CVD Thrombosis and Antithrombotic Drugs BI3BE8 09-10

BI3BE8
Cardiovascular Disease
Thrombosis
&
Anti-thrombotic drugs
NEB
n.e.barrett@reading.ac.uk
www.bb.reading.ac.uk
1
Introduction
Part 1
Normal haemostasis - and the control of bleeding
• role of platelets
• role of coagulation
From atherosclerosis to thrombosis

Clinical consequences of thrombosis
Part 2
Anti-thrombotic drugs (arterial / venous)
• anti-platelet drugs
• anti-coagulant drugs
• thrombolytic drugs
• surgery
How effective are these treatments?
2
Thrombotic Diseases:
•Myocardial infarction (MI) (blockage of coronary arteries)

•Ischaemic stroke (blockage of carotid arteries)
•Peripheral arterial disease (PAD) (narrowing of leg arteries)
•Deep vein thrombosis (DVT) (blockage of deep (leg) veins)
Other CVD Diseases (to be covered elsewhere)

•Angina (narrowing of coronary arteries
•Heart failure (inadequacy of the heart to
pump)
•Hypertension (high blood pressure)
CVD = cardiovascular disease CHD = coronary heart disease

3
Mortality per 100 000 for the
UK (2004):
• CVD 175
• Cancer 147
• Injuries 26
• HIV/AIDS <10
• Cancer is gaining on CVD – due to improvements in treatments for

CVD???
• http://www.who.int/whosis/whostat/EN_WHS09_Table2.pdf
4
The scale of the problem:
•Mortality: In the UK CVD contributed to more than 1
in 3 deaths (37%) in 2004 affecting both men and
women (BHF, 2006).
•Morbidity: As well as those dying from this

multifaceted disease there are many more living with
it. Angina MI
Males 1.1 million 970,000
Females 850,000 439,000

(BHF, 2008).
•Improvements in prevention and treatment have

reduced total mortality caused by CVD (decreased by
38% in the under 75’s in the last 10 years (BHF, 2006).
5
The scale of the problem:
Financial cost of CVD to the UK economy in 2006:
£14.4 billion (47%) healthcare costs

£8.2 billion (27%) productivity losses
£8 billion (26%) informal care
BHF, 2009
(
http://www.heartstats.org/datapage.asp?i
d=101
)
Hence the need for better, cheaper, more

effective, safer drugs.
6
Pathophysiology: An understanding of the causes of the disease
Physiology -
Haemostasis: cessation of bleeding (right place, right time).
ie. At site of injury, when risk of blood loss.
Pathology -
Thrombosis: inappropriate activation of platelets or coagulation
(wrong place, wrong time).
ie. In the absense of injury or risk of blood loss.
Reduces blood flow to tissues causing ischaemia (MI /
stroke).
Emboli may detach.
7
What causes arterial thrombosis?
• the principal stimulus is underlying atherosclerosis
What causes venous thrombosis?
• Virchow’s triad
• Stasis
• Increased coagulability
• Vessel wall injury
To understand thrombosis one needs to

understand haemostasis
8
5 Steps of Haemostasis
Vessel Spasm
Platelet plug formation
Coagulation
Clot retraction
Clot dissolution
9
Normal haemostasis
Injury to blood vessel Platelet activation Fibrin clot formation

Collagen exposed Platelet aggregation with trapped cells
Platelet adhesion Thrombus formation
Platelet plug formation coagulation
10
Adapted from Biology 6th Ed. Campbell & Reece
Normal haemostasis
1. Platelet responses
2. Damaged cells and plasma factors
Prothrombin Thrombin
Fibrinogen Fibrin
11
Adapted from Biology 6th Ed. Campbell & Reece
Normal haemostasis

