1.2.5 Haemostasis and Thrombosis

Oxford Textbook of Fundamentals of Surgery
William E. G. Thomas (ed.) et al.
https://doi.org/10.1093/med/9780199665549.001.0001
Published: 2016 Online ISBN: 9780191810817 Print ISBN: 9780199665549
CHAPTER
1.2.5 Haemostasis and thrombosis 
Downloaded from https://academic.oup.com/book/31816/chapter/266634803 by University of Sydney user on 25 September 2022

Dermot Cox
https://doi.org/10.1093/med/9780199665549.003.0011 Pages 64–71

Published: July 2016
Abstract
A nightmare scenario for any surgeon is uncontrolled bleeding in a patient either during surgery or
post surgery. This often leads to surgeons delaying surgery in patients with a perceived high risk of
bleeding, such as coronary by-pass surgery in patients on antiplatelet agents. However, another
potential complication of surgery is inappropriate clotting such as deep vein thrombosis, which can be
overlooked as it is often dealt with by physicians rather than the original surgeon. An understanding of
the physiology and pharmacology of thrombosis and haemostasis will help prevent problems from
arising and provide solutions to these problems when they arise. This chapter deals with the natural
factors involved with haemostasis and brinolysis, and the abnormalities that can occur, the
laboratory tests that are available to measure them, and the pharmacological preparations available to
treat these problems.
Keywords: haemostasis, coagulation, thrombosis, vitamin K, warfarin, heparin, fibrinolysis, platelets

Subject: Surgery, Urology, Paediatric Surgery, Cardiothoracic Surgery, Peri-operative Care, Trauma and
Orthopaedic Surgery, Upper Gastrointestinal Surgery, Colorectal Surgery, Surgical Oncology, Neurosurgery,
Breast Surgery, Transplant Surgery, Vascular Surgery, Surgical Skills
Series: Oxford Textbooks in Surgery
Haemostasis
As blood loss is such a serious threat to life, a complex system has developed to prevent catastrophic loss of
blood. To be e ective this system must be very responsive to ensure rapid sealing of damaged vessels but
not too sensitive to avoid an unwanted thrombosis. This is achieved using three interlinked systems:
coagulation, platelets, and thrombolysis.
Coagulation
The coagulation system consists of a cascade of serine proteases that activate other proteins and is
accompanied by cofactors that enhance their activity. All of these coagulation factors are synthesized in the
liver. The system is designed to generate an insoluble brin polymer that plays an important role in
preventing blood loss and wound healing. It can be separated into three separate components. The nal
stage is the generation of the brin monomer and this is activated by one of two di erent pathways: contact
1 2
(intrinsic) pathway and extrinsic pathway. Associated with this system is an anticoagulation system that
acts to control the process (Figure 1.2.5.1).

Fig. 1.2.5.1
Coagulation occurs when fibrinogen is activated to fibrin, which polymerizes forming a clot. This is the final common pathway of
coagulation. The coagulation cascade can be activated by two distinct methods. The intrinsic pathway is activated by FXII
interacting with damaged surfaces while the extrinsic pathway is activated by the exposure of tissue factor on damaged cells.
Reproduced with permission from Anaesthesia UK, Coagulation-classical model, Copyright © 2005, available from
http://www.frca.co.uk/article.aspx?articleid=100096
3
Clot formation occurs when brin polymerizes. To prevent spontaneous clot formation the polymerization
sites on brin are blocked with short peptides ( brinopeptides A and B). This inactive brin molecule is
known as brinogen and is a very signi cant component of plasma with a concentration of 2–3 g/L.
Fibrinogen is composed of three chains (α, β, and γ) and the full molecule is composed of two of each of these
4
chains giving it a molecular weight of 340 kDa.
The activation of brinogen is achieved by proteolytic cleavage of the brinopeptides by the serine protease
5
thrombin. Again, to prevent inappropriate activation of the system, thrombin exists in an inactive form
(prothrombin) at a concentration of 100 mcg/mL in plasma. Prothrombin is activated by the serine protease
factor (F) Xa that also circulates in an inactive form as FX. Once brin polymerizes it is necessary for it to be
stabilized by cross-linking the polymers with FXIIIa, which is generated from inactive FXIII by thrombin.
This is the common pathway of coagulation.

