Fibrinolysis and anticoagulant agents (2 lectures)

Class:

JC1
Module:
Fundalmentals
of Biomedicine
Code:
(1)
FUN 39 & 41
Lecturer: DR. Ganesh Shetty
Date: 11th & 13th Nov 2015

Learning outcomes
(2 lectures merged in one slide set)
Anti-coagulant drugs
1)
2)

3)

Compare and contrast the different

types of blood clotting tests.
Explain common disorders of
coagulation, their diagnosis and
treatment.
Summarize the different classes of
anti- coagulant drugs, their mode
of administration and side effects.

4) Compare and contrast Intravenous

anticoagulants: (Heparin and lowmolecular weight heparins) with
oral anticoagulants: warfarin and
the newer (oral) Anti-coagulant
Drugs.

Fibrinolysis & Thrombolytic

drugs
5) Explain the role of intact
endothelium in regulating
haemostasis.
6) Define and reproduce the
thrombolytic pathway.
7) Identify the drugs that impact on
the thrombolytic pathway.
8) Describe of the use and
limitations of these drugs in the
acute treatment of thrombotic
disorders.
9) Note: Anti-platelet Agents will
be covered in a separate lecture

Coagulation Cascade

Ca++
IX

IX

Ca++

Ca++

Ca++

http://meds.queensu.ca/medicine/deptmed/hemonc/anemia/coag/CCLM.swf

Steps of normal hemostasis

4th step in haemostasis: Fibrinolytic/

Thrombolytic Cascade

Purpose: to limit clot formation

to immediate site of injury
And to remove components of clot
after tissue repair

Fibrinolytic Cascade
FXIII

Thrombin

(generated in response to
FXIIIa
damage of endothelial cells)

Fibrinogen

Fibrin
monomer

Fibrin

Fibrin

polymer

Degradation
products

Plasminogen
Plasminoge
n Activator
Inhibitor
(PAI-1)

Plasmin
tissue
Plasminogen
Activator- tPA
(released by intact endothelial
cells)

2AntiPlasmin

Control of the Fibrinolytic Cascade

Plasminogen (PLG) is an inactive plasma protein (a pro-enzyme)

It binds to both fibrinogen and fibrin and becomes incorporated in clots

as they form
tissue Plasminogen Activator (tPA) is synthesised by intact
endothelial cells & promotes plasmin formation from plasminogen. It is
more effective on clot bound plasminogen

Note: active plasmin is clot-bound

Any inappropriate tPA in plasma is immediately inactivated by

Plasminogen-Activator-Inhibitor (PAI-1)

Any inappropriate plasmin in the plasma is inactivated by

2- antiplasmin
2-antiplasmin (AP) only inactivates free plasmin in plasma, not clot-bound
plasmin

Diagnosis

2 main tests are used to assess

blood clotting function in patients
1. Assess Extrinsic Pathway (Tissue Factor
pathway)

Prothrombin Time or PT test / INR

2. Assess Intrinsic Pathway

Activated partial thromboplastin time

aPTT test

Require blood that is either freshly drawn or

stored in an appropriate anti-coagulant

Choice of Anti-coagulant
Coagulation requires the presence of Ca++
By chelating the calcium ions, effective
anticoagulation is achieved
EDTA- irreversibly binds calcium
Citrate- binds the calcium, but not as strongly as
EDTA

Acid-citrate dextrose (ACD)- a solution of citric acid,

sodium citrate and dextrose in water.