Pathology:
Arterial thrombosis Venous thrombosis
12
Platelet Plug Formation
1. Adhesion
2. Activation (signalling and shape change)
3. Secretion
4. Aggregation
13
Blood vessel damage
14
Blood vessel damage
15
Blood vessel damage
16
Blood
Blood
vessel
vessel
damage
damage
Platelet adhesion and entrapment
17
d vessel damage
elet adhesion and entrapment
elet spreading - monolayer formation (activation)
18
vessel damage
et adhesion and entrapment
et spreading - monolayer formation (activation)
ion of thrombotic factors - activation of other pla
19
Tissue damage
Collagen
exposed
Alpha & dense

granules
Agonist receptor
20
Factors released by activated platelets
• Adenosine diphosphate (ADP)

(dense granules)
• Serotonin (5-hydroxtryptamine)
(dense granules)
• Fibrinogen
(alpha granules)
• von Willebrand Factor
(alpha granules)
• Thromboxane A2
(cytoplasm)
• Tachykinin
(unknown)
Stimulate POSITIVE FEEDBACK in thrombus formation

21
vessel damage
et spreading - monolayer formation
ation (fibrinogen cross-linking))
22
vessel damage
ation (fibrinogen cross-linking)
23
vessel damage
ation (fibrinogen cross-linking)
24
vessel damage
ation (fibrinogen cross-linking))
us formation - fibrin clot formation (coagulation)
25
More detail……
26
-granule IIb/3
GPIb complex
Dense granule
GPVI
GPCR VWF
Transient Rolling Activation

27 &
tethering secretion
GPVI
IIb/3
Fibrinogen
28
Aggregation
Platelet Agonists
Strength Agonist
Weak ADP
Adrenaline
Platelet Activating Factor
Vasopressin
Serotonin
Intermediate Thromboxane A2
Strong Collagen
Thrombin
29
Studying Platelet Plug Formation
1. Adhesion
2. Activation (signalling and shape change)
3. Secretion
4. Aggregation
30
1. Platelet adhesion
Measured by adhesion
assays or in vitro flow
assays.
Platelets labelled with
DiOC6 and flowed through a
collagen coated capillary
tube.
Can measure coverage and
depth of thrombi.
31
2.Platelet activation
• Shape change on adhesion to an ECM-
coated surface (electron microscopy).
250
*
phosphorylation levels
% Basal PKB ser473
200
150
PECAM-1 XL
IgG Control
100
50
0
cvx (ng/ml) no agonist cvx
Blot: anti- phospho-PKB (Ser473)
60 kD
Blot: anti-PKB
+ - + - PECAM-1 XL
Basal
- + - + IgG Control
• Phosphorylation / dephosphorylation
of signalling molecules (measured by 32
Western blotting).
3. Platelet Secretion
Secretion assays often performed by FACS analysis:
In platelets P-selectin is found in alpha-granules. When
the platelet is activated, granules get secreted and P-
selectin is exposed on surface. Can detect P-selectin on
the surface by FACS.
33
4. Platelet aggregation can be measured in vitro
37°C 37°C
34
4. Platelet aggregation can be measured in vitro
Platelet
Aggregation
--- Assay
Collagen added
Light
Transmission Shape change
Full aggregatio
+++
60s 35
Negative Regulation of Platelets:
Platelet activation must be confined to the site of injury
PGI2 = Prostacyclin
} produced by healthy endothelium
NO = Nitric Oxide
PECAM-1 = Platelet Cell Adhesion Molecule - 1

36
Normal haemostasis

Pathology:
37
Definition: COAGULATION
• Coagulation is the process in which the fluid

blood is converted into a gelatinous clot
• Coagulation converts the platelet plug into a

more stable clot.
38
The formation of a blood clot
• Polymerisation of fibrin
• Role of thrombin
• Clotting cascades
• Positive feedbacks
• Fibrinolysis
39
Red blood
cell
captured in
fibrin mesh
40
Fibrin is a
protein
Fibrin forms
long polymers
23 nm 41
Thrombin catalyses the conversion of fibrinogen to fibrin
FIBRIN
Thrombin
Fibrinopeptides
(a protease) a & b
Fibrinogen 42
Thrombin is generated from prothrombin
at sites of tissue injury
Injury
Fibrinogen
Prothrombin Thrombin
Fibrin
Factor XIII Factor XIIIa
Stable fibrin
hrombin is a protease. Clot formation