There are two pathways to the activation of FX. The primary pathway for activation of FX is the tissue factor
pathway where FVIIa converts FX to FXa. Tissue factor (TF) is the activator of FVII. Cells within the
circulatory system do not express TF on their surface; however, in ammatory cytokines can induce the
2
expression of TF on the surface of endothelial cells which the binds FVII converting it to FVIIa.
1
The other activation pathway is the contact pathway where FIXa converts FX to FXa. FIXa is generated from
FIX by the action of FXIa, which is generated from FXI by FXIIa. It can also be generated by FVIIa–TF
complex. FXIIa is generated from FXII when it comes into contact with surfaces hence the name contact
pathway.
Coagulation cofactors
Many of the enzymes in the coagulation cascade have very low levels of activity even in their active form.
The binding of cofactors serves to greatly increase their activity. One such cofactor is FV which when
activated by thrombin binds to FXa and greatly increases its activity. In the contact pathway, FVIII, when
6
activated by FXa or thrombin, binds to FIXa increasing its activity.
Von Willebrand factor (vWF) is a large multimeric protein that primarily mediates the interaction of
7
platelets with subendothelial matrix under high shear. However, FVIII circulates in the plasma in complex
8
with vWF, which has the e ect of prolonging the plasma half-life of FVIII.
Vitamin K
Prothrombin, FVII, FIX, and FX are characterized by the presence of a Gla domain. This is a protein domain
rich in γ-carboxyglutamate as a result of carboxylation of glutamic acids in the liver in a vitamin K-
9
dependent process. These Gla domains have a high a nity for calcium and are important in binding of the
coagulation factors to phospholipid membranes. Phospholipids are essential cofactors for coagulation and
typically they are provided by activated platelets. They facilitate the binding of coagulation factors through
their Gla domains. This serves to bring the coagulation factors into close proximity thus speeding up the
reactions.
Amplification
The coagulation system is arranged as a cascade that serves to amplify the original signal. As the key factors
are enzymes, the activation of a single enzyme leads to activation of many substrate molecules. As these are
also enzymes they in turn lead to activation of many enzyme molecules. This ampli cation is further
enhanced by feedback mechanisms. Thus, not only does thrombin activate brinogen, it also activates other
key enzymes such as FV, FVIII, and FXI while FXa also activates FVIII.
Anticoagulant system
There are a number of factors that inhibit coagulation and serve to limit the extent of coagulation. One such
inhibitor is activated protein C (APC), which is a vitamin K-dependent serine protease similar to the other
10
coagulation factors. APC is generated from protein C by the actions of thrombin in complex with
thrombomodulin, which is an endothelial cell thrombin-binding protein. When thrombin binds to
thrombomodulin it loses its ability to activate brinogen and platelets and develops an a nity for protein C.
Thus, binding to thrombomodulin changes thrombin from being a procoagulant enzyme to being an
anticoagulant enzyme. APC cleaves FVa and FVIIIa thereby inactivating them. In a manner similar to that
with the procoagulant factors, APC has a low intrinsic activity and it is only upon binding the vitamin K-