Coagulation requires the generation of

Thrombin
Heparin- prevents the actions of Thrombin (Factor
II)

Preparation of blood for analysis

Whole blood from finger-pricks, for
immediate, on-site analysis
Commonly used in coagulation clinics or hometests

Anti-coagulated blood samples are

collected in laboratory test tubes
Vaccutainers,
for remote analysis
Available in various volumes up to10ml
usually stored in an anti-coagulant:

Sodium citrate (light blue or orange)

EDTA (pink or purple)
Heparin (green)
Erythrocyte sedimentation rate (Black)

Alternatively, can be collected in absence of anticoagulant for the production of Serum (red)

Coagulation Test (1)

whole blood in Glass tube Blood clots in 5-11 min
@37oC
whole blood drawn into
doesn't clot
vaccutainer containing
anti-coagulant (citrate, heparin
or EDTA)

add Ca++ + Tissue Factor

(also called thromboplastin;
obtained from animals)

Blood clots in 12-14sec

=
Prothrombin Time or
PT
Quick test,
one stage prothrombin time accelerated
clotting time

The prothrombin time (PT) is equivalent to the time required for the
extrinsic pathway (TF) of the coagulation cascade:
A prolonged or shortened prothrombin time indicates a disorder of
clotting processes

PT Coagulation Test
Prothrombin Time (PT)
is measured in seconds
But can vary greatly from hospital to hospital due to
Source of thromboplastin, storage of thromboplastin, temperature, humidity,
equipment. . . .

A better measure is the

Prothrombin Ratio (PR)
(sec) divided
PT of
of a
a patient
normal sample
pooled plasma
(sec) by
= PT

An even better measure is the

International Normalised Ratio (INR)

is the PR which is obtained using the primary international reference
thromboplastin (Tissue Factor) preparation. This is usually a human
recombinant protein produced by genetic engineering protocols.

Factors that influence the

INR:
Drugs
Illness especially liver disease
Nutritional intake, e.g. cabbage, spinach are rich in
vitamin K and therefore lower INR
Smoking, alcohol consumption
The Roche CoaguChek XS
Physical and mental stress
Climatic variations during travel

Coaugulation Test (2)

Take anti-coagulated whole blood
Add calcium, phospholipid
and silica, celite, kaolin,
or ellagic acid

A clot will form within

~ 33 seconds
(range =25 to 39 s)
= activated Partial
Thromboplastin Time
(aPTT)
termed "partial" due to the
absence of tissue
factor from the reaction
mixture

Measures defects in Intrinsic Pathway

Diagnosing Coagulation Deficiencies:

PT and aPTT tests
A Bloody Mystery: NEJM Nov5th 2009;
http://content.nejm.org/cgi/content/full/361/19/1887

Quantitative D-Dimer Test

D-dimer is a specific degradation

fragment of cross-linked fibrin.
It is produced naturally as part of the
wound healing process by plasmin
degradation of thrombus.
It has a long half-life in plasma.
Measurement of plasma D-dimer
levels is useful to aid in the diagnosis
of systemic thrombosis,
pulmonary thromboembolism
(PTE)
disseminated intravascular
coagulation (DIC)

D-Dimer Test

Elevated levels of D-dimer indicates the

occurrence of recent thrombotic event.
However, it doesnt differentiate between appropriate
thrombosis (wound healing following surgery or
injury) or inappropriate (pathological thrombi)

A normal D-dimer concentration excludes thromboembolic events such as deep vein thrombosis and
pulmonary embolism with a very high probability.

Diagnosing Thrombotic
events:
A definitive diagnosis must be accompanied by a
image/scan
MRI scanning, angiography, CAT scans etc
For most of these a high degree of suspicion is necessary
The time required is long but the need for information is
immediate

DISORDERS OF COAGULATION
Too little coagulation:
Inherited Disorders
Haemophilia
A:
Factor VIII
B:
Factor IX
Acquired Disorders
Liver Disease
Vitamin K deficiency
Induced Disorders
Excessive demands of
coagulation system, eg caused
by severe wounds

Too much coagulation:

Venous
Due to presence of artificial surfaces eg
cardiac valve
Prolonged stasis eg after surgery or long-haul
flights
Atrial Fibrillation
Due to deficiency of regulatory factors eg
Factor V Leiden (30%);
Protein C,S (5%);
Antithrombin III(2-3%)

