Ischemic Heart

Disease and
Myocardial
Infarction
Prof Univ Dr Ion C.Tintoiu
UMT-Clinica medicina
interna
Centrul de Cardiologie al

Coronary Arteries
Normal Anatomy

Coronary Angiography

Myocardial Ischemia:

Occurs when myocardial oxygen

demand exceeds myocardial oxygen
supply

MVO2 = Myocardial Oxygen Demand

MVO2 determined by:
-Heart Rate
--Contractility
-----Wall Tension

Coronary obstruction/Cardiac
pain/Cardiac Ischemia lesion
Obstruction:
Impediment.
Stenosis Narrowing of
blood vessle

: Pain

Cardiac lesions

Angina Pectoris

.Ischemia fibrosis

Pain :

Cardiac lesions

Narrow
lumen

I) Obstruction

II) Occlusion
Occlusion:
Closed
vessel

Infarct Pain
Closure
of the
lumen

.Infarct (necrosis)

Risk Factors

family History
cigarette smoking
diabetes mellitus
hypertension
hyperlipidemia
sedentary life-style
obesity
elevated homocysteine, LP-a ?

Atherosclerotic Plaque
Evolution from Fatty
Streak

Fatty streaks present

in young adults
Soft atherosclerotic
plaques most
vulnerable to
fissuring/hemorrhage
Complex interaction
of substrate with
circulating cells
(platelets,
macrophages) and
neurohumoral factors

Plaque progression.

Fibrous cap
develops when
smooth muscle
cells migrate to
intima, producing
a tough fibrous
matrix which
glues cells
together

Screening and Diagnosis

Myocardial Ischemia

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Angiography
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Stress
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Electrocardiogram

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Angina
Pectoris
m

ISCHEMIC CHEST PAIN

EXERTIONAL ANGINA
* BRIEF EPISODES BROUGHT ON BY EXERTION AND
RELIEVED BY REST ON NTG

UNSTABLE ANGINA
* NEW ONSET
* CHANGE IN FREQUENCY/SEVERITY
* OCCURS AT REST

AMI
* SEVERE PERSISTENT SYMPTOMS
* ELEVATED TROPONIN

ISCHEMIC CHEST PAIN:

DIAGNOSIS

12 LEAD EKG
- Look for ST segment elevation (at least
1mm in two contiguous leads)
- Look for ST segment depression
- Look for T wave inversions
- Look for Q waves
- Look for new LBBB
- Always compare to old EKGs

EKG CHANGES IN
ISCHEMIC HEART
DISEASE

ST SEGMENT
DEPRESSION

T WAVE
IINVERSIONS

ISCHEMIC CHEST PAIN:

DIAGNOSTIC TESTS

CARDIAC ENZYMES
- Myoglobin
* Will rise within 3 hours, peak within 4-9
hours, and return to baseline within 24 hrs.
- CKMB
* Will rise within 4 hours, peak within 12- 24
hours and return to baseline in 2-3 days
- TROPONIN I
* Will rise within 6 hours, peak in 12 hours
and return to baseline in 3-4 days

Blood tests: used to evaluate kidney and

thyroid function as well as to check
cholesterol levels and the presence of
anemia.
Chest X-ray: shows the size of your heart
and whether there is fluid build up around the
heart and lungs.
Echocardiogram: shows a graphic outline
of the hearts movement
Ejection fraction (EF): determines how
well your heart pumps with each beat.

Coronary Artery
Angiography

Coronary Artery
Angiography

Echocardiograph
y
Ischemic Heart Disease

Ischemic Heart Disease

IVUS-Atherosclerotic
Plaque

Stable Angina

Definition
Types of Angina
Management of Angina
Antianginal drugs
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Chest pain caused by transient

myocardial ischemia due to an
imbalance between myocardial
oxygen supply and demand.
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Myocardial Blood Flow

Myocardial O2 Demands

Transient Myocardial
ischemia

Severe Chest pain

Angina Pectoris
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Angina

Angina is a type of
chest discomfort
caused by poor
blood flow through
the blood vessels
(coronary vessels)
of the heart muscle
(myocardium).

Types of Angina
1. Stable Angina.
2. Unstable Angina.
3. Variant Angina.
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Stable Angina Symptoms

mid-substernal chest pain

squeezing, pressure-like in quality (closed fist
= Levines sign)
builds to a peak and lasts 2-20 minutes
radiation to left arm, neck, jaw or back
associated with shortness of breath, sweating,
or nausea
exacerbated by exertion, cold, meals or stress
relieved by rest, NTG

1. Stable Angina .
The commonest cause is ADVANCED
ATHEROSCELEROSIS
Retrosternal pain
Radiating to left arm &
shoulder
Lasting less than 15 min.
HOME

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Stable Angina
Predisposing factors

Emotion

Heavy meals

Relieving
factors

Exertion

Rest

sublingual
nitroglycerin

Exposure to cold
weather

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Stable Angina
Anginal pain is often associated with Depression
of ST segment
Exercise ECG showing typical severe down sloping ST
segment :

Standing

1 min.

3 min.

7 min.

9 min.

In between attacks : ECG is entirely NORMAL

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Diagnosis
Exercise Treadmill Test

Management of Angina
Management of Stable Angina
Management of Unstable Angina
Management of Variant Angina
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Management of Stable
Angina
1- General measures.
2- Drug Treatment.
3- Coronary artery
revascularization.
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General measures
Treat Hypertension ,
Hypercholestrolimia
and Diabetes
Stop smoking

AVOID
Severe
exertion

Reduce weight

Heavy meal

Emotions

Graduated exercise may open new

collaterals

Cold Weather

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a. For an acute attack

b. For immediate pre-exertional
prophylaxis
c. For long-term prophylaxis
d. Antiplatelet therapy.
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Stable Angina Treatment

Risk factor modification (HMG Co-A

Reductase inhibitors = Statins)
AspirinDecrease thrombotic risc
Decrease MVO2
nitrates
beta-blockers
calcium channel blockers
ACE-inhibitors
Anti-oxidants (E, C, Folate, B6)?

What are the antianginal drugs?

Organic nitrates.
- adrenoceptor blockers.
Calcium channel blockers.

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NITRATES
Veins

Relaxation of smooth
muscles
Dilatation

Arteries
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Cellular Mechanism of Vasodilatation

Nitrates

Synthesis of
cyclic GMP

Formation of
Nitric oxide (NO)
Activation of
Guanylate cyclase

Relaxation of Vascular
smooth muscles

N.B. (-SH) groups are required

for formation of NO.

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Effect of Nitrates :
On Stable Angina :
1- Venodilatation
Preload

Arteriolar
dilatation
Afterload

Myocardial
Oxygen demand
2- Redistribution of coronary flow towards
subendocardium
3- Dilatation of coronary collateral vessels.

On Variant Angina :
Relax smooth muscles of the
epicardial coronaries relieve
coronary artery spasm

On Unstable Angina :
Dilatation of epicardial coronary
arteries + reducing O2 demands
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Preparations :
Short acting
For acute attacks
Nitroglycerin
(sublingual, buccal
spray)
Isosorbide
dinitrate(sublingual,
buccal spray)

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Long acting

For antianginal prophylaxis

Nitroglycerin
oral SR (6.25-12mg) 2-4
times/day
- 2% ointment (1-1.5
inch/4hrs)
- patches (1 patch=25mg)/day

Isosorbide dinitrate (oral) 1040mg t.d.s.

Isosorbide mononitrate (oral)

Duration of Action of Various Preparations of

Organic Nitrates
Duration of
action

Preparation
" Short-acting"
1-Nitroglycerin

a) Sublingual
b) Spray

10-30 min
10-30 min

2- Isosorbide dinitrate

a) Sublingual
b) Spray

Up to 60 min.
1.5 hours

1-Nitroglycerin

a) Oral; sustained release

b) Ointment
c) Transdermal patches

4-8 hours
3-6 hours
8-12 hours

2- Isosorbide dinitrate
3-Isosorbide mononitrate

Oral
Oral

4-6 hours
6-10 hours

" Long-acting"

Adverse Reactions :
1- Postural Hypotension &
Syncope

2- Tachycardia

3- Drug Rash

4- Facial Flushing

5- Throbbing Headache

6- Prolonged high dose

Methaemoglobinaemia
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-blockers are effective in STABLE & UNSTABLE

angina

In contrast they are not useful for

vasospastic angina (Variant) {Prinzmetal} &

may worsen the condition. This deleterious

effect is likely due to an increase in coronary
resistance caused by the unopposed effects of
catecholamines acting at -adrenoceptors.

Mechanism of antianginal action:

The effectiveness of -adrenoceptor blockers in the
treatment of exertional angina is attributable to a fall
in myocardial O2 requirement at rest & during
exertion due to :
1- A -ve chronotropic effect (particularly during
exercise).
2- A -ve inotropic effect.
3- A reduction in arterial blood pressure (particularly
systolic pressure) during exercise.
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Undesirable effects of -blockers in treatment of angina:

Rate & contractility

Systolic ejection period & left

ventricular end diastolic vol.
Myocardial O2 requirements

However the net effect of -blockers is to

myocardial O2 requirement particularly during
exercise; their potentially deleterious effects
can be balanced by concomitant use of nitrates
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Adverse Reactions :

CHF

Cold
extremities

A-V block

Worsening
symptoms of PVD

Bronchospasm

Hypotension
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Contraindications :

CHF

Peripheral
Vascular
disease

A-V block

Bronchial
asthma

Hypotension
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Used in treatment of all types of angina.

Verapamil (80-160 mg) /8 hr
Diltiazem

(60-120 mg) /8 hr

Dihydropyridine group
Nifedipine (10-40mg) /8 hr
Amlodipine

5mg/day
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Block
Voltage -dependent calcium
channels (L-type) in cardiac and
smooth muscles.
C
A
L
C
I
U
M

Mechanism of anti-anginal action :

1 - Coronary artery dilatation and relief
of coronary spasm (variant angina)
2 -Decrease myocardial O2 demand due to:
Arteriolar
dilatation

Vascular
resistance

(Verapamil & Diltiazem)

Decrease HR.
Decrease contractility
Decrease AV conductivity

Afterload

Dosage and Route of Administration

Drug

Route Dosage

Verapamil

Oral

80-160 mg every 8 hours

Nifedipine

Oral

10-40 mg every 8 hours

Diltiazem

Oral

60-120 mg every 8 hours

Adverse reactions :

Dizziness

Flushing

Ankle
edema

Constipation

Headache

A-V block & HF only

with Verapamil &
Diltiazem

Hypotension

Reflex
Tachycardia
with Nifedipine

Contraindications of
Verapamil & Diltiazem:

2 - Sinus or A-V node

1 - HF

disease.
3 - Bradycardia.