dependent cofactor protein S that it becomes fully active.
As many of the procoagulant factors are serine proteases they are susceptible to inhibition by serine
11
protease inhibitors (serpins). As its name implies, antithrombin III (AT) inhibits the activity of thrombin
but it also inhibits the activity of FXa and to a lesser extent the other serine proteases in the coagulation
system. As is frequently the case in the coagulation system, the activity of AT is under the in uence of a
cofactor, which in this case is heparin. The inhibitory activity of AT is increased around 1000-fold upon
binding to heparin. Another inhibitory serpin is protein Z-dependent protease inhibitor; in the presence of
protein Z this serpin inhibits FXa and FXIa.
The tissue factor pathway inhibitor (TFPI) inhibits FXa and FVIIa–TF–FXa complex. It is synthesized in
endothelial cells and much of it remains bound to the cell surface.
Laboratory testing
There are three basic tests that are used to assess the functional state of the coagulation system and are used
12,13
for diagnosis and management of pharmacotherapy:
◆ Prothrombin time (PT). This test measures the time to clot formation of plasma after the addition of
calcium and thromboplastin (TF and phospholipid). Thus, it measures the ability of FVII to activate FX
and produce a clot. The typical PT for normal plasma is around 12–15 seconds and depends on the
source of thromboplastin. The International Sensitivity Index (ISI) is a comparison of each batch of
thromboplastin with an international standard.
◆ Activated partial thromboplastin time (aPTT). This test activates the contact pathway by adding in
phospholipid, calcium, and kaolin and thus measures the ability FIX to activate FX and produce a clot.
Clot formation occurs between 30–50 seconds in an aPTT test in normal plasma.
◆ International normalized ratio (INR). There can be considerable variation in the PT due to the
instrument used and the source of TF. The INR controls for this and is often used to monitor
anticoagulant therapy:
ISI
INR = (PT /PT )
test normal
(where the ISI is a numerical value re ecting the results obtained by di erent commercial systems and
which allows results to be compared between centres).
Coagulation and disease
Disorders of the coagulations system can either be prothrombotic or haemorrhagic and they can either be
acquired or hereditary. The hereditary bleeding disorders are probably the major category here especially
from a surgical perspective.
Inherited haemorrhagic disorders
Haemophilias are probably the best known bleeding disorders and are due to mutations in one of the
14 15
coagulation factors: FVIII (type A), FIX (type B), and FXI (type C). Haemophilia A accounts for around

80% of all cases. These hereditary disorders are characterized by bleeding into the joints (haemarthroses) or
the muscle (haematoma). However, these are not the only inherited coagulation disorders and mutations in
16
vWF and the other key enzymes also occur.
Acquired haemorrhagic disorders
As well as the inherited disorders patients can also have an acquired disorder. An example of this is vitamin
K de ciency as this vitamin is essential for the proper function of a number of coagulation factors. While
this is more common in infants it can occur at any age. As most of the coagulation factors are synthesized in
the liver, anything that impairs liver function such as cirrhosis can lead to a serious decrease in plasma
levels of these coagulation factors. Some patients produce antibodies to coagulation factors that inhibit
their activity. This is often seen in haemophilic patients on coagulation factor replacement therapy although
17
it can also occur in patients as a result of a blood transfusion. Sepsis can lead to a condition known as
disseminated intravascular coagulation (DIC) where bacteria trigger the formation of microthrombi
throughout the circulatory system. This ongoing coagulation leads to a consumption of coagulation factors
which, as the sepsis progresses, leads to increased bleeding due to the reduced levels of coagulation factors
18
in the blood.
Inherited procoagulant disorders
Mutations in the genes for coagulation factors can lead to them becoming constitutively active leading to an
increased rate of coagulation. FVLeiden has a single point mutation that makes FVa resistant to cleavage by
APC, which is the major path for inactivation of FVa. Patients that are homozygous for this mutation have a
50-fold increased risk of venous thromboembolism. Inherited de ciencies in the anticoagulant factors such
19
as anti-thrombin, protein S, and protein C can also lead to an increase in clot formation.
Acquired procoagulant disorders

20
Hyperhomocysteinaemia is associated with an increase in venous thrombosis and acquired APC resistance
21
is associated with fetal loss during pregnancy. The contraceptive pill is also associated with an increase in
venous thromboembolism in part due to increasing levels of procoagulant factors and decreasing levels of
anticoagulant factors. Prolonged immobility can also predispose patients to venous thromboembolism such
as seen in long-haul ights. Other conditions that predispose to thrombosis formation are polycythaemia
vera and antiphospholipid syndrome.
Pharmacology of coagulation
Vitamin K antagonists
The death of cattle from internal haemorrhage in the 1920s after eating spoiled sweet clover led to the
discovery of the anticoagulant dicoumarol and subsequently (1954) its derivative warfarin became a widely
used as an oral anticoagulant. Warfarin inhibits vitamin K epoxide reductase reducing vitamin K levels. As
synthesis of prothrombin, FVII, FIX, and FX are vitamin K-dependent, this results in a reduction in their
levels and thus in the ability of blood to coagulate. As expected from its mechanism of action the clinical
e ects of warfarin take a few days to reach their maximum as it only a ects the synthesis of new

