ABDULLAH ICHSAN

D-5 | 1301 1011 0214

CVS CASE 4.2, CORONARY ARTERY DISEASE

LI: ANTICOAGULANT, THROMBOLYTIC &
ANTIPLATELET
THIS HANDOUT PROVIDES
A.
B.
C.
D.

INTRODUCTION
HEPARIN (ANTI-COAGULANT)
STREPTOKINASE (FIBRINONYTIC)
ASPIRIN (ANTIPLATELET)

NOW LETS GET INTO IT!

A. INTRODUCTION
Heparin and its low-molecular-weight derivatives are commonly used to treat
venous thromboembolism, unstable angina, and acute myocardial infarction.
Warfarin and other vitamin K antagonists are used to prevent the progression or
recurrence of acute venous thromboembolism following an initial course of heparin.
They also decrease the incidence of systemic embolization in patients with
prosthetic heart valves or after acute myocardial infarction.
Fibrinolytic agents, such as t-PA or streptokinase, reduce the mortality of acute
myocardial infarction.
The early and appropriate use of any thrombolytic drug probably transcends
possible advantages of a particular drug. Adjunctive drugs such as aspirin, heparin,
blockers, and angiotensin-converting enzyme (ACE) inhibitors reduce mortality even
further.
Contraindications to Thrombolytic Therapy
1. Surgery within 10 days, including organ biopsy, puncture of
noncompressible vessels, serious trauma, cardiopulmonary
resuscitation
2. Serious gastrointestinal bleeding within 3 months
3. History of hypertension (diastolic pressure >110 mm Hg)
4. Active bleeding or hemorrhagic disorder
5. Previous cerebrovascular accident or active intracranial process
6. Aortic dissection
7. Acute pericarditis
B. HEPARIN (ANTI-COAGULANT)
a. Mechanism of Action
Heparin is a heterogeneous mixture of sulfated mucopolysaccharides.
It binds to endothelial cell surfaces and a variety of plasma proteins. Its
biologic
activity
is
dependent
upon
the
endogenous
anticoagulant antithrombin. Antithrombin inhibits clotting factorproteases,
especially thrombin (IIa), IXa, and Xa, by forming equimolar stable complexes
with them. In the absence of heparin, these reactions are slow; in the
presence of heparin, they are accelerated 1000-fold.
1

b.

c.

d.

e.

f.

ABDULLAH ICHSAN
D-5 | 1301 1011 0214
High-molecular-weight (HMW) fractions of heparin with high affinity for
antithrombin markedly inhibit blood coagulation by inhibiting all three factors,
especially thrombin and factor Xa.
The shorter-chain low-molecular-weight (LMW) fractions of heparin inhibit
activated factor X but have less effect on thrombin than the HMW species.
Nevertheless, numerous studies have demonstrated that LMW heparins such
as enoxaparin, dalteparin, and tinzaparin are effective in several
thromboembolic conditions.
Clinical Use
Heparin is used to initiate treatment of venous thrombosis and pulmonary
embolism because of its rapid onset of action.
Heparin is used in the initial management of patients with unstable angina or
acute myocardial infarction, during and after coronary angioplasty or stent
placement, and during surgery requiring cardiopulmonary bypass.
In contrast to warfarin, heparin does not cross the placenta and has not been
associated with fetal malformations; therefore it is the drug of choice for
anticoagulation during pregnancy.
If possible, the drug should be discontinued 24 hours before delivery to
minimize the risk of postpartum bleeding.
Absorption and Pharmacokinetics
Heparin is not absorbed through the gastrointestinal mucosa and therefore is
given by continuous intravenous infusion or subcutaneous injection. Heparin
has an immediate onset of action when given intravenously.
When doses of 100, 400, or 800 units/kg of heparin are injected
intravenously, the half-lives of the anticoagulant activities are approximately
1, 2.5, and 5 hours, respectively.
Administration and Monitoring
Full-dose heparin therapy usually is administered by continuous intravenous
infusion. Treatment of venous thromboembolism is initiated with a bolus
injection of 5000 units, followed by 1200 to 1600 units per hour delivered by
an infusion pump.
Close monitoring of the activated partial thromboplastin time (aPTT or PTT) is
necessary in patients receiving UFH. Levels of UFH may also be determined
by protamine titration (therapeutic levels 0.20.4 unit/mL) or anti-Xa units
(therapeutic levels 0.30.7 unit/mL).
Weight-based dosing of the LMW heparins results in predictable
pharmacokinetics and plasma levels in patients with normal renal function.
Low-molecular Weight Heparin Preparation
The more predictable pharmacokinetic properties of low-molecular-weight
heparins, however, permit administration in a fixed or weight-adjusted
dosage regimen once or twice daily by subcutaneous injection. Since they
have a minimal effect on tests of clotting in vitro, monitoring is not done
routinely.
Enoxaparin (LOVENOX), dalteparin (FRAGMIN), tinzaparin (INNOHEP, others),
ardeparin (NORMIFLO), nadroparin (FRAXIPARINE, others), and reviparin
(CLIVARINE) differ considerably in composition.
Toxicities
2