43
Coagulation is regulated by clotting factors
Clotting Factors Are:
• Proteins
• Enzymes/ cofactors
• Found in plasma in inactive forms
• Regulate the conversion of prothrombin to

thrombin.
• Form enzyme cascades:
• One activated clotting factor activates another

clotting factor
44
• Amplification
The coagulation
pathways
Positive feedback
+ +
45
Two pathways lead to the conversion of prothrombin to
thrombin:
•Intrinsic pathway – everything necessary is in the blood

Stimulated on the contact of blood with collagen /
charged surfaces
Platelets also activated by exposed collagen and

release phospholipids eg. platelet factor
•Extrinsic pathway – cellular element required

Stimulated by tissue thromboplastin
Damaged tissue releases tissue thromboplastin / tissue

factor ie. not a plasma protein.
•Common pathway 46
• Video of coagulation pathway
www.hopkinsmedicine.org/hematology/coagu
lation.swf
47
The Plasma Clotting Factors
Name Function Pathway
brinogen Converted to fibrin
thrombin Enzyme Common
sue thromboplastin/factor Cofactor Extrin
ium Ions (Ca2+) Cofactor Com./I
ccelerin Cofactor Common
onvertin Enzyme Extrin
tihaemophilic factor Cofactor Intrin
sma thromboplastin component
Christmas Factor) Enzyme Intrinsic
t-Prower Factor Enzyme Common
a thromboplastin antecendent Enzyme Intrin
man factor Enzyme Intrinsic
brin stabilising factor Enzyme Common
48
5 Steps of Haemostasis
Vessel Spasm
Platelet plug formation
Coagulation
Clot retraction
Clot dissolution
49
Vessel Spasm:
Upon damage, blood vessel spasm

is initiated.
Direct smooth muscle cell
damage, pain receptor reflexes
and release of molecules by
endothelial cells and platelets all
induce vasoconstriction.
Thromboxane A2
Formation is inhibited by
Aspirin
50
Clot retraction: once formed, the clot retracts
Platelets
present in a
fibrin clot
are responsible
for the
phenomenon of
clot
retraction.
Although the
precise
function of
clot retraction
is not known,
it is possible
51
that it may aid
Clot dissolution – fibrinolysis
•Once blood loss has been controlled and the vessel walls
have been pulled together, blood flow must be re-
established in order for permanent tissue repair to take
place.
•The process by which the clot dissolves is called

fibrinolysis.
•Like coagulation, fibrinolysis is a series of steps

controlled by activators and inhibitors.
52
Fibrinolysis:
Dissolution of the blood clot.
From endothelial cells
Plasminogen activators
eg. Tissue-type plasminogen activator (t-PA)
Plasminogen Plasmin
Fibrin Fibrin split

clot products
53
Plasminogen
• Inactive enzyme trapped in clot
• Activated by thrombin, lysosomal enzymes from

damaged tissue and substances from endothelial cells
(t-PA)
• Becomes plasmin
• Dissolves fibrin threads
• Inactivates fibrinogen, prothrombin and clotting

factors
54
Thrombosis (inappropriate activation of platelets or
coagulation):
Arterial Thrombosis:
Myocardial infarction (blockage of coronary arteries)

Ischaemic stroke (blockage of carotid arteries)
ie. Inappropriate platelet activation
Peripheral arterial disease (PAD) (narrowing of leg arteries)

ie. Rupture leads to inappropriate platelet activation
Venous Thrombosis:
Deep vein thrombosis (DVT) (blockage of deep (leg) veins)
ie. Inappropriate coagulation