coagulation factors. Equally, its e ects can be overcome by administration of vitamin K but this will also
take a few days to act. A more rapid reversal of warfarin requires administration of fresh frozen plasma. As
warfarin is highly bound to serum albumin and is metabolized by cytochrome P450 enzymes there is
signi cant potential for interactions with other drugs, which requires constant monitoring of warfarin
22
levels using the INR.
Heparin
As heparin acts to increase the a nity of antithrombin III for both thrombin and FXa it can also be used as
an anticoagulant. Unfractionated heparin is a mixture of high-molecular-weight glycosaminoglycans
23
extracted from pig intestines and is administered by either intravenous or subcutaneous injection. Its
main advantage over warfarin is its immediate action. More recently low-molecular-weight preparations of
heparin such as enoxaparin have become more common. While these have the same mechanism of action as
heparin, they have greater inhibition of FXa than thrombin. The minimum active component of heparin was
24
identi ed as a pentasaccharide, which has been synthesized as fondaparinux. This also binds
antithrombin but the complex only inhibits FXa and not thrombin and is administered by subcutaneous
injection. The major adverse e ect of heparins is an immune-based thrombocytopenia (heparin-induced
25
thrombocytopenia (HIT)) and its occurrence appears to be related to molecular weight of the preparation.
Direct inhibitors
Recently, inhibitors of coagulation factors (FXa and thrombin) that directly inhibit their respective
coagulation factors have come to the market. The original thrombin inhibitors were not orally active and
most were based on the leech anticoagulant hirudin, along with argatroban. Dabigatran is an oral thrombin
24
inhibitor rst approved in 2008. Direct inhibitors of FXa such as rivaroxaban and apixaban have also been
26
approved. These direct-acting agents appear to be more e ective than warfarin and the main adverse
e ect is bleeding. Direct FX inhibitors may have a better pro le with respect to bleeding problems. Reversal
27
of excessive inhibition is di cult although some speci c reversal agents are under development such as
idarucizumab which has been shown to reverse the e ects of dabigatran in PIII studies and a decision on its
approval by FDA is expected by the end of 2015.
Blood coagulation factors
While pharmacotherapy has focused on inhibitors of coagulation there is also a need to treat patients with
bleeding disorders due to de ciency in coagulation factors. There are two approaches to this: fresh frozen
plasma and factor concentrates/recombinant coagulation factors. The problem with using plasma is that it
contains a large amount of unnecessary proteins. However, it is useful when there is a de ciency in multiple
coagulation factors or the de cient factor is unknown such as after warfarin therapy or as a result of DIC.
For patients with hereditary de ciencies in speci c factors, it is more appropriate to use fractionated
plasma that has been enriched for the coagulation factor or where possible to use a recombinant coagulation
28
factor such as FVIII used to treat haemophilia.

Fibrinolysis
To provide e ective control over coagulation and to remove clots after healing has occurred it is necessary
to have a system for clot removal, that is, brinolysis. The heart of this system is the serine protease
plasmin, which digests brinogen and brin into fragments D and E. As brin is polymerized, the D
fragments are linked and thus D-dimers are produced while D-monomers are produced from the digestion
29
of brinogen (Figure 1.2.5.2).
Fig. 1.2.5.2
The coagulation cascade which generates a clot is balanced by the fibrinolytic cascade which breaks down the clot. This is
mediated by plasmin which forms fibrin degradation products. Plasmin is formed by the activation of plasminogen by tissue
plasminogen activator.
From The New England Journal of Medicine, Hans P. Kohler and Peter J. Grant, ʻPlasminogen Activator Inhibitor Type 1 and
Coronary Artery Diseaseʼ, Volume 342, Number 24, p. 1792 Copyright © 2000 Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
Like the other serine proteases, plasmin exists in an inactive form known as plasminogen, which is
activated when plasminogen activators (PAs) convert it from a single-chain to a double-chain complex. The
primary PA is a serine protease synthesized by endothelial cells and is known as tissue-type PA (tPA).
Urinary-type PA (uPA; urokinase) is produced in the kidney and can also activate plasminogen.
The primary inhibitor of this system is plasminogen activator inhibitor-1 (PAI-1), which is a serine protease
30
inhibitor that exists in complex with tPA. Thus, PAI-1 levels are associated with haemorrhage/thrombotic
risk. Plasmin itself is inhibited by α2-antiplasmin.
Laboratory testing
The important test for detecting activation of the thrombolytic system is measurement of D-dimer levels.
This is used to detect deep vein thrombosis. Technically it does not measure clot formation, rather it
31
measures clot breakdown which indicates that clot formation must have occurred.
Pharmacology of thrombolysis