Treatment of an acute attack of angina

Sublingual nitroglycerin (0.5 mg ) or isosorbide
dinitrate (5 mg ) or
Oral spray nitroglycerin (0.4 mg/metered
dose), isosorbide dinitrate(1.25 mg/metered
dose)
Persistence of pain

Relief within 1-3 min.

Repeat nitroglycerin at 5 min.

interval (3 tab. max.)

Relief

not relieved

Infarction

HOSPITALIZATION

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Immediate pre-exertional prophylaxis of Angina

Sublingual nitroglycerin (0.5 mg) or isorbide
dinitrate (5 mg) should be taken 5 min.
before effort.
For Long term prophylaxis:
Long acting nitrates, Ca++ channel blockers,
-blockers or combinations of these drugs.
Antiplatelet therapy:
Aspirin in small dose (75-150 mg daily orally)
or Dipyridamole (75 mg t.d.s orally)
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Many people are able to manage

coronary artery disease with lifestyle
changes and medications.

Other

people with severe

coronary artery disease may
need angioplasty or surgery.

Coronary artery bypass grafting

(CABG)
Percutaneous Transluminal
coronary Angioplasty (PTCA)
For patients not responding to
adequate medical therapy
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Treatment of Stable Angina

-STENTS

Treatment (continued)
1) Stenting
a stent is introduced into a blood vessel on a balloon
catheter and advanced into the blocked area of the artery
the balloon is then inflated and causes the stent to
expand until it fits the inner wall of the vessel,
conforming to contours as needed
the balloon is then deflated and drawn back
The stent stays in place permanently, holding the vessel
open and improving the flow of blood.

Treatment
(continued)

2) Angioplasty
a balloon catheter is passed through the guiding catheter to
the area near the narrowing. A guide wire inside the balloon
catheter is then advanced through the artery until the tip is
beyond the narrowing.
the angioplasty catheter is moved over the guide wire until
the balloon is within the narrowed segment.
balloon is inflated, compressing the plaque against the artery
wall
once plaque has been compressed and the artery has been
sufficiently opened, the balloon catheter will be deflated and
removed.

TREATEMENT-CABG

Stable Angina - Treatment

Coronary Artery Bypass Grafting Surgery
(CABG)

Acute Coronary
Syndrome

Pathophysiology of Acute
Coronary Syndromes

Acute Coronary
Syndromes:
Terminology

Pathophysiology of all 3 is the same

Unstable Angina (UA)

ST depression, T Wave inversion or normal
No enzyme release
Non-Transmural Myocardial Infarction (NTMI or
SEMI)
ST depression, T Wave inversion or normal
No Q waves
CPK, LDH + Troponin release
Transmural Myocardial Infarction (AMI)
ST elevation
+ Q waves
CPK, LDH + Troponin release

Unstable Angina / Myocardial

Infarction
Symptoms

new onset angina

increase in frequency, duration or
severity
decrease in exertion required to
provoke
any prolonged episode (>10-15min)
failure to abate with >2-3 S.L. NTG
onset at rest or awakening from sleep

The underlying cause is

Fissuring of atheroscelerotic plaques
Platelet aggregation
Thrombosis
Coronary artery spasm

Atheroscelerotic changes

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Vulnerable Plaque

Schematic of an Unstable Plaque

Unstable Plaque:
More Detail.

Cross section of a
complicated plaque

Acute Coronary
Syndrome
Ischemic Discomfort
Unstable Symptoms

No ST-segment
elevation

Unstable
angina

History
Physical Exam

ST-segment
elevation

Non-Q
AMI

Q-Wave
AMI

ECG

Acute
Reperfusion

Definition:
Definition: NSTEMI
NSTEMI

NSTEMI is an acute process of

myocardial ischemia with sufficient
severity and duration to result in
myocardial necrosis.
The initial ECG in patients with NSTEMI
does not show ST-segment elevation.
NSTEMI is distinguished from UA by the
detection of cardiac markers indicative
of myocardial necrosis in NSTEMI and
the absence of abnormal elevation of
such biomarkers in patients with UA.
ACC/AHA Guidelines

Screening and Diagnosis

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MARKERS
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MI - Types
Transmural
(STEMI)

Full thickness

Superimposed
thrombus in
atherosclerosis

Focal damage

Sub-endocardial (NSTEMI)

Inner 1/3 to half of ventricular

wall
Decreased circulating blood
volume( shock, Hypotension,
Lysed thrombus)

Circumferential

Heart - Pathology
Ischemic Heart Disease
TTC

Diagnosis of MI:
Role of troponin i

Troponin I is highly
sensitive
Troponin I may be
elevated after
prolonged
subendocardial
ischemia
See examples below

Cardiac enzymes: overview

Legend: A. Early CPK-MB isoforms after acute MI

B. Cardiac troponin after acute MI
C. CPK-MB after acute MI
D. Cardiac troponin after unstable angina

EKG diagnosis of MI

ST segment
elevation
ST segment
depression
T wave inversion
Q wave formation

ACUTE INFERIOR MI

ST ELEVATION II, III, AVF

ACUTE ANTERIOR MI

ST SEGMENT ELEVATION V2-4

3. Variant Angina

(Prinzmetal)
Chest pain at rest due to
coronary artery spasm
ECG
changes:

The baseline ECG

With chest pain ,

marked ST segment
elevation

Acute elevation of ST
segment

Return of the ST segment to

the baseline after
nitroglycerin administration

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ACUTE MYOCARDIAL
INFARCTION
TERRITORY CORONARY EKG
ARTERY
INFERIOR
RCA
II, III, AVF
ANTERIOR

LAD

V2-4

LATERAL

CIRCUMFLE V5-6, I, AVL

X
TALL R WAVE IN V1/2
POSTERIOR VARIABLE
OR ST SEGMENT
DEPRESSION

Summary: Angina vs. MI

Type

Angina

Myocardial
Infarction

Type of
Obstructio
n

Stenosis narrowing of the Occlusion: complete

blood vessel
closure of the blood
vessel

Cardiac
lesion

Ischemic fibrosis

Infarct necrosis

Post
Grayish-white sheen.
mortem
appearance

Yellow

Type of
pain

1- pain is not
induced by
excretion
2-rapid onset
3- last for a long

1- pain is induced by
excretion
2-Paroxysmal (rapid
onset and offset)
Last for about 15 min

2. Unstable Angina .
Increased frequency, severity or duration
of pain in a patient of Stable Angina
N.B.
Pain occurs with less exertion
or at rest
Myocardial infarction may occur in 10-20% of patients.
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UA/NSTEMI
PRESENTATIONS
RestAngina* Anginaoccurringatrestandprolonged,
minutes
NewonsetAngina

usually>20

NewonsetanginaofatleastCCSClassIII

severity

IncreasingAngina
Previouslydiagnosedanginathathasbecomedistinctly
morefrequent,longerinduration, orlowerinthreshold(i.e.,increasedby
>1 CCS)classtoatleastCCS
ClassIIIseverity.

* Pts with NSTEMI usually present with angina at

rest.
Braunwald
Circulation 80:410; 1989

Angiogram in unstable angina:

eccentric, ulcerated plaque

Angiogram in unstable angina:

after stent deployment

Treatment of Acute Myocardial

Infarction

aspirin, heparin, analgesia, oxygen

reperfusion therapy

thrombolytic therapy (t-PA, SK, n-PA, r- PA)

new combinations ( t-PA, r-PA + 2b / 3a inhib)
cath lab (PTCA, stent)

decrease MVO2

nitrates, beta blockers and ACE inhibitors

for high PCWP - diuretics
for low Cardiac Output - pressors (dopamine,
levophed, dobutamine; IABP; early
catheterization

Central Role of Platelets in the Genesis of

Thrombosis
Hypercoagulability

Collagen, vWF

PCI
Plaque Rupture

Inflammation

Procoagulant
State

Cytokine
Release

TF

TF

PLT-WBC
Aggregation/
Microparticles

Adhesion/
Initial
Activation

Thrombin
P-selectin
CD-40L

Clopidogrel
(modest variable)

Granule
Secretion

ADP

Platelet

Sustained Activation

Platelet

Membrane
PLs

Stent
Thrombosis

GPIIb/IIIa
Activation

Platelet
X Aggregation

TxA2
GP IIb/IIIa Inhibitor
(potent uniform)

Myocardial Infarction

Aspirin (modest uniform)

(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)

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Mecanisme de activare si inhibare a functiei plachetare

(Meadows T, Circ. res. 2007,100,1261-75)

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Fibrinolytic
Therapy in
STEMI

Coagulation and
Tissue Plasminogen
Fibrinolysis
Activator
Coagulation Factors

Plasminogen
Fibrinogen

Plasmin
Fibrin

Fibrinolysis

Mechanism of Thrombolytic Drugs

They have a common mechanism of

converting the proenzyme

plasminogen to the active
enzyme plasmin, which lyses fibrin

clot
Plasminogen is converted to plasmin by
cleavage of the Arg-Val (560-561) peptide bond
Plasmin, the active two-chain polypeptide, is
a nonspecific serine protease capable of
breaking down fibrin as well as fibrinogen and
factors V and VIII

Fibrinolysis

Aside: other Anti-thrombotic

drug types

Anti-platelet agents include:

Aspirin (acetylsalicylic acid)

clopidogrel
dipyridamole
ticlopidine
glycoprotein IIb/IIIa inhibitors

Thrombolytic (/fibrinolytic) drugs include:

tissue plasminogen activator - t-PA - alteplase

(Activase)
reteplase (Retavase)
tenecteplase (TNKase)
anistreplase (Eminase)
streptokinase (Kabikinase, Streptase)
urokinase (Abbokinase)

Mechanism of Thrombolytic
Drugs

The plasmin(ogen) molecule has lysine binding

sites, which bind to and degrade fibrin
Fibrin-specific agents are much more active
upon binding to fibrin, thereby increasing the
affinity for plasminogen at the clot surface

