becoming
activated. Activating platelets also releases other local
mediators (see Box 4.2). Notable for our purposes is the
release of TXA2, a potent stimulator of platelets whose
synthesis and release is eectively inhibited by aspirin.
ADP
ADP
P2Y
1
basement membrane
NO
Box 4.3 Two examples of endothelial–platelet interactions
In disease states the balance of communication
is disturbed. Disruption of endothelial function has
many consequences because:
1) an intact endothelium acts as a barrier between
platelets and the collagen of the basement
membrane (see Box 4.2, Figure b, for an illustration
of the consequences of the removal of this barrier)
2) endothelial cells prevent mediators released from
platelets reaching underlying vascular smooth
anticoagulation action of warfarin (see below). is drug
plays a major role in the management of patients such as
Monique.
A decit in vitamin K will result in a potentially serious
bleeding disorder. is is a risk in newborn babies, and is
avoided by the post-partum administration of vitamin K.
Arterial and venous thrombi are not the same Arterial
and venous thrombi dier in the relative contributions of
the platelet and coagulation elements leading to thrombus
formation. Understanding the dierence between venous
and arterial thrombi helps us understand why dierent
drugs are used in their management. Arterial (white)
thrombi are mainly platelets in a mesh of brin and cell
debris. ey are formed when an atherosclerotic plaque
becomes thrombogenic and activating platelets
accumulate on its surface (see Chapter 6). is platelet
colony then recruits the coagulation cascade by the
mechanisms indicated above, leading to a brin crosslinked structure with few red blood cells. is type of
thrombus is most eectively managed by antiplatelet
therapy (which reduces the recruitment of platelets into
thrombi, as set out below). Venous (red) thrombi, by
contrast, are commonly associated with pooled static
blood (e.g. DVT), leading to coagulation cascade
activation with relatively little platelet involvement. is is
what is thought to have happened to Monique, and her
treatment regime therefore involves anticoagulant drugs.
Venous thrombi have a red colour derived from the high
number of red blood cells trapped within the brin mesh,
and a low contribution from platelets.
Endogenous brakes prevent uncontrolled
coagulation e accelerating amplication of the
coagulation cascades might seem likely to lead to the
muscle cells; when this barrier is compromised
mediators such as ADP and TXA2 stimulate these
muscle cells to contract and proliferate, contributing
both to reduced blood ow as a result of vascular
spasm, and to atherosclerosis (see Chapter 6)
3) the development of an atherosclerotic plaque
removes the local inuence of endothelial cells,
and can, when mature and rupturing, present a
focus for platelet activation (see Chapter 6).
uncontrolled spread of coagulation. Such a disastrous
outcome is prevented because the cascades are selfregulating—activation also leads to inhibition. ese
inhibitory mechanisms are central to the action of
anticoagulant drugs (see below), and are illustrated by
the following three examples.
• e plasma protein antithrombin-III (AT-III) combines
with heparin to inhibit thrombin. Other coagulation
factors are also inhibited, including factor Xa, which is
responsible for the formation of thrombin from its
prothrombin precursor (see Box 4.1).
• e heparins are a naturally occurring group of
mucopolysaccharides of varying molecular weight
which come from the vascular endothelium, mast cells,
and basophils. Endothelium-derived heparin binds
with AT-III and acts as a cofactor to greatly enhance its
inhibitory action, giving a powerful local
anticoagulant eect.
• Protein C is another plasma protein. It is activated by
thrombin, and acting together with its cofactor
protein S, inhibits factors Va and VIIIa (cofactors
which greatly enhance the action of factors Xa and
IXa, respectively.)
Clots and thrombi must be removed—incorporating
the seeds of destruction To avoid the accumulation of
clots and thrombi during a lifetime, a mechanism for their
removal is a necessity, and it is therefore not surprising
that as a thrombus forms it incorporates the mechanism
for its own destruction. is clot-dissolving process is
called brinolysis, and is achieved by the proteolytic
enzyme plasmin, which breaks down brin and can also
degrade other proteins, including brinogen and
thrombin, and factors Va and VIIIa. Several mechanisms