ABDULLAH ICHSAN
D-5 | 1301 1011 0214
Bleeding; major bleeding occurs in 1% to 5% of patients treated with
intravenous heparin for venous thromboembolism.
Heparin-Induced Thrombocytopenia; Heparin-induced thrombocytopenia
(platelet count <150,000/ml or a 50% decrease from the pretreatment value)
occurs in about 0.5% of medical patients 5 to 10 days after initiation of
therapy with standard heparin.
C. STREPTOKINASE (FIBRINONYTIC)
a. Description
Streptokinase is a protein (but not an enzyme in itself) synthesized by
streptococci that combines with the proactivator plasminogen. This
enzymatic complex catalyzes the conversion of inactive plasminogen to
active plasmin. Urokinase is a human enzyme synthesized by the kidney that
directly converts plasminogen to active plasmin. Plasmin itself cannot be
used because naturally occurring inhibitors in plasma prevent its effects.
However, the absence of inhibitors for urokinase and the streptokinaseproactivator complex permits their use clinically. Plasmin formed inside a
thrombus by these activators is protected from plasma antiplasmins, which
allows it to lyse the thrombus from within.
b. Indication and Dosage
Thrombolytic therapy in the management of acute myocardial infarction
requires careful patient selection, the use of a specific thrombolytic agent,
and the benefit of adjuvant therapy.
Streptokinase is administered by intravenous infusion of a loading dose of
250,000 units, followed by 100,000 units/h for 2472 hours.
D. ASPIRIN (ANTIPLATELET)
In platelets, the major cyclooxygenase product is thromboxane A2, a labile inducer
of platelet aggregation and a potent vasoconstrictor. Aspirin blocks production of
thromboxane A2 by acetylating a serine residue near the active site of platelet
cyclooxygenase (COX-1), the enzyme that produces the cyclic endoperoxide
precursor of thromboxane A2.
Since platelets do not synthesize new proteins, the action of aspirin on platelet
cyclooxygenase is permanent, lasting for the life of the platelet (7 to 10 days).
Repeated doses of aspirin produce a cumulative effect on platelet function.
Complete inactivation of platelet COX-1 is achieved when 160 mg of aspirin is taken
daily. Therefore, aspirin is maximally effective as an antithrombotic agent at doses
much lower than those required for other actions of the drug.
Numerous trials indicate that aspirin, when used as an antithrombotic drug, is
maximally effective at doses of 50 to 320 mg per day.

Primary Sources:
Goodman & Gilmans The Pharmacological Basis of Therapeutic
Katzung Basic and Clinical Pharmacology

ABDULLAH ICHSAN
D-5 | 1301 1011 0214
"Hai orang-orang yang beriman, bertakwalah kepada Allah sebenar-benar takwa kepada-Nya;
dan janganlah sekali-kali kamu mati melainkan dalam keadaan beragama Islam."
(QS Al-Araaf, 7:31)