Thrombolytic Drugs
Streptokinase

It is a bacterial protein produced by group C (beta)hemolytic streptococci

Mechanism: It binds to plasminogen producing an
"activator complex" that lyses free plasminogen to
the proteolytic enzyme plasmin
Plasmin degrades fibrin clots as well as fibrinogen
and other plasma proteins (non-fibrin specific)
Pharmacokinetics:
The t of the activator complex is about 23 minutes
The complex is inactivated by anti-streptococcal
antibodies & by hepatic clearance

Thrombolytic Drugs
Streptokinase

Clinical Uses:
Acute Myocardial Infarction: administered by
either the intravenous or the intracoronary route
for the reduction of infarct size & congestive heart
failure associated with AMI
Pulmonary Embolism
Deep Vein Thrombosis
Arterial Thrombosis or Embolism: It is not
indicated for arterial emboli originating from the
left side of the heart due to the risk of new embolic
phenomena such as cerebral embolism.
Occlusion of Arteriovenous Cannulae: for
clearing totally or partially occluded arteriovenous
cannulae when acceptable flow cannot be achieved

Thrombolytic Drugs
Alteplase (rt.PA)

It is a tissue plasminogen activator (t.PA)

produced by recombinant DNA technology of 527
amino acids
Cost per day is around 2200 $
Mechanism:
It is an enzyme which has the property of fibrinenhanced conversion of plasminogen to plasmin
It produces limited conversion of free plasminogen in
the absence of fibrin
When introduced into the systemic circulation it binds
to fibrin in a thrombus and converts the entrapped
plasminogen to plasmin followed by activated local
fibrinolysis with limited systemic proteolysis

Thrombolytic Drugs
Alteplase
Therapeutic Uses

Acute Myocardial Infarction in adults for the

improvement of ventricular function following AMI the
reduction of the incidence of congestive heart failure,
and the reduction of mortality associated with AMI
Acute Ischemic Stroke for improving neurological
recovery and reducing the incidence of disability.
Treatment should only be initiated within 3 hours after
the onset of stroke symptoms, and after exclusion of
intracranial hemorrhage
Pulmonary Embolism: Treatment of acute massive
pulmonary embolism

Reteplase & Tenectaplase

Reteplase is another human t-PA prepared
by recombinant mutation technology
It is fibrin-specific
It has longer duration than alteplase
Tenectaplase is another genetically
modified human t-PA prepared by
recombinant technology
It is more fibrin-specific & longer duration
than alteplase

Thrombolytic Drugs
Urokinase
It is an enzyme produced by the kidney,
and found in the urine
It is mainly used in the low molecular
weight form of urokinase obtained from
human neonatal kidney cells grown in
tissue culture
Mechanism: It acts on the endogenous
fibrinolytic system converting plasminogen
to the enzyme plasmin that degrades fibrin
clots as well as fibrinogen and some other
plasma proteins (Non-fibrin selective)

Thrombolytic Drugs
Urokinase
Urokinase administered by
intravenous infusion is rapidly cleared
by the liver with an elimination halflife for biologic activity of 12-20
minutes
Clinical Uses:
For the lyses of acute massive
pulmonary emboli

Contraindications to
Thrombolytic Therapy
Absolute contraindications include:
Recent head trauma or caranial tumor
Previous hemorrhagic shock
Stroke or cerebro-vascular events 1 year
old
Active internal bleeding
Major surgery within two weeks
Relative contraindications include:
Active peptic ulcer, diabetic retinopathy,
pregnancy, uncontrolled HTN

Fibrinolitic Therapy in
STEMI

90% of patients w/ acute STEMI have complete

occlusion of culprit artery
PCI preferred if performed w/in 90 minutes
of presentation or if transfer to
neighboring institution for PCI can occur
w/in 30-60 min.
Thombolytic therapy is the alternative
treatment
Not as effective in non-STEMI as the infarctrelated artery is not totally occluded in 60-85%
of cases

Time to presentation
Survival benefit greatest when lytics
administered within first 4 hours after onset
of symptoms, particularly within the first 70
minutes.
Mortality benefit less likely at 13-18 hours.
There MAY be benefit in patients presenting
>12hours if patient has on-going stuttering
chest pain.
AHA recommendations (2004): administer
lytics if no contraindications w/in 12 hr of
symptom onset; reasonable to administer
at 12-24 hr if continuing symptoms or
persistent ST elevation on EKG.

Adjunctive anticoagulation

Thrombin inhibition enhances coronary

thrombolysis and limits reocclusion; therefore
anti-coagulation is administered to most
patients receiving lytics.
Alteplase, reteplase, tenecteplase : UFH
at 60units/kg bolus followed by 12u/kg/hr
gtt; maintain PTT b/w 50-70 sec for 48hr.
LMWH also effective w/ tenecteplase,
although dont use it in pts>75 y/o (increased
risk of ICH) or those w/ Cr>2.5 in men or
Cr>2.0 in women.
? benefit of UFH or LMWH in
streptokinase, anistreplase, urokinase .

PCI after
thrombolytics???
This issue remains unresolved
3 possible scenarios
*Facilitated PCIlytic drug given prior to
planned PCI in attempt to achieve an open
infarct-related artery before arrival of cath
lab
*Adjunctive PCIPCI performed within hours
after thrombolysis
*Early elective PCIPCI performed within a
few days after thrombolysis

Heparin
And other current Parenteral
Anticoagulants

Unstable Angina
Anti-coagulant Therapy

Heparin
recommendation is based on
documented efficacy in many trials of
moderate size
meta-analyses (1,2) of six trials showed a
33% risk reduction in MI and death, but
with a two fold increase in major
bleeding
titrate PTT to 2x the upper limits of
normal

1. Circulation 1994;89:81-88
2. JAMA 1996;276:811-815

Unstable Angina
Anti-coagulant Therapy

Low-molecular-weight heparin
advantages over heparin:
better bio-availability
higher ratio (3:1) of anti-Xa to anti-IIa
activity
longer anti-Xa activity, avoid rebound
induces less platelet activation
ease of use (subcutaneous - qd or bid)
no need for monitoring

Prehospital
Thrombolysis

Prehospital thrombolysis
project:
Test ECG transmission

Prehospital Thrombolysis
Project:
Acute inferolateral infarct

Time and Mortality:

Primary PCI vs
Thrombolysis

12

30-day mortality (%)

10

Primary PCI
Common

total ischaemia time

4

Thrombolysis

0
0

4
6
5
3
Onset of pain to treatment (hours)

Huber K et al. Eur Heart J 2005;26:20632074.

Huber et al. Eur Heart J 2005; 26: 1063-1074

PCI after thrombolytics???

This issue remains unresolved
3 possible scenarios
*Facilitated PCIlytic drug given prior to
planned PCI in attempt to achieve an
open infarct-related artery before
arrival of cath lab
*Adjunctive PCIPCI performed within
hours after thrombolysis
*Early elective PCIPCI performed within
a few days after thrombolysis

Noncardiac
Chest Pain

Clinical Finding

Stable
Angina

Atypical Pain

ECG

Unstable
Angina

Exertional
Pain

Negative

Serum Markers
Risk Assessment

Negative
Low Probability

Diagnostic
Rule Out MI/ACS
Pathway
Negative
Discharge

Positive

Low Risk

Non-STElev. MI

ST-ElevationMI

Rest Pain, Post-MI,

DM, Prior ASA

Ongoing
Pain

ST-T-Wave
Changes

ST
Elevation
Positive

Medium-High Risk

STEMI

ASA, Heparin/LMWH +
Thrombolysis
Anti-ischemic Rx
Primary PCI
Early Conserv.
ASA + GP IIb/IIIa Inhibitor
+ Heparin/LMWH +
Anti-ischemic Rx
Early Invasive Rx

Cannon in Braunwald et al. Heart Disease. 2001.

Coronary Artery
Bypass Graft

Positive:

Relief of angina in 90% of patients

80% angina free after 5 years
Survival about 95% after 1 year
Low chance of restenosis

Negative:

2-3 days in ICU, 7-10 day total hospital stay

3-6 month full recovery time
5-10% have post-op complications
High cost ($25,000-$30,000)
Long time on CPB

Depression of the patient's immune system

Postoperative bleeding from inactivation of the blood
clotting system
Hypotension

BJ Harlan, et al; Manual of Cardiac Surgery, WebMD.com, American College of Cardiology Foundation

Minimally invasive surgery does not use

CPB
Smaller incision
Emerging as a replacement for
conventional CABG
Starting in 1990s, MIDCAB has gained
popularity
Usually conducted for LIMA to LDA
grafts
RG Cohen, et al; Minimally Invasive Cardiac Surgery

LAD exposed

Anastamosis
preformed with
assistance of
mechanical
stabilizer
Completed graft

RG Cohen, et al; Minimally Invasive Cardiac Surgery

Inoperable Coronary artery disease

How may we manage

PICVA - Basic Concept

Percutaneous In-Situ Coronary Venous
Arterialization

Selective Coronary Vein

Perfuses Myocardium
Arterial Supply From
Proximal Coronary Artery
Single Connection
Made Percutaneously
Vein Blocked Proximally
Bypasses Artery Completely

Transvascular Inc, with permission

Cardiogenic
Shock

Definition

<90 mmHg

<2.2 li/min.m2

>15 mmHg

Schematic
LVEDP elevation
Hypotension
Decreased coronary
perfusion
Ischemia
Further myocardial
dysfunction
Neurohormonal
activation
Vasoconstriction
Endorgan hypoperfusion

Currently, stenting is recommended over

surgery for one-vessel disease

In the future, drug-eluting stents will probably be used

Minimally invasive surgeries could be used in
place of stents in diabetic, and other high-risk
patients

For more than one-vessel disease, surgery is

substantially better at preventing restenosis
and so will likely continue to be used in the
future

Minimally invasive surgeries will expand and

replace most conventional CABG procedures

QUESTIONS ???