Lupus anticoagulant
Pregnancy
Smoking, obesity, age
Cancer

Arterial
Myocardial Infarction
Angina
Stroke
Peripheral Arterial Disease

Treating Coagulation Disorders

Too little coagulation:

If genetic: administer appropriate

factor

If due to Vitamin K deficiency:

Eg purified or recombinant Factor

VIII for hemophilia
Administer Vitamin K

If due to excessive demands on

haemostatic system (ie severe
wounds)

New product available for treatment:

Nova 7 (Recombinant factor VIIa)

Will only function where Tissue

Factor is present ie at site of
wound

Allows chemical cauterization of

bleeding wounds

Too much coagulation:

For prevention of Venous
Coagulation:
Anticoagulant drugs:
Oral Anti-coagulants
Warfarin (Vitamin K antagonist)

Injectable Anti-coagulants

Heparin (acts as an anti Thrombin)

New Drugs

Hirugen
Fondaparinux
Dabigitran

To prevent Arterial Thrombosis:

Antiplatelet drugs
To dissolve already-formed clots:
Thrombolytic drugs
Tissue Plasminogen Activator (tPA)
Streptokinase

Need bespoke treatment: depending on knowledge of the cause

Treatment of Venous Thrombosis

With Anticoagulant drugs:
Oral Anti-coagulants
Warfarin (Vitamin K antagonist)

Intravenous Anti-coagulants
heparin (anti-Thrombin)
New Drugs
Hirugen
Fondaparinux
Dabigitran

Vitamin K

Vitamin K is necessary for

synthesis of Gamma carboxy
glutamate (Gla) residues on
F II, VII, IX and X in the liver.

Gla residues serve as high

affinity binding sites for Ca++

Vitamin K is synthesized by
bacteria in mammalian gut

Vitamin K deficiency
Bruising
Haemorrhagic disease of the
newborn
Can be caused by Antibiotic
overdose
Alcoholic liver disease

Vitamin K

GammaCarboxy
Glutamic
Acid

Glutamic
Acid

Haemorrhagic Disease of
the newborn
Newborns are relatively vitamin K deficient for a variety
of reasons.

They have low vitamin K stores at birth,

vitamin K passes the placenta poorly,
the levels of vitamin K in breast milk are low
and the gut flora has not yet been developed

Baby presents with reports of bleeding.

The most common sites of bleeding are the umbilicus,
mucous membranes, gastrointestinal tract, and venipunctures

Treatment:
Treatment consists of vitamin K supplementation. This is often
given prophylactically to newborns shortly after birth.

Alcoholic liver disease

Alcoholics often present with bleeding disorders for a
variety of reasons.
They have low vitamin K stores often due to poor diet,
and the gut flora is often poor
In addition, since all plasma coagulation proteins and the gamma
carboxytransferase enzyme are synthesised in the liver, there
will be a reduced amount of all coagulation components in the
plasma

Patient often present with bleeding/ coagulopathy

Diagnosis?
INR, aPTT, platelet count,

Treatment?
Treatment consists of vitamin K supplementation.
Fresh frozen plasma

Coagulation Cascade

Ca++

Ca++
IX

Ca++

Ca++

Vitamin K permits the correct synthesis of factors II, VII, IX and X See:
http://www.cap.org/apps/docs/cap_press/hemostasis_testing/coagulation_pathway.pdf

Vitamin K Antagonists
Warfarin and other Coumarins (WARF, for
Wisconsin Alumni Research Foundation; 1950s) are

Vitamin K antagonists
They inhibit the Gamma-carboxylation of factors II
VII, IX and X, rendering them useless
Effects not seen until 24-48 hours after drug
administration (= time taken to deplete endogenous
stores)
Effects last 4-5 days (= time taken to regenerate
correctly synthesize the Gla-modified
Factors II, VII, IX and X)

Therapeutic uses of Warfarin

Warfarin is prescribed to people with an increased
tendency for venous thrombosis
or as secondary prophylaxis (prevention of further
episodes) in those individuals that have previously
formed a blood clot
Warfarin treatment can help prevent formation of
future blood clots and help reduce the risk of
embolism
Is safe for long-term use (except in pregnancy)
Often used in patients with artificial grafts in veins or
arteries