55
Normal haemostasis  thrombosis

Pathology:
- DVT
- MI, ischaemic stroke. (PAD) 56
Arterial Thrombosis
Thought to be caused by inappropriate activation of
platelets.
Perhaps the most common cause is rupture of an
atherosclerotic plaque.
Campbell, 2008
57
Arterial thrombosis:
•Most common sites of

atherosclerotic lesions.
•Occlusion of arteries
at these sites causes
what?
•MI
•Ischaemic stroke
•PAD
•Embolism of thrombi
from these sites travel
where, and cause what? 58
Porth, 2005
Coronary blood vessels
59
Coronary blood vessels
60
Arterial thrombosis - a consequence of plaque rupture
A complex combination of:

• changes in platelet reactivity
• plaque thrombogenicity
• rheological disturbances
• breakdown in inhibitory mechanisms
Results in an unstable atherosclerotic plaque.
61
How do atherosclerotic lesions become unstable?
Role of tissue metalloproteinases:

•Enzymes that digest proteins
Subclasses:
• collagenases
• type IV collagenases / gelatinases
• stromelysins
• Secreted in latent form

• Activated by proteases
• Neutral pH optima
Involved in both plaque rupture and fibrinolysis

62
Activation of tissue metalloproteinases
Urokininase
Plasminogen
Activator (made by macrophages)
Plasminogen Plasmin
Tissue Active tissue

Metalloproteinase metalloproteinase
(inactive)
Digestion of proteins
such as collagens,
weakening plaque 63
Potential results of
a series of plaques
fissuring
Can get repair
Can get recanalisation
66
Two mural thrombi projecting into coronary artery lumen
Note that plaque appears intact
67
A series of fissures may lead to an occluding thrombus
68
Recanalisation of coronary artery
recanalisation
Angiograph Histology
69
Fissured atherosclerotic lesion  Arterial thrombus formation
Collagen, basement membrane, Tissue factor (on
Microfilaments of elastin, macrophages & SMC)
crystalline cholesterol,
oxidised LDL
Activation of clotting cascade
Platelet activation Thrombin
Platelet aggregation Fibrin
Primary haemostatic plug Secondary haemostatic plug

(fibrin and RBCs)
Stable thrombus
Ischaemia Embolism 70
Normal haemostasis  thrombosis

Pathology:
- DVT
- MI, ischaemic stroke. (PAD) 71
Venous thrombosis: Deep vein thrombosis
• Thrombosis, (usually) in the large
veins of the leg.
•Virchow’s Triad:
•Stasis of blood
•Increased coagulability
•Vessel wall injury
• Predominantly caused by
activation of the coagulation
cascade
•Minimal role for platelets
•Lack of endothelial NO production
• Embolism of thrombi from these

sites travel to where? Venogram: visualised using X-
ray opaque dye
72
The
mammalian
circulation
system
Embolism –
where does is
go?
•Pulmonary
embolism (PE)
is potentially
fatal blockage
of the
pulmonary
arteries.
•3% risk of
fatal PE from Campbell, 2008
73
The Clinical Consequences of Thrombotic Diseases:
•Myocardial infarction (MI) (blockage of coronary arteries)
•Ischaemic stroke (blockage of carotid arteries)
•Peripheral arterial disease (PAD) (narrowing of leg arteries)
•Deep vein thrombosis (DVT) (blockage of deep (leg) veins)
74
Signs (physician measures) / symptoms (pt reports),
diagnosis and prognosis of arterial thrombosis
Myocardial Infarction (blockage of coronary arteries):