THROMBOLYTIC DRUGS
Pathophysiologic Rationale

Re-establishing coronary flow during a period of

occlusion will limit myocardial infarct (MI) size
was first demonstrated in a dog model of MI by
Reimer et al. in 1977
These experiments demonstrated that after
coronary occlusion there was a wavefront of
ischemic cell death, which progressed over time
from the subendocardium toward the epicardium
The time frame for this process was quite short,
in the range of 3 to 4 hours
Thus these studies provided the basis for the
rationale that re-canalization and reperfusion
early in the course of MI would limit myocardial
necrosis, improve left ventricular function, &
improve patient outcome

Wave-front Phenomenon of
Ischemic Cell Death

THROMBOLYTIC DRUGS
Pathophysiologic Rationale
Angiographic studies in the early
1980s showed that early in the
course of MI with ST-segment
elevation, most patients had
complete coronary occlusion
Pathologic studies established
the importance of plaque rupture
in the pathogenesis of acute
coronary syndromes

THROMBOLYTIC DRUGS
Pathophysiologic Rationale

Acute coronary
syndromes varies with
the degree of
thrombus-induced
obstruction, ranging
from a persistent
complete occlusion
corresponding to STsegment elevation MI
to a subocclusive
thrombus
corresponding to
unstable angina

Thrombolytic Therapy
Benefit

The ability of streptokinase to lyse clots was first

recognized in the 1930s
Thrombolytic therapy was not applied to acute MI
until the early 1980s after the establishment of the
central role of acute thrombotic coronary occlusion
in the pathogenesis of acute MI
Clinical trials have firmly established the benefit of
thrombolytic therapy for patients with acute MI with
ST-segment elevation within 12 hours of symptom
onset
Patients with unstable angina or MI without ST
elevation do not benefit from thrombolytic therapy
Rapid initiation of thrombolytic therapy is essential
to optimize patient outcome because each additional
hour of delay from symptom onset to treatment
corresponds to a 0.5% to 1% increase in mortality

Fibrinolysis

Mechanism of Thrombolytic Drugs

They have a common mechanism of

converting the proenzyme

plasminogen to the active
enzyme plasmin, which lyses fibrin

clot
Plasminogen is converted to plasmin by
cleavage of the Arg-Val (560-561) peptide bond
Plasmin, the active two-chain polypeptide, is
a nonspecific serine protease capable of
breaking down fibrin as well as fibrinogen and
factors V and VIII

Mechanism of Thrombolytic
Drugs

The plasmin(ogen) molecule has lysine binding sites, which bind to

and degrade fibrin
Fibrin-specific agents are much more active upon binding to fibrin,
thereby increasing the affinity for plasminogen at the clot surface

Thrombolytic Drugs
Streptokinase
It is a bacterial protein produced by group C
(beta)-hemolytic streptococci
Mechanism: It binds to plasminogen producing an
"activator complex" that lyses free plasminogen to
the proteolytic enzyme plasmin
Plasmin degrades fibrin clots as well as fibrinogen
and other plasma proteins (non-fibrin specific)
Pharmacokinetics:
The t of the activator complex is about 23
minutes
The complex is inactivated by anti-streptococcal
antibodies & by hepatic clearance

Thrombolytic Drugs
Streptokinase

It produces hyperfibrinolytic effect, which decreases

plasma fibrinogen levels for 24-36 hrs
A prolonged thrombin time may persist for up to 24
hours due to the decrease in plasma levels of fibrinogen
Efficacy: In the GISSI study the reduction in mortality
was time dependent; 47% reduction in mortality in
patients treated within one hour of the onset of chest
pain, 23% within three hours, & a 17% reduction
between three and six hours
The reduction was not statistically significant between
6-12 hrs
Hospital cost per day is minimal 280 $

Thrombolytic Drugs
Streptokinase

Clinical Uses:
Acute Myocardial Infarction: administered by either
the intravenous or the intracoronary route for the
reduction of infarct size & congestive heart failure
associated with AMI
Pulmonary Embolism
Deep Vein Thrombosis
Arterial Thrombosis or Embolism: It is not indicated
for arterial emboli originating from the left side of
the heart due to the risk of new embolic phenomena
such as cerebral embolism.
Occlusion of Arteriovenous Cannulae: for clearing
totally or partially occluded arteriovenous cannulae
when acceptable flow cannot be achieved

Thrombolytic Drugs
Streptokinase
Side-Effects:
Bleeding due to activation of
circulating plasminogen
Hypersensitivity: It is antigenic & can
produce allergic reactions like rashes
& fever (possibly via already present
Streptococcal antibodies)

Anistreplase (APSAC)

Anisoylated Plasminogen Streptokinase

Activator Complex (APSAC) IS acylated
plasminogen combined with streptokinase
It is a prodrug, de-acylated in circulation
into the active plasminogen-SK complex
Similar to SK, it has minimal fibrin
specificity & is antigenic
T1/2 is 70-120 min
Hospital cost per day is 1700 $

Thrombolytic Drugs
Alteplase (rt.PA)

It is a tissue plasminogen activator (t.PA) produced

by recombinant DNA technology of 527 amino acids
Cost per day is around 2200 $
Mechanism:
It is an enzyme which has the property of fibrinenhanced conversion of plasminogen to plasmin
It produces limited conversion of free plasminogen in
the absence of fibrin
When introduced into the systemic circulation it binds
to fibrin in a thrombus and converts the entrapped
plasminogen to plasmin followed by activated local
fibrinolysis with limited systemic proteolysis

Thrombolytic Drugs
Alteplase
Therapeutic Uses

Acute Myocardial Infarction in adults for the

improvement of ventricular function following AMI the
reduction of the incidence of congestive heart failure,
and the reduction of mortality associated with AMI
Acute Ischemic Stroke for improving neurological
recovery and reducing the incidence of disability.
Treatment should only be initiated within 3 hours after
the onset of stroke symptoms, and after exclusion of
intracranial hemorrhage
Pulmonary Embolism: Treatment of acute massive
pulmonary embolism

Thrombolytic Drugs
Alteplase
Pharmacokinetics:
It has very short t1/2 of 5 minutes

Side-Effects:
Bleeding including GIT & cerebral
hemorrhage
Allergic reactions, e.g., anaphylactoid
reaction, laryngeal edema, rash, and
urticaria have been reported very rarely
(<0.02%)

Reteplase & Tenectaplase

Reteplase is another human t-PA prepared
by recombinant mutation technology
It is fibrin-specific
It has longer duration than alteplase
Tenectaplase is another genetically
modified human t-PA prepared by
recombinant technology
It is more fibrin-specific & longer duration
than alteplase

Thrombolytic Drugs
Urokinase
It is an enzyme produced by the kidney,
and found in the urine
It is mainly used in the low molecular
weight form of urokinase obtained from
human neonatal kidney cells grown in
tissue culture
Mechanism: It acts on the endogenous
fibrinolytic system converting plasminogen
to the enzyme plasmin that degrades fibrin
clots as well as fibrinogen and some other
plasma proteins (Non-fibrin selective)

Thrombolytic Drugs
Urokinase
Urokinase administered by
intravenous infusion is rapidly cleared
by the liver with an elimination halflife for biologic activity of 12-20
minutes
Clinical Uses:
For the lyses of acute massive
pulmonary emboli

Contraindications to
Thrombolytic Therapy
Absolute contraindications include:
Recent head trauma or caranial tumor
Previous hemorrhagic shock
Stroke or cerebro-vascular events 1 year
old
Active internal bleeding
Major surgery within two weeks
Relative contraindications include:
Active peptic ulcer, diabetic retinopathy,
pregnancy, uncontrolled HTN

Fibrinolytic Inhibitors
Aminocaproic Acid & tranexamic cid
They have lysine-like structure
They inhibit fibrinolysis by competitive
inhibition of plasminogen activation
Adjuvant
Adjuvant therapy in hemophilia, fibrinolytic
therapy-induced bleeding & postsurgical
bleeding
Aprotinin is a serine protease inhibitor
It inhibits fibrinolysis by free plasmin
Used to stop bleeding in some surgical
procedures

Fibrinolitic Therapy in
STEMI

90% of patients w/ acute STEMI have

complete occlusion of culprit artery
PCI preferred if performed w/in 90 minutes
of presentation or if transfer to neighboring
institution for PCI can occur w/in 30-60 min.
Thombolytic therapy is the alternative
treatment
Not as effective in non-STEMI as the infarctrelated artery is not totally occluded in 6085% of cases

EFFICACY

Benefit first demonstrated w/ streptokinase

(GISSI-2 and ISIS-2 trials). ISIS-2 showed
combination of ASA and streptokinase
reduced mortality from 10.2% (placebo) to
7.2%.
GUSTO-I: alteplase superior to streptokinase
(although more expensive)
ASSENT-2 and GUSTO-III: newer agents like
tenecteplase, reteplase, lanoteplase as
effective as alteplase but have significantly
lower incidence of noncerebral bleeding
complications and need for transfusion.

Time to presentation
Survival benefit greatest when lytics
administered within first 4 hours after onset
of symptoms, particularly within the first 70
minutes.
Mortality benefit less likely at 13-18 hours.
There MAY be benefit in patients presenting
>12hours if patient has on-going stuttering
chest pain.
AHA recommendations (2004): administer
lytics if no contraindications w/in 12 hr of
symptom onset; reasonable to administer
at 12-24 hr if continuing symptoms or
persistent ST elevation on EKG.

Long-term survival

Long-term benefit primarily seen in

patients who achieved TIMI 3 flow w/
lytic administration. Vessel opening
(TIMI 2 or 3) reported in 60-87% of
patients receiving lytics, but
normalization (TIMI 3) in only 50-60%
of arteries. Only TIMI 3 flow
associated w/ improved LV function
and survival.

***Note: TIMI 3 flow is achieved in ~90% of patients treated with primary PCI.

Other prognostic indicatorspositive

predictors of one-year mortality

Demographics: older age (>55),

lower weight (<80kg), previous MI,
previous CABG
Larger infarctions, anterior wall
infarct, hypotension, tachycardia
(>115), longer QRS (>125), lower
EF/heart failure, cardiogenic shock
Presence of cardiac risk factors such
as smoking, HTN, prior CVA

CONTRAINDICATIONS
It is estimated that 20-30%
of patients ineligible for
thrombolytic therapy
This is what we missed on the inservice!!

ABSOLUTE
contraindications

Previous ICH
Known structural cerebral vascular lesion
Known malignant intracranial neoplasm
Ischemic CVA within 3 months prior
Suspected aortic dissection
Active bleeding or bleeding diathesis
Significant closed-head or facial trauma within 3
months prior
ADVANCED AGE IS NOT A MAJOR
CONTRAINDICATION FOR THROMBOLYTICS!
although pts >75y/o may get less overall benefit.