Pharmacology of Warfarin
Administered orally
Acts as a Vitamin K
antagonist
99% plasma protein bound
metabolised by Cytochrome P450 in liver
Slow onset and offset of action (24-72h
for onset; 2-5 days for recovery)
needs careful monitoring to avoid
excessive or insufficient dosing
The effects of warfarin are measured in
the lab by the prothrombin time (PT) test
Cheap: cost from 40 per year to
control bleeding risk
However: note there is an additional cost
of monitoring drug efficacy

Vitamin K
Antagonist

Adverse effects:
Haemorrhage
Drug interactions with other plasma protein-bound
drugs (salicylates, penicillin, dicoumarol,
sulphonamides, warfarin, clofibrate & phenytoin)
Drug interactions with other drugs which inhibit or
induce hepatic metabolism (antibiotics; alcohol,
antipsychotic drugs, antiplatelet agents)
Teratogenic; so not to be used in pregnancy
Warfarin has a low therapeutic Index and must
be carefully monitored

Warfari
n

Frequency of Anticoagulant
Monitoring
INITIATION PHASE:

the patient's status should be monitored 4-5 times per week

until some degree of consistency in the INR response is noted.

STABLE PHASE:
Once the anticoagulant dose and INR response stabilizes the INR
should be monitored at least once each 4 weeks.

TRANSITION PHASE:
A transition phase occurs whenever there are changes to
medication or medical condition or diet.
Chambers et al, 2010 reported the cost of one INR test,
ranged from $6.19 to $145.70.

The Roche CoaguChek XS

Regulation of thrombosis

The levels of Circulating Thrombin are

carefully regulated in the body to
prevent unwanted thrombosis
Pro-thrombin (Factor II) needs cascade to activate it
The coagulation cascade is regulated at every step
Because thrombin activation is the last step of the coagulation
cascade, it is the most highly regulated.

Circulating inhibitors of Thrombin exist:

main one is ANTI -THROMBIN III (ATIII)-but its not very
potent!

Also, endogenous inhibitors of Thrombin are abundant

on intact blood vessels
Thrombomodulin
heparin

Regulation of thrombosis
High levels of
antithrombin III are
present in plasma
Intact endothelium
expresses heparin
proteoglycans and
thrombomodulin on
its surface

Endogenous Heparin
Heparan sulphate proteoglycans are synthesised by
endothelial cells and expressed at the surface of
intact cells
Heparan on the surface of intact endothelial surfaces
enhances the inhibitory potency of Antithrombin III
ATIII is a weak inhibitor of thrombin
Heparan + ATIII = more potent inhibitor of Thrombin (potency
is enhanced by 1000 fold)
Heparan/ATIII complex inhibits both Thrombin (Factor IIa) &
Factor Xa

Heparin

Heparan sulfate (HS) is a linear polysaccharide found

in the cell surface of all animal tissues

It is a naturally-occurring proteoglycan with long sugar

chains

Heparin was originally isolated from liver cells, hence its

name (hepar is Greek for "liver")
The sugar chains have highly-specific binding sites for
both Antithrombin III and for Factor II.

Unfractionated
Heparin
heparin

It potentiates the action of AT III to inhibit the proteolytic

actions of Thrombin (Factor IIa) and Factor Xa
Heparinheparin
Unfractionated

Thrombomodulin
Thrombomodulin is expressed on surface of intact
endothelial cells.
It binds excess thrombin and forms a 1:1 complex
Thrombin-thrombomodulin (TT) complex acquires new
functions:
TT cannot activate fibrinogen
TT converts the regulatory protein, Protein C, to its active form
(activated protein C; APC)
APC, along with protein S, degrades Factors Va and VIIIa.
Genetic deficiencies in Protein C, Protein S or factor V (Factor
V Leiden) occur and can cause serious thrombotic episodes