• Symptoms
Central chest pain, shortness of breath, sweating, nausea/vomiting. Pain
may radiate to the jaw and arms.
• Signs
Tachycardia, low grade fever, pale clammy skin, hypo or hypertension,
altered heart sounds.
• Diagnosis
ECG, elevated troponin levels (protein released by damaged heart
muscle), elevated creatine kinase levels (released by damaged heart
muscle).
• Treatment
Thrombolytic therapy, anti-platelet therapy, -blockers, PCTA, CABG
• Prognosis
After a first myocardial infarction:1
– 23% of people die before reaching hospital
– 13% die during hospital admission
– 10% die within the first year following hospital discharge
– 5% die each year thereafter (this persists indefinitely)
75
www.merck.co
Ischaemic Stroke (blockage of carotid/cerebral
arteries):
• Symptoms
FAST (face asymmetries, arm weakness, slurred speech, time!).
• Signs
Muscle weakness, paralysis, loss of sensation
• Diagnosis
Clinical (from signs / symptoms) but neuroimaging necessary to
distinguish haemorrhagic vs ischaemic (CT or MRI).
• Treatment
Thrombolytic therapy, anti-platelet therapies, carotid
endarectomy.
• Prognosis
– Complete neurologic recovery occurs in about 10%.
– Use of the affected limb is usually limited, and most deficits
that remain after 12 mo are permanent. Subsequent strokes
often occur, and each tends to worsen neurologic function.
– About 20% of patients die in the hospital; mortality rate
increases with aging. 76
www.merck.co
Peripheral Arterial Disease (narrowing of leg arteries):

• Symptoms
Pain in calves on walking, cold feet (usually bilateral).
• Signs
Poor pulses in feet, thin skin, leg hair loss, redness with legs below
heart height, paleness when elevated, ulcers (poor healing).
• Diagnosis
Ankle-brachial index (systolic ankle BP / systolic brachial BP =
0.9 – 1.3 is normal, <0.9 indicative of PAD), ultrasound, MRI.
• Treatment
Exercise, anti-platelet therapies to reduce risk of other arterial
thrombosis and to dilate blood vessels, percutaeous
intervention. Foot care.
• Prognosis
75% of cases remain stable with life style changes and drug
treatments (but have increased risk of MI / stroke).
77
www.merck.co
diagnosis and prognosis of venous thrombosis
Deep Vein Thrombosis (blockage of leg veins):

• Symptoms
Pain in leg.
• Signs
Tenderness, swelling, redness, heat (unilateral). Fever, general
malaise, elevated WBC and erythrocyte sedimentation rate.
• Diagnosis
Ultrasound, venogram (x-ray with contrast dye), elevated D-
dimers (by-product of fibrinolysis),
• Treatment
Anti-coagulation, thrombolytic therapy
• Prevention
Exercising the legs, wearing support stockings, prophylactic
anti-coagulation.
• Prognosis
3% risk of fatal pulmonary embolism (PE)
78
www.merck.co
• Movie animation
• Discuss Angina vs MI vs
heart failure
79
Treatment vs prophylaxis:
Prophylaxis = preventative
Treatment = after it has happened
Treatment for thrombosis
A. Anti-platelet drugs prophylaxis / treatment

• Mainly prevent arterial thrombosis
B. Anti-coagulant drugs prophylaxix / treatment
C. Thrombolytic drugs treatment
D. Surgery treatment
80
Current anti-platelet drugs and their targets
Suppress platelet function - thereby prevent arterial thrombosis
Aspirin
ADP receptor antagonists
Phosphodiesterase inhibitors
Fibrinogen receptor blockers
Thrombin inhibitors
Vit. K antagonists
Heparins
81
Aspirin
Thrombin inhibitors
Vit. K antagonists
Heparins
82
Aspirin (acetyl salicilylic acid)
• Acetylates active site of cyclo-

oxygenase 1 (COX1)
• COX1 required for synthesis of
thromboxane A2 from arachidonic
acid
83
Platelet activation
leads to conversion of
arachidonic acid to
thromboxane A2.
TXA2 acts back on
platelets (autocrine
and paracrine) via the
TXA2 receptor to
trigger a pathway that
activates the
fibrinogen receptor.
84

oxygenase 1 (COX1)
acid
• Inhibits platelet aggregation
• Permanently inhibits COX1
• Irreversible effect for lifetime
of the platelet (as anucleate).
85