RELATIVE
contraindications

Poorly controlled or chronic sustained HTN

Ischemic CVA >3 months prior
Dementia
Traumatic or prolonged CPR or major surgery
within <3 wk prior
Recent (within 2-4 wk) internal bleeding
Noncompressible vascular puncture
Allergy to lytic agents
Pregnancy
Active peptic ulcer
Current use of anti-coagulants

Adjunctive anticoagulation

Thrombin inhibition enhances coronary

thrombolysis and limits reocclusion; therefore
anti-coagulation is administered to most
patients receiving lytics.
Alteplase, reteplase, tenecteplase : UFH at
60units/kg bolus followed by 12u/kg/hr gtt;
maintain PTT b/w 50-70 sec for 48hr.
LMWH also effective w/ tenecteplase,
although dont use it in pts>75 y/o (increased
risk of ICH) or those w/ Cr>2.5 in men or
Cr>2.0 in women.
? benefit of UFH or LMWH in streptokinase,
anistreplase, urokinase.

Plavix

CLARITY-TIMI 28 and COMMIT/CCS-2

demonstrated improved outcomes
when plavix given before thrombolytic
therapy.
300mg loading dose followed by 75mg
daily
In patients>75, risk of ICH not clear
with 300mg loading dose vs 75mg
loading dose

GP IIb/IIIa inhibitors

Two large trials failed to shows

survival benefit with combination
therapy (GP IIb/IIIa with
thrombolytics) compared to
conventional thrombolytic therapy,
and bleeding was increased.
DO NOT administer concurrent GP
IIb/IIIa inhibitors with thrombolytics!

Assessment of response

Relief of symptoms
Maintenance or restoration of
hemodynamic and/or electrical stability
Reduction of at least 50% of initial ST
segment injury pattern on a follow-up
EKG 60-90 min after initiation of
therapy
Serial measurements of cardiac
biomarkers

A 63-yo non-English-speaking woman comes to the

ED b/c of severe, steady precordial discomfort that
began 14 hours ago. She thought that the CP may
have been indigestion, but she had no relief with an
antacid. She has a h/o HTN. She is taking no
medication. Her HR is 92/min, and her BP is
150/90. Her chest and cardiac exam is normal.
Her EKG shows 3-mm STE in V2-V6. She is given a
chewable ASA, morphine 4mg IV, metoprolol 5mg
IV, and NTG 20mcg/min IV w/ a decrease in her CP
intensity from severe to moderate. A hospital in
the next county (1.5h away by ambulance) recently
established a program that provides 24h
angioplasty services.

Which of the following should be

considered in the decision of
whether to refer this patient for
treatment?

A)

B)

C)

D)

Angioplasty (with or without stenting)

has a better outcome than thrombolysis
in this patient
Thrombolysis has a better outcome than
angioplasty (with or without stenting) in
this patient
Thrombolysis and angioplasty (with or
without stenting) are equivalent in
outcome for this patient
Neither thrombolysis nor angioplasty
(with or without stenting) should be
performed in this patient

Which of the following should be

considered in the decision of
whether to refer this patient for
treatment?
A) Angioplasty (with or without
stenting) has a better outcome
than thrombolysis in this
patient

74yo female is admitted w/ 3h of crushing

substernal CP. She has a h/o L carotid occlusion
w/ hemiparesis occurring 3 months ago. She
also has a h/o mild HTN, hyperlipidemia, and DM
complicated by neuropathy and retinopathy. Her
meds include coumadin, atenolol, and
pravastatin. In the ED, she has a Vfib arrest and
is successfully converted to NSR after receiving
2 min of CPR. Her EKG shows SR w/ 3-mm STE
in V2-V6. The results of initial laboratory tests
are within normal limits, except for an elevated
PT w/ and INR of 1.8.

Which of the following represent an

absolute contraindication to the use of
a thrombolytic agent in this patient?
A)

B)
C)
D)

E)

L carotid occlusion w/ hemiparesis

3 months ago
CPR for 2 minutes
Patient age>70 years
Patient on coumadin with an INR of
1.8
Diabetic retinopathy

Which of the following represent an

absolute contraindication to the use of
a thrombolytic agent in this patient?
A)

L carotid occlusion w/
hemiparesis 3 months ago

Parenteral Anticoagulants
Heparins (contd.)
P ro th ro m b in
V

Heparin

T h ro m b in
Va

C a2+

X a

Factor Xa or
Thrombin

C a2+

V II

V IIa

Antithrombin III

T F , P h o s p h o lip i d , C a 2 +

B lo o d V e s s e l In ju r y

Mechanism of action: standard heparins catalyze the inhibition of Factor Xa and

thrombin by antithrombin III.
Low mol. wt. heparins (enoxaparin, dalteparin) predominantly catalyze the inhibition
of Xa.
Used in DVTs, PE, unstable angina, acute MI, during/after angioplasty or
coronary stent placement, cardiac bypass surgery
Heparins are contraindicated in bleeding disorders, hypersensitivity to heparins,
severe hypertension, renal dysfunction.

Parenteral Anticoagulants
Inhibitors of Platelet Glycoprotein IIb/IIIa
Role of Glycoprotein IIb/IIIa in thrombus formation

On unstimulated platelets,
GP IIb/IIIa is in a
conformation that has low
affinity for soluble fibrinogen.
When platelets are
activated, they undergo
morphologic and physiologic
changes, and GP IIb/IIIa
molecule alters its
conformation, becoming a
high-affinity receptor for
fibrinogen.

Each fibrinogen molecule can bind to 2 GP IIb/IIIa molecules and therefore crosslink receptors on adjacent activated platelets and ultimately lead to formation of
platelet-rich thrombi.

Parenteral Anticoagulants (GPIIb/IIIa Inhibitors)

Abciximab (ReoPro)
Is the Fab fragment of a chimeric monoclonal antibody. Administered by i.v
injection or infusion.
Used in pts. with unstable angina, post-MI and following angioplasty
Binds to platelet glycoprotein IIb/IIIa receptors to prevent adhesion of platelets to
fibrinogen.
High affinity binding of the mAb to GPIIb/IIIa leads to prolonged platelet
inhibition.
Also binds other integrin receptors on vascular endothelial cells
Adverse effects include bleeding, nausea, vomiting, hypotension, atrial fibrillation,
edema.
Hypersensitivity reactions due to antibody formation
Collagen
ADP
Thrombin

Platelet
RheoPro

Parenteral Anticoagulants (GPIIb/IIIa Inhibitors)

Eptifibatide (Integrilin)
A heptapeptide cyclized by a disulfide bridge that mimics carpet viper venom toxin
in preventing coagulation.
Eptifibatide binds to GP IIb/IIIa with high affinity and prevents the interaction with
von Willebrand factor and fibrinogen to prevent the formation of stable platelet
aggregates.
Indicated for pts. suffering from acute MI or undergoing PTCA to prevent the
formation of new clots.
Used in unstable angina
Generally used in combination with aspirin and heparin
Due to the relatively specific interaction of eptifibatide with GP IIb/IIIa no
significant adverse effects result apart from potential for severe bleeding.

Parenteral Anticoagulants (GPIIb/IIIa Inhibitors)

Tirofiban (Aggrastat)
COOH
HN

(C H 2)4O

H N S O 2(C H 2)3C H

Synthetic, nonpeptide
antagonist of the GPIIb/IIIa
receptor that prevents fibrinogen
binding to platelets.

Poor oral bioavailability requires parenteral administration of tirofiban but other

agents in this class are being devloped for oral adminstration e.g. sibrafiban,
xemilofiban and orbofiban.
Major adverse effects observed are potential for bleeding and thrombocytopenia
especially when administered in combination with heparin.
Anticoagulant effect is more reversible after withdrawal than that seen with
RheoPro.

Thrombolytic Agents
t-PA
Fibrin

Plasminogen

Physiological Fibrinolysis
Fibrinolytic system dissolves intravascular clots
as a result of plasmin activation.
Targets pathological rather than
physiological clots
Plasmin cleaves fibrin strands and coagulation
factors to dissolve clots.

Regulation of plasmin activation:

- removes unwanted fibrin thrombi but fibrin in wounds is maintained.
- endothelial cells release tissue plasminogen activator (t-PA) in response to
hemostasis.
- t-PA rapidly inactivated by plasminogen activator inhibitor 1 and 2 (unless t-PA is
bound to fibrin) to prevent systemic activation of plasminogen to plasmin.
- t-PA binds to fibrin and converts plasminogen, that is also bound to fibrin, to
plasmin.
- activated plasmin bound to fibrin is protected from the negative actions of 2antiplasmin
- pharmacological application of plasminogen activators overwhelms the inhibitory
controls on fibrinolysis.

Thrombolytic Agents
Streptokinase (Kabbikinase, Streptase)
47 kDa protein produced by -hemolytic streptococci; not an enzyme but forms
stable 1:1 complex with plasminogen.
Alters the configuration of plasminogen to expose the proteolytic catalytic site which
autocatalyzes its own activation to free plasmin.
Will activate plasminogen that is not bound to fibrin less specific than t-PA
High loading doses are required to overcome antibody inhibition; has half-life of 4080 min; streptokinase:plasminogen complex not inhibited by anti-plasminogen
inhibitors.
Adverse rxns. include bleeding, allergic rxns., anaphylaxis and fever (rare).
Allergic rxns. in pts. who have had -hemolytic streptococcal infections
Anistraplase (Eminase) is a plasminogen-streptokinase complex that is more
fibrin specific than streptokinase alone.
Streptokinase

Thrombolytic Agents
Tissue plasminogen activator (Alteplase, Activase)
Serine protease of ~ 500kDa, produced by recombinant DNA technology.
Metabolized by liver with half-life of 5-10 min.
Requires the presence of fibrin to convert plasminogen to plasmin. Effective in
lysing clots during acute MI, pulmonary embolism and DVT.
Reteplase is modified by the removal of several amino acids from the t-PA
sequence.
Urokinase (Abbokinase)
A serine protease isolated from cultured human kidney cells .
Used in the clearing of clots from IV lines.
Metabolized by liver with half-life of 15-20 min.
Is not fibrin specific and can cause systemic lytic state.
Current supply is inconsistent due to production problems

Thrombolytic Agents
Adverse effects of thrombolytic agents

Hemorrhagic toxicity is the main adverse effect in thrombolytic therapy and is

due to:
1. Lysis of fibrin in physiological thrombi
2.

Systemic lytic state

After inhibitory protein have been overwhelmed and destruction of
coagulant proteins results

3.

Can lead to intracranial hemorrhage

Excessive fibrinolysis due to t-PA can be limited with aminocaproic acid

Contraindications: GI ulcers, bleeding disorders, hypertension, recent surgery,
aortic dissection.