XII

XIIa

XI

Regulation of thrombosis by
Thrombomodulin

HK

Ca++

XIa

Ca++

IX

IXa

VIIIa

VIII

Ca++

X PL

APC

V
a

Protein C

Intact endothelial
cell

Feedback

Xa

Ca++

PL-

Prothrombin
Factor II

Fibrinogen
(factor I)

Inhibition
loop
Thrombomodulin

Thrombi
n
IIa

Fibrin
monomer

Fibrin
polymer

Factors that regulate

thrombosis

Thrombin

Control of the Coagulation

Pathway

Many mechanisms keep the coagulation cascade in check.

Abnormalities can lead to an increased tendency toward
thrombosis:
Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor
(TF). It inhibits excessive TF-mediated activation of FX.
Antithrombin III is a plasma protease inhibitor that inhibits other proteases:
thrombin, FIXa, FXa, FXIa, and FXIIa. It is constantly active, but its adhesion
to these factors is increased by the presence of heparan sulfate or the
administration of heparins

Protein C is a major physiological anticoagulant. It is a plasma protease

enzyme. Protein C is activated to activated protein C (APC) a complex
composed of thrombin & Thrombomodulin (TT). APC, along with protein S
and a phospholipid as cofactors, degrades FVa and FVIIIa.

Warfari
n

Ideal drug Target

Thrombin inhibitors as
therapeutics:

Treating venous Coagulation

Disorders
For prevention of Venous Coagulation:
Anticoagulant drugs:
Oral Anti-coagulants
Warfarin (Vitamin K antagonist)

Injectable Anti-coagulants

Heparin (acts as an anti Thrombin)

Low molecular weight heparin
New Drugs
Hirugen
Fondaparin
ux
Dabigitra
n
Riveroxib
an

Intravenous (IV) anti-coagulant

Heparin, isolated from animal tissues, is used
as a drug to treat or prevent thrombotic
disorders.
It cannot be administered orally
Because it is a protein, it would be degraded by
digestive enzymes if given orally

Therapeutic HEPARIN is prepared from

animal tissues; mainly porcine intestine or
bovine lung
Natural heparin consists of molecular chains of
varying lengths
However, the effects of natural, or unfractionated,
heparin can be difficult to predict

LOW MOLECULAR WEIGHT

HEPARIN
LMWH; fractionated
consists of only short
chains of
polysaccharide.
average
molecular
an
LMWHs
are defined
as weight of
less
thansalts
8000
Da .
heparin
having
LMWHs have increased action on
and less
Factor
X action on Thrombin
(Factor IIa) compared to
unfractionated heparin

heparin

Low molecular
weight
heparin

Unfractionated

Unfractionated heparin

Therapeutic uses of
Heparin
Heparin
is major anti-thrombotic for

treatment of deep vein thrombosis +

pulmonary embolism
used prophylactically to prevent postoperative venous thrombosis
Used in the acute treatment of
Myocardial Infarct (MI)

Pharmacology of Heparin/
LMWH

Administration is either intravenous,

subcutaneous or intramuscular
Immediate onset of action
rapidly terminated on suspension of
therapy
needs careful monitoring to avoid excessive
or insufficient dosing
The effects of heparin are measured in the
lab by aPTT test

Adverse effects:
Haemorrhage
Osteoporosis
Hypersensitivity
Heparin-induced platelet aggregation (30%)

HIT syndrome
Heparin-induced thrombocytopenia (HIT) is caused by
an immunological reaction that causes platelet activation
within the blood vessels, thereby using up coagulation
factors.
Formation of platelet clots can lead to thrombosis, while the
loss of coagulation factors and platelets may result in bleeding.