Activation of the thrombolytic pathway is an important way of removing occlusive clots in patients with
myocardial infarction. The rst such compound was streptokinase, an enzyme isolated from haemolytic
streptococci. This binds to plasminogen and activates it. Its main limitation is that it is antigenic and that
anti-streptokinase antibodies can limit its activity. This limitation has been overcome with the use of
32,33
recombinant human tPA. The other possibility for pharmacological intervention is to inhibit the
brinolytic system thus stabilizing the clots and thereby preventing blood loss. Tranexamic acid is a lysine
derivative that inhibits the conversion of plasminogen to plasmin and can be used to prevent blood loss
34
during surgery.
Platelets
Platelets are anucleate fragments of megakaryocytes and are one of the most numerous cell-like particles in
35
the blood at a concentration of 150 000–400 000 platelets/μL. As platelets are anucleate, they are
incapable of replication or protein synthesis although there is some synthesis of protein from stable mRNA
36 37
in the platelet. Platelets are critical elements of both the haemostatic and innate immune systems. This
is achieved through three distinct functions: adhesion, activation, and secretion.
Platelet function
Platelet adhesion
When a blood vessel is damaged, the subendothelial matrix is exposed which facilitates platelet adhesion by
38,39
a number of di erent surface adhesion receptors. The exposed matrix is rich in collagen and thus the
two-collagen receptors (integrin α2β1 and glycoprotein (GP)VI) are important in mediating platelet
adhesion. The integrin αIIbβ3 (GPIIb/IIIa) is also important in supporting adhesion to immobilized
brinogen. In the arterial system, platelets are exposed to high shear, which makes it di cult for these
receptors to bind to their ligand. GPIb/IX/V is a receptor for vWF (a component of exposed matrix) but only
recognizes vWF under high-shear conditions. Thus, under arterial shear, GPIb binds immobilized vWF
allowing platelets to bind transiently. This causes the platelets to roll along the surface, which serves to
slow them down su ciently to allow rm adhesion through collagen receptors or GPIIb/IIIa (Figure 1.2.5.3).
Fig. 1.2.5.3