Prehospital
Thrombolysis
Professor P J Fletcher
Director, Cardiovascular
Department
John Hunter Hospital, Newcastle

Prehospital thrombolysis

Review of evidence relating time of reperfusion

treatment to outcome
Review of evidence with prehospital thrombolysis
Progress with pre-hospital thrombolysis in Hunter
New England
Recent publications on prehospital thrombolysis
Outcome from very early prehospital
thrombolysis
Role of prehospital thrombolysis vs primary PCI
in patients seen within 2 hours of pain onset

Fibrinolysis and adjunctive

therapy
Antiplatelet therapy
Glycoprotein IIb/IIIa antagonists
Aspirin
Clopidogrel
Anti-thrombins
Unfractionated heparin
Low Molecular weight heparin
Hirudin etc

Antiplatelet therapy: aspirin +

clopidogrel
Aspirin: In ISIS-2, aspirin reduced vascular deaths, non-fatal
reinfarction and non-fatal stroke, and was not associated
with any significant increase in bleeding
Clopidogrel
CLARITY TIMI 28
COMMIT

Sabatine, Cannon Gibson et al. Clarity TIMI 28 Investigators. Addition of

clopidogrel to aspirin and thrombolytic therapy for myocardial infarction
with ST segment elevation. N Eng J Med 2005; 352:1179

Chen, Jiang, Chen. COMMIT (Clopidogrel and Metoprolol in Myocardial

Infarction Trial) collaborative group, et al. Addition of Clopidogrel to
aspirin in 45852 patients with acute myocardial infarction randomised
placebo controlled trial. Lancet 2005; 366: 1607

Prehospital thrombolysis
project:
Test ECG transmission

Prehospital Thrombolysis
Project:
Acute inferolateral infarct

Prehospital thrombolysis
project:
progress report July08-09

Total ECG transmissions: 461

Transmission failures: 26
Number of STEMIs: 21
Prehospital thrombolysis: 9
Symptom to thrombolysis: 80 (43110) min

Authors summary:

Mortality in the lower

three fifths of risk
categories is not reduced
by PCI compared with lysis
(but may be increased if
the PCI delay is long)
Higher risk patients (2/5)
benefit from PCI if ECG-toballoon time is 90 min or
less; but that advantage is
lost at a mean ECG-toballoon time of 100 min.
(longer than that, lysis may
be preferred)

Kent, D et al. AJC 2007

Time and Mortality:

Primary PCI vs
Thrombolysis

12

30-day mortality (%)

10

Primary PCI
Common

total ischaemia time

4

Thrombolysis

0
0

4
6
5
3
Onset of pain to treatment (hours)

Huber K et al. Eur Heart J 2005;26:20632074.

Huber et al. Eur Heart J 2005; 26: 1063-1074

Acute myocardial infarction:

Overviews
Gersh 2006 MCNA

The results to date of prehospital thrombolysis for acute MI are

indeed encouraging but the implementation of corresponding clinical
policies is subject to the logistic constraints of different health care
systems and geographic regions throughout the world.
White HD & Chew DP. Lancet 372: 570-584, 2008
Seminar: Acute Myocardial Infarction
The earlier that fibrinolysis is begun,

the greater the benefit with

respect to preservation of left ventricular function and reduction in
mortality which suggests an important role for prehospital
fibrinolysis.

In a study of prehospital fibrinolysis with a 26% rate of rescue PCI,

fewer patients randomised with 2 hr of symptom onset had
cardiogenic shock and more survived to 30 days compared with
primary PCI, although this finding was not statistically significant.

The development of clinical networks designed to enable prehospital

fibrinolysis could provide further mortality benefits to a broader
population of patients presenting with STEMI.

Update in reperfusion
therapy for acute myocardial
infarction
Eddy Lang MD
Attending Staff
Emergency
Department

Educational Process
Objectives

Use a problem-solving approach to

address two controversial topics in MI
reperfusion
Review databases of research evidence
Introduce the concept of the study
synopsis

Clinical Scenario

52 year old male with chest pain x 2 hrs.

No history of CAD, risk factors ++
Severe central C/P with radiation and
diaphoresis and SOB
No known bleeding
No head trauma

Clinical Scenario

Pale, diaphoretic
BP 140/70 Pulse 115 RR 24
Chest: clear
CVS: Normal HS; JVD; murmers
Abdo: soft
CNS: normal

Clinical Scenario

52 year old male with chest pain x 2 hrs.

No history of CAD, risk factors ++
Severe central C/P with radiation and
diaphoresis and SOB
No known bleeding
No head trauma

Clinical Setting

4th year resident moonlighting on a rural

rotation
Extremely well-stocked ED pharmacy
IIb/IIIa inhibitors
PCI unavailable
In addition to ASA what anti-thrombin therapy
should you give?
UFH (most familiar)? LMWH? Does it matter?

Clinical Question
In patients with acute myocardial
infarction who are receiving thrombolytic
therapy and ASA does adjuvant
antithrombin therapy with LMWH in
comparison with UFH reduce adverse
cardiac events during the following 30
days without an unacceptable increase in
bleeding?

ASSENT 3
Efficacy and safety of tenecteplase
in combination with enoxaparin,
abciximab, or unfractionated heparin:
the ASSENT-3 randomised trial in acute
myocardial infarction
The ASSENT-3 Investigators
Lancet 2001;358:60513

Breakout tasks

Develop a study synopsis

1. Maximum 5 sentences
Appraise methodology
2. Prognosis before the start of the study
3. Prognosis after the start of the study
Define the key issues in applicability
4. Why not use it

Aside from the experimental intervention,

were groups treated equally?

Conclusions

PCA:
Even with 90 min additional delay PCA
superior to lysis
Evidence behooves the interventionist to
come in at 2:00am
Referral centers are coming
Adjuvant anti-thrombotic therapy:
Enoxaparin superior to UFH

Antiplatelet and thrombolytic

drugs

Antithrombotic drugs

Fibrinolytics

Antithrombotic drugs

Fibrinolytics

Antithrombotic drugs

Fibrinolytics

Antithrombotic drugs

Fibrinolytics

The role of platelets

The role of platelets

The role of platelets

The role of platelets

Antiplatelet drugs
Antiplatelet drugs

Acetylsalicylic
acid (aspirin)

P2Y12
antagonists

Dipyridamole

GPIIb/IIIa
antagonists

Used widely
in patients
at risk of
thromboembolic
disease

Beneficial in the
treatment and
prevention of ACS
and the prevention
of thromboembolic
events

Secondary
prevention in
patients following
stroke, often in
combination with
aspirin

Administered
intravenously, are
effective during
percutaneous
coronary
intervention (PCI)

Acetylsalicylic acid
mechanism of action

Acetylsalicylic acid
mechanism of action

Acetylsalicylic acid
mechanism of action

Acetylsalicylic acid
mechanism of action

Acetylsalicylic acid
mechanism of action

Acetylsalicylic acid
pharmacokinetics
Rapid
absorption of aspirin occurs in the

stomach and upper intestine, with the peak

plasma concentration being achieved 15-20
minutes after administration

The

peak inhibitory effect on platelet

aggregation is apparent approximately one
hour post-administration

Aspirin

produces the irreversible inhibition

of the enzyme cyclo-oxygenase and
therefore causes irreversible inhibition of
platelets for the rest of their lifespan (7
days)

Acetylsalicylic acid
major use
Secondary prevention of transient

ischaemic attack (TIA), ischaemic stroke

and myocardial infarction

Prevention

of ischaemic events in
patients with angina pectoris

Prevention

of coronary artery bypass

graft (CABG) occlusion

Acetylsalicylic acid
major
drawbacks
Risk of
gastrointestinal
adverse events
(ulceration and bleeding)

Allergic

reactions

Is

not a very effective antithrombotic drug but is

widely used because of its ease of use

Lack

of response in some patients (aspirin

resistance)

The

irreversible platelet inhibition

ADP-receptor
antagonists mechanism
of action

ADP-receptor
antagonists mechanism
of action

ADP-receptor
antagonists mechanism
of action

ADP-receptor
antagonists mechanism
of action

ADP-receptor antagonists
pharmacokinetics
Both currently available ADPBoth currently available ADPreceptor antagonists are
thienopyridines that can be
administered orally, and absorption
is approximately 80-90%

Thienopyridines

are prodrugs that

must be activated in the liver

ADP-receptor
major
use
antagonists
Secondary prevention
of ischaemic

complications after myocardial

infarction, ischaemic stroke and
established peripheral arterial disease

Secondary

prevention of ischaemic
complications in patients with acute
coronary syndrome (ACS) without STsegment elevation

ADP-receptor
antagonists major
Clopidogrel is only slightly more
effective drawbacks
than aspirin
As

with aspirin, clopidogrel binds

irreversibly to platelets

In

some patients there is resistance

to clopidogrel treatment

Dipyridamole
mechanism of action

Dipyridamole
mechanism of action

Dipyridamole
mechanism of action

Dipyridamole
pharmacokinetics
Incompletely absorbed from the

gastrointestinal tract with peak plasma

concentration occuring about 75 minutes after
oral administration

More than 90% bound to plasma proteins

A terminal half-life of 10 to 12 hours

Metabolised in the liver

Mainly excreted as glucuronides in the bile;

a small amount is excreted in the urine

GPIIb/IIIa-receptor
antagonists
mechanism of action

GPIIb/IIIa-receptor
antagonists
Available
only for intravenous administration
pharmacokinetics

Intravenous administration of a bolus dose

followed by continuous infusion produces
constant free plasma concentration throughout
the infusion. At the temination of the infusion
period, free plasma concentrations fall rapidly
for approximately six hours then decline at a
slower rate. Platelet function generally recovers
over the course of 48 hours, although the GP
IIb/IIIa antagonist remains in the circulation for
15 days or more in a platelet-bound state

GPIIb/IIIa-receptor
antagonists
Prevention of ischaemic cardiac
major use

complications in patients with

acute coronary syndrome (ACS)
without ST-elevation and during
percutaneous coronary
interventions (PCI), in combination
with aspirin and heparin

GPIIb/IIIa-receptor
antagonists
Can only be administered by
major drawbacks

intravenous injection or infusion

and are complicated to manufacture

Oral

drugs have been investigated

but were not effective and have
therefore not reached the market

Thrombolytic drugs
mechanism of action

Thrombolytic drugs
mechanism of action

Thrombolytic drugs
mechanism of action

Thrombolytic drugs
mechanism of action

Thrombolytic drugs
pharmacokinetics

The plasma half-life of the third

generation drugs is 14-45 minutes,
allowing administration as a single or
double intravenous bolus. This is in
contrast to second generation t-PA,
which with a half-life of 3-4 minutes,
must be administered an initial bolus
followed by infusion

Thrombolytic drugs major use

Thrombolysis in patients with acute myocardial

infarction (MI)

Thrombolysis in patients with ischaemic stroke

Thrombolysis of (sub)acute peripheral arterial

thrombosis

Thrombolysis in patients with acute massive

pulmonary embolism

Thrombolysis of occluded haemodialysis shunts

Thrombolytic drugs
major drawbacks

Treatment

is limited to acute inhospital treatment. There is a high

risk of bleeding inherent in this
treatment

Patients

using anticoagulants are

contraindicated for treatment with
thrombolytics

Blood Clotting

Vascular Phase

Platelet Phase

Coagulation Phase

Fibrinolytic Phase

Vascular Phase

Vasoconstriction
Exposure to tissues activate
Tissue factor and initiate
coagulation

TissueFactor

Platelet phase

blood vessel wall (endothelial cells) prevent

platelet adhesion and aggregation

platelets contain receptors for fibrinogen and

von Willebrand factor

after vessel injury Platelets adhere and

aggregate.