oxygenase 1 (COX1)
acid
•Orally administerd • Irreversible effect for lifetime
•Cheap – out of patent of the platelet (as anucleate).
•A number of clinical studies have demonstrated clinical benefit.
86

oxygenase 1 (COX1)
acid
Dosage?
• Complete inhibition of platelet COX at 20-100mg/day
• >80mg/day - substantial decrease in PGI2
• Therefore higher doses may reduce effectiveness
87

oxygenase 1 (COX1)
acid
Dosage?
• Complete inhibition of platelet COX at 20-100mg/day
• >80mg/day - substantial decrease in PGI2
• Therefore higher doses may reduce effectiveness
Aspirin resistance: 5-40% of population may still have a
thrombotic event whilst taking aspirin. Gum, P.A., et al (2001). Profile 88
and
prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol, 88, 230-5.
Aspirin
Thrombin inhibitors
Vit. K antagonists
Heparins
89
ADP:
• ADP is secreted by activated platelets
• Positive feedback regulation of platelet function
• Particularly important where collagen is primary stimulus
• 2 known receptors, P2Y1 and P2Y12.
• P2Y12 is a G protein-coupled receptor
• Acts a co-stumulus for platelet aggregation
• P2Y12 antagonists have been launched to prevent thrombosis

• e.g. clopidogrel
• = orally available
90
Aspirin
Thrombin inhibitors
Vit. K antagonists
Heparins
91
Glycoprotein IIbIIIa (integrin IIb3) blockers
• Reduces fibrinogen binding (when receptor activated)

• Prevents platelet aggregation and thrombus formation
Examples:
• Abciximab (humanised monoclonal antibody)
• Aggrastat (non-peptide antag from venom protein)
• Integrilin (cyclic heptapeptide)
• All administered intravenously
92
Anti-platelet drug targets of the future?
Blocking +ve
recptors
Activating –ve
receptors
+ PECAM-1 and neurokinin receptors? 93

Anti-platelet drug targets of the future?
Blocking +ve
recptors
Activating –ve
receptors
94
Barrett et al, 2008.

• Mainly prevent venous thrombosis
95
Anti-coagulant drugs:
• Heparin - inhibits conversion of prothrombin

to thrombin (activates antithrombin II)
•Warfarin - inhibits reduction of vitamin K
• EDTA (ethylenediamine tetracetic acid) -

chelates Ca2+
• Citrate - complexes with Ca2+
96
Anti-coagulant drugs
Heparin (inhibits thrombin)
• Abundant in liver
• Straight chain sulphated glycosaminoglycan
(polymers of sulphated D-glucosamine, D-glucuronic
acid and L-iduronic acid)
• Purified from porcine intestinal mucosa or bovine
lung
• Mean Mw 15,000
• low molecular weight heparin (enzymically or
chemically cleaved) is now more widely used
• 1,000 - 10,000 Da
• Predictable dosing
• No thrombocytopenia
97
Heparin (inhibits thrombin):
• Strongly acidic
• Not absorbed through gut - therefore injected
• Effect is immediate
Mechanisms
Thrombin
Antithrombin III
(1)
Heparin
Heparin complexes with thrombin and antithrombin III - enhances

(>1000 times faster) inhibition of thrombin
98
Heparin (inhibits thrombin): Factor Xa
(2) Antithrombin III
Heparin-antithrombin III binding - conformational

change
Inhibits factor Xa (and also IXa, XIa and XIIa)
(common part of coagulation cascade)
99
Anti-coagulant drugs:
• Heparin - inhibits conversion of prothrombin

to thrombin (activates antithrombin II)
•Warfarin - inhibits reduction of vitamin K
• EDTA (ethylenediamine tetracetic acid) -

chelates Ca2+
• Citrate - complexes with Ca2+
100
The coagulation
pathways
Liver
synthesises
these clotting
factors only
if Vit K is
present.
Warfarin
inhibits
cycling of vit
K.
101
Warfarin - mechanisms
Warfarin inhibits vit. K epoxide reductase
eg prothrombin, VII, IX and X
102
*
Warfarin
• Works only in vivo