Damage to endothelial cells, such as happens with plaque rupture, leads to the exposure of subendothelial collagen. In high-
shear vessels, von Willebrand factor binds to the collagen and subsequently bonds to the platelet GPIb resulting in the rapidly
flowing platelets slowing down su iciently to allow collagen receptor (GPIa/IIa) to bind. This allows the attachment of platelets
to the subendothelium as well as activating the platelet. Platelet activation leads to production of thromboxane A2 (TxA2) by
cyclooxygenase (COX), the release of ADP, and activation of the fibrinogen receptor GPIIb/IIIa. Secreted ADP leads to activation of
further platelets via P2Y12, the ADP receptor. As fibrinogen is a bivalent molecule it can bind to two di erent GPIIb/IIIa receptors
which, if on di erent platelets, leads to platelet aggregation and thrombus formation. Damage to the endothelial layer also leads
to the exposure of tissue factor which activates FX through the extrinsic pathway. This results in the activation of thrombin which
leads to the formation of a fibrin clot as well as further activating platelets through the PAR1 receptor. Anticoagulants act to
inhibit either FXa (unfractionated heparin UFH), low-molecular-weight heparin (LMWH), or fondaparinux or thrombin (UFH,
LMWH, bivalirudin, or dabigatran). Antiplatelet agents act to prevent platelet activation by blocking P2Y12 (clopidogrel,
prasugrel, or ticagrelor), COX (aspirin), or PAR1 (atopaxar or vorapaxar).
Reproduced with permission from Scott M. Lilly and Robert L. Wilensky, Emerging therapies for acute coronary syndromes,
Frontiers in Pharmacology, Volume 2, Article 61, Copyright © 2011 Lilly and Wilensky, DOI: 10.3389/fphar.2011.00061, under
Creative Commons Attribution 4.0 International (CC BY 4.0). 10.3389/fphar.2011.00061
Platelet activation
Adhesion to collagen leads to activation of the platelets. Platelet activation can also be achieved through
39
soluble mediators such as thrombin (protease-activated receptor-1; PAR-1) and ADP (P2Y12). Bacteria and
40,41
viruses can also trigger platelet activation. Platelet activation occurs through two complex pathways.
Weak platelet agonists mediate activation through phospholipase A2, which cleaves arachidonic from the
platelet membrane. This is in turn converted to the potent platelet agonist thromboxane A2 by
cyclooxygenase (COX)-1, and thromboxane A synthase. Strong platelet agonists activate platelets through a
phospholipase C-dependent pathway. No matter how the platelet is activated the result is activation of
GPIIb/IIIa, which allows this receptor to bind soluble brinogen (resting GPIIb/IIIa only binds immobilized
42
brinogen). Fibrinogen binding to GPIIb/IIIa is mediated by the Arg–Gly–Asp (RGD)-sequence or the γ-
chain terminal dodecapeptide. As brinogen is a dimer this allows for the possibility of it binding to two
di erent GPIIb/IIIa molecules. If these are on di erent platelets this leads to platelet aggregation as
platelets are cross-linked by brinogen binding which acts to seal the damaged vessel preventing further
blood loss.
Platelet secretion
Once activated, a platelet secretes the contents of its granules. Platelets contain three types of granules: α-
granules, dense granules, and lysosomes. Between them these granules contain over 300 bioactive proteins
and numerous small molecules. The platelet secreteome contains a diverse array of molecules including
43
ADP, serotonin, chemokines, cytokines, antimicrobial peptides, and adhesion molecules.
Thus, when a blood vessel is damaged, the subendothelial cell matrix is exposed. Under high-shear
conditions, GPIb binds to vWF slowing the platelets down su ciently for collagen receptors to bind to
collagen. This activates the platelets triggering the release of ADP, which activates other platelets. Once

activated, these platelets bind brinogen which cross-links them together to form a platelet aggregate
44
which seals the blood vessel. The activated platelets also secrete antimicrobial peptides and chemokines
that attract white blood cells to the area to sterilize the wound.
Laboratory testing
The standard test for platelet function is platelet aggregation. This measures the change in light
transmission of platelet-rich plasma after the addition of a platelet agonist. As this test requires specialist
equipment, the manipulation of a fresh blood sample, and trained sta , its availability is usually con ned to
specialist centres. When used with a range of agonists it can be used to diagnose platelet disorders. The
perceived need for monitoring antiplatelet therapy and the di culties with platelet aggregometry has led to
the development of point-of-care devices for measuring platelet function and its inhibition by antiplatelet
® ®
agents. Both the Platelet Function Analyzer (PFA)-100 and Multiplate systems measure general platelet
function and are also used to monitor antiplatelet therapy. While both are reasonably automated, neither
®
are true point-of-care devices. The VerifyNow system is a point-of-care system for monitoring antiplatelet
therapy. The major problem with these systems is lack of agreement. Thus, it is not unusual for a patient to
show poor response to therapy with one device but not with the others. This means that it is di cult to
45,46
interpret the results from these assays.
Platelet disorders
Similar to the situation with coagulation disorders, there are both acquired and hereditary disorders of
platelet function. Unlike disorders of coagulation, which are associated with haemarthroses and
haematoma, platelet defects are associated with bruising and excessive bleeding from a cut.
Inherited platelet disorders

There are a number of hereditary de cits in platelet receptors; however, these are all rare disorders and are
often associated with consanguineous marriages. The two most common are Glanzmann’s thrombaesthenia
and Bernard–Soulier disease, which are due to de ciencies in GPIIb/IIIa and GPIb respectively. There are
47
also defects in platelet secretion known as storage pool de ciency.
Acquired platelet disorders
This is mainly due to thrombocytopenia although severe bleeding does not usually arise until the platelet
count drops below 10 000 platelets/μL. This usually presents as idiopathic thrombocytopenia purpura (ITP)
48
and is usually immune mediated. Some cases of ITP can be drug mediated and many drugs have been
shown to cause thrombocytopenia. The best-characterized example is heparin-induced thrombocytopenia
25
(HIT) where heparin can bind to platelet factor 4 (PF4) on the surface of platelets and this heparin–PF4
complex is antigenic leading to the formation of antiplatelet antibodies. As well as defects in platelet
numbers there can also be acquired defects in platelet function. This is primarily associated with the use of
antiplatelet agents.