HIT can (rarely) occur shortly after heparin is given, but

also when a person has been on heparin for a long
while.
Patients being treated with heparin need to be carefully
monitored for HIT (by assessing platelet count) and for
anti-coagulant effect (aPTT)

Compare and contrast

Heparin and Warfarin
Heparin
IV, IM or SubCut
Immediate onset of
action
Short term use
Cheap
Needs careful
monitoring (aPTT;
HIT)

Warfarin
Oral
Slow onset and
offset
Long term use
Cheap
Needs careful
monitorin (INR)

Newer Anti-coagulant
Agents
1
Although the safe use of warfarin is a challenge,
there has not been a market competitor for oral longterm anticoagulation in the management of venous
thromboembolism (VTE) until 2008, with the
development of 2 new oral anticoagulants:

Rivaroxaban, a direct factor Xa inhibitor

and
Dabigatran, a direct thrombin inhibitor

Newer Antithrombin Agents

Hirudin (1989) - binds to fibrinogen recognition site on
thrombin isolated from medicinal leeches
Hirugen synthetic polypeptide based on Hirudin
Argatroban (2000) direct competitive inhibitor of thrombin;
administered Intravenously
PPACK alkylates active site in thrombin
Fondaparinux is a synthetic agent composed of the five sugars in
heparin that bind to antithrombin.

Dabigatran (2005) is a new orally-active

thrombin inhibitor.
Rivaroxiban (2005) - new orally-active inhibitor
of Factor Xa

Dabigatran
is a new orally-active thrombin inhibitor
It is orally administered as a prodrug.
Marketed as Pradaxa since April 2008 in European
countries and Pradax in Canada.
In March, 2008, the European Medicines Agency
granted marketing authorisation for the prevention of
thromboembolic disease following hip or knee
replacement surgery.
It was approved for use in patients with non-valvular
atrial fibrillation in the EU in August 2011
it allows predictable anticoagulation with no need for dose
adjustments and routine coagulation monitoring

Rivaroxaban
is a new direct acting inhibitor of Factor Xa
Is the first orally-available anticoagulant drug since
Warfarin
Rivaroxaban is well absorbed from the gut and maximum
inhibition of factor Xa occurs four hours after a dose.
marketed as Xarelto.
On July 1, 2011, the U.S. FDA approved rivaroxaban
for prophylaxis of deep vein thrombosis (DVT), which
may lead to pulmonary embolism (PE), in adults
undergoing hip and knee replacement surgery
Like Dabigatran, it does not require frequent blood tests
for INR monitoring
http://www.nejm.org/doi/pdf/10.1056/NEJMra044440

New oral anticoagulant

drugs (NOADs)
may replace warfarin as the preferred anticoagulant.
uptake of their use will be affected by the cost
considerations compared to Heparin and Warfarin.
They allow predictable anticoagulation with no need
for dose adjustments and routine coagulation
monitoring
However, there is currently no antedote
In practice, warfarin remained the standard drug for
patients with atrial fibrillation and a moderate or high
risk of thrombosis up to 2012.

All agents are associated with bleeding/ stroke risk

Rivaroxaban

Dabigatrin

Cost

The costs of new anticoagulant drugs ($3000/year) are

substantially higher than those of warfarin ($48/year),

even after addition of the extra cost of INR testing and provider
visits for warfarin dose adjustment.

A Canadian study, sponsored by the manufacturer of dabigatran

(Boehringer Ingelheim) assessed its cost effectiveness
according to the age adjusted dosing schedule approved in
Europe.
Dabigatran was cost effective compared with warfarin, at $10440
(7468) per quality-adjusted life year (QALY) gained.

In another study from UK, dabigatran was unlikely to be cost

effective in clinics, such as those in the UK, able to achieve
good control of the international normalised ratio (INR) with
warfarin.