• Effects after 10 hours
• Inhibits post-translational modification
of vitamin K-dependent clotting factors:
• Prothrombin, VII, IX and X
Glutamic acid -carboxyglutamic acid
Ca2+
Vitamin K Binds to phospholipids on
cell surface 103
104
Fibrinolysis:
Dissolution of the blood clot.
Synthetic, Endogenous, from endothelial cells
drug
Plasminogen activators
eg. Tissue-type plasminogen activator (t-PA)
Plasminogen Plasmin
Fibrin Fibrin split

clot products
105
Clot-busting drugs: Fibrinolytic Drugs
• Drugs that enhance the rate of fibrin clot
destruction
• Influence the production of plasmin
• Synthetically made recombinant protein (i.e.
human gene expressed in bacteria)
• Preferentially activates plasminogen bound to
fibrin - i.e. in a thrombus
• Reduced risk of systemic bleeding
• Very expensive
eg.
•Streptokinase
•Urokinase
•Tissue-type plasminogen activator (t-PA)
106
Clot-busting / fibrinolytic drugs
Streptokinase
• Protein isolated from Streptococci
• Converts plasminogen to plasmin
• Administered by intravenous infusion
• Effects are additive with Aspirin
• Bacterial protein - may cause allergic reactions
107
Streptokinase
Urokinase
• Originally from human urine
• Now from cultured kidney cells
• Expensive - but used if allergic to streptokinase
108
Streptokinase
Urokinase
• Originally from human urine
• Now from cultured kidney cells
• Expensive - but used if allergic to streptokinase
Tissue-type plasminogen activator (tPA, Alteplase)
• Recombinant protein (i.e. human gene expressed in bacteria)
• Preferentially activates plasminogen bound to fibrin - i.e. in a
thrombus
• Reduced risk of systemic bleeding
109
• Very expensive
110
Surgical treatment for thrombosis -
occlusion of coronary arteries
i. Percutaneous transluminal
coronary angioplasty
(PTCA) “balloon angioplasty”
is more a treatment for
angina (narrowing).
ii. Stents are a more

permanent version of PTCA
(also for angina).
111
occlusion of coronary arteries
iii, Coronary artery bypass graft (CABG)
112
Occlusion of carotid arteries
iv, Carotid endarterectomy
This procedure is accompanied by administration of drugs to

prevent clotting 113
Improvements in prevention and treatment have
reduced total mortality caused by CVD (decreased
by 38% in the under 75’s in the last 10 years
(BHF, 2006).
Once study showed a 50% mortality reduction
between 1981-2000 in England & Wales (Belgin et
al (2003) Circulation, 109, 1101-1107).
•Changes in treatments (drugs and surgery)

accounted for 42% of the reduction
•The rest thought to be due to reduced risk

factors (e.g. smoking)
114
Antiplatelet drugs:
Antithrombotic drugs trialists’ collaboration, 2002 (Oxford:
http://www.ctsu.ox.ac.uk/projects/att/index_html
Meta-analysis of 287 studies - 135,000 high risk patients

Mainly treated with aspirin
Decrease non-fatal MI by 1/3
Decrease non-fatal strokes by 1/4
decrease vascular deaths by 1/6
75-150mg/day at least as effective as higher doses
“OVER 40,000 LIVES LOST WORLDWIDE EVERY YEAR BECAUSE ASPIRIN IS UNDERUSED”
Clopidogrel:
• Clinical trial of 12,000 patients (Mehta et al)
• Reduced cardiovascular events by 20%
115
Anti-coagulants:
Warfarin
• 5,500 men at high risk of CHD (Meade et al)
• Low dose reduced CHD by 21% and mortality by 17%
• No benefit for strokes (increased haemorrhagic strokes)
116
Summary
Part 1
Normal haemostasis - and the control of bleeding
• role of platelets
• role of coagulation

Clinical consequences of thrombosis
Part 2
Anti-thrombotic drugs (arterial / venous)
• anti-platelet drugs (arterial)
• anti-coagulant drugs (venous)
• thrombolytic drugs
• surgery
117
Further reading
Barrett et al (2008). Brit. J. Pharmacology 154(5):918-39.
Future innovations in anti-platelet therapies.
Furie B. and Furie B. (2008) N Engl J Med. 359(9):938-49.