Release permeability increasing factors (e.g.

vascular permeability factor, VPF)

Loose their membrane and form a viscous plug

Coagulation Phase

Two major pathways

Intrinsic pathway

Extrinsic pathway

Both converge at a common point

13 soluble factors are involved in clotting

Biosynthesis of these factors are dependent on

Vitamin K1 and K2

Normally inactive and sequentially activated

Hereditary lack of clotting factors lead to

hemophilia -A

Extrinsic Pathway

Intrinsic Pathway

All clotting factors are Initiating factor is

within the blood

outside the blood

vessels

vessels - tissue factor

Clotting slower

Seconds

Activated partial
thromboplastin test
(aPTT)

Clotting - faster - in

Prothrombin test
(PT)

IntrinsicPathway

ExtrinsicPathway
TissueInjury

BloodVesselInjury

TissueFactor

XIIa

XII

Thromboplastin

XIa

XI

IXa

IX

Xa

X
Factorsaffected
ByHeparin

VIIa

Prothrombin

Vit.KdependentFactors
AffectedbyOralAnticoagulants

Fibrinogen
XIII

VII

X
Thrombin
Fribrinmonomer
Fibrinpolymer

Anticoagulant drugs to treat

thromboembolism
DrugClass
Anticoagulant
Parenteral

Prototype
Heparin

Action
Inactivationofclotting
Factors

Anticoagulant Warfarin Decreasesynthesisof

Oral
Clottingfactors
Antiplatelet
drugs

Aspirin

Decreaseplatelet
aggregation

Thrombolytic Streptokinase Fibinolysis

Drugs

Effect
Preventvenous
Thrombosis
Preventvenous
Thrombosis
Preventarterial
Thrombosis
Breakdownof
thrombi

Heparin

Sulphated carbohydrate
Different sizebovine lungs
Administration - parenteral- Do not
inject IM - only IV or deep s.c.
Half-life 1 - 5 hrs - monitor aPTT
Adverse effect: hemorrhage
Antidote : protamine sulphate

Heparin mechanism of
action
Heparin
AntithrombinIII

Thrombin

Antiplatelet drugs

Example: Aspirin
Prevents platelet aggregation /adhesion
Clinical use - prevents arterial thrombus

Myocardial infarction (MI), stroke, heart

valve replacement and shunts

Other antiplatelet drugs are Dipyridamole, sulfinpyrazone and

Ticlopidine

Mechanism of action

Aspirin inhibits cyclooxygenase

(COX)
COX is a key enzyme involved in the
synthesis of thromboxane 2
(prostaglandins)
Inhibits platelet aggregation

Fibrinolysis

Enhance degradation of clots

Activation of endogenous protease

Plasminogen (inactive form) is

converted to Plasmin (active form)

Plasmin breaks down fibrin clots

Fibrinolysis

Exogenously administered drugs

Streptokinase - bacterial product

Urokinase - human tissue derived

- continuous use - immune reaction

no immune response

Tissue plasminogen activator (tPA) genetically cloned

no immune reaction
EXPENSIVE

Drug preparations : To reduce

clotting

Heparin (generic, Liquaemin

sodium)

Warfarin (generic , Coumadin)

Parenteral - 1000 - 40,000 U/ml

Oral : 2 - 20 mg tablets

Dipyridamole (Persantine)

Oral : 25,50,75 mg tablets

Drug preparations : to lyse clots

Alteplase recombinant (tPA, Activase)

streptokinase (Kabikinase, streptase)

20, 50 mg Lyophilized powder - reconstitute for

iv

Parenteral : 250000 - 1.5 million units per vial .

Lyophilized powder. Reconstitute for iv

Urokinase ( Abbokinase)

Parenteral : 250000 units per vial. Powder to

reconstitute to 5000 u/ml for injection

Drug preparations: clotting

deficiencies

Vitamin K ( Phytonadione (K1), Mephyton

Plasma fractions - for hemophilia

Oral : 5 mg tablets

Antihemophilic factor ( VIII, AHF)

Parenteral

Factor IX complex (konyne HT, proplex

T)

Parenteral : in vials

Drug preparations : to stop

bleeding

Systemic use : aminocaproic acid (Amicar);

Tranexamic acid (cyclokapron),Vitamin K
Local adsorbable drugs
Gelatin sponge (Gelfoam)
Gelatin film
Oxidized cellulose ( Oxycel)
Microfibrillar collagen (Avitene)
Thrombin

Intrinsic Clotting Pathway

The Clotting Cascade

Blood or collagen contact

XII

Tissue trauma

XIIa (H)

XI

Extrinsic Clotting Pathway

Tissue factor

XIa (H)
(W) VII VIIa
(W) IX

IXa (H)
CA++

PF 3

VIII (W)

Common Pathway

(W) X

Xa (H)

(Next slide)

Common Pathway

Xa (H)
Ca++

PF 3
V (W)
(H) (F)

(W) Prothrombin

Thrombin

Ca++

Fibrinogen

CA++

Fibrin
(soluble)
(H)
XIIIa

Fibrin (insoluble)

XIII

Circulatory Disorders
Antiplatelet Drugs

Aspirin, Dipyridamole (Persantine), Ticlopidine

(Ticlid)
abciximab (ReoPro), tirofiban (Aggrastat)
Action: To prevent thrombosis in the arteries by
suppressing platelet aggregation via diff. methods
Use: Prevention of MI/stroke for clients w/ family hx
- prevention of a repeat MI, stroke in clients having
TIAs
Persantine & Ticlid = similar to ASA but more
expensive
ReoPro & Aggrastat = mainly for acute coronary
syndromes. Route = IV

Circulatory Disorders
Thormbolytics

Thromboembolism - Occlusion of an artery or vein

caused by a thrombus or embolus - results in ischemia
that causes necrosis of the tissue distal to the
obstructed area.
- it takes about 1 to 2 weeks for the blood clot to
disintegrate by natural fibrinolytic mechanisms
- if new thrombus dissolved quicker damage minimized
& bld flow restored faster purpose of therapy
Thrombolytics promote fibrinolytic mechanism (convert
plasminogen to plasmin & destroys the fibrin in the
clot) - administering a thrombolytic drug = clot
disintegrates

Circulatory Disorders
Thrombolytics

Use = Acute MI - w/ in 4 hrs to dissolve clot &

unblock artery, so decrease necrosis to myocardium
& hospital stay is decreased.
Other uses: Pulmonary embolism, DVT,
Noncoronary arterial occlusion
Streptokinase, Urokinase, Tissue plasminogen
activator (t-PA), anisoylated plasminogen
streptokinase activator complex (APSAC)
Streptokinase & Urokinase are enzymes that act to
convert plasminogen to plasmin
t-PA and APSAC activate plasminogen by acting
specifically on clot.

Circulatory Thrombolytics
All 5 drugs induce fibrinolysis (fibrin breakdown)
Side effects: hemorrhage, allergic reactions (anaphylaxis) &
vascular collapse-more with Streptokinase
Onset and peak are immediate and rapid, duration can be 12h.
t-PA most expensive - $2500/tx, short t1/2 (5-7 min.) not
associated with anaphylaxis.
Aminocaproic acid (Amicar) an antithrombolytic used to stop
bleeding by inhibiting plasminogen activation. Used to stop
bleeding from heart surgery, trauma & abruptio placenta.

Circulatory Disorders
Peripheral Vasodilators

Peripheral Vasodilators - Increase bld flow to

extremities
Peripheral vascular disease is a problem in
the elderly
- Numbness & coolness of extremities,
intermittent claudication (pain/weakness of
limb when walking - symptoms absent at
rest), poss. leg ulcers
- Primary cause is hyperlipemia from
atherosclerosis & arteriosclerosis - arteries
become occluded

III. Thrombolytic Agents

Agents which reduce the formation of arterial platelet thrombi
Mechanism:
Rapid lysis of thrombi by catalyzing the formation of plasmin from
plasminogen
Endogenous plasmin breaks down fibrin promoting clot dissolution
Use:
Emergency treatment of coronary artery thrombons in M.I.
IV or intracoronary injection
DVT: rapid recanalization of occluded vessels
Toxicity:
Bleeding (intracranial, G.I.)
Allergic reactions (i.e. streptokinase)

Streptokinase:
Purified from bacteria
Continuous use: immune reaction
Forms a complex with plasminogen & catalyzes it: rapid conversion
to plasmin
Urokinase:
From cultured human kidney cells
No immune response
Directly converts plasminogen to plasmin
tPA:
Produced by recombinant techniques
No immune reaction - EXPENSIVE
Promotes conversion of plasminogen (that is found to fibrin) to
plasmin
In theory, selective for formed clots