Prothrombotic disorders
49
There is also the concept of prothrombotic states where patients have hyperactive platelets. This can be
due to the presence of plaque in the coronary arteries, infection, or polymorphisms in platelet receptors that
25
make them more reactive or even the presence of drugs such as selective COX-2 inhibitors.
Platelet pharmacology
Since myocardial infarction is ultimately due to the formation of a platelet thrombus, there has been
extensive research on antiplatelet agents.
Cyclooxygenase (COX) inhibitors

Aspirin is one of the oldest drugs in current use with a history of over 2000 years of use (at least as a herbal
extract). However, the antiplatelet properties of aspirin have only recently been identi ed. Aspirin acts to
50,51
irreversibly inhibit COX, which plays an important role in platelet activation. The major drawback with
aspirin is its e ects on the gastric mucosa where COX-1 plays an important role in production of the mucus
that protects the stomach from the surrounding acid environment and as a result some patients are prone to
gastric ulceration. Two strategies were developed to minimize this. Firstly low-dose (75 mg or 81 mg)
preparations can be used, as platelets lacking a nucleus cannot synthesize fresh COX. Since aspirin is an
irreversible inhibitor, the inhibition rapidly accumulates in the absence of fresh COX being synthesized. This
is further enhanced by the use of enteric-coated aspirin where aspirin absorption takes place in the small
intestine rather than the stomach. A lot has been made of the existence of aspirin-resistance; however,
recent studies would suggest that this is a very rare phenomenon and that it is primarily due to poor
52
compliance. There is also evidence that poor bioavailability of enteric-coated aspirin, especially in
53
patients weighing over 90 kg, also contributes to the problem.
P2Y12 antagonists
The discovery that ADP secreted from activated platelets is important in triggering further platelets led to
the development of antagonists of the platelet ADP receptor P2Y12. The original member of this group is
24,50
clopidogrel and more recently prasugrel. Both are orally active irreversible inhibitors of P2Y12. More
54
recently, new reversible P2Y12 antagonists such as cangrelor and ticagrelor have been developed.
GPIIb/IIIa antagonists
As brinogen binding to GPIIb/IIIa is critical for the formation of platelet thrombi, it has been the target for
55
antiplatelet agents. Abciximab is a monoclonal antibody to GPIIb/IIIa and was the rst in this class of
drug. Based on the idea that the amino acid sequence RGD in brinogen mediates the binding, potent
analogues were developed that can inhibit GPIIb/IIIa. Two of these—tiro ban and epti batide—were
ultimately approved. All three GPIIb/IIIa antagonists are intravenous only and are primarily used for acute
24,50
coronary syndromes and during stent placement.
Thrombopoietin receptor agonists

Thrombopoietin is the hormone that regulates platelet production. Recently synthetic agonists of its
56
receptor such as romiplostim and eltrombopag have been developed for the treatment of ITP.
Conclusion
In conclusion, an understanding of the interplay between coagulation, brinolysis, and platelet activation is
57
necessary to prevent haemorrhagic and thrombotic complications of surgery. It is also important to
appreciate the signi cance of individual factors in response to pharmacological intervention which can
58
result in patients developing excessive bleeding for the dose of drug used.
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Oxford Textbook of Fundamentals of Surgery

William E. G. Thomas (ed.) et al.

1.2.5 Haemostasis and thrombosis 

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https://doi.org/10.1093/med/9780199665549.003.0011 Pages 64–71

Keywords: haemostasis, coagulation, thrombosis, vitamin K, warfarin, heparin, fibrinolysis, platelets

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Inherited haemorrhagic disorders

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Acquired haemorrhagic disorders

Inherited procoagulant disorders

Acquired procoagulant disorders

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Inherited platelet disorders

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Cyclooxygenase (COX) inhibitors

Thrombopoietin receptor agonists

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