Mechanisms of thrombus formation.
Antiplatelet Trialists’ Colaboration (2002) Brit. Med. J. 324,

71-86. Collective meta-analysis of randomised trials of
antiplatelet therapy for prevention of death, myocardial
infarction, and strokes in high risk patients.
Mehta S.R, et al, (2001) Lancet 358, 527-533. Effects of

treatment with clopidogrel and aspirin followed by long-term
therapy in patients undergoing percutaneous coronary
intervention: the PRI-CURE study.
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CVD Thrombosis and Antithrombotic Drugs BI3BE8 09-10

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CVD Thrombosis and Antithrombotic Drugs BI3BE8 09-10

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BI3BE8

From atherosclerosis to thrombosis

•Myocardial infarction (MI) (blockage of coronary arteries)

Other CVD Diseases (to be covered elsewhere)

CVD = cardiovascular disease CHD = coronary heart disease

• Cancer is gaining on CVD – due to improvements in treatments for

•Morbidity: As well as those dying from this

Males 1.1 million 970,000

Females 850,000 439,000

•Improvements in prevention and treatment have

Financial cost of CVD to the UK economy in 2006:

£14.4 billion (47%) healthcare costs

Hence the need for better, cheaper, more

• the principal stimulus is underlying atherosclerosis

What causes venous thrombosis?

To understand thrombosis one needs to

Platelet plug formation

Injury to blood vessel Platelet activation Fibrin clot formation

Platelet plug formation coagulation

Injury to blood vessel Platelet activation Fibrin clot formation

Platelet plug formation coagulation

Alpha & dense

• Adenosine diphosphate (ADP)

Stimulate POSITIVE FEEDBACK in thrombus formation

Transient Rolling Activation

Blot: anti- phospho-PKB (Ser473)

Platelet activation must be confined to the site of injury

PECAM-1 = Platelet Cell Adhesion Molecule - 1

Injury to blood vessel Platelet activation Fibrin clot formation

Platelet plug formation coagulation

• Coagulation is the process in which the fluid

• Coagulation converts the platelet plug into a

hrombin is a protease. Clot formation

• Found in plasma in inactive forms

• Regulate the conversion of prothrombin to

• Form enzyme cascades:

• One activated clotting factor activates another

•Intrinsic pathway – everything necessary is in the blood

Platelets also activated by exposed collagen and

•Extrinsic pathway – cellular element required

Damaged tissue releases tissue thromboplastin / tissue

Platelet plug formation

Upon damage, blood vessel spasm

•The process by which the clot dissolves is called

•Like coagulation, fibrinolysis is a series of steps

Fibrin Fibrin split

• Inactive enzyme trapped in clot

• Activated by thrombin, lysosomal enzymes from

• Dissolves fibrin threads

• Inactivates fibrinogen, prothrombin and clotting

Myocardial infarction (blockage of coronary arteries)

ie. Inappropriate platelet activation

Peripheral arterial disease (PAD) (narrowing of leg arteries)

Deep vein thrombosis (DVT) (blockage of deep (leg) veins)

ie. Inappropriate coagulation

Injury to blood vessel Platelet activation Fibrin clot formation

Platelet plug formation coagulation

•Most common sites of

Arterial thrombosis - a consequence of plaque rupture

A complex combination of:

Role of tissue metalloproteinases:

• Secreted in latent form

Involved in both plaque rupture and fibrinolysis