Enzymatic Fibrin
efficiency specificity

Potential
antigenicity

Average Dosing
dose
administration

Cost

Streptokinase

High

Minimal

Yes

1.5 MU

1 hr IV infusion

Low

Antistreplase

high

Minimal

Yes

30 u

2-5 min IV
infusion

Moderate

Tissue
plasminogen
activator

High

Moderate

No

100 mg

15 mg IV bolus, 50 Moderate
mg over 30 min,
then 35 mg over
60 min

Urokinase

low

moderate

No

2 mu

1 mu IV bolus,
1 mu over 60 min

for clot
lysis

high

THROMBOLYTIC DRUGS
Drugs

that break down, or lyse,

preformed clots

Older

drugs

streptokinase and urokinase

Newer

drugs

Tissue plasminogen activator (TPA)

Anisoylated plasminogen-streptokinase
activator complex (APSAC)

THROMBOLYTIC DRUGS
(CONTD)
streptokinase

(Streptase)
anistreplase (Eminase)
alteplase (t-PA, Activase)
reteplase (Retavase)
tenecteplase (TNKase)
drotrecogin alfa (Xigris)

THROMBOLYTIC DRUGS:
MECHANISM OF ACTION
Activate

the fibrinolytic system to break

down the clot in the blood vessel quickly

Activate

plasminogen and convert it to

plasmin, which can digest fibrin

Reestablish

blood flow to the heart muscle

via coronary arteries, preventing tissue
destruction

THROMBOLYTIC DRUGS:
INDICATIONS
Acute

MI
Arterial thrombolysis
DVT
Occlusion of shunts or catheters
Pulmonary embolus
Acute ischemic stroke Code
Green

THROMBOLYTIC DRUGS:
ADVERSE EFFECTS
BLEEDING

Internal
Intracranial
Superficial

Other

effects

Nausea, vomiting, hypotension,

anaphylactoid reactions
Cardiac dysrhythmias

NURSING IMPLICATIONS
Assess:
Patient

history, medication history,

allergies
Contraindications
Baseline vital signs, laboratory values
Potential drug interactionsthere are
MANY!
History of abnormal bleeding
conditions

THROMBOLYTIC DRUGS:
NURSING IMPLICATIONS
Follow

strict manufacturers guidelines for

preparation and administration

Monitor

IV sites for bleeding, redness, pain

Monitor

for bleeding from gums, mucous

membranes, nose, injection sites

Observe

for signs of internal bleeding

(decreased BP, restlessness, increased pulse)

ANTICOAGULANTS:
PATIENT EDUCATION
Education should include:
Importance

of regular lab testing

Signs of abnormal bleeding
Measures to prevent bruising, bleeding, or
tissue injury
Wearing a medical alert bracelet
Avoiding foods high in vitamin K (tomatoes,
dark leafy green vegetables)
Consulting physician before taking other
meds or OTC products, including herbals

DRUGS
NURSING IMPLICATIONS
Monitor

for therapeutic effects

Monitor

for signs of excessive bleeding

Bleeding of gums while brushing teeth,

unexplained nosebleeds, heavier menstrual
bleeding, bloody or tarry stools, bloody urine or
sputum, abdominal pain, vomiting blood

Monitor

for adverse effects

Increased BP, headache, hematoma formation,

hemorrhage, shortness of breath, chills, fever

REVIEW
Antiplatelet agents act by:
1. preventing extension of existing
clots.
2. preventing platelets from uniting.
3. dissolving existing clots.
4. increasing blood viscosity.

REVIEW
Doses of heparin are based on what
laboratory
report?
1. warfarin serum level
2. activated partial thromboplastin time
(APTT)
3. Lee White clotting time
4. prothrombin time (PT) and INR

REVIEW
Nursing responsibilities involved in the
administration of heparin subcutaneously
include:
1. checking calculations with a second
qualified nurse.
2. using a 20-gauge needle to inject the
drug.
3. injecting the drug deep intramuscularly
(IM).
4. aspirating before injecting the drug.

REVIEW
Clopidogrel (Plavix) is used to:
1. dissolve existing arterial blood clots.
2. prevent further movement of an
embolus.
3. prevent platelet aggregation.
4. prevent extension of an existing
thrombus.

THROMBOLYSIS
Alteplase:
Pharmacodynamics
and
Dr Kevin Reiling
Pharmacokinetics

Natural Regulatory Balance

Fibrinolysis - tissue plasminogen activator (tPA)
streptokinase
- urokinase

Inactivation of procoagulant enzymes

Activated clotting factor clearance

Fibrinolysis
Injured endothelial cells
Plasminogen activators
Plasmin cleaved from plasminogen
Fibrin degrades

Primary

Plasmin
Plasminogen

Tissue Plasminogen Activators:

Family of thrombolytic drugs used in acute
myocardial infarction, cerebrovascular thrombotic
stroke and pulmonary embolism.
Alteplase
Retaplase, smaller derivative of recombinant tPA that
has increased potency and is faster acting than rtPA.
Tenecteplase, greater binding affinity for fibrin than
rtPA.

Pharmacokinetics

ADME

Broken down in digestive system, so?

Exercise and vasoactive substances such as
epinephrine, vasopressin, desmopressin, niacin or
alcohol, increase endogenous levels, so?
Endogenous levels = 46 ng/mL, so?
Natural constituent of bloodstream relatively
inactive with a VD approximating to plasma volume.

Pharmacokinetics

ME

Metabolism poorly understood but principally

hepatic with most occurring with the hepatocytes.
First reading 60
Second reading 26 @ 5 minutes later
Third Reading 12 @ another 5 minutes later
Half-life?

Pharmacokinetics
Rapidly cleared 550-680 mL/minute from plasma
giving an initial distribution phase half life (t) <5 min
and in the terminal elimination phase (t ) ~40 min.
Thus > 50% of t-PA is cleared from plasma within 5
minutes after discontinuance of an IV infusion and
approximately 80% is cleared within 10 minutes.

Giving us
Continuous infusion.
Recommended dose 0.9 mg alteplase/kg body weight
(maximum of 90 mg) over 60 minutes, with 10% of the
total dose administered as an initial intravenous bolus.
Not indicated <18 years >80 years. ????

Risks
Plasmin breaks down fibrin = fibrin degradation
products (FDPs).
FDPs compete with thrombin = slow down the
conversion of fibrinogen to fibrin (and thus
slows down clot formation).
Secondary impact tPA binds circulating
plasminogen

Other risks
Potential interactions with anticoagulants, ACE
inhibitors, platelet function altering drugs etc.
Cholesterol embolisms
Immune problems plasmin also cleaves C3
component of complement system

Have we missed anything important?

Within 3 hours of the stroke.
The efficacy of thrombolytic drugs depends on the
age of the clot. Older clots have more fibrin crosslinking and are more compacted or in plain English
older clots are more difficult to dissolve.
Beyond that time, the efficacy diminishes and higher
doses are generally required to achieve desired lysis
and the great the risk of unwanted complications.

Competency framework
the time of the onset of stroke has been
recorded and has full understanding of the
importance of this in relation to thrombolysis
Understands the pharmacodynamics and
pharmacokinetics of thrombolytic treatment with
rtPA
Understands the potential for unwanted effects

The Blood

Structure of hemoglobin
Each heme molecule combines with one oxygen
atom
Marieb and Hoehn Human Anatomy & Physiology seventh edition Pearson Benjamin
Cummings

Structure of hemoglobin and the oxygen dissociation

curve

Davidsons Principles and Practice of Medicine eighth edition, Churchill Livingstone

Normal and sickle cell RBC

In sickle cell disease hemoglobin S replaces the chain
In thalassemias, the or chains can be absent or
defective
Marieb and Hoehn Human Anatomy & Physiology seventh edition Pearson Benjamin
Cummings

The Blood
Blood Coagulation
The Platelets
Platelets are activated by thrombin, collagen, or ADP, they
discharge
their content which leads to the formation of thrombaxane
A2
Platelets adhere to exposed collagen in the presence of
von Willebrand factor (vWF)
Their life span is 8-14 days, they are destroyed in the cells of
the RE
system

The structure of a platelet

Davidsons The Priciples and Practice of Medicine, eighteenth edition Churchill Livingstone

Initial vasoconstriction and platelet plug

Vanders
Physiology eighth edition Mc Graw Hill
v

Intrinsic and extrinsic coagulation pathways

Calcium ions are essential for the coagulation

cascade
Vanders Physiology eighth edition Mc Graw Hill

The role of the liver in blood

coagulation
Vanders Physiology eighth edition Mc graw Hill

EM of a blood clot: RBCs and fibrin

NIBSC?Science Photo Libraray Taken from Vander Physiology eighth edition Mc Graw Hill

Prostacyclin (PGI2 ) and nitric oxide inhibit platelet

aggregation

Vanders Physiology eighth edition Mc graw Hill

The Blood
Anticoagulation
Natural Anticoagulants
Tissue factor pathway inhibitor (TFPI)
Plasminogen - plasmin
Heparin
Antithrombin III
Protein C
Protein S
Vitamin E quinone
Natural anticoagulants also have anti inflammatory activity

The Blood
Anticoagulation
Vitamin K antagonists
Warfarin, also known as coumadin
Interfere with the liver synthesis of coagulation factors
Effect measure by checking the protime (PT) now reported
as
international normalized ratio (INR)
Vitamin E quinone is a potent anticoagulant

Inactivation of Factors VIII & V by thrombin activated protein C

Vanders Physiology eighth edition Mc Graw Hill

Fibrinolysis, a mechanism for clot resorption

Vanders Physiology eighth edition Mc Graw Hill

The Blood
Thrombolytics
Plasminogen activates plasmin, a natural fibrinolytic agent
Tissue Plasminogen Activator (t-PTA) activates plasminogen
Plasmin dissolves an already formed clot (thrombolytic therapy)
Streptokinase and Urokinase
Thrombolytic action
Streptokinase has side effects but less costly
Urokinase has less side effects but more expensive
New drugs that interfere with fibrinogen/platelet binding are now
available

The Blood
Transfusion
The following blood elements can be transfused to cover a
deficiency
in quantity or quality of one or more of the blood components
Whole blood does not allow time for checking for the presence of
infectious agents
Packed RBCc for low Hb
Platelets for thrompcytopenia and bleeding
Plasma (fresh frozen) to replace deficient intrinsic factors
Cryoprecipitate for hemophilia

The Blood
Transfusion
Stored blood is acidified with citrates to prevent coagulation
It looses its platelets
Has more potassium, and accumulates ammonia
More hemolysed RBC as the storage is prolonged
Hemoglobin tends to hold more to O2 because of the reduction
in
2,3 diphophoglyceric acid (2.3 DPG)
The life span of RBCs stored at 4o C is about 28 days