Pharmacoeconomics: Quality Adjusted

life years (QALYs)

QALY is a measure of disease burden, including both the quality and

the quantity of life lived.
assumes that a year of life lived in perfect health is worth 1 QALY (1
Year of Life 1 Utility value = 1 QALY) and that a year of life lived in a
state of less than this perfect health is worth less than 1.
A 1995 study of the cost-effectiveness of over 500 life-saving medical
interventions found that the median cost per intervention was $42,000
per life-year saved. An acceptable QALY of $50,000 was thus
established
In Ireland, the national Centre for Pharmacoeconomics (NCPE)
deemed that

Rivaroxiban could be deemed cost-effective for the treatment of DVT and the
prevention of recurrent DVT and PE following an acute DVT in adults. However, this is
sensitive to the assumption that the cost of INR monitoring will be released from
anticoagulant services in substituted patients

National Centre for Pharmacoeconomics:

http://www.ncpe.ie/

Role of Fibrinolytic/
Thrombolytic Cascade
To limit clot formation to immediate site
of injury
To remove components of clot after
tissue repair

Thrombolytic/Fibrinolytic
drugs

include:
t-PA (formulated as a recombinant human protein)
alteplase (rtPA)
reteplase
(longer half-life)
tenecteplase

streptokinase (purified from streptococcal bacteria)

Are mimics of endogenous tPA, but are administered in very high doses
Aim is to lyse an existing thrombus in a blood vessel
are most effective if administered immediately after it has been
determined they are clinically appropriate.
Administered intravenously
The advantage of administration is highest within the first ninety
minutes, but may extend up to six hours after the start of symptoms.

are often given in combination with intravenous heparin, or LMW heparin, and
Aspirin

Thrombolytic Therapy
is used for acute treatment of :

myocardial infarction (heart attack),

ischemic stroke,
deep vein thrombosis (DVT)
Massive pulmonary embolism
Acute limb ischaemia

to clear a blocked artery and avoid permanent damage to the perfused

tissue (e.g. heart, brain, leg)

A less frequent use is to clear blocked catheters that are used in longterm medical therapy.
Note: thrombolytic therapy in strokes is controversial due to the difficulty in
differentiating between hemorrhagic and thrombotic strokes and the time involved.

Thrombolytic drug in MI

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected
acute myocardial infarction: ISIS [International Study of Infarct Survival] Collaborative Group: 349
360;1988; with permission from Elsevier.)

STREPTOKINASE vs recombinant
tPA as a thrombolytic drug

Thrombolytic therapy is given intravenously as soon as possible

after the onset of a heart attack to dissolve clots in the arteries of
the heart wall.
This reduces the amount of damage to the heart muscle.

Streptokinase is a bacterial product that

acts as a Plasminogen Activator
It is cheap
However, because of its bacterial origins,
the body will likely build up an immunity
response to it.

Recombinant tPA is identical to normal

plasma tPA
recombinant tPA is expensive
there are no problems associated with its
administration

Antibodies against Streptokinase

will inhibit its thrombolytic action
Therefore, Streptokinase should not be
used again after four days from the
first administration, as it may not be as
effective and can also cause an
allergic reaction.

For this reason, streptokinase is usually given only for a person's first heart
attack. Further thrombotic events are treated with tPA.

Side-effects of Thrombolytic
Therapy

Bleeding

Hemorrhagic stroke is a rare but serious complication of thrombolytic

therapy.

If a patient has had thrombolysis before, an allergic response against the

thrombolytic drug may have developed (especially after streptokinase).
If the symptoms are mild, the infusion is stopped and the patient is
commenced on an antihistamine before infusion is recommenced.
Anaphylaxis generally requires immediate cessation of thrombolysis.

Contra-indicated where major surgery or injury has occurred in the previous

weeks.

Also contraindicated where patient is currently being treated with

anticoagulant drugs, has a known bleeding diathesis, during pregnancy, or
if patient has a history of hemorrhagic or diabetic retinopathies or active
peptic ulcer.

Summary
Coagulation
Monitoring
coagulation

Anti-coagulant
Drugss
Oral: Warfarin
Intravenous:
Heparin
Low molecular
weight Heparin

New Oral
Anticoagulant
Drugs
Thrombin
inhibitors
(Dabigatan/
Rivaroxiban)
Fibrinolytics
Tissue
Plasminogen
Activator (tPA)
Streptokinase